Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].Br.[NH2:3][C:4]1[C:9](Cl)=[C:8]([NH2:11])[C:7](Cl)=[C:6](Cl)[N:5]=1.[H][H]>C(O)C.[Pt]=O>[BrH:1].[BrH:1].[NH2:11][CH:8]1[CH2:7][CH2:6][NH:5][C:4](=[NH:3])[CH2:9]1
Reactant: [H][H]
Reactant: Nc1nc(Cl)c(Cl)c(N)c1Cl
Agent: O=[Pt]
Agent: Br
Solvent: CCO
Product: N=C1CC(N)CCN1

Procedure:
2,4-Diamino-3,5,6-trichloropyridine dihydrobromide (1.1 g) and platinum oxide (520 mg) in ethanol (50 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen for 48 hours. The contents were filtered and the filtrate was concentrated in vacuo leaving a waxy solid. The solid was triturated with ether/EtOH to give 4-amino-2-iminopiperidine dihydrobromide as a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=114; 1H NMR (D2 O): δ3.80-3.60 (m, 1H); 3.55-3.25 (m, 1H); 3.08-2.95 (m, 1H); 2.76-2.62 (m, 1H); 2.25-2.13 (m, 1H); 1.95-1.80 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>O1CCCC1>[CH2:16]([N:12]([CH2:13][CH2:14][CH3:15])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:17][CH3:18]
Reactant: CCCN(CCC)C1=Cc2c(Br)cccc2CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reaction time: 4 h
Yield: 56.6 %

Procedure:
Alternatively, to the 8-bromo-2-dipropylamino-3,4-dihydronaphthalene (44.4 mMol) in tetrahydrofuran (100 ml) was added sodium cyano-borohydride (2.86 gm, 45.5 mMol) and the suspension was saturated with hydrogen chloride. After stirring for four hours the reaction mixture was poured into 15% aqueous sodium hydroxide (500 ml) and was stirred an additional two hours. This mixture was extracted with diethyl ether, and the ether extracts were combined, washed with water, washed with saturated aqueous sodium chloride, dried (Na2SO4) and concentrated in vacuo to give the crude title compound as a light orange oil. Purification by basic alumina chromatography (dichloromethane) gave the product as a light yellow oil (7.8 gm, 57%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([F:12])[CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>O>[F:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1F
Solvent: O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC

Procedure:
4-(Bromomethyl)-2-fluoro-1-nitrobenzene (34.72 g, 148 mmol) and triethyl phosphite (25.8 mL) were heated at 140° C. for 4 hours. Water was added and the mixture was extracted with diethyl ether. The organics were dried with magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (40.94 g). 1H NMR (CDCl3, 400 MHz): δ 8.03 (t, 1H), 7.24 (s, 1H) 7.21 (s, 1H) 4.08 (m, 4H), 3.20 (d, 2H), 1.27 (m, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl-].[Li+].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)=[CH2:15]
Reactant: Brc1ccc2nccnc2c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nccnc2c1
Temperature: 100 °C
Yield: 86.7 %

Procedure:
A mixture of 6-Bromo-quinoxaline (1.05 g, 5.02 mmol), palladium tetrakistriphenylphosphine (0.232 g, 0.2 mmol), and lithium chloride (0.639 g, 15.1 mmol) in dry toluene (50 mL) under nitrogen was treated with tributylvinyl tin (4.4 mL, 15.1 mmol) and heated to 100° C. for three hours. After cooling to room temperature the mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was discarded and the organics washed with brine (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10% ethyl acetate in dichloromethane as eluant yielded 680 mg (87% yield) of 6-Vinyl-quinoxaline as a light orange solid. 1H NMR (DMSO-d6): 8.92 (dd,2H,J=14.1,1.9 Hz), 8.10 (m,3H), 7.03 (dd,1H,J=17.7,10.9 Hz), 6.15 (dd,1H,J=17.7,0.4 Hz), 5.52 (d,1H,J=11.1 Hz). LC/MS (Method A): r.t.=1.14 min., purity=99%, calculated mass=156, [M+H]+=157.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]([NH:24][C:25](=[O:39])[CH:26]([N:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[CH3:27])[CH:10]([OH:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([CH2:8][CH:9]([NH:24][C:25](=[O:39])[CH:26]([N:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])[CH3:27])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(CC(=O)OC(C)(C)C)C(O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
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: ClCCl
Product: CC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c1c(Cl)cccc1Cl)n1ccc2ccccc2c1=O
Reaction time: 5 h
Yield: 63 %

