Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C:23]2=[O:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.[BH4-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 0.402 g (1 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one in 30 ml of tetrahydrofuran was added 38 mg (1 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with water and neutralized by adding cold 1N-hydrochloric acid in small portions. From this mixture, the tetrahydrofuran was distilled off under reduced pressure at a temperature not exceeding 20° C. and the residue was diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:10, v/v) to recover 0.250 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3β-ol (yield: 62%).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>CN(C)C=O>[ClH:27].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:23]2[CH:22]=[C:21]([CH3:28])[CH:26]=[CH:25][CH:24]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cccc(Cl)c1
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 8 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 8 g. of m-toluyl chloride was added to produce 3-hydroxy-4-(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 11.5 g. of the acetate salt, m.p. 170°-175° C. By treating a slurry of this salt in 100 ml of N,N-dimethylformamide with 40 g. of methanesulfonic acid there was obtained 10.6 g. of the corresponding methanesulfonate salt, m.p. >250° C.(uncorr.). This methanesulfonate (10 g.) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, to yield 5.4 g. of 3-hydroxy-4-(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 165°-168° C.(uncorr.).
Reaction SMILES: C(O)C.[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][N:8]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][CH2:6]1
Reactant: CC1(N)CCNCC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1(N)CCN(c2ncccn2)CC1
Yield: 65.1 %

Procedure:
2 ml of an ethanol suspension containing 260 mg of 4-amino-4-methylpiperidine (synthesized according to a method described in U.S. Pat. No. 5,821,240), 237 mg of 2-chloropyrimidine and 858 mg of potassium carbonate was stirred at 50° C. for 12 hours. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol-aqueous ammonia (300:10:1)] to obtain 259 mg of 4-amino-4-methyl-N-(2-pyrimidinyl)piperidine (Reference Example 8-1 in Table 9).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F-].[K+].[SH:19][C:20]1[S:21][C:22]([S:25][CH3:26])=[N:23][N:24]=1>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:19][C:20]1[S:21][C:22]([S:25][CH3:26])=[N:23][N:24]=1)=[N:3]2
Reactant: CSc1nnc(S)s1
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (69 mg, 0.25 mmol) in DMF (4 ml) was added potassium fluoride 40% wt on alumina (109 mg, 0.75 mmol) followed by addition of 2-mercapto-5-methylsulfanyl-1,3,4-thiadiazole (44 mg, 0.26 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:20 to afford the title compound.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25]I>CN(C)C=O.O>[C:1]([NH:9][C:10]([S:11][CH3:25])=[N:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccccc1N=C(NC(=O)c1ccccc1)SC
Reaction time: 0.5 h

