Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:39]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:1]1([N:7]([CH3:39])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCCCNS(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound (69.5 mg) obtained in Example 102-5 was treated with an anion-exchange resin (Amberlite IRA-410), and the treated product was dissolved in anhydrous methanol (2.7 ml). The solution was added with a 36% formaldehyde aqueous solution (0.025 ml). Subsequently, the solution was added with sodium cyanoborohydride (20.7 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 20 hours. After the reaction, the solution was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (34.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH:4]([CH:5](OC(=O)C)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]=1[CH3:33])=[O:18].C(OCC)C.CCCCC>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:34])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:22]=1[CH3:33])=[O:18]
Reactant: CC(=O)OC(C1C(C(=O)OCc2cccc(-c3ccccc3)c2C)C1(C)C)C(Cl)(Cl)C(F)(F)F
Agent: [Zn]
Solvent: CCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(COC(=O)C2C(C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a solution of 38.4 mg (0.074 mmol) of the stereoisomer [RF 0.39 (CH2Cl2 /hexane=1/1)] of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-acetoxy-2,2-dichloro-3,3,3-trifluoro-propyl)cyclopropanecarboxylate obtained in Example 11 and dissolved in 0.3 ml of DMF, 6 mg of zinc powder was added, and the mixture was stirred at 60° C. for 2.5 hours. After an addition of 2 ml of diethyl ether and 2 ml of pentane to the mixture, the inorganic salt was filtered off through a silica gel short column. The silica gel was washed with diethyl ether, and the organic layers were combined and concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 29.8 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:24]3[N:25]=[C:26]([NH2:42])[C:27]4[N:28]=[CH:29][N:30]([C:40]=4[N:41]=3)[C@@H:31]3[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]3[OH:33])[CH2:9][CH2:8]2)=[O:11])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: C#CCC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-10-021. 4-nitrobenzyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-109 (0.743 g, 2.458 mmol) was added to a solution of 2-iodoadenosine (0.658 g, 1.674 mmol) according to general procedure 2. Yield: 0.694 g, 42%. 1H NMR (CD3OD) δ 8.29 (s, 1H), 8.18-7.56 (2×d, 4H), 5.94 (d, 1H), 5.23 (s, 2H), 4.69 (m, 2H), 4.31-4.14 (2×m, 3H), 3.84-3.74 (2×d, 2H), 3.10-2.90 (bs, 4H), 2.44 (d, 5H), 1.91-1.40 (2×m, 5H). m/z MH+=568.10. HPLC rt=5.8 min.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH:30]C(=O)C(F)(F)F)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1>CO>[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:20][C@H:21]([OH:37])[C@@H:22]([NH2:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
55 ml of a 1N K2CO3 solution are added dropwise to 3.12 9 (5.5 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S) -(trifluoroacetyl)amino-6-phenyl-2-azahexane in 55 ml of methanol and the mixture is stirred at 70° C. for 9 hours. The mixture is cooled and ≈30 ml of methanol are evaporated off; methylene chloride and water are added and the aqueous phase is separated off and extracted with methylene chloride; the organic phases are washed with water, dried (Na2SO4) and concentrated by evaporation, yielding the title compound: HPLC20-100 : tRet =11.9; FAB MS (M+H)+ =469.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:10]2[CH2:11][CH:12]=[C:13]([CH2:14][OH:15])[C@H:9]2[C@H:8]([OH:16])[O:7][CH:6]=1)=[O:4].FB(F)F.[CH2:21](OCC)C.C(=O)(O)[O-].[Na+]>CO>[OH:15][CH2:14][C:13]1[C@@H:9]2[C@@H:10]([C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][O:7][CH:8]2[O:16][CH3:21])[CH2:11][CH:12]=1
Reactant: COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=COC(OC)[C@@H]2C(CO)=CC[C@H]12
Reaction time: 3 h

Procedure:
Genipin (5 g, 22.1 mmol) was dissolved with 250 ml of methanol and catalytic amount of trifluoroboron diethylether was added, and stirred for 3 hours, then saturated sodium bicarbonate solution was added to finish the reaction. Under reduce pressure, methanol was removed and extracted with ethylacetate, and dried, filtered and concentrated with anhydous magnesium sulfate. Oily phase of methyl (3aS,7aS)-1-hydroxymethyl-7-methoxy-3,7,3a,7a-tetrahydro-6-oxaindene-4-carboxylate (5.26 g, 7S:7R=1:3) was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2].Cl.[CH3:33][NH:34][CH3:35].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:34]([CH3:35])[CH3:33])=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCl)c(F)c3)oc2c1F
