Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:15]1[C@H:14]([CH3:13])[CH2:18][O:17][C:16]1=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1COC(=O)N1
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)c(F)c1
Yield: 92 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-3-fluorobenzoate (1.2 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1.2 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[C:24]([OH:30])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:39]O>>[F:1][C:2]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[C:24]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=2)[O:30][CH2:39][C:38]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: COc1cc(O)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1cc(OC)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90E and ethyl glycolate were processed as described in Example 62A to provide the title compound. MS (ESI+) m/z 593 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>CN(C=O)C.O>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:9]2[C:8](=[O:11])[N:6]3[N:7]=[C:2]([Cl:1])[C:3]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[C:4]([C:12]4[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=4)[C:5]3=[N:10]2)=[CH:36][CH:35]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Temperature: 75 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (750 mg, 1.92 mmol), prepared as described in Example 1F, in DMF (10 mL) was added K2CO3 (270 mg, 1.95 mmol) and 4-(trifluoromethyl)benzyl bromide (460 mg, 1.92 mmol). The reaction mixture was stirred at 75° C. for 1 h under Argon. It was cooled to RT diluted with water (50 mL) and the solid was collected by filtration. The solid was washed with water (25 mL×2) and dried in a vacuum oven at 50° C. overnight to give the title compound, 2-(4-(trifluoromethyl)benzyl)-6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (990 mg, 94%) as yellow powder. HPLC: 4.23 min; MS: M+H=549.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][N:18](S(C(F)(F)F)(=O)=O)[N:19]=3)[CH2:15]2)[C:10]1=[O:30].[C:40]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:49]2[CH2:50][CH2:51][CH:46]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:47][CH2:48]2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:22][CH2:21][C:20]3[C:16](=[CH:17][NH:18][N:19]=3)[CH2:15]2)[C:10]1=[O:30]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CCc2nn(S(=O)(=O)C(F)(F)F)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1[C@H](Cc2c(Cl)cc(N3CCC(c4ccccc4)CC3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
Heat a solution of (3R,5S)-Trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 43) (0.10 g, 0.155 mmol) and 4-phenylpiperidine (0.063 g, 0.39 mmol) in 1-methyl-2-pyrrolidine (2.5 mL) to 201° C. for 1.5 hours in a microwave reactor. Cool the reaction to room temperature and treat with 2M LiOH (1 mL) and stir for 16 hours at room temperature. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product. Purify with a 0 to 5% methanol in CH2Cl2 gradient to afford 0.039 g (48%) of the title compound. MS (m/z): 523 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:15])[C:12]([Cl:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1c[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-chloro-1H-indole (15 g) in diethyl ether (300 mL) was cooled to 0° C. and treated with a solution of oxalyl chloride (9.4 mL) in diethyl ether (30 mL). The mixture was stirred for 16 hours at room temperature. Filtration gave 2-(6-chloro-1H-indol-3-yl)-2-oxoacetyl chloride as a crystalline material (15.5 g). A part of this product (2.5 g) was dissolved in dry tetrahydrofuran (25 mL) and added dropwise to a solution of 1-(1H-indol-4-yl)piperazine (1.4 g) and triethylamine (15 mL) in tetrahydrofuran (100 mL). After stirring for 16 hours the reaction mixture was concentrated in vacuo. The remaining oil was purified by flash chromatography (eluent: ethyl acetate/methanol/triethylamine 85:10:5) giving 1-(2-(6-chloro-1H-indol-3-yl)-1,2-dioxoethyl)-4-(1H-indol-4-yl)piperazine (1.6 g) as a crystalline material. This product was suspended in tetrahydrofuran (25 mL) and added dropwise to a suspension of lithium aluminium hydride (1.5 g) in tetrahydrofuran (50 mL). The mixture was refluxed for 4 hours and cooled to 0° C. followed by subsequent addition of water (3 mL), 15% aq. sodium hydroxide (1.5 mL), and water (7.5 mL). Filtration and standard work-up gave a yellow oil which was converted to the title oxalate salt (1.5 g) from an acetone solution by addition of oxalic acid. Mp 229-31° C. 1H NMR (DMSO-d6): 3.10 (t, 2H); 3.25-3.55 (m, 10H); 6.45 (s, 1H); 6.50 (d, 1H); 6.90-7.10 (m, 3H); 7.25-7.35 (m, 2H); 7.45 (s, 1H); 7.65 (d, 1H); 11.12 (s, 2H), MS m/z (%): 379 (MH+, 18%), 214 (16%), 199 (17%), 178 (16%), 143 (13%).
