Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(O)c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Yield: 40 %

Procedure:
A 158 g (1.0 mole) quantity of benzenesulfonic acid, 94 g (1.2 moles) of benzene and 5 g of 12-tungstophosphoric acid (H3PW12O40.29H2O) were refluxed with heating and stirring to undergo reaction for 30 minutes. The reaction mixture was analyzed by highperformance liquid chromatography, which showed that the conversion of benzenesulfonic acid was 30%. To the reaction mixture was added the same amount (10 g) of polyphosphoric acid as in Example 15. The mixture was refluxed for 5.5 hours. The same treatment as in Example 15 was followed, giving 87 g of diphenylsulfone in a yield of 40%.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][NH:8][CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][CH2:36][C:37](Cl)=[O:38]>O>[CH2:19]([O:18][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][N:8]([CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[C:37](=[O:38])[CH2:36][Cl:35])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)CCl
Reactant: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(CN(CC1OCC(C)C(C)O1)C(=O)CCl)OCCCC

Procedure:
N-(2,2-Dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[C:32]([C:39]([F:40])([F:42])[F:41])[CH:31]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 93 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (1.04 g, 4.97 mmol), K2CO3 (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.37 g, 93%) as an orange solid. LCMS (m/z, ES+)=592.2 (M+H+).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]1=[O:16])[CH2:2][CH2:3][CH2:4][CH3:5].O1C2C=CC(O)=CC=2OC1.[O:27]1[C:31]2[CH:32]=[C:33]([OH:36])[CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28]1>>[OH:15][C:8]1([C:34]2[C:33]([OH:36])=[CH:32][C:31]3[O:27][CH2:28][CH2:29][C:30]=3[CH:35]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1=[O:16]
Reactant: CCCCCN1C(=O)C(=O)c2ccccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (90%) as a white powder: MS (ES+) m/z 376.3 (M+23).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>CN(C)C=O>[Cl:25][C:4]1[C:3]([CH2:1][CH3:2])=[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=2)[N:6]([CH3:17])[N:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cnn(C)c1-c1csc(C(=O)OC)c1
Solvent: CN(C)C=O
Product: CCc1c(Cl)nn(C)c1-c1csc(C(=O)OC)c1
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A solution of methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (202 mg, 0.81 mmol) and NCS (108 mg, 0.81 mmol) in N,N-dimethylformamide (4 ml) was stirred in a sealed tube for 1 h at 100° C. Additional NCS (108 mg, 0.81 mmol) was added and the solution stirred 1 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (2-30% EtOAc in hexanes) affording methyl 4-(3-chloro-4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (135 mg, 0.45 mmol, 56% yield) as a yellow oil: LCMS (ES) m/e 285 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:31])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:22]([C:23]([NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:24])=[C:21]([F:31])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
A mixture of 4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoic acid (100 mg, 0.24 mmol), EDCI (69 mg, 0.36 mmol), DMAP (44 mg, 0.36 mmol) and methanesulfonamide (34 mg, 0.36 mmol) in DCM (15 mL) was stirred at room temperature for 18 h. The mixture was diluted with DCM (10 mL) and washed with HCl (2 N, 15 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (20%-50% CH3CN/H2O in 0.1% NH4HCO3) to give target compound (40 mg, 34%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.29 min, m/z: 495.1 [M+H]+. 1H-NMR (500 MHz, MeOH-d4,): δ 7.54-7.46 (m, 10H), 7.29 (d, J=8.0 Hz, 1H), 6.64 (d, J=12.0 Hz, 1H), 5.83 (s, 1H), 5.29-5.26 (m, 1H), 4.75-4.71 (m, 2H), 4.41-4.38 (m, 2H), 3.37 (s, 3H), 2.22-2.18 (m, 1H), 1.03-0.99 (m, 2H), 0.75-0.42 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(Cl)=O.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[N:44]([CH2:54][C:55](O)=[O:56])[CH2:43][C@H:42]1[CH3:58])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[N:44]([CH2:54][C:55]([N:15]2[C:9]3[CH:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=4)[N:12]=[CH:11][C:10]=3[C:13]([CH3:17])([CH3:16])[CH2:14]2)=[O:56])[CH2:43][C@H:42]1[CH3:58])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[C@@H]1CN(CC(=O)O)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3)ncc21
Agent: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4)cc32)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a stirred solution of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (0.11 g, 0.43 mmol) and diisopropylethylamine (0.082 mL, 0.061 g, 0.47 mmol) in DCM (3 mL) at 0° C. under nitrogen was added chloroacetyl chloride (0.036 mL, 0.051 g, 0.45 mmol) and the mixture was stirred at 20° C. for 1 h. Further diisopropylethylamine (0.22 mL, 0.166 g, 1.29 mmol) was added, followed by a solution of (2R,5S)-4-carboxymethyl-2-methyl-5-morpholin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (0.141 g, 0.47 mmol) in DCM (2 mL). The mixture was stirred at 35° C. for 64 h, then the mixture was partitioned between saturated aqueous NaHCO3 and DCM (×3) and combined organic extracts were dried and evaporated. Chromatography (SiO2, gradient elution with 0-100% EtOAc in 40-60 PE) gave the title compound (0.184 g) as an oil. MS: [M+H]+=596.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([CH:23]=3)[NH2:22])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH:26]1[CH:30]=[C:29]([CH2:31][C:32](Cl)=[O:33])[S:28][CH:27]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH:22][C:32](=[O:33])[CH2:31][C:29]4[S:28][CH:27]=[CH:26][CH:30]=4)[CH:23]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1N
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Yield: 83.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)aniline (400 mg, 1.14 mmol) and thiophene-2-acetyl chloride (148 mL, 1.50 mmol) were coupled according to the procedure of Example 56, Step G to give the desired product (454 mg, 84%). 1H NMR (400 MHz, d6-DMSO) δ 9.51 (s, 1H), 8.87 (D, J=7.2 Hz, 1H), 8.42-8.38 (m, 2H), 8.27 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.37-7.36 (m, 1H), 7.30 (dd, J=8.4 and 2.0 Hz, 1H), 7.19-7.16 (m, 2H), 7.09 (d, J=5.6 Hz, 1H), 6.96-6.94 (m, 2H), 3.98 (s, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[F:18])[CH2:4][CH2:5][C:6](OCC)=[O:7])#[N:2]>[Ni].N>[F:18][C:12]1[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:3]1[CH2:1][NH:2][C:6](=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)CCC(C#N)c1cccc(F)c1F
Agent: [Ni]
Agent: N
Product: O=C1CCC(c2cccc(F)c2F)CN1
Reaction time: 18 h