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CN(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-(chloroacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (2.02 g, 4.44 mmol) in dimethylformamide (50 mL) were added dimethylamine hydrochloride (1.81 g, 22.2 mmol) and diisopropylethylamine (3.90 mL, 22.4 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added thereto, and the crystals precipitated were collected by filtration to afford compound 1f (1.97 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([NH2:30])=[NH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: COc1ccccc1NC(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: COc1ccccc1Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(2-methoxyphenyl)guanidine were converted to I-16 (39%): HRMS Calcd. for C11H11ClN4O2: 367.0961, Found 367.0947.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:9]([C:10]1[CH:15]=[N:14][CH:13]=[N:12][CH:11]=1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: BrCc1ccccc1
Product: N#Cc1ccc(N(Cc2ccccc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and benzyl bromide
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:26]([C:25]3[C:24]([F:23])=[N:32][CH:31]=[CH:30][CH:29]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: O=C(Cl)c1cccnc1F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1ncccc1-c1nc2cc(Br)ccn2n1
Yield: 70.7 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.2 g, 5.67 mmol) and 2-fluoronicotinoyl chloride (1.81 ml, 11.3 mmol) as starting materials. The reaction affords 7-bromo-2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.175 g, 70.8%) as light brown solid. MS: m/z=294.9 (M+H+).
Reaction SMILES: C[C:2]1[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:4]([CH:8]=[CH:9][N:10]=1)C(O)=O.[CH3:23][Mg]I.CC[O:28][CH2:29][CH3:30]>O1CCCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([C:3]3[CH:2]=[N:10][CH:9]=[CH:8][C:4]=3[C:29]([OH:28])([CH3:30])[CH3:23])[S:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: C[Mg]I
Reactant: Cc1nccc(C(=O)O)c1-c1nc(-c2ccc(Cl)cc2)cs1
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccncc1-c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (141) (857 mg, 2.5 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) and a 2M solution (3 ml, 6.0 mmol) of MeMgI in ether was added under ice-cooling. The reaction mixture was stirred at room temperature for one hr.
Reaction SMILES: CC1[N:3]([C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][N:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:6][CH2:5][CH2:4][NH:3][C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Reactant: Clc1cccc([C@@H]2CO2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccncc1-c1cccc(NCCNC[C@H](O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
A solution of methyl 3-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]isonicotinate (0.25 g) and (R)-3-chlorostyrene oxide (0.13 g) in anhydrous toluene (2 ml) was heated at reflux (ca. 110° C.) for 18 h. The mixture was cooled to ca. 50° C., 1M sodium hydroxide solution (4.8 ml) and methanol (3 ml) were added over 5-10 min. The apparatus was configured to distill out 4 ml of solvents under atmospheric pressure. The homogeneous mixture obtained was heated at reflux for 2 h. The mixture was cooled to <50° C., and concentrated hydrochloric acid (36%, 0.3 ml) was added dropwise to adjust pH to 7. The aqueous solution was loaded on to silica gel column and eluted with a mixture of dichloromethane and methanol (8/2, v/v). The product was isolated as 0.2 g (57%) of hygroscopic brown solid.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=4)[NH:23][C:19]=3[CH:20]=[N:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:36]([C:38]1[NH:42][C:41](C=O)=[C:40]([CH3:45])[N:39]=1)[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[Pd]>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[NH:25][C:18]3[C:17]([N:14]4[CH2:15][CH2:16][N:11]([CH2:9][C:41]5[NH:42][C:38]([CH2:36][CH3:37])=[N:39][C:40]=5[CH3:45])[CH2:12][CH2:13]4)=[CH:22][N:21]=[CH:20][C:19]=3[N:23]=2)=[CH:27][CH:28]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(C(=O)OCc5ccccc5)CC4)cncc3[nH]2)cc1
Reactant: CCc1nc(C)c(C=O)[nH]1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(C)c(CN2CCN(c3cncc4nc(-c5ccc(C(C)(C)C)cc5)[nH]c34)CC2)[nH]1