Reaction SMILES: [C-]#N.[K+].C[N:5](C)C=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=O)[O:12][C:11]1=O>O>[NH:5]=[C:9]1[C:13](=[O:12])[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]1[CH3:11]
Reactant: CN(C)C=O
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CN1C(=N)C(=O)c2ccccc21
Yield: 49 %

Procedure:
To a suspension of 1.3 g. (0.021 moles) of pulverized potassium cyanide in 75 ml. of dimethylformamide (distilled over calcium hydride) at 100° C. is added dropwise, over a period of 15 minutes, a solution containing 3.6 g (0.02 moles) of 1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione in 35 ml. of dimethylformamide (distilled over calcium hydride), after which time the reaction mixture is stirred at 100° C. for an additional 5 minutes. The resultant mixture is then poured into cold water and extracted into three 250 ml. portions of ether. After drying the organic phase over sodium sulfate, the excess solvent is removed and the resultant precipitate is filtered, washed with ether and dried in vacuo to yield 2-imino-1-methyl-3-indolinone, m.p. 99°-102° C. (Yield: 49%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:7][CH2:8]Cl)[CH2:4][CH2:5]Cl.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:2][N:3]1[CH2:7][CH2:8][N:16]([C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of N-methylbis(2-chloroethyl)-amine hydrochloride (9.8 g) and 3-nitroaniline (7.0 g) in 1-butanol (100 ml) was heated at reflux for 60 h then cooled to room temperature. Sodium carbonate (2.8 g) was added and the mixture heated at reflux for a further 18 h. The mixture was cooled to 0° C. and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200 ml) and sodium hydroxide solution (1M, 150 ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200 ml). The combined organic layers were dried (K2CO3) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an orange oil. The oil crystallized on standing and the resultant solid was triturated with petrol (60/80) to give the desired piperazine (5.64 g). 1H NMR (360 MHz, CDCl3) δ 2.37 (3H, s), 2.58 (4H, t, J=5 Hz), 3.30 (4H, t, J=5 Hz), 7.18 (1H, dd, J=9 and 3 Hz), 7.35 (1H, t, J=8 Hz), 7.64 (1H, dd, J=9 and 2 Hz), 7.71 (1H, d, J=2 Hz). MS (CI, NH3) 222 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[O:14]C)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:14])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1C(C)C)OCCO2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(O)ccc2c1OCCO2
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a solution of 5-isopropyl-6-methoxy-2,3-dihydro-benzo[1,4]dioxine (1.011 g, 4.9 mmol) in 15 ml CH2Cl2 at −78° C. was added BBr3 (7.3 ml, 7.3 mmol). The solution was allowed to warm to room temperature. After 16 hours the solution was cooled to −78° C., quenched with H2O, warmed to room temperature and extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography (7:3 hexane/ethyl acetate) afforded 5-isopropyl-6 hydroxy-2,3-dihydro-benzo[1,4]dioxine (0.622 g, 63%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:25]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)Nc3n[nH]c4ccc(OCc5ccccc5)cc34)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2ccc(OCc3ccccc3)cc12)c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-(4-{[5-(benzyloxy)-1H-indazol-3-yl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.19 mmol) in dioxane (4 mL), 4M HCl in dioxane (0.72 ml, 2.88 mmol) was added. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the crude was diluted with Et2O and decanted, to give after filtration, the final compound as hydrochloride salt (80 mg, 93%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:18]3[NH:17][C:16]4[CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:18]3[NH:17][C:16]4[CH2:19][CH2:20][NH:21][CH2:22][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(OCCN4CCCCC4)cccc3c2C1
Agent: Cl
Solvent: CO