Procedure:
A mixture of ethyl 4-cyano-4-(2,3-difluorophenyl)butanoate (18.5 g, 73.1 mmol), Raney nickel (slurry in water, ca. 30 g), and ammonia (2.0 M in EtOH, 550 mL) was stirred vigorously under an atmosphere of hydrogen (ca. 1 atm) for 18 h. The reaction mixture was filtered through a pad of Celite®, washing with EtOH, and the filtrate was concentrated in vacuo to give a crude solid. Recrystallization from EtOAc afforded the title compound. MS: m/z=211.9 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.CN(C)C=O.Br[CH2:22][CH2:23]Cl.Cl>CCOC(C)=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: ClCCBr
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.60 g, 15 mmol) was added to a solution of ethyl (6-chloropyridin-3-yl)acetate (1.0 g, 0.0050 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) at rt under an atmosphere of nitrogen. After 30 minutes, 1-bromo-2-chloro-ethane (0.84 mL, 0.010 mol) was added to the mixture at 0° C. The reaction mixture was stirred at 35° C. for 4 hours and then at room temperature overnight. The mixture was poured into a mixture of ice-water (50 ml) and EtOAc (50 ml) and the resulting mixture was acidified (to pH 2) by slow addition of 6 N HCl. The layers were separated and the organic layer was washed successively with water and brine, dried over MgSO4 and concentrated. The residue was chromatographed by combiflash (ethyl acetate in hexanes: 80%, on silica gel) to afford the desired product. LC/MS: 226.0 and 228.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[CH3:11].Br[C:13]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+]>O.C(O)C.C1(C)C=CC=CC=1>[CH3:11][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1cc(F)ccc1Br
Reactant: Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(F)ccc1-c1ccc(F)c(C)c1
Yield: 98.7 %

