Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Cl:7].[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1>C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>[Cl:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[C:13]1[CH:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1sccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccsc2Cl)c1
Temperature: 90 °C

Procedure:
3-bromo-2-chlorothiophene (1.00 mL), 3-aminophenylboronic acid (2.2266 g) and palladium tetrakistriphenylphosphine (544.8 mg) were combined in a mixture of 40 mL of dimethoxyethane and 15 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was then dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was purified using silica gel chromatography eluting with a 1:1 solution of DCM/Hexanes, followed by a 4:3 solution of DCM/Hexanes and finally a 2:1 solution of DCM/Hexanes, to give 1.80 g of 3-(2-chlorothiophen-3-yl)benzenamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].O.[OH-].[Na+].[CH3:30][C:31]([CH3:33])=[O:32]>>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([CH2:30][C:31](=[O:32])[CH3:33])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: CC(C)=O
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1OC)C(CC(C)=O)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Berberine hydrochloride (10.0 g, 26.90 mmol), water (40 mL), acetone (10 mL), 50% aqueous sodium hydroxide (15 mL) was introduced into a reaction vessel. The reaction mixture was stirred vigorously for 30 min at room temperature. The resulting precipitate was collected and washed with 80% methanol (2×10 mL) and then dried to afford 1-(9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-yl)-propan-2-one (8.5 g, 80%) as a yellow solid. LC/MS m/e calcd for C23H23NO5 (M+H)+: 394.44, observed: 336.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3 H) 2.31 (dd, J=14.65, 4.80 Hz, 1 H) 2.66-2.75 (m, 1 H) 2.75-2.82 (m, 1 H) 2.94 (dd, J=14.65, 6.57 Hz, 1 H) 3.16-3.25 (m, 1 H) 3.25-3.30 (m, 1 H) 3.77 (d, J=2.02 Hz, 6 H) 5.21 (dd, J=6.32, 4.80 Hz, 1 H) 5.97-6.03 (m, 3 H) 6.72 (d, J=8.34 Hz, 1 H) 6.76 (s, 1 H) 6.87 (d, J=8.34 Hz, 1 H) 7.25 (s, 1 H).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=2[CH:15]=1.O>CN(C=O)C>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:13][C:14]3[CH:24]=[CH:23][C:17]4[N:18]=[C:19]([S:21][CH3:22])[O:20][C:16]=4[CH:15]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: c1ncc2nc[nH]c2n1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(Cn3cnc4cncnc43)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a stirred solution of 9H-purine (784 mg, 6.53 mmol) in DMF (16 mL) was added NaH (60% dispersion in mineral oil, 373 mg, 9.33 mmol), portionwise at 0° C. After stirring for 30 min, 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.3 g, 6.22 mmol) was added to the mixture. The reaction mixture was allowed to warm to rt and stir for 3 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (150 mL×4). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light yellow solid (569 mg, 32.7%). 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 7.69 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 5.59 (s, 2H), 2.70 (s, 3H). LCMS (ESI) m/z 298 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:27]2[CH2:33][CH:32]([OH:34])[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH:21]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.[CH3:42]B1OB(C)OB(C)O1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[OH:34][CH:32]1[CH2:31][N:30]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:29][CH2:28][N:27]([C:3]2[C:2]([CH3:42])=[CH:7][CH:6]=[C:5]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:18]=[N:19][N:20]([CH2:22][C:23]([F:25])([F:24])[F:26])[CH:21]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[N:4]=2)[CH2:33]1
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)ccc2Br)CC(O)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-n2ncc3cnc(-c4cnn(CC(F)(F)F)c4)cc32)nc1N1CCN(C(=O)OC(C)(C)C)CC(O)C1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
A mixture of tert-butyl 4-(3-bromo-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-1,4-diazepane-1-carboxylate (244 mg, 0.38 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (194 mg, 1.53 mmol), Pd2 dba3 (174 mg, 0.19 mmol), Pcy3 (107 mg, 0.38 mmol), and Cs2CO3 (500 mg, 1.53 mmol) in 1,4-dioxane (10 mL) was heated in a microwave oven at 110° C. for 1.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/petroleum Ether (20%˜80%) as eluting solvents to afford tert-butyl(±)-6-hydroxy-4-(3-methyl-6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a white solid (120 mg, 55%). MS (ESI) m/z: 573 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([O:16]C)=[O:15])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1c(C(=O)OC)cnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C(=O)O)cnn1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylate (315 mg, 1.37 mmol) in ethanol (5 ml) was added 10M sodium hydroxide (0.410 ml, 4.10 mmol). The reaction mixture was heated to 80° C. After 3 hours, the reaction mixture was cooled and quenched with 1N HCl until the pH ˜1. The reaction mixture was diluted with chloroform and water, the organics were separated, then dried over magnesium sulfate, filtered, and concentrated to afford 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:20])=[CH:16][CH2:15][CH2:14][CH2:13]4)[CH3:2]>CC(C)=O.[Cr](O)(O)(=O)=O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:20])=[CH:16][CH2:15][CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Yield: 83.4 %

