Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[N:33]4[C:28]([CH:29]=[N:30][C:31](S(C)=O)=[N:32]4)=[CH:27][CH:26]=3)[C:19]=2[O:18][CH2:17][CH2:16]1.C([O-])(=O)C.[K+].CS(C)=O>>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[N:33]4[C:28]([CH:29]=[N:30][C:31]([NH:14][C:11]5[CH:12]=[CH:13][C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:9][CH:10]=5)=[N:32]4)=[CH:27][CH:26]=3)[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc4c3OCCO4)n2n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc6c5OCCO6)n4n3)cc2)CC1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
A mixture of 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.086 g, 0.45 mmol), 7-(2,3-Dihydro-1,4-benzodioxin-5-yl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.08 g, 0.20 mmol) and Potassium acetate (0.12 g, 1.2 mmol) in Dimethyl sulfoxide (0.9 mL, 10 mmol) was heated in sealed tube at 140° C. for 4 hours. Dilution of the mixture with water (20 mL) and extraction with DCM, gave a brown solid. Purification by prep plate chromatography with DCM-methanol (10-1) gave [7-(2,3-Dihydro-1,4-benzodioxin-5-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.057 g, 50%). MP: 212-213° C.; LCMS (m/e) 443 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 9.16 (s, 1H), 8.91 (s, 1H), 7.60-7.58 (d, 2H, J=9.00 Hz), 7.44-7.42 (dd, 1H, J=4.97 Hz), 7.02-6.96 (q, 2H, J=8.04 Hz), 6.93-6.92 (d, 1H, J=4.65 Hz), 6.88-6.87 (d, 1H, J=4.64 Hz), 6.81-6.79 (d, 2H, J=9.01 Hz), 5.76 (s, 1H), 4.30-4.25 (d, 4H, J=4.88 Hz), 3.32 (s, 3H), 3.03 (s, 3H), 2.45-2.43 (t, 1H, J=4.76 Hz), 2.21 (s, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)OCC[O:18]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCCCCCC.CCOCC>C1COCC1>[CH:2]1([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(CCC1CCCCC1)OCCCCC1(c2ccccc2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOCC
Product: O=C(CCC1CCCCC1)OCCCCC(=O)c1ccccc1
Yield: 59.6 %

Procedure:
This compound was synthesised as described under 1.e) with 2.0 ml of a 1N solution of HCl, 4.12 g (11.4 mmol) of 4-(2-phenyl-1,3-dioxolan-2-yl)butyl 3-cyclohexylpropionate obtained under a) in 20 ml of THF for 19 h. Column chromatography (SiO2, heptane/ether 3:2) afforded 2.15 g (60%) of a yellow oil containing small amounts of impurities, which can be distilled off (Kugelrohr, 150° C./1×102 Pa).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2(O)[CH2:18][CH2:17][CH2:16][N:15]3[CH:19]=[N:20][CH:21]=[C:14]23)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[ClH:29]>>[ClH:29].[C:1]([NH:5][C:6](=[O:23])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]3[N:15]([CH:19]=[N:20][CH:21]=3)[CH2:16][CH2:17][CH:18]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C2(O)CCCn3cncc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)NC(=O)c1ccc(C2=CCCn3cncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1.85 mmol of N-tert-Butyl-4-(8-hydroxy-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide in 6 ml of 2M HCl is stirred at 50° C. for 20 hours. The reaction mixture is cooled to room temperature and cautiously adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane (3×)—the combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is obtained as a grey solid. Rt=5.54.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][O:16][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ncsc2CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2ncsc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.25 g), dihydropyrane (0.84 mL) and p-toluenesulfonic acid hydrate (0.10 g) in AcOEt (12 mL) was stirred at 20° C. for 3 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>C(OCC)(=O)C>[OH:17][CH2:16][CH2:18][NH:19][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: NCCO
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: CCOC(C)=O
Product: Cc1nc(NCCO)nnc1-c1ccccc1
Yield: 88.7 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (3 g) and ethanolamine (3 g) was heated at 150° to 160° C. for 5.25 hours. The reaction mixture was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was crystallized from a small amount of diethyl ether and then diisopropyl ether was added thereto. The crystals were collected by filtration, washed with diisopropyl ether and dried to give 3-(2-hydroxyethylamino)-5-methyl-6-phenyl-1,2,4-triazine (2.82 g).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][OH:17]>CN(C=O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Br)nn(CCCO)c1Br
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A mixture of 3,5-dibromo-4-nitropyrazole (2) (2.0 g; 7.38 mmol) in DMF (9.5 ml) was added over 15 minutes to a suspension of NaH (0.32 g, 8.0 mmol; 60% dispersion in oil, prewashed with hexane) in DMF (16 ml) with stirring and under an inert atmosphere. After stirring for 15 minutes, a solution of 3-bromo-1-propanol (1.0 g; 7.19 mmol) in DMF (3.2 ml) was added dropwise. The reaction mixture was heated at 80° C. for 2 hours (monitored by TLC) and the DMF was then evaporated off under reduced pressure. A mixture of DCM/water (20 ml, 1/1) was added. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude reaction product was obtained as a black oil (1.9 g, 79%), which was used without further purification in the amination step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([CH2:18][O:19][NH2:20])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19]/[N:20]=[C:1](/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)\[CH3:2])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Product: C/C(=N\OCc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76.4 %

