Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)S([N:7]1[CH:11]=[C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]1[C:17]([OH:40])([CH3:39])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([NH:31]C(=O)OC(C)(C)C)=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)(=O)=O>CO>[NH2:31][C:26]1[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:17]([C:8]3[NH:7][CH:11]=[C:10]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=3)([OH:40])[CH3:39])=[CH:20][CH:21]=2)=[CH:29][N:28]([CH3:30])[N:27]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(CC(C)(O)c3nc(CC(C)(C)C)c[nH]3)cc2)c(N)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of tert-butyl [4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazo 1-2-yl]-2-hydroxypropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (33 mg, 0.06 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was purified with high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 368.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Br:14])=[CH:9][C:8]=1[F:15].[CH2:16]([O:18]CC)C>O>[Br:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([CH:16]=[O:18])=[C:8]([F:15])[CH:9]=1
Reactant: CCOCC
Reactant: Fc1cc(Br)c(F)cc1Br
Agent: [Li]CCCC
Solvent: O
Product: O=Cc1cc(F)c(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at −70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluting with 5% ethyl acetate/hexane, gave a yellow oil (1.82 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)(=O)C.CCCCCC>[C:10]1([CH2:9][CH2:8][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(CCNc2ccccc2)cc1
Yield: 78 %

Procedure:
According to GWM, 0.011 mol (=1.00 ml) of aniline and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:3) as eluent, the product N-phenylethylaniline being obtained as a yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22]C(=O)C(F)(F)F)=[CH:19][CH:18]=1.Cl.ClCCl.CO>CO>[NH2:22][CH2:21][C:20]1[CH:29]=[CH:30][C:17]([NH:16][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]#[CH:11])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(CNC(=O)C(F)(F)F)cc1
Reactant: C#CCNc1nc(Cl)ncc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C#CCNc1nc(Nc2ccc(CN)cc2)ncc1C(F)(F)F
Yield: 37.4 %

Procedure:
A mixture of 2-chloro-4-(prop-2-ynylamino)-5-trifluoromethyl-pyrimidine (235 mg), N-(4-aminobenzyl)-2,2,2-trifluoro-acetamide (410 mg) and hydrochloric acid (37% in water, 0.2 mL) in methanol (5 mL) was refluxed for 1 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the aqueous phase extracted with ethyl acetate, the combined organic phases dried (Na2SO4), concentrated, filtered through silica using dichloromethane/methanol, and the filtrate evaporated. To a solution of the residue in methanol (9 mL), tetrahydrofuran (9 mL) and diethyl ether (4-5 mL) was added lithium hydroxide (150 mg) and the mixture was refluxed for 6 h, after which it was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with additional ethyl acetate, the combined organic phases dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (120 mg).
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[C:9]=2[C:10](=[O:12])[CH:11]=1)([O:3]CC)=[O:2].O>C(O)(=O)C>[C:1]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([OH:18])[C:9]=2[C:10](=[O:12])[CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cc(=O)c2c(O)c(Cl)ccc2o1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(=O)c2c(O)c(Cl)ccc2o1

Procedure:
2-carboethoxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran is dissolved in glacial acetic acid and water (5:1) and the solution refluxed for 4 hours. This is cooled and the resulting solid collected and washed with water to give 2-carboxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=[C:7]([NH:6][CH2:5][C:4]([OH:23])=[O:3])[N:12]=1
Reactant: CCOC(=O)CNc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2cc(Cl)nc(NCC(=O)O)n2)c1C

Procedure:
To the suspension of N-[4-chloro-6-(2,3-xylidino)-2-pyrimidinyl]-aminoacetic acid ethyl ester (2.23 g; examples 3a and 5) in ethanol (27 ml) at 60° C., 1N NaOH (13.5 ml) is added, and the mixture is heated for 5'; then diluted with water, evporated under vacuum and extracted with diethyl ether (2×20 ml). After acidification with glacial acetic acid, the precipitate is filtered and washed with water to neutrality. The solid is then dried under vacuum with CaCT2, and 1.9 g of the desired acid are obtained (I, 1). With the same method the following compounds have been prepared:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([S:32]([NH:35][CH3:36])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-methyl-benzenesulfonamide (example B.27) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 58%). MS (ISP) 508.3 [(M+H)+]; mp 202-203° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]2=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=3)[C:11]([C:13]([O:15]CC)=[O:14])=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1.Cl>C1COCC1.C(O)C>[NH2:3][C:4]1[C:9]2=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=3)[C:11]([C:13]([OH:15])=[O:14])=[CH:12][N:8]2[N:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(-c2c(C(=O)O)cn3ncnc(N)c23)cc1F
Temperature: 65 °C
Yield: 99.5 %

