Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:15][C:16]1([CH3:28])[C:20](=[O:21])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH2:17]1>C1COCC1>[CH3:15][C:16]1([CH3:28])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:21])[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH2:17]1
Reactant: CC1(C)CC=C(c2ccccc2)C1=O
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C2(O)C(c3ccccc3)=CCC2(C)C)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
To a −78° C. solution of p-bromothioanisole (5 g) in 100 mL of THF was added a solution n-BuLi (10 mL, 2.5 M in hexane). After stirring for 45 min. at −78° C., a solution of the product of Step 3 (2.4 g) in 10 mL of THF was added dropwise. The reaction mixture was stirred for 10 min. and then quenched with 100 mL of saturated solution of NH4Cl. The product was extracted with 300 mL of 2:1 hexanes/EtOAc. The extract was dried over Na2SO4 and concentrated. Th e residue was purified by chromatography eluting with 10:1 hexane/EtOAc to give 3.5 g of the title compound.
Reaction SMILES: [C:1](=[O:14])([O:6][CH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[O:2][CH:3](Cl)[CH3:4].[I-:15].[Na+]>C(#N)C>[C:1](=[O:14])([O:6][CH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[O:2][CH:3]([I:15])[CH3:4]
Reactant: [I-]
Reactant: CC(Cl)OC(=O)OC(C(C)C)C(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)OC(C(C)C)C(C)C

Procedure:
A mixture of 1.78 g of 1-chloroethyl 2,4-dimethyl-3-pentyl carbonate and 5 g of sodium iodide is stirred in 30 ml of acetonitrile at 70° C. for 4 hours and concentrated. The residue is extracted with ether and concentrated to give crude 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate. In 30 ml of dimethylformamide is dissolved 3.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and with ice-cooling and stirring, the above 1-iodoethyl 2,4-dimethyl-3-pentyl carbonate is added thereto at one stroke, followed by stirring for 5 minutes. The reaction mixture is poured into a mixture of 150 ml of ethyl acetate and 150 ml of ice-cooled 20% aqueous sodium chloride. The organic layer is separated, washed with two 150-ml portions of saturated aqueous sodium chloride and extracted with 40 ml of 1N hydrochloric acid. The extract is subjected to column chromatography using Diaion MCI® GEL CHP-20P (Mitsubishi Chemical Industries Limited, Japan), elution being carried out with acetonitrile-0.01N hydrochloric acid. The fractions containing the desired product are combined and lyophilized to give 940 mg of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:20][CH2:21]3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Reactant: Clc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The 5-bromo-2-chloro-1H-benzoimidazole (0.115 g, 0.5 mmol, Example 23b), 1-(3-chloropyridin-2-yl)piperazine (0.198 g, 1 mmol, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 207-208° C. MS (ESI, pos. ion) m/z: 394 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([C:18]2[C:19](=[O:39])[N:20]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:21][CH2:22][C:23]=2[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[Cl:32])[CH3:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[Cl:32])[C:23]3[CH2:22][CH2:21][N:20]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:19](=[O:39])[C:18]=3[C:16]=2[CH3:17])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)C1=C(Nc2ccc(F)cc2Cl)CCN(N2CCCCC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O[Si](C)(C)C(C)(C)C)cc1)CCN(N1CCCCC1)C2=O
Temperature: 100 °C

Procedure:
3-{2-[4-(tert-Butyldimethylsilanyloxy)phenyl]-1-methyl-2-oxo-ethyl} -4-(2-chloro-4-fluorophenylamino)-5,6,3′,4′,5′,6′-hexahydro-2′H-[1,1′]bipyridinyl-2-one (1.135 g, 1.94 mmol) was suspended in toluene (5 ml) and toluene-4-sulfonic acid (0.037 g, 0.19 mmol) was added. The reaction mixture was heated in a microwave oven at 100° C. for 30 min. Water/toluene were added to the reaction mixture and the phases separated. The organic phase was washed with water, dried (MgSO4), filtered and evaporated to yield the crude product (crude 0.929 g).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:19](=[O:27])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[C:19](=[O:27])[C:18]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=c1c(I)c(OCc2ccccc2)ccn1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
N-Iodosuccinimide (2.64 g, 11.74 mmol) was added to a solution of intermediate D1 (3.0 g, 11.74 mmol) in acetic acid (40 ml). The reaction mixture was stirred at room temperature for 1 hour, after which it was concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM as eluent) and finally recrystallized from diethyl ether to yield intermediate D6 (4.12 g, 92%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cc(C)ccc1C(=O)O
Product: COc1cc(C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 48 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxy-4-methyl-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=75:5:20 to 60:20:20, 155 mg, 48%) which was obtained as a white solid. MS: m/e=348.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[OH-].[Na+]>O.CO>[CH3:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12]
Reactant: COC(=O)c1ccc2c(c1C)SCCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1SCCC2=O

