Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH:3]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#N)[N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.S(=O)(=O)(O)[OH:20].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[N:4]1([CH:3]2[C:9]3[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:20])[O:1][C:2]2([CH3:18])[CH3:17])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CC(C)(O)C(c1ccccc1C#N)n1ccnc1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2ccccc2C1n1ccnc1

Procedure:
Crude 2-(2-hydroxy-1-imidazol-1-yl-2-methyl-propyl)-benzonitrile (1.75 g) is dissolved in dioxane (15 mL) and water (15 mL). Sulfuric acid (1.5 mL, 29.0 mmol) is added and the mixture is stirred at reflux for 2 h. After cooling down, the pH is adjusted with solid sodium bicarbonate. The mixture is extracted with ethyl acetate and the combined organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-(imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; MS (ESI) m/z 242.9 (M+H); 1H NMR (400 MHz, MeOD) δ ppm. 1.30 (s, 3 H), 1.53 (s, 3 H), 5.76 (s, 1 H), 6.98 (s, 1 H), 7.09 (s, 1 H), 7.52 (d, J=7.6 Hz, 1 H), 7.64-7.73 (m, 1 H), 7.76-7.85 (m, 1 H), 7.89 (s, 1 H), 8.25 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)S(O[CH2:18][CH:19]([F:21])[F:20])(=O)=O>>[Cl:1][C:2]1[N:10]=[C:9]([O:11][CH2:18][CH:19]([F:20])[F:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH:19]([F:21])[F:20])=[O:5]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: O=C(O)c1ccc(O)nc1Cl
Product: O=C(OCC(F)F)c1ccc(OCC(F)F)nc1Cl
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (2.9 g, clear colorless oil) from 2-chloro-6-hydroxynicotinic acid (1.8 g, 11 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate by the similar manner in Step-3 of Amine-13.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][O:6][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CCOC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
10 g of 2-ethoxypropanol was dissolved in 59 ml of pyridine and the solution was cooled to below 5° C. To the solution under stirring was added 22 g of p-toluenesulfonic acid chloride. After that, the mixture was stirred for 5 hours at room temperature and left standing overnight. Cold water was added thereto, and the mixture was subjected to extraction with ether. The ether extract was washed with water, followed by distilling-off of the ether to obtain 24 g of p-toluenesulfonic acid 2-ethoxypropyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].O.[OH-].[Na+].Cl>C1COCC1>[CH3:16][O:15][C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1ccc(C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1OC
Reaction time: 24 h

Procedure:
2-Methoxy-1,4-bis (methoxycarbonyl)benzene (1.61 g, 7.20 mmol) from Step 2 was dissolved in 20 mL of 1:1 THF:H2O and to the stirred solution was added 1N NaOH (7.2 mL, 7.2 mmol). After 24 h, the reaction was acidified to pH 2 with 1N HCl. The reaction was concentrated under reduced pressure and then extracted with CHCl3. The CHCl3 layer was dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 93:7 CHCl3 :A, where A=95:5 MeOH:HOAc. 1-Methoxycarbonyl-2-methoxybenzene 4-carboxylic acid was obtained as an oil (30% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[CH2:18][C:19](=O)[CH3:20]>C(O)(=O)C>[OH:15][C:5]1[C:6]([OH:14])=[N:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:12][C:17]([CH3:16])=[CH:18][C:19]([CH3:20])=[N:1][C:2]=3[C:3]=2[N:4]=1
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC1=CC(C)=Nc2c(ccc3nc(O)c(O)nc23)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 1,0 g (10 mmol) 2,4-pentanedione in 15 ml glacial acetic acid was stirred at 25° C. for 20 h. The precipitate was filtered off and washed with ethanol and ether to give 0,43 g (67%) 2,3-dihydroxy-8,10-dimethyl-7H-pyrazino(2,3-g)(1,5)benzodiazepine, m.p.>300° C. NMR (DMSO-D6): 7.07 (2H,s), 2.33 (3H,s), 2.27(3H,s).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1N