Product: c1cc(OCCN2CCCCC2)c2[nH]c3c(c2c1)CNCC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl 6-(2-(piperidin-1-yl)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.33 g, 3.32 mmol) was added to HCl in MeOH (reagent 10, 25 ml) at 25° C. under air. The resulting solution was stirred at room temperature for 3 days. The solvent was removed under reduced pressure to afford (1.00 g, 100%) as a yellow gum. Material was used crude.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:2][CH3:3].[Cl:13][CH:14]=[CH:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:13]/[CH:14]=[CH:15]/[CH2:16][N:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCNCc1cccc(O)c1
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCN(C/C=C/Cl)Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 3.30 g (20 mmol) of N-propyl-3-hydroxybenzylamine in 20 ml of dimethyl sulfoxide were added 1.82 g (20 mmol) of 1,3-dichloropropene (E/Z=2/1) and 1.38 g (10 mmol) of ground potassium carbonate under ice cooling. The mixture was stirred for 1.5 hours at room temperature and for 3 hours at 50° C., poured into 70 ml of ethyl acetate, washed with 50 ml×2 of water and 50 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 2.29 g (yield: 48%) of the above identified compound as an oil.
Reaction SMILES: [CH2:1]([C:3]([CH3:6])=[N:4][OH:5])[CH3:2].[N:7]1[C:14](Cl)=[N:13][C:11](Cl)=[N:10][C:8]=1Cl>N1C=CC=CC=1>[CH3:6]/[C:3](=[N:4]\[O:5][C:8]1[N:10]=[C:11]([O:5]/[N:4]=[C:3](/[CH3:6])\[CH2:1][CH3:2])[N:13]=[C:14]([O:5][N:4]=[C:3]([CH2:1][CH3:2])[CH3:6])[N:7]=1)/[CH2:1][CH3:2]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCC(C)=NO
Solvent: c1ccncc1
Product: CCC(C)=NOc1nc(O/N=C(/C)CC)nc(O/N=C(\C)CC)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cold (0° C.) solution of ethylmethyl-ketoxime (4.18 g, 0.048 mol) in dry pyridine (16 ml) is added cyanuric chloride (2.21 g, 0.012 mol). An exothermic reaction occurs and the temperature rises to 16° C. The solution is then stirred 12 h at room temperature and then poured into 150 ml of ice-cold water. The resulting emulsion is extracted with dichloromethane (3×30 ml), the extracts are dried over MgSO4 and the solvent is evaporated. The residue is chromatographed (silica gel, CH2Cl2—C2H5O(CO)CH3 8:3) to afford 3.72 g of the title compound as a colorless oil which slowly solidifies on standing, mp. 51-56° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:37](OCC)(=[O:39])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:39][CH3:37])[CH:15]=1)[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 56 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (10.5 g, 20 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was added 10% palladium on activated carbon (2 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (4.87 g, 56% yield)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([N+:16]([O-])=O)[C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[N:4]1)[CH3:2]>C(O)(=O)C.Cl.[Pd]>[NH2:16][C:8]1[C:9]2[O:15][CH2:14][O:13][C:10]=2[CH:11]=[C:12]2[C:7]=1[C:6](=[O:19])[C:5]([C:20]([OH:22])=[O:21])=[N:4][N:3]2[CH2:1][CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2c([N+](=O)[O-])c3c(cc21)OCO3
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCn1nc(C(=O)O)c(=O)c2c(N)c3c(cc21)OCO3
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a suspension of 1-ethyl-5-nitro-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (4.25 g, 13.83 mmol) in Acetic Acid (100 mL) and hydrochloric acid (30 mL) in parr shaker bottle was added Pd/C (0.6 g, 5.64 mmol) and the mixture was hydrogenated at 50 psi on a parr shaker for 5 h. The mixture was filtered. The filtrate was allowed to drop into 500 ml of water and the precipitate was collected by filtration, dried to afford 5-amino-1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (3.6 g, 12.99 mmol, 94% yield). LCMS: (M+H)+: 278.2
