Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.CO>CN(C=O)C>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:25][CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nc2c(N)nc3cc(OCCc4c[nH]c5ccccc45)ccc3c2s1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 1.0 mmol) and anhydrous DMF (2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq., 3.0 mmol) and a solution of 3-(2-bromoethyl)indole (1.0 eq., 1.0 mmol) dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture drop-wise to water (60 ml) with stirring. A precipitate formed. The solid was collected by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from methanol to provide a peach colored crystalline solid, mp 218-220° C. MS (APCI) m/z 389 (M+H)+. Anal. calcd for C22H20N4OS.0.8 CH3OH: C, 66.13; H, 5.65; N, 13.53. Found: C, 66.43; H, 5.03; N, 13.90.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)=[CH:5][CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:29].[Na+].OO>C1COCC1>[F:17][C:16]([F:19])([F:18])[C:13]1[N:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:29])=[CH:8][CH:7]=2)=[CH:15][N:14]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of 5-[(4-ethenylphenyl)oxy]-2-(trifluoromethyl)pyrimidine (100 mg, 0.376 mmol) and 9-BBN (1.503 mL, 0.751 mmol) in THF (5 mL) under nitrogen, which was stirred overnight was added NaOH (0.501 mL, 1.503 mmol) and H2O2 (0.460 mL, 4.51 mmol). The mixture was heated at 60° C. for 1 h, and then quenched with NH4Cl sat. solution after cooling. The organic layer was separated and washed with Na2SO3 solution and brine. The organic layer was dried by Na2SO4. Concentration then afforded the title compound (80 mg, 0.281 mmol, 74.9% yield). LCMS: rt=2.82 min, [M+H+]=285
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1>>[CH3:38][O:37][C:35]([C:33]1[O:34][C:30]([CH2:29][N:9]2[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[S:14][C:11]=3[C:12](=[O:13])[N:7]([OH:6])[C:8]2=[O:21])=[CH:31][CH:32]=1)=[O:36]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: COC(=O)c1ccc(Cn2c(=O)n(O)c(=O)c3sc4ccccc4c32)o1

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with methyl 5-chloromethyl-2-furoate and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 3.64 (s, 3H); 5.60 (s, 2H); 6.48 (d, J=3 Hz, 1H); 7.09 (d, J=3 Hz, 1H); 7.32 (dd, J=8 Hz, 1H); 7.44 (dd, J=8 Hz, 1H); 7.92 (d, J=9 Hz, 1H); 8.00 (d, J=8 Hz, 1H); Ret. time=2.33 min., m/z=373.0.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([O:28][C:29]([NH:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCC(O)C(N)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(O)C(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a stirred mixture of Racemate-ethyl 3-amino-4-hydroxycyclohexanecarboxylate (4.7 g, 25 mmol) in 120 mL of dichloromethane was added triethylamine (3.03 g, 30 mmol), followed by the addition of N-(benzyloxycarbonyloxy)succinimide (6.55 g, 26.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then diluted with 200 mL of dichloromethane. The solution was washed with 5% citric acid solution (2×150 mL), 5% potassium carbonate solution (2×150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel chromatography (ethyl acetate:petroleum ether=1:4˜2:5), to thereby give the title compound (7.0 g, 87%) as a yellow oil. MS (ES+) C17H23NO5 requires: 321, found: 322 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.S(=O)(=O)(O)[OH:15].[OH-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:13])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(N)c2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc(N)c2cccnc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A reaction mixture of 5-amino-quinoline-8-carbonitrile (1000.00 mg; 4.29 mmol; 1.00 eq.) in sulfuric acid (5.00 ml; 93.80 mmol; 21.86 eq.) was stirred at 100° C. for 1 h. The reaction mixture was then cooled, poured into ice and neutralized with 2N sodium hydroxide to PH=9. The precipitate was filtered, washed with water and dried to afford 5-aminoquinoline-8-carboxamide (800 mg, yield 74.3%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[CH:5].C(NCC)C.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>[Cu]I>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:5]#[C:4][CH2:3][CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:24]=1
Reactant: C#CCC(O)CCCCOC1CCCCO1
Reactant: Brc1cccnc1
Agent: [Cu]I
Solvent: CCNCC
Product: OC(CC#Cc1cccnc1)CCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.84 g (25.8 mmol) 4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne, 4.7 mL diethylamine, 10 mL (100 mmol) 3-bromopyridine, 0.032 g copper (I) iodide, and 0.187 g bis-triphenylphosphine palladium (II) chloride is stirred at room temperature for 18 hours. The solvent is evaporated and the residue taken up in ether. The ether layer is washed with saturated aqueous sodium bicarbonate, water, brine, dried, filtered and evaporated to get an amber oil which is purified by chromatography using ether as the eluent to give 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne; NMR (CDCl3): delta 4.6 (brs,1H), 2.6 (d,2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)=[CH:16]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:28]=1)=[CH:16]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
4-Nitrobenzaldehyde (0.3 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red solid. Recrystallization from methanol gave the product (450 mg), mp 181-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:15][C@H:14]([C:16](O)=[O:17])[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:16]([C@H:14]1[CH2:15][C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]1([CH3:20])[CH3:19])(=[O:17])[NH2:30]
Reactant: CC1(C)[C@@H](C(=O)O)C[C@H]1NC(=O)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H](C(N)=O)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A mixture of (1S,3R)-3-(((benzyloxy)carbonyl)amino)-2,2-dimethylcyclobutanecarboxylic acid (2.6 g, 9.38 mmol), ammonium chloride (2.0 g, 37.5 mmol), TEA (2.84 g, 28.2 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.35 g, 14.1 mmol) in dry DMF (52 mL) was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the crude product, which was purified by HPLC (10-50% acetonitrile in water) to afford the title compound (1.86 g, 6.71 mnmol, 66% yield for two steps). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.40-7.30 (m, 5H), 5.51-5.37 (m, 1H), 5.27-5.17 (m, 1H), 5.15-4.96 (m, 3H), 3.96-3.87 (m, 1H), 2.48-2.39 (m, 1H), 2.37-2.27 (m, 1H), 2.15-2.05 (m, 1H), 1.31 (s, 3H), 0.96 (s, 3H). MS (ESI) m/z 277.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:36][C:32]4[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=4)[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5]
Reactant: Cn1ccnc1C=O
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5nccn5C)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and 1-methyl-1H-imidazole-2-carbaldehyde (33 mg) in tetrahydrofuran (3 ml) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (14 mg, yield 12%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 103° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][C:3]=1[C:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl.O>[Pd].C(O)(=O)C>[CH2:22]([C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:2]=1[OH:1])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(C(=O)CCCCC)c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCc1ccc(O)c(CCCCCC)c1
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A mixture of 31.04 g of 1-(2-hydroxy-5-tetradecylphenyl)-1-hexanone, 8.4 g of 5% palladium on carbon, 5 ml of concentrated hydrochloric acid, 95 ml of water and 100 ml of glacial acetic acid was hydrogenated in a Parr apparatus for 16 hours, then filtered and the solvents removed. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (40:1), giving 12.3 g of the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:17][C:16]([F:19])([F:18])[C:3]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)([OH:13])[OH:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(O)(O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a mixture of 4-nitro-benzoic acid methyl ester (1.8 g, 9.9 mmol), trimethyl-trifluoromethyl-silane (2.0 ml, 12.8 mmol) and anhydrous dichloromethane (20 ml), cooled at −78° C., was added a solution of tetrabutylammonium fluoride in dichloromethane (1 M, 0.5 ml) previously dried over 4A molecular sieves. After stirring for 72 hours, hydrochloric acid (1 M, 50 ml) was added. The mixture was treated with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (100 ml). The organic extract was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) providing 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethane-1,1-diol (1.1 g, 47% yield).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>O1CCOCC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:16][NH:17][C:18]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)=[S:47])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CNC(=O)c1ccc2[nH]c(=O)oc2c1)CN1CCC(Cc2ccccc2)CC1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC(CNC(=S)c1ccc2[nH]c(=O)oc2c1)CN1CCC(Cc2ccccc2)CC1
Yield: 79.1 %

