Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[OH-:9].[Na+].Cl>>[CH3:1][NH:2][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:9]
Reactant: [OH-]
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: [Na+]
Product: CNCCCCC(=O)O
Temperature: 25 °C

Procedure:
A stirred solution of 1-methyl-2-piperidinone (4.40 mL, 40.0 mmol) in aqueous sodium hydroxide (4 M, 11.0 mL, 44.0 mmol) was heated at 100° C. for 15 h. The reaction mixture was cooled to room temperature and then acidified to pH 2 with concentrated hydrochloric acid. The mixture was then concentrated under reduced pressure to give crude 5-methylaminopentanoic acid as a pinkish white solid. To the crude 5-methylaminopentanoic acid was added MeOH (40.0 mL, 987 mmol) and concentrated hydrochloric acid (0.33 mL, 4.0 mmol). The resulting cloudy solution was heated at 60° C. for 39 h at which time LC-MS showed remaining starting material. Additional concentrated hydrochloric acid (0.33 mL, 4.0 mmol) was added and the resulting mixture was heated at 60° C. for 33 h and then at 65° C. for an additional 24 h. LC-MS showed remaining starting material. The reaction mixture was concentrated under reduced pressure and a solution of hydrogen chloride in MeOH (1.25 M) was added to the residue. The resulting mixture was heated at 60° C. for 72 h at which time no remaining starting material was observed by LC-MS. The reaction mixture was partially concentrated under reduced pressure and the solid material that formed was removed by filtration, washing with MeOH. The filtrate was then concentrated under reduced pressure to provide methyl 5-methylaminopentanoate hydrochloride (7.57 g, 100% yield) as a light yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl.O>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.850 ml (10 mmol) oxalyl chloride in 20 ml CH2Cl2 is added dropwise to a iced-cooled solution of 1.10 g (5 mmol) 4-bromo-2-methylbenzoic acid in 30 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 1 h at RT. The solvent is evaporated to dryness, the resultant colorless residue is dried under vacuum and then diluted with 25 ml CH2Cl2. This solution is then added dropwise to a mixture of 1.01 g (10 mmol) of N-methylpiperazine in 25 ml CH2Cl2. After 1 h 30, the reaction mixture is diluted with water and the two phases are separated. The aqueous phase is re-extracted with CH2Cl2 and the combined organic extracts are successively washed with a sat.solution of NaHCO3, water, sat. brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[N:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:6]2[N:5]=1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[NH:26][C:27](=[O:29])[CH3:28]>>[C:20]([CH2:19][CH2:18][N:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:22][C:23]3[CH:24]=[C:25]([NH:26][C:27](=[O:29])[CH3:28])[CH:30]=[CH:31][CH:32]=3)=[N:5]2)=[CH:10][CH:11]=1)#[N:21]
Reactant: CS(=O)c1ncc2ccc(-c3cccn3CCC#N)n2n1
Reactant: CC(=O)Nc1cccc(N)c1
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccn4CCC#N)n3n2)c1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 3-[2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrol-1-yl]-propionitrile (93 mg, 0.31 mmol) was coupled to 3′-aminoacetanilide (62 mg, 0.41 mmol) at 120° C. for 135 h to afford titled compound. Yield of TFA salt: 29 mg (19%) of gold powder. LC/MS: 386 (M+H); HPLC: 97% pure, RT=2.65 min; mp: 131-139° C.; 1H NMR: (DMSO, δ) 9.75 (s, 1H), 9.44 (s, 1H), 8.96 (s, 1H), 7.69 (s, 1H), 7.53 (d, J=7.4 ,1H), 7.12 (m, 3H), 6.95 (d, J=4.4, 1H), 6.90 (d, J=4.4, 1H), 6.58 (dd, J=7.9, 3.6, 1H) 6.26 (dd, J=3.6, 3.4, 1H), 4.24 (t, J=6.3, 2H), 2.83 (t, J=6.3, 2H), 2.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][S:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][S:10]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][N:18]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CS(=O)(=O)c1ccc(=O)[nH]n1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc(S(=O)(=O)CC(O)c2ccc(Cl)cc2)n[nH]1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A suspension was prepared of 6-[2-(4-chloro-phenyl)-2-oxo-ethanesulfonyl]-2H-pyridazin-3-one (1.0 mmol, 312 mg) prepared according to Example 17 in methanol (10 mL). Sodium borohydride (1.5 mmol, 55 mg) was added to the suspension at room temperature and stirred for 1 hour. The reaction mixture was evaporated and the residue was triturated with 10% hydrochloric acid (5 mL). The resulting white precipitate was filtered and air-dried to afford the title compound (69%, 218 mg); mp, 178-179° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][CH:11]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:18](=[O:19])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: OCCCCCCBr
Product: O=C(CCc1ccc(O)cc1)OCCCCCCBr
Yield: 70 %