Reaction time: 12 h
Yield: 34.6 %

Procedure:
4-[2-(4-tert-Butyl-phenyl)-3H-imidazo[4,5-c]pyridin-7-yl]-piperazine-1-carboxylic acid benzyl ester 7 (12 mg, 0.026 mmol) was dissolved in THF (2 ml) with 10% Pd/C (10 mg) and allowed to stir under a hydrogen atmosphere for 12 hours. The reaction was judged complete by MS. 2-Ethyl-5-methyl-3H-imidazole-4-carbaldehyde 8 (7 mg, 0.05 mmol) and sodium triacetoxyborohydride (15 mg. 0.072 mmol) were added, and the reaction was allowed to stir for 12 hours. It was judged complete by MS, and the crude was purified by HPLC (Method E) to yield the title product 9 (4 mg (25%), 0.009 mmol). 1H NMR (CD3OD-d4): δ 8.58 (s, 1H), 8.12 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 3.93 (m, 5H), 3.25 (s, 3H), 3.05 (m, 3H), 2.79 (q, J=7.4 Hz, 2H), 1.35 (s, 9H). MS (ESI-POS): [M+H]+=458; MS (ESI-NEG):[M−H]−=456.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14]N.[N:16]1C=CC=[CH:18][CH:17]=1>>[CH3:18][C:17]1[N:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[CH:7][C:2]2=[N:14][N:16]=1
Reactant: NN
Reactant: Clc1cc(-c2ccncc2)ccn1
Reactant: c1ccncc1
Product: Cc1nnc2cc(-c3ccncc3)ccn12
Reaction time: 8 h

Procedure:
A mixture of 1.3 g of 2-chloro-4,4'-bipyridine and 6.5 ml of anhydrous hydrazine in 40 ml of dry pyridine was refluxed for 24 hours under argon and then concentrated. The residue was dissolved in methylene chloride, treated with activated carbon and the solvent was removed giving an oil which was crystallized from ether-hexane-methylene chloride. A 1.3 g portion of these crystals of 2-hydrazino-4,4'-bipyridine was combined with 50 ml of triethyl orthoacetate and heated on a steam bath for 1 hour. After standing overnight, hexane was added and after further standing, crystals separated. These crystals were collected and recrystallized from acetonehexane, giving the desired product as off-white crystals, mp 223°-226° C.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1cccn1C
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccn3C)nc(=O)c1-2
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Sodium spheres (1.0 g, 43.5 mmol) were dissolved in ethanol (50 mL) at reflux and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.2 g, 10 mmol), followed by methyl 1-methylpyrrole-2-acetate (3.06 g, 20 mmol) in ethanol (30 mL) were added. The reaction mixture was refluxed under argon overnight, cooled to room temperature and evaporated to dryness. The residue was dissolved in water, the solution was cooled and the resulting solid was collected by filtration to afford recovered starting material. The filtrate was chilled, a solid formed which was collected by filtration, slurried with water and acidified with 2N HCl. The mixture was cooled and the product was collected by filtration and dried at 110° C. in vacuo to afford 1.2 g of 1-cyclopentyl-3-ethyl-6-(1-methyl-2-pyrrolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 214.5-216.5° C. Additional product (0.6 g) was also obtained by acidifying the filtrate with acetic acid, collecting the product by filtration and recrystallizing it from ethyl acetate.
Reaction SMILES: C(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)(=[O:3])C.C(#N)C.ON1C(=O)CCC1=O.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:3]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C

Procedure:
N-Acetyl-L-tyrosine (1.68 g, 7.53 mmol) was taken up in 94 mL of ethyl acetate/26 mL of acetonitrile and stirred at room temperature. N-Hydroxysuccinimide (NHS, 0.87 g, 7.56 mmol) was added and the resulting solution cooled to 0° C. under N2 (g) in an ice-water bath. To the cold, stirring solution was then added dicyclohexylcarbodiimide (DCC, 1.55 g, 7.52 mmol) predissolved in 3 mL of ethyl acetate. The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight with continued stirring. The insoluble dicyclohexylurea (DCU) was removed by filtration and the resulting filtrate concentrated to a solid residue under reduced pressure. Trituration of this residue with warm ethyl acetate and subsequent storage at 4° C. then afforded a white solid. This was isolated by vacuum filtration, washed with cold ethyl acetate and dried in vacuo to yield the product in greater than theoretical yield (due to contamination with residual DCU). 1H-NMR (300 MHz, CDCl3): δ 2.00 (s, 3H); 2.87 (s, 4H); 3.22 (m, 2H); 4.05 (m, 1H); 5.80 (d, 1H, J=7.2 Hz); 6.96 (AB quartet, 4H, J=8.4 Hz).