Procedure:
2-Oxo-2,3-dihydrobenzoxazole-6-carboxylic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide (686 mg, 1.31 mmol) and Lawesson's reagent (530 mg, 1.31 mmol) in dioxane (5 mL) were heated under reflux conditions for 2 hours. The solvent was removed, and the product was purified by chromatography (silica gel, 0-50% EtOAc in heptane) to give 2-oxo-2,3-dihydrobenzoxazole-6-carbothioic acid [3-(4-benzylpiperidin-1-yl)-2-(tert-butyldimethylsilanyloxy)propyl]amide (559 mg, 79%): as a green gum:
Reaction SMILES: CN[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)=[NH:20])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.C1C2[N:29]([CH2:30]C=C(C3C4C(=CC=C(N)C=4)NC=3)C2)[CH2:28]C1.I.CSC(C1SC=CC=1)=N>C(O)C>[CH2:3]1[CH:4]2[N:29]([CH2:30][CH:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:19]([C:21]5[S:22][CH:23]=[CH:24][CH:25]=5)=[NH:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:5]2)[CH2:28][CH2:8]1
Reactant: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Reactant: CNC1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Agent: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1)c1cccs1
Reaction time: 24 h
Yield: 79 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2×20 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15); ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C=O>[CH3:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[N:13]=[C:12]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[N:11]([CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:49][CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCBr)cccc32)CC1
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and 4-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:34]([O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])=[CH:33][C:17]=1[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH2:18][C:17]2[CH:33]=[C:34]([CH:35]=[CH:36][C:16]=2[Cl:15])[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:20]([CH3:32])=[C:21]3[CH3:31])=[O:29])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride the (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[K+]>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:17][C:15](=[O:16])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(Br)c1cccc(Br)n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)=O)c1cccc(Br)n1
Temperature: 120 °C

Procedure:
Methyl bromo(6-bromopyridin-2-yl)acetate (Example 360, Step 1) (500 mg, 1.62 mmol) and KOAc (635 mg, 6.47 mmol) were taken up in DMF (3.0 mL) and heated to 120° C. for 20 minutes in a microwave. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-40% EtOAc/hexanes) afforded the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH:14]([N:27]1[C:35]2[C:30](=[CH:31][C:32](Br)=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:37]([OH:39])=[O:38])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:27]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:28]([C:37]([OH:39])=[O:38])=[CH:29]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1cccc(-c2ccc3c(c2)cc(C(=O)O)n3C(c2ccccc2)c2ccccc2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 109 except that 3-acetamidobenzeneboronic acid and 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid were used.