Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]4([CH:31]([OH:33])[CH3:32])[CH2:30][CH2:29][NH:28][CH2:27]4)=[O:25])[CH:21]=3)[N:16]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[N:74]=[CH:73][CH:72]=[CH:71][N:70]=3)=[CH:65][CH:64]=2)[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]4([CH:31]([OH:33])[CH3:32])[CH2:30][CH2:29][N:28]([CH2:54][C:55](=[O:56])[N:57]5[CH2:62][CH2:61][N:60]([C:63]6[CH:64]=[CH:65][C:66]([C:69]7[N:70]=[CH:71][CH:72]=[CH:73][N:74]=7)=[CH:67][CH:68]=6)[CH2:59][CH2:58]5)[CH2:27]4)=[O:25])[CH:21]=3)[N:16]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2)CC1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 8 h

Procedure:
Added Cesium carbonate (60 mg, 0.184 mmol) to a solution of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) (60 mg, 0.098 mmol) and 2-chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (50 mg, 0.158 mmol) in DMF (2 ml) at room temperature, then stirred overnight.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:40])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]([C:37](=[O:39])[CH3:38])[O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:24][CH2:23]2)[CH:17]([CH:41]([OH:43])[CH3:42])[C:16]3=[O:44])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:49].O>[Pd].O1CCOCC1>[Na+:49].[C:37]([N:28]([CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:40])[CH:18]3[N:15]([C:16](=[O:44])[CH:17]3[CH:41]([OH:43])[CH3:42])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)N(CC1CC(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N(CC1CC(SC2=C(C(=O)[O-])N3C(=O)C(C(C)O)C3C2C)CO1)OCc1ccccc1
Yield: 26.5 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.272 g of product from Example 74, 0.0402 g of sodium bicarbonate, 2 ml of water, 11.3 ml of dioxane, and 0.110 g of 10% palladium/carbon to give 0.059 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=O)=[O:13])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:23])=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([Cl:23])(=[O:15])=[O:13])=[CH:7]2
Reactant: O=S(=O)(O)c1ccc2c(Br)cccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a round bottom flask was added 5-bromonaphthalene-2-sulfonic acid (5.00 g, 17.41 mmol), followed by DMF (17.41 mL) to generate a deep green heterogeneous solution. Thionyl chloride (2.54 mL, 34.8 mmol) was added dropwise using a syringe at rt, and the solution turned orange and heat was evolved. The solution became homogeneous. The solution was maintained at rt for 18 h. The resulting orange solution was poured into a separatory funnel containing ice and diluted with DCM (200 mL). When the ice melted, the mixture was shaken and then the resulting layers were separated. The aqueous layer was extracted with DCM (1×50 mL). The combined organic layers were washed with water (3×200 mL), then dried over Na2SO4 and concentrated to provide 5-bromonaphthalene-2-sulfonyl chloride (5.00 g, 16.36 mmol) as a brown oil, which was used immediately without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=[S:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:12][S:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCC2CO2)cc1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CCCC2CS2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(3-phenylpropyl)oxirane (Example 35b) (2.0 g, 0.0123 mol) and triphenylphosphine sulphide (3.62 g, 0.0123 mol) in toluene (20 ml), trifluoroacetic acid (1.40 g, 0.0123 mol) was added over 5 min. After stirring for 1 hour at room temperature, the reaction mixture was washed with water, sodium hydrogen carbonate solution and again with water. After drying (MgSO4) and removal of solvent at reduced pressure, the product contaminated with triphenylphosphine oxide was isolated as a crystalline mass. Attempted purification of the thiirane resulted in its extensive decomposition and it was therefore used in its crude state.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[NH2:16])=[CH:4][CH:3]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:16][C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[S:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(Sc2ccc(F)cc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(F)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine was reacted with the product from Example 119A using the procedure from Example 102 substituting 2-(4-Fluoro-phenylsulfanyl)-5-methyl-phenylamine for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96-1.19 (m, J=6.25 Hz, 4H), 2.22-2.42 (m, 1H), 2.33 (s, 3H), 7.02-7.28 (m, 6H), 7.33 (s, 1H), 7.56 (d, J=8.46 Hz, 1H), 8.46 (s, 1H), 8.66 (d, J=8.09 Hz, 1H), 10.03 (s, 1H); MS (ESI)+ m/z 403 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.CCOCC>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)cc1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 1-(4-methoxyphenyl)piperidin-4-one (5.65 g, 27.6 mmol) and (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.65 g, 30.3 mmol) in MeOH (200 mL) was added STAB (10.49 