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:33])(=O)C>C(OCC)(=O)C.CO>[ClH:33].[C:17]1([CH2:16][O:15][C:11]2[CH:10]=[C:9]([C@@H:6]3[NH:5][C@H:4]([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]3)[CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3)c2)CC[C@H]1C(N)=O
Reactant: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: NC(=O)[C@@H]1CC[C@H](c2cccc(OCc3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-{3-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D54, 142 mg, 0.358 mmol) in a mixture of ethyl acetate (2.3 ml) and methanol (0.23 ml) was added acetyl chloride (64 μl, 2.5 eq) at 0° C. The mixture was shaken for 1.5 h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (71 mg, 60%); Rt (HPLC): 3.51 min. MS: (ES/+) m/z: 297 [MH+], C18H20N2O2 requires 296; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.52 (br. s., 1H), 8.41 (br. s., 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.31-7.50 (m, 6H), 7.26 (t, 1H), 7.10 (d, 1H), 7.06 (dd, 1H), 5.13 (s, 2H), 4.62 (dd, 1H), 4.32 (dd, 1H), 2.24-2.44 (m, 2H), 2.09-2.23 (m, 1H), 1.93-2.09 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:27][C:28]1[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:11]3[C:15]4=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]4[N:13]=[C:12]3[CH2:22][CH3:23])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)#[N:35]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2[nH]ccc2c1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2Cc2ccccc2C#N)c1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of the product of Example 2, Step A, (75 mg, 0.25 mmol) in 3 mL of DMF was added 11 mg (0.27 mmol, 1.1 eq) of 60% NaH followed by α-bromo-o-tolunitrile (58 mg, 0.30 mmol, 1.2 eq). The mixture was stirred for 16 hours and then concentrated in vacuo. The resultant oil was flash chromatographed with 1:1 hexane/ethyl acetate to yield the titled compound (98 mg, 95%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[C:13](=[CH:18][CH:19]=1)[C:14]([O:16][CH3:17])=[O:15])(OCC)=O)C.[CH2:24]([C:26]1([C:31]2[S:35][C:34]([CH:36]=O)=[CH:33][CH:32]=2)[O:30][CH2:29][CH2:28][O:27]1)[CH3:25].CC(C)([O-])C.[K+]>C1COCC1>[CH2:24]([C:26]1([C:31]2[S:35][C:34](/[CH:36]=[CH:9]/[C:10]3[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[C:13](=[CH:18][CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:33][CH:32]=2)[O:27][CH2:28][CH2:29][O:30]1)[CH3:25]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Reactant: CCC1(c2ccc(C=O)s2)OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1(c2ccc(/C=C/c3ccc(C(=O)OC)c(C(=O)OC)c3)s2)OCCO1
Reaction time: 24 h

Procedure:
18.5 g (53.7 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)phthalate and 9.5 g (44.7 mmol) of 5-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-2-carbaldehyde (described in Example 6(b)) are dissolved in 200 mL of anhydrous THF. 6.02 g (53.7 mmol) of potassium tert-butoxide are added and the mixture is stirred for 24 h. After the usual treatment and chromatography on silica gel (eluent: 8 heptane/2 ethyl acetate), the desired product is obtained in the form of a yellow oil (m=9.53 g, Y=53%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.Cl[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]>C1COCC1>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)cc2)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of (4-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)phenyl)methanol (Ito, K. et al., WO 2010/067131) (8.50 g, 35.0 mmol) and 1H-imidazole (2.71 g, 39.8 mmol) in dry THF (100 mL) under N2 was added chlorotriisopropylsilane (8.16 mL, 38.1 mmol) and the reaction mixture maintained at RT for 5 days. The resulting mixture was evaporated in vacuo and the residue was partitioned between EtOAc (250 mL) and water (100 mL). The organic layer was separated and was washed with (water (100 mL) and brine (80 mL) and then dried and evaporated in vacuo to afford the title compound, Intermediate A12 as a dark red solid (14.6 g, 97%); Rt 3.26 min (Method 2); m/z 402 (M+H)+, (ES+).