Procedure:
A stirred solution of 2,6-dichloro-benzoic acid 4-tert-butoxycarbonyl-2-hydroxy-3-[2-(1-oxo-1H-isoquinolin-2-yl)-propionylamino]-butyl ester (183 mg, 0.32 mmol) in anhydrous DCM (3 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (147 mg, 0.34 mmol) at 0° C. The resulting mixture was kept at 0° C. for 5 h, diluted with DCM, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulphate. The organic layer was removed and the aqueous layer re-extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography using as eluent 60:40 petrol/EtOAc to afford the sub-title compound as a colorless foam (116 mg, 64%): 1H NMR (400 MHz, CDCl3) δ 1.2-1.4 (9H, 2×s), 1.7 (3H, d), 2.7-3.0 (2H, m), 4.9-5.1 (4H, m), 5.8 (1H, m), 6.6 (1H, 2×d), 7.2-7.6 (7H, m), 8.4 (1H, m); MS (FAB+ve) 576.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:39])[CH2:17][CH:18]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8]2)=[CH2:4].CCN(CC)CC.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[C:33]1([CH:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)(=[O:22])=[O:21])[CH2:17][C:16]([NH:15][CH:11]2[CH2:10][CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3](=[CH2:4])[CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])[CH:14]=[CH:13][C:12]2=3)=[O:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CO)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(COS(C)(=O)=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Temperature: 0 °C

Procedure:
To a flask charged with N-[6-(1-hydroxymethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (Step F, 558 mg, 1.0 mmol, 1.0 eq) was added CH2Cl2 (7 mL) and Et3N (0.18 mL, 1.3 mmol, 1.3 eq). The suspension was cooled to 0° C., purged with N2, and then added the CH2Cl2 solution (1 mL) of methanesulfonyl chloride (Aldrich, 0.1 mL, 1.3 mmol, 1.3 eq). The mixture was concentrated in vacuo after 1 h. The crude was dried on vacuum and used for next step directly.
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=4)[O:18][N:17]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][N:7](C([O-])=O)[CH2:6]1)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[CH3:30][CH:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:11]4[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=4[CH:15]=3)[N:20]=2)=[CH:22][C:23]=1[C:31]([F:33])([F:34])[F:32])[CH3:29]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)[O-])CC4C(C)(C)C)no2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl-7-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 44) (550 mg, 1.06 mmol) was dissolved in 4M HCl in dioxane (5 ml) and the solution stirred for 2 h. The title compound was filtered off as a white solid and dried in a vacuum oven (259 mg, 0.57 mmol). δH (d6DMSO, 400 MHz): 9.23 (2H, brs), 8.40 (1H, dd), 8.31 (1H, d), 7.96 (1H, d), 7.93 (1H, dd), 7.59 (1H, d), 7.44 (1H, d), 4.98 (1H, septet), 3.27-3.18 (8H, m), 1.36 (6H, d); MS (ES): C22H22F3N3O2 requires 417; found 418 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=4)[C:21]=3[CH3:39])[N:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:27]([NH:26][C:22]2[C:21]([CH3:39])=[C:20]([C:14]3[N:13]=[C:12]([NH:11][C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:40])=[O:3])=[CH:10][CH:9]=4)[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=3)[CH:25]=[CH:24][CH:23]=2)=[O:38])=[CH:29][CH:30]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)O)cc2)n1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of give 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid ethyl ester (6) (300 mg; 0.56 mmol), 1N NaOH (5 mL), and ethanol (5 mL) was heated at reflux for 1 hr. The mixture was cooled to room temperature and the resulting slurry was washed with ethyl acetate (2×40 mL) and the ethyl acetate was decanted off. The aqueous slurry was taken to pH 5 with 1N HCl, filtered, washed with water and then diethyl ether to give 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid (7) as a gray solid (110 mg), MS 511.46 (M+H).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:29]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1)(=[O:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:29]([O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[CH2:39][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: CC(=O)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1cccc(COc2ccccc2Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (150 mg) in N,N-dimethylformamide (1 mL) were added 3-bromomethylphenyl acetate (131 mg) and potassium carbonate (105 mg), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1˜5/1) to give 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (12 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 5 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[C:9]([Cl:21])[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)=[CH:11][C:2]=1[Br:1])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCCOc1cc(Cl)c(Cc2ccc(CC)cc2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 2-(2-bromo-5-chloro-4-(4-ethylbenzyl)phenoxy)ethanol (AU) (1.85 g, 5 mmol) in anhydrous DMF (10 mL), NaH (0.36 g 15 mmol) was added in portions, and the mixture was stirred at room temperature for 2 hours. Then allyl bromide (1.82 g, 15 mmol) was added dropwise, and the mixture was heated to 45° C. overnight. The reaction was quenched with the saturated NH4Cl and the mixture was extracted with EtOAc, and then washed with water and brine. After drying with anhydrous Na2SO4, the organic portion was filtered and concentrated. The residue was purified by flash chromatography to give AV as an oil (1.74 g, yield 85%). 1H-NMR (CDCl3, 300 MHz) δ 7.31 (s, 1H), 7.13 (m, 4H), 6.94 (s, 1H), 5.94 (m, 1H), 5.26 (m, 2H), 4.14 (m, 4H), 3.96 (s, 2H), 3.84 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][N+]([O-])=O)=[C:10]([F:16])[C:9]([F:17])=[C:4](C(OC)=O)[C:3]=1[C:18]([O:20]C)=[O:19].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]([F:16])[C:9]([F:17])=[CH:4][C:3]=1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1c(F)c(F)c(C[N+](=O)[O-])c(F)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Yield: 86.1 %