Procedure:
A mixture of 4-fluoro-3-methylphenylboronic acid (6.5 g, 42.5 mmol), methyl 2-bromo-5-fluorobenzoate (10.0 g, 42.9 mmol), tetrakis (triphenylphospine) palladium(O) (1.0 g, 0.87 mmol, 0.2 eq), toluene (100 mL), 2M aqueous sodium carbonate (50 mL) and ethanol (25 mL) was refluxed for 9 h. The reaction mixture was then poured into 50 mL each of concentrated ammonium hydroxide, 2M aqueous sodium carbonate, and water, the organic phase was separated, and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, and concentrated to leave an oil which was chromatographed on silica gel using hexane to provide 11 g (98%) of the ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])[CH2:16][CH2:15]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (10 g), tert-butyl 1-piperazinecarboxylate (10.5 g) and 4-dimethylaminopyridine (6.3 g) in CH2Cl2 (200 mL) was treated with a catalytic amount of HOBT (0.2 g). The resulting mixture was cooled to 0° C., and EDCl (10.8 g) was added. The reaction was then slowly warmed to ambient temperature and stirred for 24 h then concentrated under reduced pressure. Water was added to the resulting residue. The product precipitated and was washed with water (2×50 mL) and Et2O (30 mL). The resulting solid was dried under reduced pressure to yield (18.2 g). MS (electrospray): exact mass calculated for C18H22ClN3O3, 363.13; m/z found, 362.3 [M−H]−.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.O>C(#N)C>[F:14][C:2]1([F:1])[CH2:7][C@H:6]([OH:8])[C@@H:5]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:10]=2)[CH2:4][CH2:3]1
Reactant: O[C@H]1CC(F)(F)CC[C@@H]1c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cn2cc([C@H]3CCC(F)(F)C[C@@H]3O)cn2)cc1
Yield: 24.6 %