Procedure:
Dissolve 13β-ethyl-gon-4-en-17β-ol (0.29 g.) in acetone (40 cc.) and 8N-chromic acid dropwise with stirring until the solution become permanently orange and then add isopropanol (3 cc.) and evaporate the solution to small bulk (ca. 5 cc.). Add water and extract the mixture with ether. Wash, dry and evaporate the ethereal solution to obtain 13β-ethyl-gon-4-en-17-one (0.24 g.), m.p. 101°-102° C. Purify by recrystallization from methanol to obtain the pure product, m.p. 102.5°-103.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:27]([NH2:29])=[O:28])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C(F)=C(NC2C3C(=[CH:47][C:48](OC)=[C:49]([O:52][C@H]4CCNC4)C=3)N=CN=2)C=CC=1F>>[C:49]([N:24]1[CH2:25][CH2:26][C@H:21]([O:20][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][C:16]=2[O:30][CH3:31])[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[C:3]=2[F:32])[CH2:22][C@H:23]1[C:27]([NH2:29])=[O:28])(=[O:52])[CH:48]=[CH2:47]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCN[C@H](C(N)=O)C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1O[C@H]1CCNC1
Product: C=CC(=O)N1CC[C@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@H]1C(N)=O
Yield: 69 %

Procedure:
The procedure of step (1-7) was repeated except for using the compound obtained in step 4) instead of N-(3-chloro-2,4-difluorophenyl)-7-methoxy-6-((3S)-pyrrolidin-3-yloxy)quinazolin-4-amine to obtain the title compound (10 mg, 69%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:24])[N:19]=[C:20]([CH2:21][CH2:22][CH3:23])[N:13]2[N:12]=1)[CH2:2][CH3:3].[Cl:25][S:26](O)(=[O:28])=[O:27]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:24])[N:19]=[C:20]([CH2:21][CH2:22][CH3:23])[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: CCCOc1ccccc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(CCC)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 2.80 g (8.6 mmol) of 2-(2-propoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are added slowly to 5.13 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 3.50 g (96%) of a colourless foam. Rf=0.49 (dichloromethane/methanol=95:5)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:45][CH:46]=[CH:47][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:45][CH:46]=[CH:47][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CNC(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.013 g, 0.020 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.009 g, 72% yield) as the dihydrochloride salt. MS ESI (+) m/z 563 detected.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:23][OH:24])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:12]1)[CH2:23][OH:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-carbamic acid tert-butyl ester. (0.46 g, 1.24 mmol) in dichloromethane (6 ml) is treated with trifluoroacetic acid (2 ml) and the reaction mixture stirred for 1 hour at ambient temperature. The solvent is evaporated and the residue dissolved in water. The resulting aqueous solution is basified with saturated aqueous NaHCO3 and extracted into dichloromethane. The dichloromethane is dried over MgSO4 and evaporated to afford (S)-2-amino-4-[3-(4-chlorophenoxy)-azetidin-1-yl]-butan-1-ol as a clear oil. [MH]+ 271.0
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[C:14]([SH:16])[N:15]=2)[C:11]=1[OH:12])=[O:5])C.[OH-].[Na+].Cl>O>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:13]=[C:14]([SH:16])[N:15]=2)[C:11]=1[OH:12])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2nc(S)nn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2nc(S)nn2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
The product obtained in Step 1 of Example 48 (2.5 g) was added to a solution of 1.3 g sodium hydroxide dissolved in 20 ml of water and stirred at room temperature for four hours. The pH of the solution was adjusted to 1-2 with 6N hydrochloric acid. The formed crystals were collected by filtration, washed with 30 ml of water and dried, affording 2.2 g of the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:24][N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:30]
Reactant: CN(C)C(=O)CCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCC(=O)N(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N,N-dimethylsuccinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(dimethylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=898; RT=1.15 min; UPLC Method I
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[CH3:41][C:42]([CH3:44])=O.[OH-].[Na+]>CO.C(O)(=O)C>[CH3:41][CH:42]([N:4]1[CH2:3][CH2:2][N:1]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]4[C:32]([NH:33][CH:34]([CH3:36])[CH3:35])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:25][CH2:26]2)=[O:20])=[CH:13]3)=[O:8])[CH2:6][CH2:5]1)[CH3:44]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCNCC4)ccc3[nH]2)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NC(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
To a solution of 1-[5-(1-piperazinylcarbonylamino)-indole-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (EXAMPLE 46, 0.41 g) in methanol (50 ml) is added sodium cyanoborohydride (53 mg) and acetone (1 ml). Additional sodium cyanoborohydride (44.3 mg total) and excess acetone are added in portions until the reaction is complete as judged by TLC on silica gel. The mixture is acidified with acetic acid, neutralized with 50% aqueous sodium hydroxide and concentrated. The residue is dissolved in methylene chloride, washed with water, saturated potassium carbonate solution, and saline and dried over sodium sulfate followed by concentration. The resulting material is purified by chromatography on silica gel (100 ml) packed in methanol/chloroform (1/99) and eluted with a methanol/chloroform gradient (1→5%) to give the title compound, NMR (chloroform-d) 9.14, 7.71, 7.33, 7.17, 6.95, 6.86, 6.74, 4.06, 3.58, 3.20, 2.78, 2.60, 1.27, 1.08 δ.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]4[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:22]3[CH2:27][CH2:26][N:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[C:33]1([S:39]([N:42]=[C:43]=[O:44])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CS(C)=O>[CH2:31]([S:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:13]2[C:12]3[C:16](=[C:17]([C:19]([NH2:21])=[O:20])[CH:18]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH2:1][N:2]([C:43]([NH:42][S:39]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)(=[O:41])=[O:40])=[O:44])[CH2:3]5)[CH:11]=3)[NH:15][CH:14]=2)[CH2:23][CH2:24]1)(=[O:29])=[O:30])[CH3:32]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(=O)NS(=O)(=O)c4ccccc4)C5)cc23)CC1
Yield: 36.9 %