Procedure:
41.1 g (0.17 mol) of methyl 8-methylthiochroman-4-one-7-carboxylate are hydrolyzed under reflux with 10.3 g (0.26 mol) of NaOH in a mixture of 400 ml of water and methanol. The methanol is then distilled off and the residue is diluted with water and acidifed with 2N hydrochloric acid. The useful product precipitates out and is filtered off with suction, washed with water and dried.
Reaction SMILES: [C:1]([N:4]1[C@H:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]1[CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)(=[O:3])[CH3:2].[H-].[Na+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]1[C@H:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:6]=2[C@H:5]1[CH2:27][C:28]12[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)c2[nH]c3ccccc3c2C[C@H]1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)c2c(c3ccccc3n2Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (1R,3S)-benzyl 2-acetyl-1-(1-adamantyl)methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (6.3 g, 12.7 mmol) in dry DMF (50 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/0.56 g, 14 mmol) in dry DMF (20 ml) under nitrogen at room temperature. The reaction mixture was stirred for 15 minutes at room temperature to which was added dropwise a solution of benzyl bromide (1.6 ml, 13.5 mmol) in DMF (10 ml). The reaction was stirred for a further one hour, diluted with ethyl acetate (150 ml), washed successively with 2N HCl (150 ml), brine (3×150 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as a yellow foam which was used without further purification. (7.45 g, 100%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=4)=[CH:17][C:11]=3[N:10]=2)C(=O)C2=CC=CC=C12.O.NN.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([C:18]3[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:17][C:11]=2[N:10]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN3C(=O)c4ccccc4C3=O)nc2c1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Yield: 50.9 %

Procedure:
25.9 g (62 mmol) of 6-[2-(3-phthalimidopropyl)-1H-benzimidazol -5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 16.0 ml (330 mmol) of hydrazine hydrate are boiled under reflux in 300 ml of ethanol for 1 5 hours. The thick suspension obtained is concentrated by evaporation under vacuum and the residue is taken up with 500 ml of 2N hydrochloric acid and the solution is filtered. The filtrate is concentrated by evaporation under vacuum and after the addition of 100 ml of ethanol it is again concentrated by evaporation. The solid obtained as residue is taken up with 200 ml of saturated potassium carbonate solution and the mixture is extracted with 3×100 ml of isopropanol. The combined organic phases are dried and concentrated by evaporation under vacuum. 13·9 g (79%) of a colorless solid are obtained after recrystallization from ethanol/water.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](O)=[O:22])=[CH:16][CH:15]=1>CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:22])[N:4]([CH2:3][CH:2]([F:12])[F:1])[C:5]3[C:6]([N:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:16][CH:15]=1
Reactant: Nc1ccccc1NCC(F)F
Reactant: O=C(O)C(=O)c1ccc(Cl)cc1
Solvent: CO
Product: O=c1c(-c2ccc(Cl)cc2)nc2ccccc2n1CC(F)F
Yield: 31.7 %

Procedure:
To a solution of 400 mg (2.32 mM) of N-(2,2-difiuoroethyl)benzene-1,2-diamine in 7 ml of methanol were added 428 mg (2.32 mM) of 4-chloro-α-oxo-benzeneacetic acid. The mixture was refluxed for 3 h. A solid was filtered, washed and dried under vacuum to give 236 mg of 3-(4-chlorophenyl)-1-(2,2-difluoroethyl) quinoxalin-2(1H)-one Yield: 32%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:21][CH2:20]1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Product: CCOC(=O)CCCN1CCN(c2ccccc2OC)CC1

Procedure:
Ethyl 4-(4-(2-methoxyphenyl)piperazin-1-yl)butanoate (17c) (Scheme 3) was synthesized from ethyl 4-bromobutanoate 16 and the piperazine 4 (R12═OMe, R13═H) according to protocol described for 17a (Example 19). Brown oil, 9.6 g (99%). 1H NMR (400 MHz, CDCl3): δ 1.23 (t, J=7.2 Hz, 3H), 1.82 (quintet, J=7.2 Hz, 2H); 2.35 (t, J=7.2 Hz, 2H); 2.43 (t, J=7.2 Hz, 2H); 2.63 (broad s, 4H); 3.07 (broad s, 4H); 3.84 (s, 3H); 4.13 (q, J=7.2 Hz, 2H); 6.83-6.99 (m, 4H). MS (ESI): m/z=307.50 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>O1CCOCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[CH:3]=[C:2]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][N:10]=2
Reactant: Fc1ccccc1-c1cc(Cl)c2nccnc2n1
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cc(Nc2ccncc2)c2nccnc2n1
Reaction time: 0.08 h

