Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[H-].[Na+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[O:12]=[C:10]1[C:2]2=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]2[CH2:19][CH:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O

Procedure:
A stirred solution of ethyl indole-2-carboxylate (5.67 g, 30 mmol) in 400 ml of toluene under N was treated with sodium hydride (1.44 g, 36 mmol). Ethyl acrylate (3.6 ml, 33 mol) was added and the mixture was heated at reflux. Additional portions of ethyl acrylate (6 mmol) and sodium hydride (16 mmol) were added after 3 hr. After a total time of 6 hr, t.l.c. indicated that all starting material are consumed. The mixture was quenched with ethanol and treated with water, dilute HCl, and methylene chloride. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2,3-dihydro-1-oxo-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole, which was used directly in the next step.
Reaction SMILES: F[C:2](F)(F)[C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:5][CH:4]=1.[CH3:20][O-:21].[Na+].C[OH:24]>>[CH3:20][O:21][C:2]([C:3]1[NH:7][C:6]([C@@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])=[N:5][CH:4]=1)=[O:24]
Reactant: C[O-]
Reactant: CO
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)[nH]1
Agent: [Na+]
Product: COC(=O)c1cnc([C@H](C)NC(=O)OC(C)(C)C)[nH]1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(5-(trifluoromethyl)-1H-imidazol-2-yl)ethylcarbamate (200 mg, 716 μmol) in methanol (6 mL) was added sodium methoxide (77.4 mg, 1.43 mmol). The mixture was heated in microwave at 100° C. for 60 min. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, then washed saturated aqueous sodium carbonate, brine, then dried (sodium sulfate), filtered and concentrated in vacuo to give 2-((S)-1-tert-butoxycarbonylamino-ethyl)-3H-imidazole-4-carboxylic acid methyl ester (154 mg, 80%) as a yellow solid. This was used directly in the next step without further purification. LCMS, [M+H]=270.
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[CH:26]=[CH:25][C:24]=1[C:30]1[C:35]([C:36]2[NH:37][CH:38]=[CH:39][N:40]=2)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44]C2C=CC([N+]([O-])=O)=CN=2)[N:31]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[C:35]([C:36]2[NH:40][CH:39]=[CH:38][N:37]=2)=[CH:34][N:33]=[C:32]([NH:41][CH2:42][CH2:43][NH:44][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[N:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccccc3Cl)n2)nc1

Procedure:
[4-(2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 2-chlorobenzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:13]2=[O:29])=[CH:8][C:7]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O.ClCCl.O>>[CH3:31][O:30][C:7]1[CH:8]=[C:9]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:13]2=[O:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:3]=[O:2]
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1OCC(OC)OC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1OCC=O

Procedure:
A solution of 2-[4-(2,2-dimethoxyethoxy)-3-methoxyphenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one (94 mg) in 10:10:1 TFA/dichloromethane/water (2 mL) was stirred at room temperature for 2 h. The solvent was removed in vacuo. The product with the molecular weight of 409.44 (C23H23NO6) was obtained in this way; MS (ESI): 428 (M+water+H+).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(F)S(O[C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=O)=O>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)cn1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (1.6 g, 4.08 mmol) is coupled to pyridyl triflate 67 (982 mg, 4.08 mmol) using Method A to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[O:4][N:3]=1.[N+](=[CH2:11])=[N-]>CCOCC>[CH3:11][N:3]1[C:2](=[O:1])[C:6]([CH3:7])=[C:5]([CH3:8])[O:4]1
Reactant: Cc1onc(O)c1C
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: Cc1on(C)c(=O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-hydroxy-4,5-dimethylisoxazole (7 g, 62 mmol) in ether (50 mL) was added diazomethane until a persistent yellow colour was obtained. The reaction was stirred for another 30 min at room temperature. The ether was evaporated off and the residue purified by column chromatography on silica gel using ether as eluent. 4 g of the desired material was obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(CC)n(-c2cccc3nc(Oc4c(C)cc(Cl)cc4Cl)n(C)c23)n1
Yield: 78.3 %

Procedure:
A suspension of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole (92 mg, 0.318 mmol), 2,4-dichloro-6-methylphenol (114 mg, 0.643 mmol), potassium carbonate (89 mg, 0.643 mmol) in N,N-dimethylformamide (1.5 ml) was stirred at 90° C. for 5.5 days (2,4-dichloro-6-methylphenol and potassium carbonate were added in three equal portions each over 5.5 days). After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249 mmol, 78.3%) of the title compound as an oil. The oil was crystallized from hexane to give 70 mg (51%) as a pale yellow crystal.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1>ClCCl>[ClH:3].[Cl:3][CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(N2CCOCC2)ncn1
Solvent: ClCCl
Product: Cl
Product: ClCc1cc(N2CCOCC2)ncn1