Procedure:
A mixture of 4.6 g of compound 42, 6.8 g of tributyltin hydride, 300 mg of α,α'-azobisisobutyronitrile and 70 ml of benzene was refluxed for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue was subjected to silica gel (50 g) column chromatography eluting with benzene. The procedure gave 2.45 g of title compound 45as a light yellow coil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][OH:15])[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1.[CH3:20][C:21]1[CH:26]=[C:25](O)[CH:24]=[C:23]([CH3:28])[C:22]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:16][CH:17]=[CH2:18])([CH2:14][O:15][C:25]2[CH:26]=[C:21]([CH3:20])[C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:23]([CH3:28])[CH:24]=2)[CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Reactant: C=CCC(CO)(CC=C)c1ccc(C(=O)OC)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)(COc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A solution of 4-(1-allyl-1-hydroxymethyl-but-3-enyl)-benzoic acid methyl ester (0.768 g, 2.95 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.861 g, 3.23 mmol), and triphenylphosphine (1.180 g, 4.50 mmol) in toluene (30 mL) is treated with 1,1′-(azodicarbonyl)-dipiperidine (1.182 g, 4.68 mmol) and stirred overnight at 80° C. The reaction mixture is then cooled to room temperature, diluted with MeOH, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% EtOAc to 40% EtOAc to provide 0.964 g (64%) of the title compound as a clear syrup. 1H NMR (CDCl3): δ 8.02-8.00 (m, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.46-7.44 (m, 2H), 7.26 (d, J=7.8 Hz, 2H), 6.68 (s, 2H), 5.60-5.54 (m, 2H), 5.08-5.00 (m, 4H), 4.15 (s, 2H), 3.91 (s, 3H), 2.66 (d, J=7.6 Hz, 4H), 1.99 (s, 6H).
Reaction SMILES: FC(F)(F)S(OC1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)(=O)=O.[CH3:30][C:31]([O-:33])=[O:32].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CS(C)=O>[C:31]([C:30]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)([OH:33])=[O:32]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1Cc2ccc(C(=O)O)cc2Cc2ccccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.9 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(trifluoromethanesulfonyioxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (808.9 mg, 1.89 mmol), KOAc (742 mg, 7.56 mmol), Pd(OAc)2 (21.2 mg, 0.095 mmol), 1,1'-bis(diphenylphosphino)ferrocene (210 mg, 0.38 mmol), and anhydrous DMSO (11 mL) was purged with carbon monoxide (three evacuation/CO flush cycles, followed by bubbling CO through the mixture for 5 min), then was stirred under a balloon of CO in an oil bath set at 70° C. After 3.5 h, the reaction was diluted with H2O (11 mL), cooled to 0° C., and acidified with 1.0 N HCl (ca. 8 mL). CH2Cl2 extraction (3×30 mL), drying (Na2SO4), concentration, and reconcentration from toluene left a reddish-orange liquid (2-3 mL). Chromatography (silica gel, 3:2:0.1 EtOAc/toluene/AcOH; mixed fractions again with 1:1:0.1 EtOAc/toluene/AcOH) gave the title compound (581.9 mg, 95%) as a viscous, yellow oil which partially crystallized in high vacuum at 40° C: TLC Rf (3:2:0.1 EtOAc/toluene/AcOH) 0.60; 1H NMR (250 MHz, CDCl3) δ 7.95 (d, J=1.5 Hz, 1H), 7.87 (dd, J=7.8, 1.5 Hz, 1H), 7.00-7.35 (m, 5H), 4.40 (d, J=15.2 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.97 (d, J=15.2 Hz, 1H), 3.82-4.00 (m, 1H), 3.43 (dd, J=15.3, 4.0 Hz, 1H), 3.07 (dd, J=15.3, 9.5 Hz, 1H), 2.69 (dd, J=15.8, 4.8 Hz, 1H), 2.53 (dd, J=15.8, 9.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H); FTIR (CCl4) 2357-337 (broad), 1735, 1692, 1280 cm-1 ; MS (ES) m/e 342.2 (M+NH4)+, 325.2 (M+H)+, 307.2 (M+H-H2O)+.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].Cl[C:6]1[C:11]([O:12][CH3:13])=[CH:10][N:9]=[C:8]([O:14][CH3:15])[N:7]=1.C(O)(=O)C.[Cl-].[Na+]>CN1CCCC1=O>[CH3:15][O:14][C:8]1[N:7]=[C:6]([NH:3][C:2]#[N:1])[C:11]([O:12][CH3:13])=[CH:10][N:9]=1
