Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CC(=O)Cl
Reactant: CCCCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-pentylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (170 mg, 0.57 mmol) and triethylamine (86 μL, 0.86 mmol) in methylene chloride (30 mL) was added dropwise acetyl chloride (41 μL, 0.57 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue crystallized from diethyl ether/hexane. This gave 120 mg (62% yield) of the title compound as white crystals: mp 119-120° C. [α]21D +25° (c 0.97, chloroform); EIMS (70 eV) m/z (relative intensity) 343 (49, M+).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]([CH3:15])[S:6]([C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7].O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:15][N:5]([CH2:4][CH:3]=[O:2])[S:6]([C:9]1[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=1)(=[O:7])=[O:8]
Reactant: COC(CN(C)S(=O)(=O)c1cnn(C)c1)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CN(CC=O)S(=O)(=O)c1cnn(C)c1
Yield: 92 %

Procedure:
Alternatively, 1-methyl-1H-pyrazole-4-sulfonic acid (2,2-dimethoxy-ethyl)-methyl-amide (1.0 equivalents) is suspended in toluene (5 volumes) and water (0.5 volumes) and trifluoroacetic acid is added keeping the temperature below 25° C. The resulting solution is allowed to stir for at least 8 hours below 25° C. and sampled for reaction completion. Once the reaction is deemed complete the solution is concentrated to an oil. The resulting oil is dissolved in brine (7.5 volumes) and water (2.5 volumes). Potassium carbonate is added portion wise to keep the temperature below 25° C. until a pH of 7.5 is achieved. The reaction is then washed with methylene chloride (3×10 volumes) and the combined organic layers are dried with sodium sulfate (200 wt %). The slurry is then filtered and the cake washed with methylene chloride (2×3 volumes). The resulting filtrate is held under vacuum for ≧24 hr., to concentrate the title preparation to a viscous amber oil (92% yield).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[S:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14].C=O.[CH2:30]1N2CN3CN(C2)CN1C3>CN(C)C=O.O>[C:23]([C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=1[OH:27])[CH2:30][N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[S:12])([CH3:26])([CH3:25])[CH3:24]
Reactant: S=c1[nH]nc(-c2ccccc2)o1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(Cn2nc(-c3ccccc3)oc2=S)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
35.6 g of 5-phenyl-1,3,4-oxadiazole-2-thione (0.2 mol), 41.2 g of 2,6-di-tert.-butylphenol (0.2 mol), 6,6 g of paraformaldehyde (0.22mol) and 0.5 g of hexamethylenetetramine in 130 ml of dimethylformamide and 13 ml of water are heated to 110°C for 7 hours, whilst stirring. After cooling, the reaction mixture is stirred into 500 ml of ice water and the product which precipitates is isolated. For purification, the reaction product is repeatedly digested with methanol, filtered off and dried. 3-(3,5-di-t-Butyl-4-hydroxybenzyl)-5-phenyl-1,3,4-oxadiazole-2-thione (stabiliser N0. 6), thus obtained, has a melting point of 166°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:18](O)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1>C(Cl)Cl>[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([NH:38][C:18](=[O:19])[C:17]2[CH:16]=[C:15]([O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:23]=[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:21]=2)=[N:34]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
Oxalyl chloride (7.71 mL, 89.7 mmol) was added dropwise to a suspension of 3,5-dibenzyloxybenzoic acid (20.0 g, 59.8 mmol) in DCM (0.5 L) under argon. The reaction was stirred at RT for 6 hours after which time the volatiles were removed in vacuo. The residue was taken up in DCM (300 mL) and a solution of 1-methyl-1H-pyrazol-3-amine (5.81 g, 59.8 mmol) in DCM (50 mL) was added dropwise. The resulting solution was stirred for 16 hours at RT after which time a precipitate had formed. The solid was isolated by filtration and recrystallised from ethanol to give the title compound as a white solid (14.8 g). 1H NMR δ (d6-DMSO): 3.84 (3H, s), 5.17 (4H, s), 6.59 (1H, d), 6.84 (1H, t), 7.33-7.46 (12H, m), 7.62 (1H, d), 10.83 (1H, s); m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>C1(C)C=CC=CC=1.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][Cl:29])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: C#CCCCCl
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#CCCCCl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis-(triphenylphosphine)palladium(0) (0.2 g, 0.174 mmol), copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) were dissolved in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g, 5.20 mmol) was added via syringe and the mixture stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 mL), extracted with 0.5 N HCl (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield an orange oil. The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane afforded the ester as a white solid (0.96 g, 68%): mp 84.8–85.9° C. 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.33 (d, 1H, J=2.6 Hz), 7.14 (d, 1H, J=2.6 Hz), 5.79 (q, 1H, J=6.7 Hz), 4.37–4.29 (m, 2H), 3.75 (t, 2H, J=6.7 Hz), 2.67 (t, 2H, J=6.7 Hz), 2.11–2.03 (m, 2H,), 1.35 (t, 3H, J=7.2 Hz). FABLRMS m/z 424.1 (M+NH4+). ESHRMS m/z 424.0694 (M+NH4+, Calc'd. 424.0694). Anal. Calc'd. for C18H15Cl2F3O3: C, 53.09; H, 3.71;, Cl, 17.41. Found: C, 53.02; H, 3.90; Cl, 17.63.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3](=O)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:2]([C:3]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:25]([OH:27])=[O:26])[CH:28]=2)[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=1)([CH3:18])([CH3:17])[CH3:1]
Reactant: CC(C)(C)C(=O)CC1C(=O)CCc2ccccc21
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(n1-c1ccc(O)c(C(=O)O)c1)CCc1ccccc1-2