Procedure:
1 N aqueous sodium hydroxide (253 mL, 253 mmol) was added to a suspension of ethyl 4-amino-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (40.0 g, 127 mmol) in THF (400 mL) and ethanol (400 mL). The reaction mixture was heated (65° C.) for 16 h and then cooled to rt. Hydrogen chloride (4 N in 1,4-dioxane, 70 mL, 280 mmol) was added and the volatiles were removed under reduced pressure. The residue was washed with water (200 mL) and then triturated with acetone and diethyl ether to give the desired product (36.3 g 99%) containing trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 12.20-12.30 (br s, 1H), 8.03 (s, 1H), 7.94-8.05 (br s, 1H), 7.89 (s, 1H), 7.02 (dd, J=12.4, 2.0 Hz, 1H), 6.73-6.92 (m, 2H), 5.22-5.47 (br s, 1H), 5.12-5.25 (br s, 1H); ES-MS m/z 288.0 (MH)+; HPLC RT (Method A) 1.13 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:19]#[N:20])(C)C>C(OCC)C.[I-].[Zn+2].[I-]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH2:19][NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To neat 1-benzyl-4-piperidone (2.22 mL, 12 mmol) was added trimethylsilyl cyanide (1.95 mL, ˜15 mmol) and zinc iodide (˜5 mg). The solution was stirred for 6 hours or until reaction was completed as indicated by tlc. This oil was dissolved in diethyl ether (30 mL), filtered to remove some solid and added dropwise to a solution of diethyl ether (15 mL) containing 1M lithium aluminium hydride/diethyl ether (30 mL). After stirring at ambient temp. for 2 hours, the reaction was carefully quenched with aqueous sat'd sodium sulfate. This suspension was diluted with more diethyl ether, filtered to remove solids, and the solvent evaporated under partial vacuum to give the crude title compound as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13]N1C(=O)CCC1=O>>[Cl:13][C:10]1[S:9][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc(Nc2nccs2)nc1
Product: Clc1cnc(Nc2ccccn2)s1
Reaction time: 8 h

Procedure:
Pyridin-2-yl-thiazol-2-yl-amine (5-2) and 1.2 equivalents of N-chlorosuccinimide were combined in a flame dried flask and allowed to stir together overnight under argon in anhydrous dioxane (0.25 M). The dioxane solution was then diluted with water and the resulting product filtered off. 1H-NMR (DMSO-d6) δ11.463 (1H,s) 8.30 (dd, 1H, J=4.9, 0.9 Hz) 7.73 (t, 1H, J=8.42 Hz) 7.38 (s, 1H) 7.03 (d, 1H, J=8.4 Hz) 6.96 (t, 1H, J=5.9 Hz). MS [M+H]+=211.9.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:24]1([C:30]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:43]1([C:30]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39]([N:12]4[CH2:11][CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=5)[CH2:14][CH2:13]4)(=[O:40])=[O:41])=[CH:38][C:32]=3[O:31]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Fc1ccc(C2C=CNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
4-(4-Fluorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (2.56 g, 12 mmol) was suspended in methylene chloride (150 ml). Ethyldiisopropylamine (4.2 ml, 25 mmol) was added and the solution was stirred for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.72 g, 10 mmol) was added and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by column chromatography on silical gel (100 g, dichloromethane eluant). The product was stirred with n-hexane, filtered and dried to yield the sulfonamide as white crystals (3.86 g, 75%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:6][C:5]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2)=[O:17].Cl>O.CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2)=[O:17]
Reactant: COC(=O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 54.1 %

Procedure:
A solution of sodium hydroxide (0.475 g) in water (30 ml) was added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid, methyl ester (Example 6b, 2.3 g) in methanol (30 ml) After 5 h the reaction mixture was reduced to half volume in vacuo and acidified with dilute hydrochloric acid. A white solid precipitated and was collected by filtration and dried in vacuo at 50° C., to give the subtitled compound (1.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34]Br)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12].CN(C=O)C>CC(C)=O>[CH2:11]([C@H:13]1[CH2:18][C@H:17]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C@H:14]1[O:32][C:33](=[O:36])[CH2:34][O:5][C:4](=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)[CH3:12]
Reactant: CC(C)(C)CC(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)(C)C
Yield: 61 %

Procedure:
In 10 ml of acetone is dissolved 1.16 g of 3,3-dimethylbutyric acid, and 5.0 ml of 2N-NaOH is added, followed by addition of 1.15 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF. The mixture is refluxed for 5 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is chromatographed on a silica gel column. Following passage of 200 ml of n-hexanediisopropyl ether (3:7), elution is carried out with a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.76 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1(C)C=CC=CC=1>[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:11]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C1CCCCN1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cccnc1N1CCCCC1=O
Reaction time: 5 h

Procedure:
To a suspension of 1.1 g of 60% sodium hydride in 10 ml of toluene is added 5 g of 2-oxopiperidine, followed by addition of 6.4 g of 2-chloro-3-(4-chlorobenzoyl)pyridine. The mixture is stirred at 90°-100° C. for 5 hours. After water is poured into the reaction mixture, the solvent of the toluene layer is distilled off. The residue is recrystallized from methanol to give 2-(2-oxopiperidino)-3-(4-chlorobenzoyl)pyridine, m.p. 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: C=CC(=O)O
Solvent: CCOCC
Product: COc1cccc(SCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 113.8 h
Yield: 36.4 %