Procedure:
From 6-bromo-1-hexanol and 3-(4-hydroxyphenyl)propionic acid. Working up by means of distillation. Yield: 70%. Boiling point: 205° C. (0.05 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][NH2:23])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(=NN)c2ccc(Cl)cc2)cc1
Yield: 96 %

Procedure:
0.7 of magnesium(scraped shape) and 100 mg of a chip of iodine were added to 5 ml of anhydrous diethyl ether. 10 ml of anhydrous diethyl ether solution of 5.6 g of p-bromochlorobenzene was dropwise added thereto under nitrogen stream at a rate that was just fast enough to maintain a gentle reflux. This solution was stirred at room temperature for 20 minutes to react them, a solution of 4.8 g of p-tert-butylphenyl acetonitrile in 5 ml of anhydrous diethyl ether was dropwise added thereto at a rate that was just fast enough to maintain a gentle reflux. The solution was further stirred for 30 minutes to react them. After completion of the reaction, a mixture solution of 10 g of ice and 130 ml of 6N-hydrochloric acid was added thereto and a reaction product was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The redisue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.3 g of 4'-chloro-2-(4-tert-butylphenyl)acetophenone. (2) 1.3 g of (4.5 mmol) of 4'-chloro-2-(4-tert-butylphenyl)acetophenone was dissolved in 15 ml of ethanol, and 0.2 g (4.5 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for three hours. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.3 g of [4'-chloro-2-(4-tert-butylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:27][C:26]=2[Cl:38])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: CCCCOCCOCc1ccc(OCC2CO2)cc1
Product: CCCCOCCOCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-n-butyloxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=NC=[CH:17][CH:18]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[N:24]1C=CC(CC(=O)C)=C[CH:25]=1>>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:24]=[CH:25][CH:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5]
Reactant: CC(=O)Cc1ccncc1
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccnc1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccncc1

Procedure:
Compound 17 was prepared as described for the preparation of Compound 16 using commercially available (4-pyridyl)acetone.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[O:20])[CH2:11]1)=[O:7])(C)(C)C.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)=[O:20])[CH2:11]2)=[O:7])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-1-methyl-1 H-indole-3-carboxamide (0.44 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.26 g) to give N-(3-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)propyl)-1-methyl-1H-indole-3-carboxamide.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:43])([F:42])[C:10]1[CH:11]=[C:12]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:13]([N:15]([CH:17]([CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][C:19]([OH:21])=O)[CH3:16])=[O:14].[CH:44]1([C:50]2[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:50]2[CH:51]=[CH:52][C:53]([NH:54][C:19](=[O:21])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]3[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=[C:10]([C:9]([F:42])([F:8])[F:43])[CH:11]=3)[CH3:16])[CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:55][CH:56]=2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)Nc1ccc(C2CCCCC2)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of 0.05 ml (0.362 mmol) of triethylamine and 37 mg (0.0726 mmol) of 3-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-4,4-diphenyl-butanoic acid in 0.5 ml of methylene chloride and a solution of 30.6 mg (0.289 mmol) of 1-propanephosphonic acid anhydride in 0.5 ml of methylene chloride are added in succession to 15.2 mg (0.087 mmol) of 4-cyclohexylaniline and the mixture is left to stand at room temperature for 24 hours. The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The organic phase is concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/methanol (95:5) Rf =0.44
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][O:22][S:32]([CH3:35])(=[O:34])=[O:33])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc2c(c1)COC(c1ccc([N+](=O)[O-])cc1)OC2
Yield: 15.8 %

Procedure:
3 g (10 mmol) of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol in 50 ml of dichloromethane are introduced into a flask. 1.54 g (12 mmol) of diisopropylethylamine are added and 1.37 g (12 mmol) of mesyl chloride in solution in 10 ml of dichloromethane are added dropwise at −5° C. After 1 hour 30 minutes of reaction at −5° C., 20 ml of a 5% sodium bicarbonate solution are added, the phases are separated by decantation and the organic phase is washed with water. It is dried over sodium sulfate and the solvent is evaporated off. The crude product is purified by silica gel chromatography (heptane/ethyl acetate: 3/2) to give 0.6 g of methanesulfonic acid [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.Cl.[N:9]([O-])=[O:10].[Na+]>O>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:9]=[O:10]
Reactant: Cn1nccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc(N=O)c1N
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 5-amino-1-methylpyrazole (100 g) in water (700 ml) were added concentrated hydrochloric acid (86 ml) and sodium nitrite (63.9 g) in water (200 ml) at a temperature below 10° C. The reaction mixture was stirred at 5° C. for 30 minutes. The precipitated solid was collected by filtration and dried to give 5-amino-1-methyl-4-nitrosopyrazole (117 g).
Reaction SMILES: Br[C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:22][O:21][C:20](=[O:23])[O:19]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([N:10]([CH2:17][CH:18]1[CH2:22][O:21][C:20](=[O:23])[O:19]1)[C:3]1[C:2](/[CH:26]=[CH:25]/[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1)=[O:16]
Reactant: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Reactant: C=CC(=O)OCCCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)/C=C/c1ccc(OC)nc1N(CC1COC(=O)O1)C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A mixture of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-2,2-dimethyl-N-[(2-oxo-1,3-dioxolan-4-yl)methyl]propanamide (5.722 g, 14.722 mmol), Pd(PtBu3)2 (151 mg, 0.296 mmol), Pd2(dba)3 (135 mg, 0.149 mmol), in 1,4-dioxane (40 ml) was treated with N,N′-dicyclohexylmethylamine (3.48 ml, 16.265 mmol) and n-butyl acrylate (2.54 ml, 17.743 mmol) and the mixture was then heated at 80° C. for 1 h. The reaction was then cooled, treated with water (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a yellow oil (6.156 g, 96%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[CH2:46][CH2:45][N:44]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]3[C:8](=[O:28])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:37])([F:36])[F:1])[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:43][CH2:42]1)(=[O:40])[CH3:39]
Reactant: COc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: CC(=O)N1CCNCC1
Product: COc1ccccc1-c1cc(N2CCN(C(C)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 50.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 18; 82.0 mg) was reacted with 1-acetylpiperazine (57.7 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (48.2 mg, 50%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]Br>C(Cl)(Cl)Cl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(NC(=O)c2ccccc2)cc1