Procedure:
A mixture of 15.2 g. (0.062 mole) of 1-(3,3-dimethyl-2-oxobutyl)-2-tetralone, 9.5 g. (0.062 mole) of 5-aminosalicylic acid, and 50 ml. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours, cooled and filtered. The collected solid was washed with acetic acid and petroleum ether and then recrystallized from acetonitrile to provide 10.4 g. (46%) of off-white crystals, m.p. 258°-260°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][S:14](Cl)(=[O:16])=[O:15])#[N:12].C(NS(CC#N)(=O)=O)C1C=CC=CC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:14]([CH2:13][C:11]#[N:12])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: N#CCS(=O)(=O)Cl
Agent: N#CCS(=O)(=O)NCc1ccccc1
Product: N#CCS(=O)(=O)NCCCc1ccccc1

Procedure:
N-3-Phenyl-n-propyl cyanomethylsulfonamide was prepared with 3-phenyl-n-propylamine and cyanomethylsulfonly chloride under similar conditions as described for N-benzyl cyanomethylsulfonamide (Part A, M40).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(CCCCO)cc1
Reaction time: 6 h
Yield: 94.6 %

Procedure:
Methyl 4-(4-hydroxy-1-butynyl)phenylacetate (10.6 g, 0.0485 mol) was dissolved in methanol (200 mL), then 10% palladium on carbon (1.1 g) was added, and the mixture was stirred under hydrogen (50 psi). After 6 hours, additional 10 % palladium on carbon (1 g) was added, and the mixture was stirred overnight. The catalyst was filtered through celite, the filtrate was concentrated and dried in vacuo to give 10.20 g (94.5%) of methyl 4-(4-hydroxy-1-butyl)phenylacetate as a yellow liquid. FAB-MS m/z=223 (M+H); HRMS calcd for C13H19O3 (M+H) 15 223.1334, found 223.1328.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([CH3:6])=O.C(O)C.O.[NH3:17].[C:18]([NH:21][C:22]1[C:29]([Cl:30])=[CH:28][C:25]([CH:26]=O)=[C:24]([O:31][CH3:32])[CH:23]=1)(=[O:20])[CH3:19]>O1CCOCC1>[OH:1][N:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:6])[N:17]=[C:26]1[C:25]1[CH:28]=[C:29]([Cl:30])[C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][C:24]=1[O:31][CH3:32]
Reactant: N
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C=O
Reactant: CC(=O)C(=NO)c1cccnc1
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(NC(C)=O)c(Cl)cc1-c1nc(C)c(-c2cccnc2)n1O