g, 49.5 mmol) in small portions. The reaction mixture was stirred overnight, then was concentrated to 1/10 of the original volume. NaOH (100 mL, 1N aqueous) and CH2Cl2 (100 mL) were added and the organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated. Upon the addition of ether, tert-butyl {(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}carbamate (6.98 g, yield 67.5%) precipitated as a white solid. The resulting solid was dissolved in CH2Cl2 (50 mL) to which was added 4N HCl/dioxane (50 mL). After 2 h at room temperature, ether was added until (3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-amine precipitated (as the HCl salt) from the solution, and was collected by filtration as a white solid (6.40 g, 52% over 2 steps).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:18])[CH:10]([Cl:4])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulfuryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0°) solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J. Org. Chem., 65:8402-8405 (2000).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>ClCCl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
3-Nitrobenzoyl chloride (2 g, 10.77 mmol) was loaded into a round bottomed flask, placed under a N2 atmosphere and dissolved in anhydrous dichloromethane (10 mL). The mixture was cooled to 0° C. and N,N-dimethylethylenediamine (0.98 mL, 8.98 mmol) was added to the reaction. The reaction was allowed to warm to room temperature and left to stir for 18 h. After 18 h the reaction had given a precipitate which was isolated by filtration and washed with dichloromethane to give 2.28 g of a white solid, which was partitioned between dichloromethane and a saturated aqueous NaHCO3 solution. The organic layer was removed under educed pressure and the aqueous layer was then re-extracted dichloromethane. The organic layers were combined, dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound as a yellow solid. MS: 193, 238; 1H NMR (400 MHz, dmso-d6): 2.19 (6H, s), 2.42 (2H, t, J 6.8 Hz), 3.39 (2H, q, J 12.4 Hz, 6.7 Hz), 7.78 (1H, t, J 7.9 Hz), 8.29 (1H, ddd, J 7.9 1.8, 1.1 Hz), 8.38 (1H, ddd, J 8.1 Hz, 2.3, 1.0 Hz), 8.68 (1H, t, J 1.8 Hz), 8.81 (1H, t, J 5.7 Hz).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C[Si](C)(C)[C:22]([F:25])([F:24])[F:23].[F-].[Cs+].Cl>C1COCC1>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3](=[O:19])[C:22]([F:25])([F:24])[F:23])=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-benzyloxy-phenyl)-acetic acid methyl ester (11.7 mmol, 3.0 g), trimethyl-trifluoromethyl-silane and cesium fluoride in THF may be stirred at room temperature for 2 h. Hydrochloride may be added upon consumption of ester as indicated by TLC. The mixture may be stirred further at room temperature until the intermediate disappears as indicated by TLC to provide 3-(4-benzyloxy-phenyl)-1,1,1-trifluoro-propan-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccccc2NCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.6 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethyl]-1,2-benzenediamine (212 mg, 0.75 mmol) and pyridine (4 mL) in chloroform (2 mL) at 0° C. was treated with a solution of 4-methoxybenzoyl chloride (128 mg, 0.75 mmol) in chloroform. The mixture was allowed to warm to room temperature and stir for 17 h. The mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with 1 N NaOH (2×), water (3×), brine (1×), dried (K2CO3), and concentrated. The residue was purified by RPHPLC, yielding 52 mg (17%) of the title compound as a hydrochloride salt.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([F:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([F:16])[CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: FC(CN1CCOCC1)c1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(F)CN4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[2-(6-bromopyridin-2-yl)-2-fluoroethyl]morpholine (80 mg, 0.28 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (81 mg, 0.28 mmol) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>ClCCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1cc(N2CCC(NC3CC3)CC2)ccc1[N+](=O)[O-]
Yield: 93.2 %

Procedure:
1-(3-Methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18, 0.70 g, 2.80 mmol), cyclopropanamine (0.160 g, 2.80 mmol) and sodium triacetoxyborohydride (0.889 g, 4.20 mmol) in DCE (15 mL)/THF (5 mL) were stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10% MeOH/EtOAc) to give the title product (0.76 g, 93%). m/z 292.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[Br:24]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:24][C:13]1[NH:14][C:15]2[C:11]([N:12]=1)=[C:10]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@H:18]1[CH3:23])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]1[CH3:1])[N:16]=2
Reactant: BrBr
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]cnc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(Br)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.4 %