Reactant: COc1ncc(OC)c(Cl)n1
Reactant: N#CN
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: COc1ncc(OC)c(NC#N)n1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a 100 milliliter (mL) three-neck round bottom flask were added sequentially 7.8 grams (g) (121.53 millimole (mmol)) of sodium hydrogen cyanamide and 34.2 g of N-methyl-2-pyrrolidinone (NMP) in one portion, and the slurry mixture was cooled in an ambient temperature water bath. To this mixture was added 10.0 g (54.99 mmol) of 96% 4-chloro-2,5-dimethoxypyrimidine (1; CDMP) in one portion. The mixture was allowed to stir at ambient temperature (<20° C.). After 65 hours (h), 3.55 g (59.11 mmol) of glacial acetic acid was added in one portion and the internal pot temperature rose from 18° C. to 23° C. This reaction slurry was pipetted over 87.1 g of crushed ice and the ice was allowed to melt. To this mixture was added 10.3 g of sodium chloride. The mixture was allowed to stand until the crushed ice was fully melted. Once melted, the cold slurry was suction filtered and the filter cake was washed with one 10 mL portion of water and then two 20-mL portions of water. The wet cake was isolated to afford 9.39 g (80.2% pure by NMR assay using benzyl acetate) of 2,5-dimethoxy-4-cyanoaminopyrimidine (2) as a light yellow solid mp 164-171° C. in 76% yield; 1H NMR (DMSO-d6, 400 MHz) δ 3.72 (s, 3H), 3.94 (s, 3H), 7.46 (s, 1H), 12.48 (br s, ˜1H); 13C NMR (DMSO, 100 MHz) δ 55.21, 56.60, 116.20, 121.8 (br s), 138.9, 153.9, 162.6 (br s).
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: O=C(O)c1cc(F)ccc1-n1cccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid (CAS number 1152964-04-9; 75 mg, 0.37 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].[CH2:16](Cl)[CH2:17][OH:18].[OH-].[Na+]>O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][CH2:16][CH2:17][OH:18])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc([N+](=O)[O-])c(NCCO)cc1Cl
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc(NCCO)c(Cl)cc1NCCO
Temperature: 130 °C
Reaction time: 3 h

Procedure:
79.0 g (0.33 mole) of 1-beta-hydroxyethylamino-2-nitro-4-amino-5-chlorobenzene were dissolved in 150 ml methylglycol and 36 g (0.5 mole) ethylenechlorohydrin. 19.8 g of NaOH dissolved in 180 ml water were then added while stirring over a period of 3 hours at a bath temperature of 130°C. The final product was removed by suction after cooling and was recrystallized from water. Yield: 35 g 1,4-di-(beta-hydroxyethylamino)-2-nitro-5-chlorobenzene; m.p.: 127°-128°C. Analysis: C10H14N3O4Cl
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:23]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:27]=[CH:26][N:25]=[CH:24]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NCCCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCCCn1ccnc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 1.58 g of 6-chloronicotinic acid and 1.62 g of 1,1'-carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then 1.52 g of 1H-imidazole-1-pentanamine was added. The procedure of Example 36 was followed to conclusion and gave 2.3 g of the compound of the Example as white crystals, mp 110°-112° C.