Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:31]([O:34][CH2:35][CH2:36]Br)(=[O:33])[CH3:32].Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:35]([O:34][C:31](=[O:33])[CH3:32])[CH3:36])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CC(=O)OCCBr
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) in dimethylformamide (1 ml) was added 2-bromoethyl acetate (54 mg). After stirring for 2 hours at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml), phosphate buffer (pH 7, 10 ml×2), and saturated aqueous NaCl (10 ml), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals were filtered, and dried under reduced pressure to give the title compound (50 mg).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)nc1I
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (50 mg) was dissolved in acetonitrile (2 ml) to prepare a solution. Methyl iodide (148 mg) and potassium carbonate (87 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform to give 6-fluoro-2-iodo-3-methoxypyridine (52 mg, yield 100%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1>C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:7][CH:8]=1
Reactant: N#Cc1ccccc1-c1ccc(C(Br)Br)cc1
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
After the dropwise addition of the solution prepared by dissolving the mixture of 4'-dibromomethyl-2-cyanobiphenyl and 4'-bromomethyl-2-cyanobiphenyl in toluene was terminated, the mixture was allowed to react up to a point where the above suspension no longer absorbs hydrogen gas. After the reaction was terminated, Pt--C and sodium hydroxide were filtered off, and the reaction mixture was then concentrated to distill off methanol and toluene. The resulting crude 4'-methyl-2-cyanobiphenyl was purified by distillation, to give 21.7 g of 4'-methyl-2-cyanobiphenyl having an LC purity of 98.1%.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:50]CCl>CO.CS(C)=O.CO>[ClH:50].[NH2:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1.[NH2:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1
Reactant: COc1cc(C(=O)N2CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Reactant: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@@H](O)[C@@H](N)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Product: Cl
Reaction time: 1 h

Procedure:
To a flask containing tert-butyl((3S,4R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-4-hydroxypiperidin-3-yl)carbamate (143 mg, 0.249 mmol) in dichloromethane (DCM) (1.5 mL) was added TFA (0.307 mL, 3.98 mmol) and the reaction was stirred for 1 h. LCMS showed complete reaction. The reaction mixture was concentrated in vacuo to afford a brown oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow oil—97% purity by LCMS. The crude product (104 mg) was taken up in DMSO/MeOH (1:1, 1.8 mL) and further purified by MDAP (Method E, 2 injections). The appropriate fractions were combined and concentrated in vacuo to afford the desired product as a colourless oil—((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (71 mg, 0.150 mmol, 60.1% yield). The free base (71 mg) was dissolved in dichloromethane (DCM) (1 mL) in a vial and HCl (2M in Et2O) (0.075 mL, 0.15 mmol) was added. The resultant suspension was sonicated for 5 min and allowed to stand for 15 min. The solvent was then removed under a positive pressure of nitrogen and the product dried in vacuo to afford ((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (78 mg, 0.153 mmol, 61.3% yield) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (560 mg, 1.80 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine (620 mg, 2.70 mmol) to afford the desired product (335 mg, 43%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.9, 2.1 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 4.12-3.84 (m, 1H), 2.91-2.72 (m, 1H), 2.42-2.26 (m, J=6.6 Hz, 8H), 2.21 (d, J=11.6 Hz, 2H), 1.94 (d, J=12.1 Hz, 2H), 1.75-1.59 (m, 1H), 1.59-1.35 (m, 2H), 1.25-0.98 (m, 6H).
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2][CH3:3].[C:7]([O:10][C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>>[C:1](=[O:6])([O-:4])[O:2][C:3]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1.[C:7]([O:10][CH3:11])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccccc1
Reactant: COC(=O)OC
Product: COC(C)=O
Product: O=C([O-])Oc1ccccc1

Procedure:
reacting dimethyl carbonate with at least a portion of the phenyl acetate from step A to produce a phenyl carbonate and methyl acetate;
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.111 mmol), phenylboronic acid (20 mg, 0.166 mmol) and K3PO4 (58.8 mg, 0.217 mmol) in DMF-water (4.5:0.5 mL) was added PdCl2(PPh3)2 (3.8 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-phenyl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (4 mg). 1H NMR (TFA salt, CD3OD) δ (ppm): 7.79-7.65 (m, 2H), 7.3 (s, 1H), 7.2-7.1 (m, 4H), 7.1-7.0 (m, 2H), 6.9 (d, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.61-3.60 (m, 1H), 3.25-3.2 (m, 1H), 3.05-3.00 (m, 1H), 2.9 (s, 3H), 2.4 (s, 3H), 2.4-2.39 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]([NH:17][CH:18]4[CH2:23][CH2:22][S:21][CH2:20][CH2:19]4)=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.[OH2:42]>ClCCl>[O:42]=[S:21]1(=[O:39])[CH2:22][CH2:23][CH:18]([NH:17][C:16]2[C:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=4)[N:9]=[CH:10][C:11]=23)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1NC1CCSCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1NC1CCS(=O)(=O)CC1
Reaction time: 8 h

