Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].O.Cl[CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)CCl
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 100 °C

Procedure:
In a 500-ml three-necked flask, 4-cyanoaniline (100 g, 847.4 mmoles) was placed, followed by addition of 300 ml of water and attachment of a water cooling pipe, a mechanical stirrer and a dropping funnel. The flask was heated on an oil bath heated at 100° C. To the flask, an aqueous solution (water 150 ml) of monochloroacetic acid (104 g, 1116 mmoles) was added dropwise for about 30 minutes, followed by reflux with heating for 2.5 hours. After cooling naturally, about 100 ml of ethyl acetate was added to the flask to dissolve an insoluble matter. An organic layer was separated by a separatory funnel. The residual water layer and an aqueous layer obtained by extracting the organic layer with 100 ml of 5% (by weight) NaOH solution were combined, followed by acidolysis with 1/10N HCl. A precipitate produced was filtered and washed with water several times. After drying in an oven heated at 60° C. for 3 hours, the dried precipitate was dried in a vacuum desiccator overnight. The resulting product was a beige powder which showed no melting point but decomposed at 233.1° C. The yield was 38.8 g (26%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[C:13]([C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([C:16]1[CH:17]=[C:18]([C:22]([NH:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:19]=[N:20][CH:21]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cncc(C(=O)O)c1
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cncc(C(=O)Nc2ccc(F)cc2NC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.082 g, 0.495 mmol) in dichloromethane were added the title compound from Step A (0.090 g, 0.545 mmol), HATU (0.207 g, 0.545 mmol), HOAt (0.074 g, 0.545 mmol), and diisopropylethylamine (0.35 mL, 1.98 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 314.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.33 (s, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 8.02 (br s, 1 H), 7.19-7.16 (m, 1 H), 6.91 (d, J=10.5 Hz, 1 H), 6.50-6.47 (m, 1 H), 4.64 (br s, 1 H), 2.69 (s, 3 H), 2.45-2.44 (m, 1 H), 0.78-0.77 (m, 2 H), 0.52-0.51 (m, 2 H).
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:14])[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[CH3:15][C:16]([CH3:18])=[O:17]>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH2:6][C:5]([CH3:14])=[CH:4][CH:3]=[CH:2][C:16]([CH3:18])([OH:17])[CH3:15])[CH3:10]
Reactant: CC(C)=O
Reactant: CCOC(CC(C)=CC=CBr)OCC
Product: CCOC(CC(C)=CC=CC(C)(C)O)OCC

Procedure:
By proceeding as in Example 1, but starting with 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene (0.43 g; 1.63 mmol) and an excess of acetone (0.4 g i.e. 4 equivalents), 1,1-diethoxy-3,7-dimethyl-7-hydroxy-3,5-octadiene, or C10 diethyl hydroxyacetal, (0.4 g) is obtained. After hydrolysis and purification by flash chromatography, eluting with a mixture of petroleum ether and diethyl ether (96/4 by volume), this compound yields dehydrocitral (0.121 g). The yield is 49.6%, based on the 6-bromo-3-methyl-1,1-diethoxy-3,5-hexadiene employed. The structure of the product obtained is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:23])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>N1C=CC=CC=1.O>[C:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)c3ccccc3)CC[C@@H]12
Yield: 100 %

Procedure:
3-Acetoxy-oestra-1,3,5(10)-trien-17β-ol (500 mg., 1.6 mmole) in pyridine (2 ml.) was treated with benzoyl chloride (1.0 ml.) at room temperature for 16 hr. The stirred mixture was then slowly diluted with water (10 ml.), followed by methanol (5 ml.). The crystalline precipitate was filtered off, washed with water and dried to give the title compound (665 mg., 100%), m.p. 148.5°-150.5°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH2:4][CH2:3]1.[CH:21]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:21]1([CH2:27][NH:28][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:9]=2[NH:8][C@H:5]2[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Reactant: NCC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCC1)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (120 mg), cyclohexanemethylamine (53.3 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimde hydrochloride (107 mg) and 1-hydroxybenzotriazole (81.0 mg) in anhydrous dimethylformamide (3 mL) was stirred for 18 hours at ambient temperature. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was triturated with diisopropyl ether to give N-cyclohexylmethyl-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide (157 mg) as yellow powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH2:27][CH2:26]4)=[C:21]([C:22]#[N:23])[CH:24]=3)=[O:15])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccn(-c2ccc(Cl)cc2)c1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(Cl)cc3)c2)ccc1N1CCN(C2CCOCC2)CC1
Yield: 36.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)pyrrole-3-carboxylic acid (0.5 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.7 g), the title compound (0.4 g) was obtained, melting point: 224° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([N+:22]([O-:24])=[O:23])=[C:19](O)[CH:20]=1>>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2[N+](=O)[O-])C1

Procedure:
Prepared analogously to XVI.1 from 2.3 g trans-(3-Hydroxy-cyclobutyl)-carbamic acid tert-butyl ester, 1.6 g 5-fluoro-2-nitrophenol and 2.423 mIDIAD.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[CH2:18][CH2:19][CH3:20].[OH-].[Na+:22]>CO>[CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:17])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[CH2:18][CH2:19][CH3:20].[Na+:22]
Reactant: CCCc1c(C(=O)O)c(=O)cc(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)[O-])c(=O)cc(-c2ccccc2)n1C
Yield: 96.7 %