Procedure:
A solution of 36 ml of thionyl chloride in 30 ml of dichloromethane was added dropwise, at 0° C., to a solution of 3 g of 4-hydroxymethyl-6-morpholinopyrimidine in 30 ml of dichloromethane. The reaction solution was allowed to reach room temperature and was concentrated in vacuo. Addition of diethyl ether resulted in precipitation of 3.2 g of 4-chloromethyl-6-morpholinopyrimidine hydrochloride (melting point 139° C. [decomposition]).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48](F)(F)F)=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([CH3:48])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: c1cc(N2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nn(CC(=O)N2CCN(c3ccncc3)CC2)c(C)c1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d, 2H), 5.41 (s, 2H), 3.83 (m, 2H), 3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=O)[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[H][H].[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:9]([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:15]=1)=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1cccc(OCC(=O)c2ccc3ccccc3c2)c1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OCCc2ccc3ccccc3c2)c1)C(=O)O
Yield: 35.7 %

Procedure:
Palladium hydroxide carbon (50% water content, 180 mg) was added to a solution of N-t-butoxycarbonyl-3-[(2-naphthoyl)methoxy]-L-phenylalanine methyl ester (400 mg, 0.863 mmol) in methanol (13 ml) and the mixture was stirred in hydrogen stream at room temperature for 20 hrs. The catalyst was filtered off and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=7) to give N-t-butoxycarbonyl-3-[2-[2-(5,6,7,8-tetrahydro-naphthyl)]ethoxy]-L-phenylalanine methyl ester (132 mg, 34%) and methyl ester of N-t-butoxycarbonyl-3-[2-(2-naphthyl)ethoxy]-L-phenylalanine (134 mg, 34%) (in turn of elution).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Br:4][CH:5]([CH3:9])[C:6](Br)=[O:7].[C:10](=O)(O)[O-].[Na+].COS(OC)(=O)=O>[OH-].[K+]>[C:2]([N:3]([CH3:10])[C:6](=[O:7])[CH:5]([Br:4])[CH3:9])#[N:1]
Reactant: CC(Br)C(=O)Br
Reactant: N#CN
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Product: CC(Br)C(=O)N(C)C#N
Reaction time: 1 h
Yield: 35.6 %

Procedure:
10.5 g (0.25 mole) of cyanamide are dissolved in 250 ml of 2N potassium hydroxide solution and the solution so obtained is cooled to +10° C. At this temperature 26.5 ml (0.25 mole) of 2-bromopropionyl bromide are added dropwise and the reaction mixture is stirred for one hour at the same temperature. Then 16.8 g (0.2 mole) of sodium bicarbonate are added. 63 g (0.5 mole) of dimethylsulfate are subsequently added dropwise at 20° C. and the reaction mixture is stirred for 4 hours and extracted with methylene chloride. The combined orgnaic phases are dried over sodium sulfate and concentrated by evaporation, affording as residue 27.5 g of crude product. Vacuum distillation of this crude products yields 13.6 g (28.5% of theory) of 2-bromopropionic acid N-cyano-N-methylamide with a boiling point of 45°-47° C. at 0.008 mbar.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[C:5]([F:8])([F:7])[F:6].Cl.O.C(OCC)(=O)C>C1COCC1>[F:6][C:5]([F:7])([F:8])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([OH:3])[CH3:9]
Reactant: COc1ccc(C(C)(O[Si](C)(C)C)C(F)(F)F)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 144 h
Yield: 81.3 %