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-(tetrahydro-2H-thiopyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (500 mg, 0.00117 mole) (example 4) was taken in dichloromethane (5 ml). At 0° C., m-chloroperbenzoic acid (600 mg, 0.00352 mole) was added and the mixture was stirred overnight. Water was added and extraction was done using dichloromethane. The organic layer was washed with saturated ammonium bicarbonate and then with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:3]=1
Reactant: Ic1c[nH]c2ncncc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 201, 735 mg, 3.00 mmol) in DMF (5 mL) at 0° C. was added to sodium hydride (132 mg, 3.30 mmol, 60% in oil). The mixture was stirred at room temperature for 30 minutes, cooled to −20° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.58 mL, 3.30 mmol) added. The reaction mixture was stirred at −20° C. for 3 hours then water (30 mL) was added. The mixture was extracted with EtOAc (2×50 mL) and the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The crude solid was purified by column chromatography on silica gel, eluting with a gradient of heptane:EtOAc 100:0 to 50:50), to afford the title compound as a white solid in 61% yield, 691 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[CH:13][C:12]=1[F:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:22]([CH2:23][CH:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([F:25])[CH:13]=3)[CH2:18][C:19]([OH:21])=[O:20])[NH:9][C:4]=2[CH:3]=1.[ClH:1]
Reactant: O=C1CC(c2ccc(Cl)c(F)c2)CC(=O)O1
Reactant: Nc1ccc(Cl)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)c(F)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-chloro-1,2-phenylenediamine and 3-(4-chloro-3-fluorophenyl)glutaric anhydride, 4-(5-chloro-2-benzimidazolyl)-3-(4-chloro-3-fluorophenyl)butanoic acid•HCl was obtained as light red solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1)[CH3:20]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 97.4 %

Procedure:
To a solution of 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (500 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (401 mg) and tripotassium phosphate (591 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (161 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D75) (548 mg) as a brown oil. MS (ES): C24H24N2O2S requires 404. found 405.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.N[C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1N.IC1C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: Ic1ccccc1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccccc3)c3cc(Cl)ccc23)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.252 g, 0.759 mmol), (±)-trans-1,2-diaminocyclohexane (18 μL, 0.15 mmol), iodobenzene (103 μL, 0.911 mmol), K3PO4 (0.402 g, 1.89 mmol) and copper(I) iodide (0.0072 g, 0.04 mmol) were dissolved in toluene (0.750 mL) and the reaction vessel was purged with N2 (g) for 1 minute. The reaction was heated to 120° C. and stirred overnight. Standard workup procedure followed by silica gel chromatography (0-20% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][OH:43])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][O:43][S:52]([CH3:51])(=[O:54])=[O:53])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[N:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(COS(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [1.21 g, 1.98 mmol, Intermediate (78)] in dichloromethane (25 mL) at 0° C. was added triethylamine (0.29 mL, 2.28 mmol) and methane sulfonyl chloride (0.34 mL, 4.40 mmol). The mixture was stirred at 0° C. for 30 minutes then at room temperature for 4 hours. It was diluted with dichloromethane then washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (dichloromethane/methanol, 90/10 as eluant) to produce 2-(1-tert-butoxycarbonyl-5-methanesulfonyloxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [0.85 g, 62%, Intermediate (79)] as a yellow foam. LC/MS: 689.3 (M+H), RT=2.58 minutes.
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[NH2:31][CH2:30][CH2:29][C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][CH:15]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:39])=[CH:6][CH:5]=3)[C:8]([C:10]3[O:11][CH:12]=[CH:13][CH:14]=3)=[O:9])[CH2:16][CH2:17]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCNC(=O)OC(C)(C)C)CCCCC3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.9 %

Procedure:
To a solution of tert-butyl 2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethylcarbamate (synthesized in Example 17) (1.14 g) in methanol (4 mL) was added a 4N hydrochloric acid/dioxane solution (3 mL). The solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, chloroform-methanol (20:1)] to give the title compound (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>O.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2/[C:9](=[CH:21]\[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)/[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1
Reactant: O=Cc1ccccn1
Reactant: COc1cc2c(cn1)CC(=O)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(cn1)/C(=C\c1ccccn1)C(=O)CCC2
Temperature: -70 °C

Procedure:
A flask was charged with 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (23.0 g, 120 mmol), THF (1000 mL) and picolinaldehyde (32.2 g, 301 mmol). The mixture was cooled to an internal temperature of about −70° C. then lithium bis(trimethylsilyl)amide [1 M solution] (126 mL, 126 mmol) was added over about 30 min keeping the internal temperature below about −65° C. The mixture was allowed to warm to about −10° C. in the cold bath. Acetic acid (13.8 mL, 241 mmol) then water (150 mL) were added. The mixture was concentrated under reduced pressure then partitioned between water (250 mL) and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic solutions were with brine (100 mL) then dried over MgSO4 then filtered The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using a gradient from 0-75% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield (E)-3-methoxy-9-(pyridin-2-ylmethylene)-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (127, R5=Pyridin-2-yl) (36.15 g, 107%) 1H NMR showed material to contain picolinaldehyde and EtOAc. The material was used in the next step without further purification; LC/MS, method 3, Rt=1.90 min, MS m/z 281 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.54-8.52 (m, 1H), 7.73 (s, 1H), 7.68-7.65 (m, 1H), 7.65 (s, 1H), 7.29-7.25 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 2.78 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.1 Hz, 2H), 2.05-1.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:19][NH2:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[Cl:17][C:15]1[N:14]=[C:13]([NH:20][CH3:19])[CH:12]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=1
Reactant: CN
Reactant: Clc1ccn2c(-c3cc(Cl)nc(Cl)c3)cnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNc1cc(-c2cnc3cc(Cl)ccn23)cc(Cl)n1

Procedure:
7-Chloro-3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1.0 eq, 0.64 mmol, 190 mg), methyl amine (8M in EtOH, 3.5 eq, 2.2 mmol, 0.28 ml) and Cs2CO3 (2.5 eq, 1.59 mmol, 518 mg) are dissolved in DMF (2 ml) and the reaction mixture is heated using microwave radiation at 160° C. for 30 min, it is diluted with CH2Cl2. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford [6-chloro-4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-pyridin-2-yl]-methyl-amine as a brown solid; [M+H]+=294