Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].C(=O)([O-])O.[Na+]>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].C1(C)C=CC=CC=1>[C:2]1([N:13]2[CH2:12][CH2:11][NH:10][C@@H:9]([CH3:8])[CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CNCCN1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2ccccc2)CCN1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of bromobenzene (300 mg), (S)-2-methylpiperazine (230 mg), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (48 mg), sodium tert-butoxide (266 mg), tris-(dibenzylideneacetone)dipalladium(0) (26 mg) and toluene (15 ml) was stirred at 100° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and saturated aqueous sodium hydrogencarbonate solution was added thereto. The organic layer was separated, washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol 20:1) to give the title compound in a pure form.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(OCc2csc(C3CCN(c4ncccn4)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-yl]-piperidine hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.) and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at 90° C. for 1.5 hours. The solvent was removed in vacuo. The residue was purified on silica gel (60% EtOAc in hexanes) to afford the desired product. 1H NMR (CDCl3): δ 8.32 (2H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 6.49 (1H, t, J=4.8 Hz), 5.24 (2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:17]([CH3:19])=[O:18])[CH:4]=1.N1C=CC=CC=1.[CH2:26]([O:29][C:30](Cl)=[O:31])[CH:27]=[CH2:28]>C1COCC1.C(Cl)Cl>[CH2:26]([O:29][C:30]([O:1][CH2:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:17]([CH3:19])=[O:18])[CH:4]=1)=[O:31])[CH:27]=[CH2:28]
Reactant: CC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2=O
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)OCc1cc(C(C)=O)cc2c1C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Hydroxymethyl-3-methylcarbonyl-9-fluorenone (135 mg) was dissolved in THF (4 ml), cooled to 0° C. under N2. Pyridine (51 μl, 1.2 eq) was added followed by allyloxycarbonyl chloride (70 μl, 1.2 eq). The reaction mixture was allowed to stir overnight allowing it to come to room temperature. The reaction mixture was diluted with methylene chloride, washed with water, sat'd NaCl sol'n, dried and evaporated. The product was purified by preparative tlc (80 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][C:7]([C:18]3[CH:19]=[C:20]([O:24][C:32](=[O:35])[CH2:33][CH3:34])[CH:21]=[CH:22][CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:6]2)[CH2:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(C2(c3cccc(O)c3)CCCN(CC3CC3)C2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1cccc(C2(c3ccc(C)cc3)CCCN(CC3CC3)C2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.4 %

Procedure:
To a solution of 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenol (65 mg, 0.15 mmol) in CH2Cl2 (2 ml) at room temperature were added DMAP (18 mg, 0.15 mmol), triethylamine (0.071 mL, 0.52 mmol) and propionyl chloride (0.038 mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was partitioned between 5 mL CH2Cl2 and 5 mL of aqueous saturated NaHCO3. The aqueous layer was washed with CH2Cl2 (3×5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (1:1) afforded 58 mg of propionic acid 3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenyl ester. 1HNMR (400 MHz, CDCl3) δ 7.33 (d, 2H), 7.26-7.19 (comp, 3H), 7.16-7.03 (comp, 2H), 6.89-6.86 (m, 1H), 3.59-3.43 (comp, 2H), 3.35-3.19 (comp, 2H), 2.59-2.53 (q, 2H), 2.52-2.41 (comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44 (comp, 2H), 1.31-1.19 (t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp, 3H), 100-0.91 (m, 1H), 0.59-0.49 (comp, 2H), 0.19-0.11 (comp, 1H); MS (M+1) 463.3.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:17]=2)=[CH:3]1
Reactant: O=C1CCOCC1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1cc(C2=C(c3cccc(NC4CCOCC4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.7 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and tetrahydro-4H-pyran-4-one (65 mg, 0.65 mmol) in MeOH (8 mL) was stirred at room temperature for 40 min., and then NaCNBH3 (63 mg, 1.0 mmol) was added. After stirring the reaction mixture overnight the volatiles were removed under vacuo and the residue was purified by preparatory TLC (3% MeOH/CH2Cl2) to give 3-(1-methylindol-3-yl)-4-(3-tetrahydropyran-4-ylaminophenyl)-1H-pyrrole-2,5-dione (88.2 mg, 70%). LC/MS: M+ 401(98.6%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:12][CH2:13]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(N2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (Aldrich, 3.0 g, 15 mmol) in THF (25 mL), morpholine (Aldrich, 1.56 g, 18 mmol) and Ti(OiPr)4 (Aldrich, 5.58 mL) were added successively and the mixture was stirred at room temperature for 1 hour. Then, 15 mL of ethanol was added and followed by sodium cyanoborohydride (0.63 g, 10.05 mmol). The resulting mixture was stirred at room temperature over night and the reaction was quenched with addition of water (4 mL). The mixture was stirred for 30 minutes and the white solid was filtered out and the filtrate was evaporated. The residue was partitioned between ether and water and the organic layer was separated and dried with sodium sulfate. Removal of solvent gave a white solid which was treated with 40 mL of 50% TFA in methylene chloride. The solution was stirred at room temperature for 1 hour and the solvent was removed. The residue was lyophilized to give a white solid. 5.48 g, 98%. MS (m+H)+: 171.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][NH:16][C:17](=O)[C:6]2=1.O=P(Cl)(Cl)[Cl:21]>O1CCOCC1>[Cl:21][C:17]1[CH:6]2[CH:7]([NH:8][C:9]3[C:5]2=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=3)[N:14]=[CH:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]c3nc[nH]c(=O)c3c2cc1OC
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C1C(Cl)=NC=NC1N2
Temperature: 0 °C
Reaction time: 36 h
Yield: 773.3 %