Procedure:
Acetophenone (20) (150 mg, 1.25 mmol) was condensed with compound 19 (280 mg, 1.37 mmol) according to the general procedure II-A defined above. After heating the reaction mixture for 2 h it was cooled and the solvent removed under reduced pressure. The resulting solid was filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30252 (258 mg, 77%) as a pale-yellow solid, m.p. 91.3-92.3° C.
Reaction SMILES: [C:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:18][CH2:19][C:20](O)=[O:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(Cl)Cl>[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH:28][C:20](=[O:21])[CH2:19][O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)c1ccc2ccccc2c1OCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)COc1c(C(=O)OC(C)(C)C)ccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of (2-carbo-tert-butoxy-1-naphthyloxy)acetic acid (1.20 g, 3.97 mmol, see Example 165, Part A) and valine methyl ester hydrochloride (0.932 g, 5.56 mmol) in N-methylpyrrolidone(7.5 mL)-CH2Cl2(7.5 mL) at room temperature under nitrogen was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophate (2.11 g, 5.56 mmol) and diisopropylethylamine (2.42 mL, 13.9 mmol). After stirring at room temperature for 3.5 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with EtOAc-hexane (1:9 to 3:7) to give the title compound (1.40 g, 85%) as a colorless oil. TLC(EtOAc-hexane; 1:1) Rf=0.76.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].Br[CH2:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:18]1([C:16]([C:15]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[C:11]=2[CH3:12])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a mixture of 2′-hydroxy-5′-nitroacetophenone (5.00 g), 2-bromo-1-cyclohexylethanone (6.79 g) synthesized in Example A51(1) and N,N-dimethylformamide (50 mL) was added potassium carbonate (7.63 g), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (4.18 g, 53%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[C:9](C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39](C2C=C(C=O)C=NC=2)[O:38]1.C(N)C(C)C.[BH3-]C#N.[Na+]>>[CH3:3][CH:1]([CH3:2])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([B:39]2[O:40][C:41]([CH3:43])([CH3:42])[C:37]([CH3:52])([CH3:36])[O:38]2)[CH:8]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)CN
Product: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([N:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH2:38][C:39]([NH:41][C@@H:42]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:43]([C:45]2[O:46][CH2:47][C:48]([CH3:51])([CH3:50])[N:49]=2)[OH:44])=[O:40])[C:28](=[O:59])[CH:27]1[CH:60]([CH3:62])[CH3:61])(=[O:25])[CH3:24].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(O)(C)(C)C>[C:23]([N:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH2:38][C:39]([NH:41][C@@H:42]([CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:43]([C:45]2[O:46][CH2:47][C:48]([CH3:51])([CH3:50])[N:49]=2)=[O:44])=[O:40])[C:28](=[O:59])[CH:27]1[CH:60]([CH3:62])[CH3:61])(=[O:25])[CH3:24]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(O)C2=NC(C)(C)CO2)C(=O)C1C(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C2=NC(C)(C)CO2)C(=O)C1C(C)C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
Dess-Martin oxidizing reagent (293 mg) and tert-butanol (650 μl) are added to a solution of (1RS,2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol (93.3 mg, Compound No. 9-1) in methylene chloride (2.5 ml), and the mixture is stirred for one day. A saturated aqueous sodium hydrogencarbonate solution (6 ml) and an aqueous sodium thiosulfate solution (6 ml) are added to the reaction mixture, and the whole is stirred and then extracted with ethyl acetate. The extract is washed with an aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (43.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].N1C=CC=CC=1.[N+:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[S:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)(=[O:26])=[O:27]
Reactant: CNc1ccccc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(c1ccccc1Cl)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-N-methylaniline (4.96 mmol, 1.1 eq., 702 mg) and pyridine (5.86 mmol, 464 mg) in 20 mL of methylene chloride was added 3-nitrobenzenesulfonyl chloride (4.51 mmol, 1.0 g) in one portion. The reaction mixture was stirred 16 hr and diluted with methylene chloride and water. The aqueous layer was separated and extracted once with methylene chloride. The combined organic layers were extracted once with a saturated solution of aqueous sodium carbonate, once with water, and then dried over sodium sulfate. The crude product was purified using flash chromatography (10-60% ethyl acetate/hexane) to give N-(2-chlorophenyl)-N-methyl-(3-nitrophenyl)sulfonamide which solidifies on standing. 1H NMR (300 MHz) 3.29 (s, 3H), 7.25-7.45 (m, 4H), 7.71 (t, J=7.82 Hz, 1H), 8.06 (d, J=7.82 Hz, 1H), 8.40-8.50 (m, 1H), 8.60-8.65 (m, 1H). MS (ESI): m/e 327.13, 329.13 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:13]3[CH:15]=[CH:16][S:17][C:12]=3[CH2:11][CH2:10][C:9]=2[CH:8]=[N:7]1)=[N+:2]=[N-:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[S:17][CH:16]=[CH:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCn1ncc2c1-c1ccsc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: [N-]=[N+]=NCCn1ncc2ccc3sccc3c21
Yield: 73.6 %