Procedure:
Trimethyl-[2,2,2-trifluoro-1-(4-methoxy-3-methylphenyl)-1-methylethoxy]silane (711 mg) was dissolved in THF (20 ml) and 1N HCl solution (20 ml) was added. After stirring at room temperature for 6 days, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane→heptane:ethyl acetate 7:3) to obtain the title compound (442 mg). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 1.76 (s, 3H), 2.24 (s, 3H), 3.84 (s, 3H), 6.83 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl.CCOC(C)=O.C(=O)(O)[O-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH3:15])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCCN(C)c1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Example 619, Step 1) (0.54 g, 1.7 mmol) in 20 ml EtOH was added SnCl2 (0.51 g, 2.67 mmol). The mixture was sealed and was heated to 80° C. for 12 h. An additional amount of SnCl2 (0.51 g, 2.67 mmol) was added and heating continued for 12 h. The reaction was cooled to ambient temperature, and was poured into a mixture of EtOAc and saturated aqueous sodium bicarbonate. The mixture was filtered through celite, and the organic layer was removed. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried with Na2SO4, filtered, and concentrated to give a cloudy oil. This material was filtered through silica gel with 90/10/1 dichloromethane/MeOH/conc. NH4OH and concentrated in vacuo to give the title compound as a red oil. MS (ES+): 285.9 (M+H)+. Calc'd for C12H20BrN3: 286.21.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].C(OCC)C>C(O)C.C(O)(C)C>[Cl-:24].[CH2:1]([NH+:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][NH2+:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:24]
Reactant: CC(C)(C)OC(=O)N1CC2CCN(Cc3ccccc3)CC2C1
Reactant: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CC(C)O
Product: [Cl-]
Product: c1ccc(C[NH+]2CCC3C[NH2+]CC3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.355 g of tert-butyl 5-benzylhexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (4.28 mmol) were dissolved in 10 ml of ethanol. To the solution 20 ml of 5 N HCl in isopropanol were added and the obtained mixture was stirred at room temperature for 16 h. After addition of diethyl ether the product precipitated. The product was filtered and after an additional washing with diethyl ether, the product was dried. Additional product was obtained by concentration of the filtrates and crystallization from diethyl ether. Combined amounts of product were 1.07 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>C(#N)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][I:37])[CH:6]=[CH:7][CH:8]=1
Reactant: II
Reactant: COc1cccc(CCCO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COc1cccc(CCCI)c1
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
A magnetically stirred solution of 3-(3-methoxyphenyl)propan-1-ol (62.48 g, 375.9 mmol), triphenylphosphine (128.6 g, 490.4 mmol), and imidazole (35.53 g, 516.7 mmol) in anhydrous acetonitrile (300 mL)/anhydrous diethyl ether (600 mL) at 5° C. was treated portion wise with iodine (136.20 g, 536.6 mmol). The yellow suspension turned orange with the last addition. The suspension was stirred 45 min, filtered, the cake washed with fresh diethyl ether (300 mL), the combined filtrate was concentrated in vacuo to 300 mL and diluted with diethyl ether (200 mL). The resultant organic solution was washed with saturated sodium thiosulfate (2×500 mL), saturated cupric sulfate (2×500 mL), brine (2×500 mL), filtered and concentrated in vacuo. The residue was digested with hexanes (300 mL), filtered and concentrated in vacuo. Kugelrohr distillation (0.1 torr, 120° C.) provided the desired product as a yellow liquid (88.10 g, 85%): 1H NMR (CDCl3) δ 7.20 (t, J=8 Hz, 1 H), 6.81-6.73 (m, 3 H), 3.81 (s, 3 H), 3.17 (t, J=8 Hz, 2 H), 2.70 (t, J=8 Hz, 2 H), 2.14 (quint, J=8 Hz, 2H).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:15][CH:14]=1)[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1ccc(Cc2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1