Procedure:
A warm solution of 4'-benzamidoacetophenone (1.031 g) in chloroform (100 ml) was treated with bromine (0.22 ml). After dilution with more chloroform (50 ml), the resulting solution was washed with 2N-sodium hydroxide solution (2×25 ml) and water (50 ml), dried (MgSO4) and evaporated to a white solid (1.315 g). This was crystallised from ethanol to give the title acetophenone (922 mg); m.p. 171°-174°.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[O:14][CH2:13][CH:12]([CH3:15])[NH:11][C:10]=12)=[O:4].ClS([N:22]=[C:23]=[O:24])(=O)=O.C(N(CC)CC)C>ClCCl>[F:17][C:7]1[CH:6]=[C:5]2[C:10]3[N:11]([CH:12]([CH3:15])[CH2:13][O:14][C:9]=3[C:8]=1[F:16])[C:23](=[O:24])[NH:22][C:3]2=[O:4]
Reactant: COC(=O)c1cc(F)c(F)c2c1NC(C)CO2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COc2c(F)c(F)cc3c(=O)[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
A solution of 1.5 g (6.2 mmol) of 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylic acid methyl ester (Example 32a) in 25 mL of dichloromethane is cooled to −20° C. and treated dropwise with 0.92 g (6.5 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at room temperature for 18 hours and the solvent removed in vacuo. The residue is treated with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried (MgSO4), filtered, and concentrated in vacuo. The residue is dissolved in 50 mL of tetrahydrofuran, and the resulting solution is treated with 5.0 g (5.0 mmol) of triethylamine. After heating at reflux for 4 hours, the solvent is removed in vacuo, and the residue is triturated with 5 mL of dichloromethane/ethyl acetate (80:20). The insoluble material is removed by filtration, washed with the above solvent mixture (2 mL) to give 0.25 g of the title compound, mp 259–261° C. The filtrate is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethyl acetate (80:20) to give 0.38 g of starting material. Continued elution afforded an additional 0.2 g of the title compound. 1H NMR (400 MHz, CDCl3): 11.78 (s, 1H), 7.50 (m, 1H), 4.68 (m, 1H), 4.52 (d, 1H), 4.17 (d, 1H), 1.23 (d, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[CH2:23]([S:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2)[CH2:24][CH2:25][CH3:26]
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: CCCCS
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCSc1c2sc3ccccc3nc-2ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of phenothiazin-3-one (0.21 g) in 20 ml THF was added triethylamine (0.28 ml) and n-butanethiol (0.2 ml). The mixture was refluxed for 15 hours and then cooled to room temperature. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.22 g) was added and the reaction was stirred for 2 hours at 25°. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound, m.p. 72° C.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O.O>[Si:22]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([OH:12])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C(=O)O)ccc1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.8 %

Procedure:
To a solution of vanillic acid (2.0 g, 11.89 mmol) in N,N-dimethylformamide (50 ml), imidazole (4.04 g, 59.45 mmol) and tert-butyldimethylchlorosilane (4.48 g, 29.72 mmol) were added. The reaction was stirred at room temperature for 24 hours. he mixture was poured in water (70 ml) solution and extracted with diethyl ether (3×70 ml) The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-C18 HS, eluent: gradient acetonitrile/water 65/35 (600 ml), to acetonitrile/water 80/20 during 1200 ml). The product (0.70 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1>[Br:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.2 %

Procedure:
To a solution of 2-amino-3-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in dioxane (170 mL) was added phosgene (20% in toluene, 42.0 mL, 79.9 mmol) over a period of 15 mins. The reaction was stirred at ambient temperature for 48 h and then concentrated in vacuo. The resulting solid was crushed and further dried in vacuo to yield the desired product (12.6 g, 114%) which was used in the subsequent step without further purification.