Procedure:
A mixture of 5-amino-2,4-dichloropyrimidine (0.32 g) (obtained as described in Chem. Pharm. Bull., (JAPAN), 1958, 6, 343-346) and a solution of sodium methoxide in methanol (from sodium (0.05 g) and methanol (25 ml)) was heated at reflux for 15 minutes and allowed to cool. Volatile material was removed by evaporation and a small volume of water added. The mixture was extracted twice with ether and the combined extracts were dried (MgSO4) and evaporated to give 5-amino-2-chloro-4-methoxypyrimidine (0.2 g) as an oil; 1H NMR (d6 -DMSO): 3.92 (s, 3H), 5.25 (s, 2H), 7.72 (s, 1H); mass spectrum (+ve CI): 160 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([OH:27])=O)=[CH:5]1.C([N:30](CC)CC)C.ClC(OCC)=O.N>CN(C)C=O.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[S:17][CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[N:20]=3)[CH:12]=2)[C:7](=[O:24])[C:6]([C:25]([NH2:30])=[O:27])=[CH:5]1
Reactant: CCN(CC)CC
Reactant: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(=O)O)cn(CCF)c3c2)n1
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1csc(/C=C/c2ccc3c(=O)c(C(N)=O)cn(CCF)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
The 1-(2-fluoroethyl)-7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (174 mg, 0.450 mmol) obtained in (B) was dissolved in dimethylformamide (3 ml), added with triethylamine (0.126 ml, 0.900 mmol) and ethyl chloroformate (0.086 ml, 0.900 mmol) under ice cooling, and then the mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, stirred for 30 minutes and further stirred at 0° C. for 1 hour. The reaction mixture was added with concentrated aqueous ammonia (0.15 ml) and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated to obtain the title compound (164 mg, 94%) as pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]([F:31])([F:30])[C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:27]5[CH2:28][CH2:29][C@@H:25]([C:24]([F:31])([F:30])[F:23])[CH2:26]5)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: FC(F)(F)[C@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC[C@@H](C(F)(F)F)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-(trifluoromethyl)pyrrolidine (1.2 equiv) to give 213 (15.8 mg, M+1 435.1)
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[NH2:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1)=[O:4]
Reactant: NCCC1OCCO1
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1OCCO1)C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 69.63 g of 2-chloro-3-(phenylmethoxy)propanoyl chloride (prepared according to the procedure described in Inorg. Chem., 31. 2422, 1992) (0.299 mol) in 90 ml of CHCl3 was added to a solution of 35.49 g of 2-(2-aminoethyl)-1,3-dioxolane (prepared according to the procedure described in EXAMPLE 4) (0.303 mol) and to 60.3 g of triethylamine (83 ml; 0.596 mol) in 100 ml of CHCl3 under inert atmosphere, keeping the temperature at 0°-5° C. The reaction mixture was stirred for 5 h at 25° C., then was washed with H2O. The organic phase was dried and evaporated to dryness, the residue was purified by flash chromatography. 61.68 g of the desired product (0.197 mol) were obtained.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:20])(C(C)(C)C)(C)C.CCN(CC)CC>CC#N>[OH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccccc2)c(O)c1
Yield: 76.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N.HF (100 uL, 0.62 mmol) in acetonitrile for 10 minutes at 23° C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%). mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CCNC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC3)nc21
Yield: 88.6 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.0 g), pyrrolidine (1.31 g), and acetonitrile (80 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with 5% hydrochloric acid (25 ml) and the mixture was heated on a steam-bath for several minutes and then cooled. The resulting precipitate was collected, washed with water, and recrystallized from chloroform-ethyl acetate to give 1.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid, m.p. 299°-300° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([CH3:16])[CH:14]=O)C>C(O)C.O>[CH3:16][C:13]1[CH:12]=[N:1][C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:14]=1
Reactant: CCOC=C(C)C=O
Reactant: NC1=CC(=O)CCC1
Solvent: CCO
Solvent: O
Product: Cc1cnc2c(c1)C(=O)CCC2
Yield: 48.4 %

Procedure:
A mixture of 3-aminocyclohex-2-enone (11.1 g., 0.1m) and 3-ethoxy-2-methylacrolein (11.4 g, 0.1m) was heated at 120° for 16 hours in a flask equipped for downward distillation. The ethanol-water distillate (6.5 ml.) was discarded and the residual oil distilled at 0.2 mm Hg to give 3-methyl-7,8-dihydro-5(6H)quinolone as a colourless oil b.p. 78°-80° (7.8 g, 48%) which solidified on standing and was recrystallized from 40- 60° petroleum ether as colourless needles m.p. 45°. Found: C, 74.81; H, 6.97; N, 8.91%. C10H11NO requires: C, 74.51; H, 6.88; N, 8.69%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[H-].[Na+].[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32].C>CN(C=O)C.O>[C:31]([NH:35][C:36]([NH:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)(C)C)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
To a solution of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine (0.48 g) from Example 20 in DMF (5 mL) was added 60% sodium hydride suspension (46 mg), and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added t-butyl isocyanate (0.113 g), and the mixture was stirred for 18 hours. The reaction mixture was diluted with water and the insoluble material was collected by filtration. The solid was suspended in water (20 mL) and acidified with 1.ON HCl to form a solution. Activated charcoal was added to the solution, and the suspension filtered through celite, washing with water. The filtrate was made basic with 1.0 N NaOH, and the insoluble product was collected by filtration and washed with water. A 180-mg sample of the product was further purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 86% of 0.1% trifluoroacetic acid in water/14% acetonitrile to 14% of 0.1% trifluoroacetic acid in water/86% acetonitrile over a 22-minute time period to afford 165 mg of 1-tert-butyl-3-[6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidin-7-yl]-urea, mp dec >80° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[CH:40][N:41]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1nccs1
Product: C[C@@H](c1ccc(-c2nccs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[S:26]([CH2:30][CH2:31][NH2:32])[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][S:26][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCSCCN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCSCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2′-sulfanediyldiethanamine. MS obsd. (ESI+) [(M+H)+] 457, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (dd, J=7.83, 1.26 Hz, 1 H), 7.84 (d, J=7.33 Hz, 1 H), 7.65 (td, J=7.58, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.51-7.39 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.14 (s, 2 H), 3.65-3.50 (m, 4 H), 2.92-2.79 (m, 4 H), 2.78-2.68 (m, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylsulfamoyl chloride (81 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 77%). 1H NMR (400 MHZ, CDCL3) δ7.19 (D, 2H), 6.93-6.91 (D, 2H), 4.05 (T, 2H), 3.78-3.76 (M, 2H), 3.59-3.54 (M, 2H), 3.17-3.15 (D, 2H), 2.76-2.70 (M, 12H), 2.15-2.06 (M, 4H), 1.90-1.87 (M, 6H).
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:7]2)[CH2:5][O:4][C:3]1([CH3:23])[CH3:22]>CO.[Pd]>[OH:1][CH:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][O:4][C:3]1([CH3:23])[CH3:22]
Reactant: CC1(C)OCC2(CCN(C(=O)OCc3ccccc3)CC2)C1O
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC2(CCNCC2)C1O
Reaction time: 0.5 h