Reaction SMILES: [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.[BH4-].[Na+]>>[CH3:30][CH2:29][C@H:5]1[C@@H:6]([OH:28])[C@@H:7]2[C@H:22]([CH2:21][CH2:20][C@:19]3([CH3:27])[C@@H:11]([C@@H:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH3:18])[CH2:10][CH2:9][C@H:8]32)[C@:23]2([CH3:26])[C@H:4]1[CH2:3][C@H:2]([OH:1])[CH2:25][CH2:24]2
Reactant: 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
Agent: [BH4-]
Agent: [Na+]
Product: 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

Procedure:
reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (6) with NaBH4 to form crystalline obeticholic acid, and
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2]>CCO.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (1.5 g), Fe (2.6 g), and CaCl2 (260 mg) in EtOH (30 mL) and H2O (6.0 mL) was heated at 100° C. for 6 h. After cooling to rt, the precipitate was removed by Celite, and the filtrate was concentrated. The residue was partitioned between AcOEt and sat.NaHCO3aq. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=3/2 to 1/1). The is obtained solid was rinsed with iPr2O-hexane to give N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g) as a pale pink solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl 6-bromohexanoate was prepared by dropwise addition of a solution of 6-bromohexanoyl chloride (20.0 mL) in 100 mL of methylene chloride to a solution of 66.22 mL of benzyl alcohol in 60 mL of pyridine. The mixture was cooled using an ice-water bath for 90 min, then stirred at room temperature for 18 h. The solution was extracted with 200 mL of 1 N HCl followed by 2×150 mL of sat. NaHCO3. The extracts were discarded and the solution dried over Na2SO4. The solution was filtered and the solvent removed in vacuo to give an oil. This oil was purified on silica gel, eluting with a gradient of chloroform in hexanes. Fractions containing the product (TLC Rf 0.52, CHCl3/hexanes 6:4) were combined and the solvent removed to give 24.4 g.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([NH:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 93.6 %

Procedure:
A solution of 1.25 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 80 ml of ethanol was hydrogenated over 10% palladium-on-carbon at 20° C. and under atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 0.844 g of 1-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide as a pale yellow gum; MS: m/e 348 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[S:10]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1
Yield: 98.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (39.4 g), 1-mesylpiperazine hydrochloride (55.7 g) and triethylamine (116 ml) in ethanol (500 ml) was stirred at reflux temperature for 4 hours. The mixture was then stirred at room temperature for 12 hours. The solid, which had separated, was collected by filtration, slurry washed with ethanol (2×80 ml, 160 ml) then with diethyl ether (150 ml), and dried to give 1-(6-chloropyrimidin-4-yl)-4-mesylpiperazine as a cream solid (71.9 g). mp 200–202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][CH2:12][C:13](O)=[O:14].C(OCC)(=O)C>FC(F)(F)S(O)(=O)=O>[Cl:10][CH2:11][CH2:12][C:13]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[CH:4][C:5]=1[OH:8])=[O:14]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Cl)c(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(CCCl)c1cc(Cl)c(O)cc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chlorobenzene-1,3-diol (100 g, 692 mmol) and 3-chloropropanoic acid (75.1 g, 692 mmol) in trifluoromethanesulfonic acid (295 ml) was stirred at 75° C. for 30 minutes. The reaction was cooled to ambient temperature and slowly poured into a 2 L beaker filled with ice. To the slurry was added ethyl acetate with stirring until all solids dissolved. The mixture was poured into a separatory funnel, the aqueous layer was removed and the resulting organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatograph (silica) eluting with a solvent system mixture of 15% ethyl acetate/hexanes to provide the desired product (162.6 g, 86%).