Procedure:
3-Methoxythiophenol (5.70 g, 41 mmol) was placed in a flask with acrylic acid (2.36 g, 33 mmol) and stirred at room temperature for 113.8 hours. The reaction mixture was dissolved in ether and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated HCl, extracted with ether, dried over MgSO4, and concentrated in vacuo to give the 3-(3-methoxyphenylthio)propanoic acid (2.55 g, 37%) as a white solid: mp 39°-42° C.; 1H NMR (CDCl3) 300 MHz 7.21 (m, 1H) 6.91 (m, 2H) 6.77 (d, J=8.3 Hz, 1H) 3.79 (s, 3H) 3.16 (t, J=7.5 Hz, 2H) 2.68 (t, J=7.3 Hz, 2H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[N:15]=1)=[O:9]>C(O)=O>[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH:5]=[O:7])=[CH:20][CH:19]=2)[N:15]=1)=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(SCc2csc(NC=O)n2)cc1
Solvent: O=CO
Product: O=CNc1ccc(SCc2csc(NC=O)n2)cc1
Temperature: 50 °C
Yield: 96.1 %

Procedure:
A mixture of acetic anhydride (1.84 g) and formic acid (0.9 g) was heated at 50° C. for 0.5 hours with stirring. The solution was cooled at room temperature and to the solution was added the 2-formylamino-4-(4-aminophenylthiomethyl)thiazole (1.6 g). The mixture was stirred at room temperature for 6.5 hours and then the mixture was poured into ice-water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (1.7 g, yield: 96.7%). mp: 195°-197° C. (dec.)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18]1OCCOCCOCCOCCOC1.IC>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C1COCCOCCOCCOCCO1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 278 mg, 6.96 mmol) was suspended in THF (5 mL) and cooled to 0° C. trans-tert-Butoxy-N-(4-hydroxycyclohexyl)carboxamide (1 g, 4.64 mmol) and 15-crown-5 (0.965 mL, 4.88 mmol) were added and the reaction mixture was stirred at 0° C. for about 30 minutes. Iodomethane (0.289 mL, 4.64 mmol) was added and the reaction stirred at 0° C. for about 1 hour after which the LCMS showed it was complete. The reaction was quenched with methanol, the solvents removed in vacuo and the crude purified by column chromatography (SiO2, 8:2 n-hexanes/ethyl acetate) to afford 642 mg of the methyl ether. ES-MS: 230 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 379.06 g/mol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=1.[F:11][C:12]1([F:58])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([O:28]CC4C=CC(OC)=CC=4)[CH2:25][C:24]([CH3:39])([CH3:38])[CH2:23][C:22]=3[N:21]=[C:20]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[C:19]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:14][CH2:13]1>>[F:58][C:12]1([F:11])[CH2:17][CH2:16][CH:15]([C:18]2[C:27]3[CH:26]([OH:28])[CH2:25][C:24]([CH3:38])([CH3:39])[CH2:23][C:22]=3[N:21]=[C:20]([CH:40]3[CH2:45][CH2:44][N:43]([C:2]4[N:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][N:3]=4)[CH2:42][CH2:41]3)[C:19]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:49][CH:48]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CC(C)c1cnc(Cl)nc1
Product: CC(C)c1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-(propan-2-yl) pyrimidine instead of 5-bromo-2-chloropyrimidine, and from 96 mg (0.14 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 47 mg of the title compound was obtained as a white solid (yield: 50%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>COCCOC>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[S:31])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=O)cc1
Solvent: COCCOC
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCCC2=S)cc1

Procedure:
A suspension comprising 5.5 g of 1-[4-(diethylamino)benzenesulphonyl]-2-piperidinone and 3.74 g of Lawesson reagent in 80 cm3 of ethylene glycol dimethyl ether is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is then evaporated to dryness. The residue is chromatographed on silica (eluant: ethyl acetate/n-hexane, 1:1) and 4 g of product (m.p. 135°-140° C.) are obtained, which product is purified by 3 successive crystallizations in ethanol. 2 g of expected pure product are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=O)[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].N1C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:37][OH:38])[CH3:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 160 °C

Procedure:
A mixture of 1-[6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]ethanone (Example 454, 19 mg, 0.0378 mmol), hydroxylamine hydrochloride (2.9 mg, 0.042 mmol), pyridine (0.15 mL), and ethanol (0.15 mL) was heated in a microwave reactor at 160° C. for 10 min. The volatiles were removed, and the residue was triturated with hexane/DCM. The solid was collected and dried to provide the title compound. LC/MS: m/e 504.0 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 8.88 (1H, s), 8.45 (1H, s), 7.78 (1H, s), 7.73 (1H, d, J=7.5 Hz), 7.64 (1H, d, J=8.5 Hz), 7.27 (1H, d, J=8.4 Hz), 7.20 (2H, d, J=8.0 Hz), 7.14 (1H, d, J=7.3 Hz), 6.97 (2H, d, J=7.8 Hz), 4.70-4.95 (2H, br), 2.05 (3H, s), 1.23 (9H, s).