Procedure:
A suspension of 6,7-dimethoxy-3H-pyrimido[4,5-b]indol-4(9H)-one 6 (2.8 g), POCl3 (20 mL) and p-dioxane 65 mL was heated at reflux for 6 hrs, then stirred at 25 0° C. for 36 hrs. The obtained mixture was filtered and concentrated. The crude product was purified by column chromatography using 1% MeOH/DCM to give title compound 773.3% (2.2 g) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[C:25]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[C:20]([CH3:23])([CH3:24])[CH2:21][CH3:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(C)(C)c1ccc(Oc2ccncc2N)c(C(C)(C)CC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)c1ccc(Oc2ccncc2NC(=O)c2ccccc2)c(C(C)(C)CC)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Amino-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine (3.0 g, 9.2 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 10° C. Benzoyl chloride (1.3 g, 9.2 mmol) in tetrahydrofuran (10 mL) was added dropwise. Triethylamine (0.93 g, 9.2 mmol) in tetrahydrofuran (5 mL) was added and the mixture warmed to room temperature and stirred for 2 hours. The mixture was submitted to standard aqueous acidic workup. The crude solid obtained was recrystallized from acetonitrile to yield the title product as a white solid in 80% yield, m.p. 253° C. Mass spectral and NMR data were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:31](=O)([O-])[O-].[K+].[K+].CI.[ClH:39]>CN(C)C=O.C(OCC)C.O>[ClH:39].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH3:31])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 117 mg, 0.27 mmol) was dissolved in dimethylformamide (2 ml) and potassium carbonate (149 mg, 1.08 mmol) and methyl iodide (0.02 ml, 0.32 mmol) added and the mixture stirred at room temperature for 1 hour. The reaction mixture was poured into water then extracted with ethyl acetate (×2), dried (MgSO4), and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [7.5%-10% methanol in dichloromethane] to give a yellow oil. The oil was dissolved in diethyl ether (2 ml) and 1 equivalent of1N hydrogen chloride in diethyl ether added to give the title compound as a yellow solid which was filtered and dried at 60° C. in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH3:26])=[O:11]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 1.18 g, 6.15 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.33 g, 6.15 mmol) in dichloromethane (170 mL) were added HOBT (941 mg, 6.15 mmol) and N-methyl morpholine (2.02 mL, 18.45 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (2.11 g, 11.07 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction was quenched with the addition of 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL), and brine, and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.9 g (49%) as solid.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[N:20]=[CH:21][N:22]([C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=4)[CH:23]=3)=[C:17]([CH3:33])[O:16][N:15]=2)=[CH:10][CH:9]=1>>[CH:1]1([NH:6][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:22]3[CH:23]=[C:19]([C:18]4[C:14]([C:11]5[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=5)=[N:15][O:16][C:17]=4[CH3:33])[N:20]=[CH:21]3)=[CH:25][CH:26]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3CCCC3)cc2)cn1
Yield: 76 %