Procedure:
2.1 g (0.0067 mol) of 1-methyl-6-phenyl-2-propyl-4-oxonicotinic acid is suspended in 50 ml of methanol and to it there is added 0.295 g (0.0074 mol) of sodium hydroxide pellets. The solution is concentrated in vacuo to afford 1.9 g (97% yield) of product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:19]=[O:20]>O>[N:1]1[CH:2]=[C:3]([CH:19]=[O:20])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1ccn2ccnc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 9.4 g (0.1 mole) of 2-aminopyridine and 19.2 g (0.11 mole) of 45% aqueous chloroacetaldehyde was stirred, during which spontaneous heating occurred. When the exothermic reaction subsided, the mixture was dissolved in methanol containing 15 ml of concentrated aqueous ammonia and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Distillation at 80-83° and 0.2 mm Hg pressure yielded 10.5 g of imidazo[1,2-a]pyridine as an oil. A solution of 9.5 g (80.5 mmole) of imidazo[1,2-a]pyridine in 60 ml of dimethylformamide was heated to 90°. Phosphorus oxychloride (9.27 ml, ca. 100 mmole) was added dropwise over a twenty minute period, and the mixture was stirred at 90° for two hours and at room temperature for an additional twenty hours. The mixture was diluted with 60 ml of water and made basic with 30% aqueous sodium hydroxide. The resultant solid was collected by filtration, washed with water, and air dried to yield 1.8 g of 3-imidazo[1,2-a]pyridinecarboxaldehyde as the analytically pure p hydrate. [Calcd. for C8H6N2O.H2O: C, 58.53; H, 3.68; N, 17.06. Found: C, 58.77; H, 3.68; N, 17.48.]To a solution of 1.6 g (10 mmole) of 3-imidazo[1,2-a]-pyridinecarboxaldehyde in 15 ml of methanol was added 204 mg (5.4 mmole) of sodium borohydride. After one hour the mixture was acidified with concentrated hydrochloric acid and then concentrated in vacuo. Recrystallization of the residue from ethanol yielded 707 mg of 3-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt. A 500 mg (2.7 mmole) portion of the hydroxymethyl compound was dissolved in 3.0 ml of concentrated hydrochloric acid and heated at 80° for one hour. The mixture was concentrated in vacuo and the residue was recrystallized from isopropyl alcohol to yield 465 mg of 3-chloromethylimidazo[1,2-a]pyridine as the hydrochloride salt. A mixture of 390 mg (1.92 mmole) of the chloromethyl compound and 288 mg (1.92 mmole) of 2-mercaptobenzimidazole in 7 ml of isopropyl alcohol was stirred for one hour. The precipitate that formed was collected and partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether yielded the title compound as an analytically pure solid. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: OCc1ccc(F)cc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Charged [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol (568 mg, 2.31 mmol, EXAMPLE 119, part A), Pd/C (65 mg) and methanol (6 mL) to a flask, the mixture was then purged with hydrogen, stirred at room temperature overnight. It was then filtered, filtrate concentrated to give a residue which was purified by flash column chromatograph to give 214 mg of the title compound (37%). 1H NMR (400 MHz, CDCl3): δ 1.42 (1H, t, J=5.2 Hz), 2.83-2.98 (4H, m), 4.59 (2H, d, J=5.6 Hz), 6.88-6.98 (4H, m), 7.08-7.11 (2H, m), 7.29-7.33 (1H, m).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15].[C:16]1([N:22]=[C:23]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[CH:25]S(C2C=CC=CC=2)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH:25]=[CH:24][C:23](=[N:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Sc1ccccc1Br
Reactant: O=S(=O)(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SC=CC(=Nc1ccccc1)Oc1ccccc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium hydride (60% in oil: 0.026 g) was suspended to DMF (2 ml), and 2-bromothiophenol (0.10 g) was added thereto under ice-cooling. Furthermore, phenyl N-phenyl-3-(phenylsulfonyl)acrylimidate (0.20 g) was added thereto, and stirred for one hour under ice-cooling. After the reaction, water and ethyl acetate were added to the reaction mixture, and extracted. The organic layer was washed with aqueous saturated sodium chloride solution, dried, and distilled off the solvent. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-(2-bromophenylthio)-N-phenylacrylimidate (0.19 g).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16]([OH:19])=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:24][N:12]1[C:13]2[C:14]([C:20]([F:21])([F:23])[F:22])=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:17][C:18]=2[C@@H:10]2[CH2:9][NH:8][CH2:26][CH2:25][C@H:11]12
Reactant: BrCc1cccnc1
Reactant: CN1c2c(cc(O)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1c2c(cc(OCc3cccnc3)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method as a white solid (48 mg, 49%) from (4aS,9bR)-8-hydroxy-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 71, 100 mg, 0.27 mmol), 3-bromomethyl-pyridine (141 mg, 0.56 mmol) and K2CO3 (156 mg, 1.12 mmol). MS (ESI): 364 (base, M+H).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]1[N:16]=[C:15]([NH:17][NH2:18])[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:13]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:12]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH3:32]OC(OC)OC.FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[C:15]3[N:16]([CH:32]=[N:18][N:17]=3)[C:11]([NH:10][C:2]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)([CH3:1])[CH3:3])=[N:12][C:13]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: COC(OC)OC
Reactant: CC(C)(Nc1nc(NN)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Nc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)c1ccccc1