Procedure:
Benzyl 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (from step (iii) above; 180 mg) was dissolved in methanol and palladium on carbon (5%) was added. The mixture was hydrogenated at atmospheric pressure for 30 min. The catalyst was removed by filtration through Hyflo™ and the solvent was evaporated in vacuo to afford the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[O:8][C:7]1[CH:23]=[CH:24][CH:25]=[CH:26][C:6]2=1.Cl.O1CCOCC1>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:6]3[CH:26]=[CH:25][CH:24]=[CH:23][C:7]=3[O:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]=12
Reactant: Cc1ccn2c1C1(CCN(C(=O)OC(C)(C)C)CC1)Oc1ccccc1-2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccn2c1C1(CCNCC1)Oc1ccccc1-2
Reaction time: 1 h

Procedure:
To tert-butyl 3-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (first eluting peak from step 2 (1.0 g, 2.8 mmol) was added hydrogen chloride in 1,4-dioxane (7.0 mL of 4.0 M, 28 mmol) and the mixture stirred 1 h, then filtered and rinsed with 1:1 ether/isopropanol to give 3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] as a pink solid. ESI-MS m/z calc. 254.3, found 255.3 (M+1)+; Retention time: 1.14 minutes (3 min run).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CCO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1cncc(C2=CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cncc(C2CCOCC2)c1
Temperature: 23 °C
Reaction time: 19 h

Procedure:
To a flask containing 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine (61.6 mg, 0.35 mmol) in EtOAc (3.0 mL) and EtOH (1.0 mL) was added 10% palladium on activated carbon (75.7 mg, 0.071 mmol). After purging, the mixture was stirred under an atmosphere of hydrogen at 23° C. The reaction was monitored with TLC and LC-MS. After 19 h, the reaction was filtered through Celite™. After concentration, the residue was identified as 5-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine that was used without purification. Mass Spectrum (pos.) m/e: 179.1 (M+1).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[C:10](F)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([O:24]CC)=[O:23])=[CH:14][C:13]=2[CH:27]=1>>[Cl:8][C:9]1[C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:12]2[O:17][CH:16]([C:18]([F:20])([F:21])[F:19])[C:15]([C:22]([OH:24])=[O:23])=[CH:14][C:13]=2[CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Sc1ccccc1
Product: O=C(O)C1=Cc2cc(Cl)c(Sc3ccccc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from benzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 271.7-274.4° C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.60 (m, 6H), 6.29 (s, 1H), 5.74 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz). FABLRMS m/z 385 (M−H). ESHRMS m/z 384.9904 (M−H, Calc'd 384.9913). Anal. Calc'd for C17H10ClF3O3S: C, 52.79; H, 2.61; Cl, 9.17; S, 8.29. Found: C, 52.80; H, 2.49; Cl, 9.71; S, 8.37.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]C)=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].B(Br)(Br)Br.O>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:20][CH:21]=1)#[N:2]
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(O)cc21
Temperature: 10 °C
Yield: 22 %

Procedure:
A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (85 mg, 0.23 mmol) in CH2Cl2 (2 mL) is cooled to −5° C. A solution of boron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH2Cl2) is added and the reaction mixture is allowed to warm to 10° C. over 4 h. The reaction mixture is poured into H2O and extracted with EtOAc (3×). The combined organic phases are washed with H2O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/CH2Cl2, 5-10%) gives 18 mg (22%) of N-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]methanesulfonamide as a tan solid.