Procedure:
As described for Example 71c, cyclopentylamine was converted, using 4-{4-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (56 mg, 0.17 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (54 mg, 76%) which was obtained as an off-white solid. MS: m/e=430.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([O:26]CC)=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2.[CH3:29][Zn]C>C1COCC1.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>[CH3:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([OH:26])=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2
Reactant: C[Zn]C
Reactant: CCOC(=O)c1cc(CN2CCc3cc(Br)ccc3C2)c2ccccn2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCN(Cc1cc(C(=O)O)c(=O)n3ccccc13)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 1-[(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate (0.045 g, 0.10 mmol) in 1 mL THF under nitrogen was added 1.0 M dimethylzinc solution in THF (0.112 mL, 0.112 mmol), and tetrakis(triphenylphosphine)palladium (0) (10 mol %). The reaction mixture was stirred at 60° C. for 4 hours, quenched with 1 mL of saturated aqueous ammonium chloride, then cooled to rt and concentrated in vacuo. To a solution of the resultant brown residue in 1 mL DMSO was added saturated aqueous lithium hydroxide (0.3 mL). After 2 hours, the reaction was acidified with 1 N HCl to pH ˜2, filtered and subjected to purification via reverse phase HPLC to provide the title compound which gave a mass ion (ES+) of 349.0. 1H NMR (400 MHz, DMSO) δ 10.07 (br s, 1H), 9.46 (d, J=6.8 Hz, 1H), 8.70 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.22-8.19 (m, 1H), 7.76 (t, J=6.6 Hz, 1H), 7.20-6.97 (m, 3H), 4.89 (s, 2H), 4.40-4.34 (m, 2H), 3.76-3.60 (m, 2H), 3.10-3.02 (m, 2H), 2.26 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7][CH3:8].[F:18][C:19]1[C:26]([CH3:27])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe].O>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=3)[C:6]=2[O:7][CH3:8])=[C:26]([CH3:27])[C:19]=1[F:18])#[N:22]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(C#N)c1F
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(-c2ccc(C#N)c(F)c2C)cnn1-c1ccc(C(=O)O)cn1
Yield: 46.6 %

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)nicotinic acid (500 mg, 1.677 mmol), 2-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (876 mg, 3.35 mmol), THF (10.500 mL), and water (3.50 mL) in a microwave vial. Degassed with nitrogen then added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1093 mg, 1.677 mmol) and sodium carbonate (711 mg, 6.71 mmol). The reaction was degassed 2 minutes more, then capped and subjected to microwave irradiation at 110° C. for 1 hour. The reaction mixture was then diluted with EA (20 mL) and washed with water (20 mL). A precipitate was observed in the aqueous layer which was filtered and the solids collected to give 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)nicotinic acid (275 mg, 0.781 mmol, 46.5%) which was dried under vacuum and used in the next step without further purification. ESI-MS m/z [M+H]+ 353.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][CH:15]([F:18])[CH2:16]I.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][CH:15]([F:18])[CH2:16][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: FC(F)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC(F)F)C1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) and 1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.403 ml) and the mixture was stirred at 70° C. for 72 hours. The reaction mixture was concentrated and the crude product was purified on silica gel with methanol/dichloromethane.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4](/[C:5](=[CH:29]\[CH3:30])/[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[H][H]>[Pd]>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: [H][H]
Reactant: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Pd]
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
reacting E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5) with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (6),
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:16])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)Cl.O>[CH3:15][S:14]([C:10]1[N:9]=[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc(N)nc2C)n1
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N)ncc1-c1ccnc(S(C)=O)n1
Yield: 17.2 %

Procedure:
To a suspension of 4′-Methyl-2-methylsulfanyl-[4,5′]bipyrimidinyl-2′-ylamine (19) (380 mg, 1.629 mmol) in DCM (3.258 mL) was added mCPBA (402 mg, 1.629 mmol). The reaction turned to a brown solution, and immediately the reaction was complete. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 2-10% MeOH in DCM to give the desired product (70 mg, 17%). MS (ES+): m/z=250.1 (100) [MH+]. HPLC: tR=0.64 minute over 3 minutes.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[C:3]1([N:2]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[NH:16][C:17]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC1CCCCC1=O
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c2c(n1-c1ccccc1)CCCC2
Temperature: 125 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of 1.94 g (0.01 mol) of 2-aminocyclohexanone hydrobromide, 1.19 g (0.01 mol) of phenyl isocyanate and 4 ml of pyridine is stirred at 125° C. for 4 hours. Water is added, the mixture is stirred until crystallization is obtained, drained, washed with water and dried. The compound is purified by flash chromatography on silica, eluting with a 95:5 CH2Cl2/CH3OH mixture. 0.7 g of product is recovered. Yield=33% (m.p.=224° C.).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 40 °C
Yield: 98.1 %

Procedure:
Into 200 ml of methanol, 11.8 g (50.2 mmol) of ethyl 2-methyl-3-(2-nitrophenyl)-2-propenate were dissolved; and, with 200 ml of a 2-N aqueous sodium hydroxide solution being added thereto, the mixture was stirred at 40° C. for one night. After the completion of the reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure. After the pH was adjusted to 1 with 1-N hydrochloric acid being added thereto, the resulting residue was dissolved in ethyl acetate. After being washed three times with water, the solution was dried for one night with sodium sulfate anhydride being added thereto. After sodium sulfate was filtered out from the dried solution, the filtrate was concentrated under a reduced pressure, whereby 10.2 g of the aimed compound were obtained as a crystal (yield: 98.0%).