Procedure:
2-((1-methyl-1-phenylethyl)amino)-4-hydrazino-5-(4-fluorophenyl)-6-(4-pyridyl)pyrimidine (95.1 mg, 0.23 mmol) was combined with trimethylorthoformate (58.4 mg, 0.54 mmol) in CH2Cl2 (ca. 5 mL). Trifluoroacetic acid (62.6 mg, 0.54 mmol) was added and the solution was maintained for 1 h. The reaction mixture was washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography to provide the product as an off-white solid; MS m/z (M+H)+ 425; C25H21FN6 requir. 424.5.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[N+:19]([O-])=O>C1(C)C=CC=CC=1.[Pt]>[CH3:1][CH:2]([CH3:22])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[NH2:19]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Oc2ccccc2)n1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(NCC(C)C)c(N)c(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(2-Methylpropyl)-6-methyl-3-nitro-2-phenoxypyridin-4-amine (530 g) from Part C was dissolved in warm toluene (2.5 L). 5% Platinum on carbon (50 g) wetted with toluene was added to the resulting solution under a nitrogen atmosphere. The resulting mixture was placed in a hydrogenator, flushed multiple times with hydrogen, and filled to a hydrogen pressure of 345 kPa. The reaction was monitored by TLC and HPLC. The reaction mixture turned warn after 30 minutes, and was allowed to cooled to room temperature over 3 hours. The reaction was complete, and the resulting reaction mixture was filtered through a CELITE pad, washed with hot toluene (2 L). The CELITE pad was also washed with isopropyl alcohol. The solvent was removed from the filtrate under reduced pressure, and the resulting black oil was dissolved in dichloromethane. The resulting solution was washed with water (3×1 L), dried with magnesium sulfate, and concentrated under reduced pressure to a green solid (427 g). NMR analysis of the solid indicated sufficient purity for carrying the product on to the next step.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH:21]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)n(CC(=O)OC(C)(C)C)c2c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)n(CC(=O)O)c2c1
Reaction time: 1 h
Yield: 98 %

Procedure:
To methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate in DCM/H2O (2:1; 0.15 M), TFA (>300 eq) were added at RT and the reaction left stirring for 1 h. The volatiles were removed in vacuo, and the residue diluted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound (98%). (ES+) m/z 392 (M+H)+
Reaction SMILES: [C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C)C)[CH:17]=3)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[O:8])=[CH:3][CH:2]=1.C(OCC)C.[ClH:48]>>[ClH:48].[C:1]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](OC(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: Cl
Solvent: CCOCC
Product: O=C(O[C@H]1CNCC[C@@H]1c1cccc(O)c1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The (+/−)-tert-butyl (3R,4R)-3-[(1,1′-biphenyl-4-ylcarbonyl)oxy]-4-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)piperidine-1-carboxylate (91 mg, 0.16 mmol) was dissolved in 4 N Hydrogen chloride in dioxanes (3.0 mL). The solution was stirred for 4 H at room temperature and diethylether (10 mL) was added. The solution was kept at room temperature for 16 H and solids formed. The (+/−)-(3R,4R)-4-(3-hydroxyphenyl)piperidin-3-yl 1,1′-biphenyl-4-carboxylate hydrochloride (56 mg, 0.13 mmol) was obtained as a white solid. HRMS m/z 374.1753 (calcd for M+H 374.1751.)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)([F:6])[F:5].[C:14]([O-:17])(=[S:16])[CH3:15].[K+]>CN(C=O)C.O>[F:5][C:4]([F:6])([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][CH2:2][S:16][C:14](=[O:17])[CH3:15]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCC(F)(F)c1ccc(F)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.25 g, 1.2 mmol) in dry DMF (1 ml) is added potassium thioacetate (0.41 g, 3.60 mmol) at RT. The reaction mixture is heated at 60° C. for 1.5 h. After completion of the reaction, the mixture is diluted with water (30 ml) and extracted with EtOAc (3×30 ml). The organic layer is washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 1% EtOAc/hexane) to yield ethanethioic acid S-[3,3-difluoro-3-(4-fluorophenyl)-propyl]ester (0.26 g, 1.05 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCCCOc1ccc(S(=O)(=O)Nc2nc(CC(=O)OCC)cs2)cc1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-n-butoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (11.8 mg) with purity >90%. LCMS (pos) m/z 399.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: C1CCNC1
Product: N#Cc1c(N2CCCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 244 mg (3.43 mmol) of pyrrolidine to give 29 mg (27% of theory) of the title compound.