Procedure:
2-((S)-3-Methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (786 mg, 2.47 mmol) were dissolved in CH2Cl2 (25 mL). Bromine (0.16 mL, 3.09 mmol) diluted in 2 mL of CH2Cl2 was added slowly within 2 minutes. The reaction mixture was stirred for 6 hours at room temperature. Aqueous Na2S2O3 (10 mL) was added to the reaction mixture, and stirring was continued for 15 minutes. The organic layer was washed with brine and aqueous NaHCO3. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 2/3 to 4/1) to give the product as a foam (455 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: O=C=Nc1ccccc1Cl
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4Cl)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-chlorophenylisocyanate (0.00669 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.6 Hz, 3H), 2.59 (br. s., 2H), 3.78 (t, J=5.8 Hz, 2H), 4.28 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.45-6.55 (m, 1H), 7.08-7.17 (m, 1H), 7.18-7.32 (m, 2H), 7.36-7.46 (m, 2H), 7.60 (dd, J=8.1, 1.5 Hz, 1H), 7.69 (s, 1H), 8.23 (br. s., 1H). MS (ES+): m/z 575.03/577.01 (98/100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([NH:5][CH3:6])=O.B.O1CCCC1.CO>O1CCCC1>[N:16]1([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH:2]([OH:1])[CH2:3][NH:5][CH3:6])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: CNC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CNCC(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropanamide (900 mg, 2.8 mmol) in anhydrous tetrahydrofuran (50 mL) at room temperature under nitrogen was added dropwise a solution of borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 13.9 mL, 13.9 mmol) and the mixture heated to reflux for 3 hours. The reaction mixture was then cooled to 50° C., methanol (20 mL) was added, and the mixture stirred at 50° C. for 1 hour. The cooled reaction mixture was then concentrated under reduced pressure to afford a white solid. Purification by flash chromatography (silica, 15% methanol/dichloromethane) afforded 272 mg (32%) of (1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol as a yellow syrup. The product was dissolved in absolute ethanol (4 mL), a solution of hydrogen chloride (4 M in 1,4-dioxane, 0.28 mL, 1.12 mmol) added, the solution stirred for 10 minutes then concentrated under reduced pressure to afford a white foam. Crystallization from 1: 1: 1 v/v absolute ethanol : diethyl ether: hexane (12 mL) at −35° C. afforded 81.3 mg (8%) of (1SR,2RS)-1-(1H-indol-1-yl)-1-(4-methoxyphenyl)-3-(methylamino)propan-2-ol hydrochloride as a hygroscopic white solid. MS (ES) m/z 311.3 ([M+H]+); HRMS: calcd for C19H22N2O2+H+, 311.17540; found (ESI, [M+H]+), 311.176.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)C.[H-].[Na+].[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][CH2:24][CH2:25]Br)([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[CH2:16]([O:20][C:21](=[O:27])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1)[CH2:25][CH2:24][CH2:23][NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27])[CH3:17]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(CCCNC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reaction time: 0.05 h
Yield: 137.7 %

Procedure:
A solution of (4-bromo-phenyl)-acetic acid ethyl ester (2.31 g, 9.50 mmol) in dimethylsulfoxide (6 mL) was added to the suspension of sodium hydride (407 mg, 60% in oil, 10.17 mmol) and stirred 3 min. A solution of (3-bromo-propyl)-carbamic acid tert-butyl ester (2.03 g, 8.52 mmol) in dimethylsulfoxide (6 mL) was added to the solution and stirred at 50° C. for 30 min. The resulting solution was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried by passing through Celite column, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting ethyl acetate/hexane (4/1 to 3/1, v/v) to afford 3-(4-Bromo-phenyl)-6-tert-butoxycarbonylamino-hexanoic acid ethyl ester (2.43 g, 74%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]2)=[O:21])=[CH:18][CH:17]=1.CCN(CC)CC>CN(C=O)C>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:23]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(C(=O)c2ccc(Cl)cc2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (500 mg) in DMF (5 mL) was added (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (951 mg) and Et3N (1.15 mL). After stirring for 3 hours at 120° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (601 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:19][C:8]1[C:9]2[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCN(CCC)c1cccc2[nH]c(=O)n(C)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Yield: 27.7 %

Procedure:
A mixture of 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoylperoxide in carbon tetrachloride (20 ml) was refluxed for 60 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 30% ethyl acetate/n-hexane to afford 73 mg (28%) of the title compound.