Procedure:
To a suspension of 1-hydroxyimino-1-(3-pyridyl)acetone (3.3 g) in a mixture of dioxane (80 ml), ethanol (20 ml) and conc. ammonia water (40 ml) was added 4-acetamido-5-chloro-2-methoxybenzaldehyde (4.54 g) and the resultant mixture was stirred at ambient temperature for 3 days. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and 5% hydrochloric acid. The separated aqueous layer was adjusted to pH8.0 with 20% potassium carbonate under stirring and the precipitate was collected by filtration and dried to give 1-hydroxy-2-(4-acetamido-5-chloro-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (3.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:13](=[O:24])[NH:14][C@H:15]1[CH2:21][CH2:20][C@@H:19]([CH3:22])[NH:18][CH2:17][CH:16]1[OH:23])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([N:34]=[C:35]=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([NH:34][C:35]([N:18]1[CH2:17][CH:16]([OH:23])[C@@H:15]([NH:14][C:13](=[O:24])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:25])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:21][CH2:20][C@H:19]1[CH3:22])=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@H](CC(C)C)N=C=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NCC1O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
[(S)-3-Methyl-1-((4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (Example 12a-i, 500 mg, 1.4 mmol) was dissolved in THF (7 ml), then (S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester (180 mg, 1.05 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 1% to 2% MeOH/CH2Cl2) to yield the title compound as a white solid (91%, 506 mg): LC/Electrospray mass spec: M+H+=529.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2cncc(Br)c2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cncc(Br)c2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.3 %

Procedure:
A mixture of 4-bromomethyl-2-(5-bromo-pyridin-3-yl)-thiazole-5-carboxylic acid ethyl ester (880 mg, 2.18 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (552 mg, 2.18 mmol) and potassium carbonate (452 mg, 3.27 mmol) in anhydrous dimethylformamide (8 mL) was stirred at room temperature for 24 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (495 mg): MS: (+) m/z 600.40, 602.20 (M+Na+, 79Br/81Br).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:15]1.[Cl-].[NH4+].C1C[O:29]CC1>CCCCCC.CCOC(C)=O>[OH:29][CH:18]([CH2:17][C:14]1([CH3:13])[CH2:15][CH2:16]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCC1(C)CC1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(O)CC1(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (1.9 mL, 13 mmol) in dry THF (20 mL) at 0° C. under inert atmosphere was added n-butyllithium (5.2 mL of a 2.5 M solution in hexane, 13 mmol) dropwise over a period of 5 min. The solution was cooled to −78 ° C. and ethyl 3-(1-methyl-cyclopropyl)propanoate (1.87 g, 12 mmol) was added dropwise over a period of 5 min. The solution was stirred at −78 ° C. for 1 h at which time (+)-camphorsulfonyloxaziridine (3.5 g, 15 mmol) was added all at once. The resulting suspension was stirred at −78 ° C. for 30 min and then allowed to warm to ambient temperature over 30 min. EtOAc (50 mL) and saturated aqueous ammonium chloride (25 mL) were added and the organic layer was separated and washed with water (20 mL), dried (MgSO4), and filtered. The solvents were removed under reduced pressure and the resulting oily solid was stirred in ether (15 mL) for 30 min. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography using a gradient elution of 10% to 15% EtOAc in hexanes to give ethyl 2-hydroxy-3-(1-methyl-cyclopropyl)propanoate as a colorless liquid. TLC Rf=0.5 (20% EtOAc-hexanes); HPLC RT=2.73 min (Method A); 1H NMR 400 MHz, CDCl3, 4.31 ppm (M, 1H)4.23 ppm (m, 2H), 2.65 ppm (d, J=6.1 Hz, 1H), 1.76 ppm (dd, J=4.2, 14.6 Hz, 1H), 1.54 ppm (dd, J=8.4, 14.6 Hz, 1H), 1.30 (t, J=8 Hz, 3H), 1.14 ppm (s, 3H), 0.42 ppm (m. 1H), 0.30 ppm (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([OH:14])=O)[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[C:20]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)([C:22]1NC=CN=1)=O.NC1C=CC=CN=1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([NH:28][C:27]3[CH:20]=[CH:22][CH:29]=[CH:30][N:31]=3)=[O:14])[N:9]=[CH:10][C:5]2=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Nc1nc(-c2ccco2)c2cnn(CC(=O)O)c2n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Nc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2cnn(CC(=O)Nc3ccccn3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A solution of 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-1-ylacetic acid (200 mg, 0.77 mmol) in DMF (3 mL) was treated with carbonyl diimidazole (125 mg, 0.77 mmol), stirred at room temperature for 2 h, treated with 2-aminopyridine (72 mg, 0.77 mmol), heated to 50° C. for 3 h, cooled and diluted with water. The resulting white solid was filtered, suspended in MeOH, treated with HCl in dioxan (4-M, 1 mL) diluted with diethyl ether and filtered to give the title compound (187 mg, 59%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH:33]3[CH2:36][O:35][CH2:34]3)[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH:33]4[CH2:34][O:35][CH2:36]4)[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=C1c2ccc(Cl)nc2CN1C1COC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4c(n3)CN(C3COC3)C4=O)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (55 mg, 0.176 mmol) and 2-chloro-6-oxetan-3-yl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39.6 mg, 0.176 mmol) as the starting materials.
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br>>[I:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[OH:27]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(C=O)cc(OC)c21
Reactant: COc1ccccc1[Mg]Br
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(C(O)c3ccccc3OC)cc(OC)c21