Procedure:
2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.42 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-(4ethylbenzyl)benzo[b]thiophene (2.7 mmoles, 0.69 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.43 g (45%) of an orange solid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.N1CCCCC1.N1CCCCC1.N(C(O)=O)=NC(O)=O.[CH:34]1([C:37]2[CH:41]=[N:40][N:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][C:49]([F:52])([F:51])[F:50])[C:38]=2[CH2:53][OH:54])[CH2:36][CH2:35]1.[C:55]([O:59][C:60](=[O:70])[NH:61][C:62]1[CH:67]=[CH:66][C:65](O)=[CH:64][C:63]=1[CH3:69])([CH3:58])([CH3:57])[CH3:56]>C1(C)C=CC=CC=1>[C:55]([O:59][C:60](=[O:70])[NH:61][C:62]1[CH:67]=[CH:66][C:65]([O:54][CH2:53][C:38]2[N:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][C:49]([F:52])([F:50])[F:51])[N:40]=[CH:41][C:37]=2[CH:34]2[CH2:35][CH2:36]2)=[CH:64][C:63]=1[CH3:69])([CH3:58])([CH3:57])[CH3:56]
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Reactant: OCc1c(C2CC2)cnn1-c1ccccc1OC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(O)N=NC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Tri-n-butylphosphine (1.9 mL, 7.5 mmol) and azodicarboxylic acid dipiperidine (1.90 g, 7.54 mmol) are added to a mixture of [4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (1.50 g, 5.03 mmol), (4-hydroxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.03 mmol) and toluene at room temperature. After 1 h, additional tri-n-butylphosphine (0.6 mL) is added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is purified by flash chromatography (20 to 50% EtOAc/heptane) to give the title compound (1.92 g, 76%). LC-ES/MS m/e 504.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:51])=[C:6]([CH2:8][N:9]([CH3:50])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:52](Cl)(Cl)=[O:53]>C(#N)C.ClCCl.CN1C(=O)N(C)CCC1>[Br:51][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:50])[C:10](=[O:11])[C@H:12]([NH:24][C:25]1[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=1)[C:31]([N:35]([C:36]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:42])[C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:30][CH:29]=[CH:28]3)[C:13]1[CH:14]=[C:15]([CH3:23])[C:16]([C@@H:19]([CH3:22])[CH2:20][O:21][C:52](=[O:53])[NH:1]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2Br)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
A solution of 1A (1.173 g, 1.538 mmol) in acetonitrile (8 mL), dichloromethane (8 mL) and DMPU (0.6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.837 mL, 1.692 mmol). The mixture was stirred at 0° C. for 15 min. and then bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h (via a syringe pump) into a solution of TEA (2.144 mL, 15.38 mmol) in dichloromethane (400 mL) at 40° C. The yellow solution was stirred for an additional 30 min. Reaction mixture was concentrated, suspended in EtOAc (250 mL), washed with water (2×200 mL), brine (1×100 ml) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by Isco: (40 g) 50-100% EtOAc/hexanes. Fractions were combined and concentrated under reduced pressure to give product as a mixture of diastereomers. The diastereoisomers were separated by chiral HPLC (Chiral OD 10 um 4.6×250 mm; sol. A heptane; sol. B 50% MeOH-50% EtOH) to give 1B (0.200 g, 0.254 mmol, 33.0% yield): MS (ESI) m/z: 788.1 [M+1]+; Purity 95%; 1H NMR: (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=5.50 Hz), 7.68 (1H, d, J=6.05 Hz), 7.60 (1H, d, J=9.34 Hz), 7.51 (1H, d, J=6.05 Hz), 7.46 (1H, d, J=7.70 Hz), 7.40 (1H, d, J=8.24 Hz), 7.27 (1H, dd, J=8.79, 2.20 Hz), 7.22 (1H, s), 6.87 (1H, d, J=2.20 Hz), 6.63 (1H, dd, J=8.52, 2.47 Hz), 5.99 (1H, d, J=2.20 Hz), 5.71 (1H, s), 5.35 (1H, d, J=17.04 Hz), 4.65 (1H, t, J=11.27 Hz), 3.95 (1H, dd, J=10.99, 4.40 Hz), 3.65 (1H, s), 3.44-3.53 (1H, m), 3.34 (3H, s), 2.31 (3H, s), 1.31 (3H, d, J=7.15 Hz), 1.27 (18H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](SC2C=CC=CC=2)[N:3]=1.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([CH:28]2[CH2:30][CH2:29]2)[N:3]=1
Reactant: Br[Mg]C1CC1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(N)nc(C2CC2)c(C#N)c1-c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon, 2-amino-4-(1,3-benzodioxol-5-yl)-6-(phenyl-sulfanyl)-3,5-dicyanopyridine [preparation analogously to J. M. Quintela, J. L. Soto, Anales de Quimica 79, 368–372 (1983)] (100 mg, 0.27 mmol) is dissolved in absolute THF (3 ml). 1,3-Bis(diphenylphosphino)propanedichloronickel(II) (4.4 mg, 0.008 mmol) is added, the color of the solution changing to pink. On slow dropwise addition of cyclopropylmagnesium bromide (1M solution in THF; 0.644 ml, 0.644 mmol), a clear change in color to brown-red can be observed. The solution is heated at 50° C. for 3 hours. After only about 5 minutes, the solution turns green. 1N hydrochloric acid (1 ml) is added and the mixture is then diluted with diethyl ether. Solid sodium carbonate and water are added. The phases are separated and the organic phase is dried over magnesium sulfate, filtered and concentrated. The mixture is separated by silica gel column chromatography (toluene:ethyl acetate=2:1).