Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C@H:4]1[C@H:6]([CH:7]=[C:8]([Cl:13])[C:9]([F:12])([F:11])[F:10])[C:5]1([CH3:15])[CH3:14])=[O:3].N1C=CC=CC=1.[C:22]([CH:24]([OH:38])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)#[N:23]>O>[Cl:13][C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C@@H:6]1[C@H:4]([C:2]([O:38][CH:24]([C:22]#[N:23])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:26]=2)=[O:3])[C:5]1([CH3:15])[CH3:14]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the residue of (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane (obtained in Example 18) was added a mixture of pyridine (0.12 g) and (+)-α-cyano-3-phenoxybenzyl alcohol (0.33 g) and the mixture thus obtained was stirred for a period of 16 hours at the ambient temperature. Water (20 ml) was added and the mixture extracted with diethyl ether (3×10 ml). The combined extracts were washed with water, saturated sodium bicarbonate solution, and water and dried over anhydrous sodium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was subjected to preparative thick-layer chromatography, using 2 mm thick silica on glass with chloroform as eluent, to yield (+)-α-cyano-3-phenoxybenzyl (+)-cis-3-(2-chloro3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (Rf 0.52), and the corresponding trans isomers (Rf 0.42), each containing about 90-95% of the Z-isomer. Spectral data : infra red (CHCl3) 1740, 1660, 1590, 1480, 1460 cm-1 ; n.m.r. (CCl4): 6.90-7.50 τ, 1.60-2.70 τ, 1.50-1.00 96 , and specific peaks at 6.3 τ(benzylic H), 6.85, 6.50, 6.11 and 5.84 τ (vinylic H) tentatively assigned to the Z-cis, E-cis, Z-trans and E-trans isomers respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.C(NC1C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[C:8](=[N+:35]=[N-:36])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)c1sccc1Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1sccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl 3-(3-chloro-2-thienyl)-3-oxopropanoate (1.26 g, 5.42 mmol) was dissolved in anhydrous acetonitrile (10 mL), treated with triethylamine (0.63 mL, 6.2 mmol, 1.15 equiv) and cooled to 0° C. To the mixture was added 4-acetamidobenzenesulfonyl azide (1.43 g, 6.0 mmol, 1.1 equiv) and after 10 minutes at 0° C., the mixture was warmed to ambient temperature. To the mixture, additional acetonitrile (20 mL) was added and the mixture was stirred at ambient temperature for an additional 45 minutes. The mixture was treated with sodium hydroxide (10 mL, 1 N aqueous), sodium carbonate (25 mL, aqueous saturated) and water (75 mL) and then extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[NH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[C:9]([CH:8]=1)=[N:22][N:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:13]=2[CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#CC2CC2)c(Cl)c1
Reactant: NNc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)c1ccc2c(CC3CC3)n(-c3ccncc3)nc2c1
Yield: 41.8 %

Procedure:
The reaction was performed according to example 1 using 138.4 mg 3-chloro-4-cyclopropylethynyl-benzoic acid tert-butyl ester, 101.9 mg 4-hydrazinopyridine hydrochloride (1.4 equiv.) and 456.2 mg Cs2CO3 (2.8 equiv.) with a reaction time of 4 hours at 110° C. This afforded 73.0 mg (42%) of the title compound. 1H-NMR (DMSO-d6) δ 0.14-0.18 (m, 2H), 0.40-0.45 (m, 2H), 0.91-1.00 (m, 1H), 1.59 (s, 9H), 3.16 (d, 2H, J=6.8 Hz), 7.54 (dd, 1H, J=8.9, 1.3 Hz), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.99 (dd, 1H, J=8.9, 0.8 Hz), 8.85 (dd, 2H, J=4.5, 1.6 Hz); HRMS (FAB): Calculated for C21H24N3O2 (M+H+) 350.1869, found 350.1864.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH2:11].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CO[C:48](=O)[C:49]1[CH:54]=[CH:53][C:52](Cl)=[CH:51][C:50]=1[NH:56][C:57]([CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)=O>CN(C=O)C>[CH2:50]([N:56]1[C:3](=[O:12])[C:4]2[C:5](=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=2)[N:11]=[C:57]1[CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][N:60]1[C:65](=[O:73])[C:66]1[CH:71]=[CH:70][C:69]([CH3:72])=[CH:68][CH:67]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:48]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C1CCCCN1C(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Yield: 21 %