Procedure:
To 0.10 g of 2-[[(benzoylamino)thioxomethyl]amino]-N-methylbenzamide in 2.0 ml of N,N-dimethylformamide was added 0.35 ml of 1N sodium hydroxide at 0° C., followed by 0.04 ml of methyl iodide. The solution was stirred and allowed to reach room temperature over 30 minutes. This was diluted with water to give 0.074 g of N-benzoyl-N'-(2-methylaminocarbonylphenyl)carbamimidothioic acid, methyl ester as colorless crystals, mp 193°-195° C. This compound was reacted with sodium hydride in tetrahydrofuran by refluxing for 21/2 hours to give N-(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl)benzamide, mp 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]1[CH2:25][OH:26]
Reactant: CC(C)c1nc(CO)n(Cc2cccc([N+](=O)[O-])c2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2cccc(N)c2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
In ethyl acetate was dissolved 64 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(m-nitrobenzyl)-1H-imidazole (103b), and platinum sulfided carbon was added. After replacement with hydrogen atmosphere, the mixture was catalytically hydrogenated under atmospheric pressure at room temperature. After 3 hours, the mixture was filtered through Celite, the filtrate was distilled off under reduced pressure, and diethyl ether was added. Crystals precipitated were filtered, and 25 mg of Compound I-118 was obtained (yield 42%). mp 145-148° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].[CH2:16](N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH2:9][C@@H:10]([OH:14])[C:11]([O:13][CH3:16])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: CCN(CC)CC
Reactant: Cc1cc(CC(=O)C(=O)O)cc(C)c1N
Solvent: C1CCOC1
Product: COC(=O)[C@H](O)Cc1cc(C)c(N)c(C)c1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a mixture of 20.0 g (82.1 mmol) 3-(4-amino-3,5-dimethyl-phenyl)-2-oxo-propionic acid and 25.7 mL (189 mmol) triethylamine in 400 mL THF was cooled to −35° C. Then a solution of 40.0 g (125 mmol) (1R)—B-chlorodiisopinocampheylborane in 100 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C. The reaction mixture was kept for 1 h at this temperature, the cooling bath was removed and the reaction mixture was stirred overnight at RT. THF was evaporated down i.vac., the residue was combined with methanolic HCl (1.25 M) and stirred for 2 h at RT. It was evaporated down i.vac., the residue was taken up in 2 M HCl and extracted exhaustively with EtOAc. The aqueous phase was made alkaline with semiconc. NaOH and exhaustively extracted with EtOAc. The combined organic phases were dried over Na2SO4, suction filtered through activated charcoal and evaporated down. The product was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:8](NC)[CH2:7][CH2:6]2.C([N:23]([CH2:26][CH3:27])[CH2:24]C)C.C(Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:27]([CH2:26][NH:23][CH2:24][C@H:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCN(CC)CC
Reactant: CN[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@H](CNCCc1ccccc1)[C@@H]2c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of cis-6-methoxy-2-methylamino-1-phenyl-1,2,3,4-tetrahydronaphthalene (3.55 g, prepared according to Process 1), triethylamine (3.12 cm3) and N,N-dimethylformamide (40 cm3) was added benzyl bromide (1.60 cm3). The mixture was warmed to 80° C. and stirred for 2 h. Upon cooling, the solvent was evaporated under reduced pressure to afford a brown oil. This was purified by column chromatography [silica, eluting with petroleum ether (b. p. 40-60° C.)-ethyl acetate (4:1)] to afford the title compound (3.52 g) as a light brown oil which solidified on standing.
Reaction SMILES: CCCC[CH2:5][CH3:6].C1C=CC=CC=1.S(=O)(=O)(O)[OH:14].[CH3:18][C@H:19]1[O:35][C:33](=[O:34])[CH2:32][C@@H:31]([OH:36])[C@H:30]([O:37][CH3:38])[C@@H:29]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[C@@H:43]([O:47][C@@H:48]3[O:53][C@@H:52]([CH3:54])[C@H:51]([O:55][C:56]([CH2:58][CH:59]([CH3:61])[CH3:60])=[O:57])[C@@:50]([OH:63])([CH3:62])[CH2:49]3)[C@H:42]([N:64]([CH3:66])[CH3:65])[C@H:41]2[OH:67])[C@@H:28]([CH2:68][CH:69]=[O:70])[CH2:27][C@@H:26]([CH3:71])[C@@H:25]([OH:72])[CH:24]=[CH:23][CH:22]=[CH:21][CH2:20]1>C(OCC)(=O)C.CO>[CH3:18][C@H:19]1[O:35][C:33](=[O:34])[CH2:32][C@@H:31]([O:36][C:5]([CH3:6])=[O:14])[C@H:30]([O:37][CH3:38])[C@@H:29]([O:39][C@@H:40]2[O:45][C@H:44]([CH3:46])[C@@H:43]([O:47][C@@H:48]3[O:53][C@@H:52]([CH3:54])[C@H:51]([O:55][C:56]([CH2:58][CH:59]([CH3:60])[CH3:61])=[O:57])[C@@:50]([OH:63])([CH3:62])[CH2:49]3)[C@H:42]([N:64]([CH3:66])[CH3:65])[C@H:41]2[OH:67])[C@@H:28]([CH2:68][CH:69]=[O:70])[CH2:27][C@@H:26]([CH3:71])[C@@H:25]([OH:72])[CH:24]=[CH:23][CH:22]=[CH:21][CH2:20]1
Reactant: CCCCCC
Reactant: O=S(=O)(O)O
Reactant: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)C=CC=CC[C@@H](C)OC(=O)C[C@H]1O
Agent: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]1O
Agent: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)/C=C/C=C/C[C@@H](C)OC(=O)C[C@H]1OC(C)=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CO[C@@H]1[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)[C@@H](O)C=CC=CC[C@@H](C)OC(=O)C[C@H]1OC(C)=O

Procedure:
After developing the plate in a developer composed of n-hexane:benzene:methanol:ethyl acetate=30:10:25:8:20, and product spots were tested by color development with sulfuric acid to try to detect 3-acylated leucomycin A1. As a result, it was found that from among about 200 transformed strains, Streptomyces lividans 53A strain (hereafter, referred to as "strain 53A") produced leucomycin A3, i.e., 3-O-acetyl leucomycin A1. The leucomycin produced by the strain 53A was identified to be leucomycin A3 from results of analyses of TLC, HPLC, UV spectrum, NMR spectrum, antibacterial spectrum and the like.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Solvent: c1ccncc1
Product: C=CCN(CC=C)c1nc(NC(C)=O)n2oc(=O)nc2n1

Procedure:
6 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are stirred at room temperature for 18 hours with 60 ml. of absolute pyridine and 8 ml. of acetic acid anhydride. The solvents are distilled off at 40° C. and the residue is dissolved in 220 ml. of methylene chloride. The solution obtained is washed with 1-N-hydrochloric acid, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}acetamide having a melting point of 164°-165° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[O:16]1[C:17]2([CH2:18][CH2:19][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[CH:49][N:50]=[C:24]34)[CH2:21][CH2:22]2)[O:13][CH2:14][CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.27 g, 64%).
Reaction SMILES: Br[C:2]1[C:15](Br)=[CH:14][C:5]2[O:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[O:9][C:4]=2[C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[H][H]>CO.[C].[Pd]>[NH2:17][C:3]1[C:4]2[O:9][C:8]([F:10])([F:11])[C:7]([F:13])([F:12])[O:6][C:5]=2[CH:14]=[CH:15][CH:2]=1
Reactant: O=[N+]([O-])c1c(Br)c(Br)cc2c1OC(F)(F)C(F)(F)O2
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2c1OC(F)(F)C(F)(F)O2
Yield: 77.7 %