Procedure:
To a solution of 5-(2,3-dihydro-1H-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.066 mmol) in DMSO (1.0 mL), was added benzenesulfonyl isocyanate (15 mg, 0.079 mmol). The resultant mixture was stirred overnight at room temperature. Mixture purified by Gilson Preparatory HPLC to give 15.5 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[N:4][O:5][N:6]=1.O=S(Cl)Cl.[CH3:14][CH2:15]O>>[NH2:1][C:2]1[C:3]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nonc1N
Yield: 50 %

Procedure:
To a solution of 4-amino-1,2,5-oxadiazole-3-carboxylic acid (0.25 g, 1.9 mmol) in 2 mL of EtOH was added SOCl2 (0.2 mL) dropwise, under cooling with an ice-bath. The resulting mixture was refluxed for 4 hours and then concentrated. The oil was diluted with 50 mL of H2O and extracted with diethyl ether (3×100 mL). The combined organic layer was dried over MgSO4 and concentrated to give a white solid (0.15 g, 50%). 1H NMR (DMSO, 500 MHz) δ 6.39 (s, 2H), 4.39 (q, 2H), 1.35 (t, 3H). Mass Spec. FIA MS 158.1 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[O:11]=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[O:11]=[C:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=C1CCNCC1
Product: N#CCc1ccc(N2CCC(=O)CC2)cc1

Procedure:
Moreover, the 4-fluoro-phenyl-acetonitrile can be reacted with 4-oxo-piperidine, to yield the 4-(4-oxo-piperidino)-phenylacetonitrile, which is hydrolyzed to the free acid and the acid esterified, to yield corresponding ethyl esters. The carbonyl group therein is reduced with one equivalent of Grignard compounds, e.g. methyl-, ethyl- or n-propyl-magnesium bromide, to yield the ethyl 4-[4-hydroxy-4-(methyl, ethyl or n-propyl)-piperidino]-phenyl acetate. Analogously, the α-[3-chloro-4-(4-hydroxy-4-methyl-piperidino)-phenyl]-propionate is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4](I)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[N:20][CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)(=[O:17])=[O:16]>>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:22]2[CH:21]=[N:20][CH:19]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[CH:23]=2)[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Product: CC(=O)c1cc(Cl)c(F)c(-c2cncc(S(C)(=O)=O)c2)c1O
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example 127, step A, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (See, Example 172, Step 2) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (PepTech Corp., Cat. No. BE358) as the starting materials in 87% yield. LCMS for C14H12ClFNO4S (M+H)+: m/z=344.0. Found: 343.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:12][CH3:13].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:32][CH:31]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([N:12]([CH2:11][C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH3:13])=[O:40])=[CH:32][CH:31]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c[nH]c2c(F)cccc12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1c[nH]c2c(F)cccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 17.7 %

Procedure:
According to the procedure of Example 24, except substituting 7-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[α]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.285 g, 1.74 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 18%) was prepared as a white powder: MS (ES) m/e 325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)N3CCC(O)CC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and 4-hydroxypiperidine gave 176. MS: (ESI+) 497.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:27]([O:29][CH3:30])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(N)cc2)no1
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 88 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-phenylpropanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 88% of the title compound. MS (ESI): m/z 503.2 (M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 9.43 (d, 1H), 9.33 (s, 1H), 8.63 (s, 1H), 8.16 (dt, 1H), 7.84 (d, 2H), 7.61 (d, 2H), 7.56 (s, 1H), 7.27 (d, 4H), 7.23 (m, 2H), 7.15 (t, 1H), 7.00 (m, 1H), 4.74 (m, 1H), 3.65 (s, 3H), 3.23 (m, 2H).