Procedure:
A 1.00 g of 1-(2-azidoethyl)-4,5-dihydro-1H-thieno[2,3-g]indazole was dissolved in 30 ml of dioxane, 2.80 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added at room temperature, and the mixture was heated under reflux for 8 hours. The reaction mixture was cooled, poured into sodium bicarbonate aqueous solution and then extracted with chloroform. The organic layers were combined and dried with anhydrous magnesium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 0.73 g of 1-(2-azidoethyl)-1H-thieno[2,3-g]indazole as a pale brown oil.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C@@H:16]([OH:17])[C@@H:15]2[C@H:10]([CH2:11][CH2:12][C@:13]3([CH3:28])[C@@H:20]([C@@H:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:19][CH2:18][C@H:14]32)[C@:9]2([CH3:29])[C@H:4]1[CH2:5][C@H:6]([OH:30])[CH2:7][CH2:8]2.COC(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@@H](C[C@H](O)CC2)/C(=C/C)/C3=O)CC1)C.[OH-].[Na+]>>[OH:30][C@@H:6]1[CH2:7][CH2:8][C@@:9]2([CH3:29])[C@H:4](/[C:3](=[CH:2]/[CH3:1])/[C:16](=[O:17])[C@@H:15]3[C@@H:10]2[CH2:11][CH2:12][C@@:13]2([CH3:28])[C@H:14]3[CH2:18][CH2:19][C@@H:20]2[C@H:21]([CH3:22])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:5]1
Reactant: CC[C@H]1[C@@H](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: C/C=C1\C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: 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

Procedure:
The present invention relates to a process for preparing obeticholic acid Form 1, wherein reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid is carried out at a temperature at about 20° C. to about 60° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH2:35])[CH2:32]2>>[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH:35][C:21]([C:15]1[CH:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=3)[C:16]=1[S:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:32]2
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)OC)cc1