Procedure:
In an ice bath at −15° C., pure compound of Formula 202 (7.2 g, 29 mmol) was combined with 2-amino-4-chloro-benzoic acid methyl ester (4.5 g, 24 mmol), PyBroP (2.3 g, 4.9 mmol) and diisopropylethylamine (0.95 mL, 5.4 mmol) in DMF (30 mL). The resulting mixture was stirred ovemight, allowing the temperature to rise to room temperature with the bath. The solution was concentrated under vacuum and the residue partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (3×100 mL) and concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 40% ethyl acetate/hexanes as eluent to give 2.66 g (21% yield) of the desired product of Formula 203, 4-chloro-2-{[1-(4-methyl-benzoyl)-piperidine-2-carbonyl]amino}-benzoic acid methyl ester, as a crystalline solid. LRMS (MH+) m/z 472.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)[C:24]1=[S:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(N=C=S)cc1
Reactant: O=C(O)CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(N2C(=O)CN(Cc3ccccc3)C2=S)cc1
Yield: 75.4 %

Procedure:
A mixture of N-benzyl glycine (8.7 g), 4-n-butylphenyl-isothiocyanate (8.55 g), triethyl amine (5.5 g) and chloroform (150 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and water (2×200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (11.4 g) as an off-white solid, m.p. 149°-151° C. Anal. Calcd. for. C20H22N2O S: C, 70.97; H, 6.55; N, 8.28. Found: C, 70.81; H, 6.76; N, 8.32. Mass spectrum (EI, M.+) m/z 338.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:32]2[CH:33]=[CH:34][NH:30][N:31]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc[nH]n3)c2F)c1
Reaction time: 8 h
Yield: 49.4 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 1H-pyrazole-3-carboxylic acid (9.01 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.016 g, 50%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.11 (br. s., 1H), 7.79 (d, 1H), 7.62 (t, 1H), 7.36-7.46 (m, 4H), 6.75 (d, 1H), 4.59-4.69 (m, 2 H). LCMS m/z 404.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(N[C@H](C([O:22][CH2:23][C@H:24]([CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:25][N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][C:29]([NH2:36])=[N:28][C:27]1=2)=O)C(C)C)(OC(C)(C)C)=O>>[OH:22][CH2:23][C@H:24]([CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:25][N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][C:29]([NH2:36])=[N:28][C:27]1=2.[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h

Procedure:
Chilled trifluoroacetic acid (2.0 g) was added to (R)-9-[2-(N-Boc-L-valyloxymethyl)-4-(stearoyloxy)butyl]guanine (180 mg; 0.25 mmol) and the solution kept at room temperature for 1 h, evaporated to a small volume, and lyophilized repeatedly with dioxane until a white amorphous powder was obtained. The yield of title compound, obtained as the trifluoracetate salt, was quantitative.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:23][C:24]([F:35])([F:34])[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)=[O:26]>O.C(OCC)(=O)C>[C:10]1([CH2:9][CH2:8][CH2:7][NH:33][CH:30]2[CH2:29][CH2:28][N:27]([C:25](=[O:26])[C:24]([F:23])([F:34])[F:35])[CH2:32][CH2:31]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N1CCC(NCCCc2ccccc2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.38 mL of (3-bromopropyl)benzene, 0.76 g of potassium carbonate and 0.64 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thereto were further added 2 mL of N,N-dimethylformamide, 0.40 g of 1-(trifluoroacetyl)piperidine-4-amine dihydrochloride and 0.60 g of potassium carbonate, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.99 g of a yellow oily substance, N-(3-phenylpropyl)-1-(trifluoroacetyl)piperidine-4-amine. (2) To 3 mL of a dichloromethane solution containing 0.99 g of N-(3-phenylpropyl)-1-(trifluoroacetyl)piperidine-4-amine, 0.82 g of di-tert-butyl dicarbonate was added under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Thereto was further added 0.20 g of di-tert-butyl dicarbonate, and the mixture was left to stand at room temperature overnight. The solvent was removed under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 0.63 g of a colorless oily substance, tert-butyl (3-phenylpropyl) (1-(trifluoroacetyl)piperidin-4-yl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH3:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C.[H][H]>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH3:17])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)c(C)n1
Solvent: CCO
Product: Cc1cn(-c2ccc(N)c(C)c2)c(C)n1