Procedure:
A solution of 52.2 mg (0.20 mmol) 8-chloro-6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazine in 1 ml dioxane was heated to 80° C. under nitrogen. Then 20.7 mg (0.22 mmol) 4-aminopyridine and 47.3 mg (0.42 mmol) potassium-tert-butoxide were added and the mixture was stirred at the same temperature for 5 minutes. Water was added to the reaction mixture. The resulting precipitate was filtered off and washed with water. The filtrate was extracted several times with dichloromethane; the organic phase was dried over sodium sulphate and evaporated. The residue was combined with the filtrate and purified by preparative HPLC. The fractions containing product were evaporated and partitioned between sodium hydrogen carbonate solution and dichloromethane. The organic phase was dried over sodium sulphate and evaporated yielding [6-(2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-8-yl]-pyridin-4-yl-amine as yellow crystals HPLC/MS (A): 1.37 min, [M+H] 318.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][N:16]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:17]>C(O)C>[CH3:15][N:16]([C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: CN(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(N(C)C)cc2)[nH]c1=O
Reaction time: 19 h
Yield: 55.6 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 4-(N,N-dimethylamino)aniline (19 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 19 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (15.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1>[CH3:30][O:31][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(-c4ccccc4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.CN(C=O)C.C(=O)([O-])O.[K+].Cl[CH2:56][O:57][C:58](=[O:67])[C:59]([CH3:66])([CH3:65])[CH2:60][O:61][CH2:62][O:63][CH3:64]>C(OCC)(=O)C>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[N:15]=[C:14]([O:16][CH2:56][O:57][C:58](=[O:67])[C:59]([CH3:65])([CH3:66])[CH2:60][O:61][CH2:62][O:63][CH3:64])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: COCOCC(C)(C)C(=O)OCCl
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 60 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (120 mg) and DMF (3 mL), potassium hydrogen carbonate (30 mg) and 3-methoxymethoxy-2,2-dimethylpropionic acid chloromethyl ester (54.8 mg) were sequentially added, and the resulting mixture was stirred at 60° C. for 14 hours. To the mixture, ethyl acetate (100 mL) was added. The resulting mixture was sequentially washed three times with water (50 mL) and with saturated aqueous sodium chloride solution (50 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate and methanol-ethyl acetate) to obtain the captioned compound (40 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[Cl:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33].N1C=CC=CC=1>ClCCl>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOc1ccc(NS(=O)(=O)CCCCl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
368 mg (1.0 mmol) of the compound from example 44A are reacted with 266 mg (1.5 mmol) of 3-chloropropanesulfonyl chloride and 0.81 ml (10.0 mmol) of pyridine in 12 ml of dichloromethane for 3 hours.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH3:14].C(O)(C)C.C(=O)=O>C1(C)C=CC=CC=1>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: O=C1CCCCCN1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCN1CCCCCC1=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
In a 1 liter 3-neck flask equipped with a dry ice-isopropanol condenser, an addition funnel and a mechanical stirrer was placed 10.2 g of 50% sodium hydride-mineral oil dispersion (5.1 g NaH, 0.2125 M) and 150 ml of petroleum ether. The suspension was momentarily stirred and then sodium hydride was allowed to settle. Most of the petroleum ether was pipetted out and 200 ml of dry toluene was added. To this was added dropwise a solution of 20 g (0.177 M) of azacycloheptan-2-one in 100 ml of dry toluene. The mixture was refluxed for 1 hour and then cooled to room temperature. A solution of 30.75 g (0.25 M) of 1-bromopropane in 100 ml of dry toluene was added dropwise under stirring. Upon completion of the addition, the mixture was warmed to 80°-100° and the temperature was maintained there for 4 hours. Then the isopropanol-dry ice condenser was replaced with a water condenser and the reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled, filtered and the filtrate was concentrated to a yellow oil. Distillation afforded 22.2 g (81%) of colorless product; b.p. 83°-86°/0.25 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[CH3:6])[CH3:2]>C1COCC1.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH2:14])[CH:8]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-hydroxy-3-nitro-phenyl)-propionic acid ethyl ester (9.71 g) in THF (40 mL) and EtOH (40 mL) was slowly added 10% Pd/C (0.89 g) at room temperature. After being hydrogenated for 0.5 h with H2 balloon, the reaction mixture was filtered through celite pad and washed with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=2:1) to afford the product as pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[NH2:24]>>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:28][CH:27]=1)(=[O:25])[NH2:24]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C(N)=O)cc3)c(F)cn2c1=O
Yield: 85.9 %

Procedure:
Ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and (4-carbamoyl-phenyl)-boronic acid (305.7 mg, 1.85 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (540 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12](C(Cl)(Cl)Cl)=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[C:24]([O-:27])(O)=[O:25].[Na+]>>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:24]([OH:27])=[O:25])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(C(Cl)(Cl)Cl)n(-c2ncccc2Cl)n1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc(CO)nn1-c1ncccc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
38.7 g (0.1 mol) of [1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanol and 10 g of H2SO4 (as 10% solution in water) were stirred for 3 hours at 80° C. The mixture was cooled to 0° C., made neutral with NaHCO3 solution and the precipitate was filtered off, washed with acetonitrile and dried. Yield 90%. M.p. 178-180° C.