Procedure:
The title compound is prepared from 4-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde and 2-methoxyphenyl-magnesium bromide as described in example 35.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N([CH2:30][CH3:31])CC)C.[I:32][C:33]1[CH:43]=[CH:42][C:36]([CH2:37][S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.Cl>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([N:17]([S:38]([CH2:37][C:31]3[CH:30]=[CH:43][C:33]([I:32])=[CH:34][CH:35]=3)(=[O:40])=[O:39])[S:38]([CH2:37][C:36]3[CH:42]=[CH:43][C:33]([I:32])=[CH:34][CH:35]=3)(=[O:40])=[O:39])=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)Cc1ccc(I)cc1
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)Cc3ccc(I)cc3)S(=O)(=O)Cc3ccc(I)cc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Yield: 31.8 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (681 mg, 2.13 mmol) was dissolved in anhydrous dichloromethane (40 mL), and to this was added triethylamine (1.20 mL, 8.53 mmol), and cooled to 0° C. To this was added 4-iodobenzylsulfonyl chloride (prepared by the method described in Liu, S. et al., Org. Lett., 3, 1571-1574 (2001)) (2.70 g, 8.53 mmol), and heated to reflux for 26 h after warming to room temperature. After cooling to room temperature, to this were added 2 M hydrochloric acid and dichloromethane and after separating the aqueous layer and organic layer, the organic layer was washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (100 g, n-hexane/ethyl acetate=4/1), to the obtained product was added dichloromethane, and filtered to remove insolubles. After this procedure was repeated 5 times, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was recrystallized from ethyl acetate to give 5-(4-acetoxyphenyl)-3-benzyl-2-bis(4-iodobenzylsulfonyl)aminopyrazine (c-46) as a colorless solid (597 mg, 31.8%). Rf=0.21 (n-hexane/ethyl acetate=4/1). Mp. 166-167° C. 1H NMR. (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.89 (s, 2H), 5.00 (d, 2H, J=13.6 Hz), 5.19 (d, 2H, J=13.6 Hz), 7.11-7.17 (AA′BB′, 2H), 7.19-7.34 (m, 9H), 7.78-7.83 (AA′BB′, 4H), 8.07-8.15 (AA′BB′, 2H), 9.19 (s, 1H). 13C NMR (67.8 MHz, DMSO-d6) δ 20.9, 37.5, 60.5 (2C), 96.3, 126.4, 126.5 (2C), 128.1 (2C), 128.5 (2C), 129.5 (2C), 132.0, 133.6 (4C), 137.4, 137.7 (4C), 139.2, 140.9, 151.2, 152.5, 155.5, 168.9. IR (KBr, cm−1) 519, 575, 627, 704, 775, 835, 912, 1013, 1057, 1159, 1200, 1254, 1356, 1377, 1483, 1601, 1757. Anal. Calcd. For C33H27I2N3O6S2: C, 45.06; H, 3.09; N, 4.78. Found: C, 45.18; H, 3.24; N, 4.78.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NC(=O)C1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: NC(=O)C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid amide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid amide following General Procedure B.