Procedure:
62 g (150 mmol) of 6,7-dibromo-5-nitro-2,2,3,3-tetrafluoro-benzo(1.4)dioxane, 41 g (300 mmol) of potassium carbonate and 5 g of palladium-carbon (10% strength) are stirred at 50° C. and a hydrogen pressure of 90 bar in 500 ml of methanol in an autoclave for 20 hours. The reaction mixture is filtered, the filtrate is mixed with 500 ml of water and extracted thoroughly with ether, and the extract is dried over sodium sulphate and concentrated. Vacuum distillation yields 26 g (78% of theory) of 5-amino-2,2,3,3-tetrafluoro-benzo(1.4)dioxane having a boiling point of 99° to 101° C./16 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:11](=[O:20])[C:10]=2[CH:21]=1)(=[O:5])=[O:4].CO.[BH4-].[K+].[OH-].[K+]>O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([OH:20])[C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
3-Dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-one (6.9 g., 0.022 mole) and 100 ml. of absolute methanol are stirred and heated to refluxing. A solution of 1.6 g. (0.0296 mole) of potassium borohydride in 12 ml. of water containing one pellet of potassium hydroxide is added dropwise at a rate such that reflux is maintained without external heating. After another 11/2 hours at reflux, the solution is evaporated to dryness under reduced pressure. The residual white solid is suspended in water, collected, and crystallized from 95% ethanol. The yield of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol is 6.05 g. (87%), m.p. 150°-152°C. The melting point is unchanged by further recrystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[NH:7]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C.OC[CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:14])[NH:7]2
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: OCCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: Cl
Product: O=C(OCCN1CCOCC1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1 g) in 4(2-hydroxyethyl)-morpholine (10 ml) at room temperature was added p-toluene sulphonic acid (20 mg), and the reaction mixture was warmed to 80° C. for 3 hours. The cooled mixture was treated with diethylether (50 ml), the resulting precipitate collected and dissolved in methanol (10 ml) and treated with hydrogen chloride in ethylacetate (2 ml of 5M). The mixture was stirred for 30 minutes and the resulting precipitate collected and recrystallised from ethanol-water to give 2-(4-morpholinyl)ethyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate hydrochloride (0.45 g), m.p. 233° C. (dec). δ (360 MHz, D2O) 3.35 (4H, bs, morpholinyl-3,5-H), 3.55 (2H, t, CH2N), 4.06 (4H, bs, morpholinyl-2,6-H), 4.85 (2H, t, CO2CH2), 6.73 (1H, s, 3-H), 7.25 (1H, d, 6-H) and 7.40 (1H, d, 8-H). (Found: C, 46.94; H, 4.23; N, 6.84, Cl, 25.92%. C16H16Cl2N2O4. HCl. 0.4H2O requires C, 46.73; H, 4.26; N, 6.81; Cl, 25.86%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2>C(Cl)Cl>[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][N:44]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and isobutyryl chloride (44 mg, 0.41 mmol), in methylene chloride (0.5 ml) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 2% methanol/methylene chloride gave 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline (90 mg, 52%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:30]1([C:35]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.76 g (5.08 mmol) of ethyl 5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylate were dissolved in 12 ml of dichloromethane, and 0.77 g (7.62 mmol) of triethylamine were added at 0° C. 0.89 g (6.61 mmol) of cyclopentanecarbonyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 2.1 g (100% of theory)
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([CH2:10][C:11]#[N:12])[CH:9]=1>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH3:12].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1
Reactant: N#CCc1cc(Cl)ccc1F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N
Product: NCCc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (1.73 g, 45.51 mmol) was added portionwise to a solution of 5-chloro-2-fluorophenylacetonitrile (1.04 g, 6.15 mmol) and cobalt (II) chloride hexahydrate (2.18 g, 9.22 mmol) in methanol (30 mL) and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered though Celite®, concentrated in vacuo and the residue was partitioned between 1M hydrochloric acid (40 mL) and dichloromethane (40 mL). The aqueous phase was separated, basified to pH 11 with 1M ammonia solution and extracted with dichloromethane (2×40 mL). The combined organic solution was washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2, to afford the title compound as a yellow oil in 33% yield, 350 mg. 1H NMR (400 MHz, CDCl3) δ: 7.28 (1H, m), 7.22 (1H, m), 7.05 (1H, m), 2.85 (2H, m), 2.77 (2H, m) ppm; LRMS APCI m/z 174 [M+H]+