Procedure:
The following compound was prepared similarly to Preparation 56, using 1-(3-methyl-4-nitrophenyl)-2,4-dimethylimidazole and 5% palladised charcoal/H2 as the starting materials and ethanol as the solvent. The crude solid melted at 78°-82°. Recrystallisation from toluene gave 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole, m.p. 118°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([CH2:23][CH3:24])[C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][CH2:12]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:59]([C:61]1[CH:62]=[CH:63][C:64]([N:67]2[CH2:72][CH2:71][CH:70]([C:73](O)=[O:74])[CH2:69][CH2:68]2)=[N:65][CH:66]=1)#[N:60]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14][N:13]([C:73]([CH:70]3[CH2:69][CH2:68][N:67]([C:64]4[CH:63]=[CH:62][C:61]([C:59]#[N:60])=[CH:66][N:65]=4)[CH2:72][CH2:71]3)=[O:74])[CH2:12]2)[CH2:23][CH3:24])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A mixture of 125 mg (0.36 mmol) ethyl-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid 4-fluoro-phenyl ester, 137 mg (0.36 mmol) HATU, 63 uL (0.36 mmol) DIPEA and 69.4 mg (0.3 mmol) 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in 4 mL DMF was shaken for 2 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 106 mg (63%) of the title compound as off-white solid. MS m/e: 560.2 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH2:13])=[O:11])=[CH:5][C:4]=1[O:16][CH3:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH:13][C:26](=[S:27])[NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:11])=[CH:5][C:4]=1[O:16][CH3:17]
Reactant: COc1cc(C(C)(C)C(=O)NN)ccc1Cl
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanehydrazide hydrochloride (6.88 g, 0.02 mol) and 4-fluorophenylisothiocyanate (3.96 g, 0.03 mol, 1.05 eq.) in DCM (500 mL) at 0° C. was added Et3N (7 mL, 1.29 mol, 2.0 eq.) and the resulting solution was stirred for 1.5 h at room temperature. The reaction mixture was washed with 1M HCl, satd NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with DCM/Et2O, collected by filtration and dried to give 2-(2-(4-Chloro-3-methoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)hydrazine carbothioamide (8.13 g, 83% as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32-7.30 (d, 1H), 7.25-7.22 (m, 2H), 7.01-7.05 (t, 2H), 6.95-6.94 (d, 1H), 6.93-6.90 (dd, 1H), 3.88 (s, 3H), 1.64 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.49 min.; [M+H]+: 443.14 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54](CO)=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][C:54]2[CH:57]=[CH:58][C:51]([C:50]([F:60])([F:59])[F:49])=[CH:52][CH:53]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 61 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (112 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-trifluoromethylbenzyl alcohol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:33]([O:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48])[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][CH2:36][O:35][CH2:33][CH3:34])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(F)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(4-fluoro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[l-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([OH:25])=O)=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:26]#[N:27].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:17][CH2:18]3)[C:14]3[C:19]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:25])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:26]#[N:27]
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)c2n1C1CC1
Reactant: NC1CCCC1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)NC3CCCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylic acid (132 mg, 0.36 mmol) in DMF (3 mL) was added cyclopentanamine (0.10 mL, 1.0 mmol), N-ethyl-N-isopropylpropan-2-amine (0.060 mL, 0.36 mmol) and 1 h-benzotriazol-1-yl-oxytripyrrolidinophosphonium (190 mg, 0.36 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent gave 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-cyclopentyl-1-cyclopropyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, MeOH-d4) δ 8.03 (1H, s), 7.70 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.28 (1H, t, J=8.0 Hz), 6.03 (1H, q, J=8.0 Hz), 4.45-4.38 (1H, m), 4.11 (1H, dd, J=8.0, 4.0 Hz), 3.53-3.44 (1H, m), 2.15-2.05 (2H, m), 1.88-1.78 (2H, m), 1.75-1.60 (4H, m), 1.38-1.10 (3H, m), 1.00-0.92 (1H, m); LC-MS (ESI) m/z 431.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([Si](C)(C)C)=[CH:30][C:29]=1[F:38])=[O:4].[I:39]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([I:39])=[CH:30][C:29]=1[F:38])=[O:4]
Reactant: ClI
Reactant: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (1.78 g, 3.20 mmol) in DCM (35 mL) was added iodine monochloride (1M in DCM, 6.40 mL) dropwise over 10 minutes. The mixture was stirred for 1 hour then quenched by the addition of saturated sodium thiosulphate solution. The solution was partitioned between ethyl acetate and an saturated solution of sodium hydrogencarbonate. The organic layer was separated, washed with water then brine, dried (Na2SO4), filtered and evaporated to give a residue. The residue was purified by flash chromatography (Si-PPC, cyclohexane:ethylacetate, gradient 100:0 to 0:100) to provide the title compound as a yellow oil (1.52 g, 79%). LCMS (method B): RT=3.47 min, M+H+=612.