Procedure:
A solution of the (1S*,2R*)-5,5-difluoro-2-(1H-pyrazol-4-yl)cyclohexanol (0.24 g, 1.17 mmol) prepared in Example 143c, potassium carbonate (0.32 g, 2.34 mmol) and 4-methoxybenzyl chloride (0.16 mL, 1.17 mmol) in acetonitrile (5.9 mL) was stirred at 80° C. for 12 hours. After allowing to cool, water (20 mL) was added to the reaction solution, and an organic layer was extracted with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (92.9 mg, 25%) as a colorless solid.
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56].Cl>C1COCC1.CCOC(C)=O>[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH:56][C:2](=[O:3])[NH:1][C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (610.0 mg, 1.071 mmol) in THF (10 mL) was added N,N-diisopropylethylamine (0.559 mL, 3.21 mmol) and N,N-dimethylethylenediamine (0.353 mL, 3.21 mmol). The reaction mixture was stirred at 25° C. After 18 h, the reaction mixture was diluted with EtOAc (50 mL) and treated with 1N HCl (5 mL). The mixture was concentrated to a paste and then triturated with EtOAc, filtered and washed with Et2O. The white solid was saved and the liquid filtrate was concentrated and the trituration and filtration steps were repeated twice more. The combined white solid product was dried in a vacuum oven to give the title compound (650.0 mg, 0.958 mmol, 90% yield). LCMS: m/e 658.4 (M+H)+, 4.25 min (method 8). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.9 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, dd, J=6.3, 1.7 Hz), 4.8 (1H, s), 4.6 (1H, s), 3.9 (3H, s), 3.7-3.8 (1H, m), 3.5-3.6 (1H, m), 3.2 (2H, br. s.), 2.9 (6H, br. s.), 2.7-2.7 (1H, m), 2.6 (1H, d, J=13.4 Hz), 2.4 (1H, dd, J=11.6, 8.2 Hz), 2.1 (1H, dd, J=17.2, 6.3 Hz), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.8 (1H, d, J=12.8 Hz), 1.7 (3H, s), 1.7 (1H, d, J=6.7 Hz), 1.6-1.7 (1H, m), 1.5-1.6 (2H, m), 1.5 (4H, d, J=2.7 Hz), 1.3-1.4 (5H, m), 1.2-1.3 (1H, m), 1.1 (3H, s), 1.0-1.1 (2H, m), 1.0 (3H, s), 1.0-1.0 (3H, m), 0.9 (6H, s). 13C NMR (CHLOROFORM-d) δ ppm 14.2, 15.8, 16.3, 18.4, 19.2, 19.5, 20.7, 21.1, 25.0, 27.1, 29.1, 29.5, 29.6, 33.3, 35.3, 35.4, 36.0, 37.2, 37.3, 40.3, 41.4, 41.7, 43.4, 46.7, 49.3, 51.7, 52.6, 53.4, 58.9, 63.9, 77.3, 109.8, 123.9, 127.6, 128.2, 129.8, 145.9, 148.5, 149.4, 157.5, 167.0.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:12][C:10]1[N:11]=[C:3]2[C:2]([C:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=3)=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[N:9]=1
Reactant: Cc1cc(Br)c2nc(N)nn2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2nc(N)nn2c1

Procedure:
A mixture of 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.14 g, 5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.39 g, 7.5 mmol), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (204 mg, 250 μmol) and an aqueous solution of Na2CO3 (2 N, 12.5 mL, 25 mmol) in dioxane (50 mL) was stirred at 110° C. over night. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue purified by silica gel chromatography using EtOAc as eluent. The title compound was obtained after stirring with diethyl ether, filtration and drying as a light yellow crystalline solid (1.54 g, 93%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)(=O)C.[ClH:13]>>[ClH:13].[CH3:12][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)OCc1cccc(C)n1
Agent: Cl
Product: Cc1cccc(CO)n1

Procedure:
A solution of (6-methylpyridin-2-yl)methyl acetate (1.0 g) in concentrated HCl (3 mL) was refluxed for 1 h. The reaction mixture was then concentrated in vacuo to obtain the crude product. The crude material was azeotroped with toluene, and the residue obtained was filtered and dried in vacuo to afford (6-methylpyridin-2-yl)methanol hydrochloride (811 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10]/[N:11]=[C:12](/[NH:15][C:16]#[N:17])\[NH:13][CH3:14].[C:18]([OH:30])(=[O:29])/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:25]([OH:26])=[C:23]([OH:24])[CH:22]=1>ClCCl>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10]/[N:11]=[C:12](/[NH:15][C:16]#[N:17])\[NH:13][CH3:14].[C:18]([O-:30])(=[O:29])/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:25]([OH:26])=[C:23]([OH:24])[CH:22]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: CN/C(=N\CCSCc1nc[nH]c1C)NC#N
Solvent: ClCCl
Product: O=C([O-])/C=C/c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.26 g (0.5 cmole) cimetidine and 0.95 g (0.5 cmole) of caffeic acid (97%) were suspended in 12 ml of dichloromethane. The mixture was stirred for 2 hours at room temperature, followed by filtration and washing with dichloromethane. Dry weight: 2.17 g. Quantitative yield. M.p.: 126°-130° C. IR FIG. 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccccc1OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOc1ccccc1C(=O)O
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirred solution of Ethyl 2-Ethoxy-benzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Ethoxy-benzoic Acid (7.6 g, 80%).