Procedure:
Prepared from 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate#35) and 2-adamantylamine hydrochloride by the same procedure as used for Intermediate #6.
Reaction SMILES: [OH-].[Na+].[OH:3][C@:4]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[C:6]([CH3:15])([CH3:14])[CH2:5]1.Cl>O>[OH2:3].[OH:3][C@:4]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[C:6]([CH3:14])([CH3:15])[CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2nccs2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)C[C@@](O)(c2nccs2)CC[C@@H]1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of methyl(1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate (10 g, 54.28 mmol)) in THF (16.3 g) was added additional THF (184 mL) followed by thiazole (6.93 g, 81.42 mmol). The resulting solution was then cooled to −78° C. Boron trifluoride diethyletherate (9.24 g, 65.14 mmol) was added over 24 minutes and the resulting mixture aged at −78° C. for 5 minutes. n-Butyllithium (2.5M in hexanes, 20.05 g, 71.98 mmol) was added to the mixture subsurface over 4 hours and the mixture was aged for 15 mins. Sodium hydroxide (1M aqueous solution, 54.3 mL, 54.3 mmol) was added followed by MTBE (54 mL) and the mixture was warmed to 20° C. The aqueous layer was separated and the organic layer was washed with a half saturated aqueous solution of sodium chloride (54 mL) resulting in a light yellow solution of methyl(1S,4R)-4-hydroxy-2,2-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate, which was then concentrated under partial vacuum to a low volume. Methanol (124 mL) was added and the solution concentrated to an oil under partial vacuum. The solution was then diluted with methanol (124 mL) and heated to 40° C. A solution of 1M sodium hydroxide (92 mL, 92.0 mmol) was added over 5 minutes and the resulting mixture heated to 50° C. then aged for 16 hours before being cooled to 20° C. The solution was washed three times with dichloromethane (124 mL, 62 mL, 62 mL) and the aqueous methanol solution of the product was crystallised by addition of GM aqueous HCl (15.3 mL, 92 mmol) over 30 mins. The slurry was aged for 2 hours then the mixture was concentrated under partial vacuum to a total volume of 124 mL. The solid was collected by filtration and washed with water-methanol (1:1 v:v, 62 mL) then water (62 mL) to give the title compound (11.44 g, 41.86 mmol, 99.9% ee) as a pale yellow solid. MS ESI: [M+H]+ 256.1 NMR (400 MHz, DMSO-d6): 11.89-12.09 (br s, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 5.79 (s, 1H), 3.36 (br s, 2H), 2.13-2.20 (m, 2H), 1.95-2.09 (m, 1H), 1.76-1.91 (m, 3H), 1.53-1.65 (m, 2H), 1.11 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17]OCC)[O:11][C:10]3[C:21]4[C:26]([CH:27]=[CH:28][C:9]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].[BH4-].[Na+].Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]#[N:15])=[C:12]([NH:16][CH3:17])[O:11][C:10]3[C:21]4[C:26]([CH:27]=[CH:28][C:9]2=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: CCOC=NC1=C(C#N)C(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1=C(C#N)C(c2ccc(Cl)c([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Temperature: 0 °C

Procedure:
4-(4-Chloro-3-nitrophenyl)-2-ethoxymethyleneamino-4H-naphtho[1,2-b]pyran-3-carbonitrile (4.3 g) was dissolved in tetrahydrofuran (70 ml), and to this solution, with stirring, was added sodium borohydride (2.7 g), in portions. After one hour the suspension was cooled in ice-water and 1 molar hydrochloric acid (20 ml) was added dropwise, followed by water (200 ml). A yellow product was filtered off, washed with water and dried. This material was dissolved in hot chloroform and passed down a chloroform--`flash silica` column. Fractions containing product were bulked, evaporated to dryness, and triturated with ether to give 4-(4-chloro-3-nitrophenyl)-2-methylamino-4H-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 278.5°-279° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6]([OH:21])[N:5]=[C:4]([S:22][CH3:23])[N:3]=1>P(Cl)(Cl)(Cl)=O>[CH3:18][O:17][C:13]1[C:12]([CH3:19])=[CH:11][C:10]([C:9]2[O:21][C:6]3[N:5]=[C:4]([S:22][CH3:23])[N:3]=[C:2]([OH:1])[C:7]=3[N:8]=2)=[CH:15][C:14]=1[CH3:16]
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C
Yield: 61.7 %

Procedure:
10.1 g of N-(4,6-dihydroxy-2-methylsulfanyl-pyrimidin-5-yl)-4-methoxy-3,5-dimethyl-benzamide in 55 ml of phosphorus oxychloride were heated to 60° C. for 3 h. After cooling, the resulting solid was collected by filtration with suction and washed with methyl tert-butyl ether. The solid was then dissolved in a mixture of dichloromethane and tetrahydrofuran, washed with a saturated aqueous sodium hydrogencarbonate solution, dried and concentrated in vacuo. 5.9 g of the title compound were obtained.