Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]=1[NH2:8].[CH:17](O)=O>>[O:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15]
Reactant: Nc1c(N)n(CC2CCCO2)c(=S)[nH]c1=O
Reactant: O=CO
Product: O=c1[nH]c(=S)n(CC2CCCO2)c2nc[nH]c12
Temperature: 70 °C
Yield: 87 %

Procedure:
5,6-Diamino-1-(2-tetrahydrofuryl-methyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.25 g, 1.0 mmol) was dissolved in formic acid (1 mL) and heated at 70° C. for 0.5 h. After a few minutes a pink solid formed in the solution. The excess of formic acid was evaporated off and the resulting solid dissolved in 10% sodium hydroxide solution (4 mL). This solution was heated at 70° C. for 40 minutes, then neutralized with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried, giving pure product (0.23 g, 87%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[CH2:22][C:21]3=[O:29])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:42])[C:39]([Cl:41])=[O:40]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:41].[CH3:37][N:38]([CH3:42])[C:39](=[O:40])[O:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:21](=[O:29])[CH2:22][C:23]([CH3:27])([CH3:28])[CH2:24][C:25]3=[O:26])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)N(CCCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCN1C(=O)CC(C)(C)CC1=O
Product: Cl
Reaction time: 8 h
Yield: 80.4 %

Procedure:
5.0 g (12.54 mmol) of rac-cis-1-[5-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)pentyl]-4,4-dimethylpiperidine-2,6-dione were dissolved in 250 ml of toluene, treated with 2.67 g (3.7 ml; 26.4 mmol) of triethylamine, 1.62 g (1.4 ml, 15.4 mmol) of dimethylcarbamoyl chloride and 250 mg of 4-dimethylaminopyridine and stirred overnight in an oil bath at an oil bath temperature of 110°. After cooling the organic phase was washed in succession with water, sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated. The brown oil obtained (6.3 g) was chromatographed over a 30-fold amount of silica gel with methylene chloride/ethyl acetate 1:1 and the purified base (5.9 g of pale yellow oil) was converted into the hydrochloride in the usual manner. After crystallization from ethyl acetate/ether there were obtained 5.1 g (80%) of rac-cis-3-[5-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)pentyl]-2,3,3a, 4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride in the form of yellowish crystals of m.p. 133°-135° (dec.).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([NH:14][C:15](=[O:29])[CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][S:18]C(=O)C)[CH2:5][S:6]SC[C@H](N)C(O)=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].SC[C@H]([C@@H](CS)O)O.O>CO>[CH2:22]([CH:16]([CH2:17][SH:18])[C:15]([NH:14][C@H:4]([C:3]([OH:30])=[O:2])[CH2:5][SH:6])=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H](CSSC[C@H](N)C(=O)O)NC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](CS)C(=O)O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
N-(S-Acetyl-2'-benzyl-3'-mercaptopropionyl)cystine methyl ester (50 mg) was dissolved in degassed methanol (5 ml) and treated with sodium sulfide nonahydrate (300 mg) and dithiothreitol (122 mg). The mixture was stirred at RT for 14 hours then poured into water (30 ml) and extracted with chloroform (2×20 ml), the aqueous phase acidified to pH 1-2 and re-extraced with ethyl acetate (3×10 ml), dried, (MgSO4) filtered and evaporated to a clear oil, the title compound as an approximately equimolar mixture of diastereoisomers, in 86% yield.
Reaction SMILES: ClCCC([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=O.[Cl-:18].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[K+]>>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[C:7](=[O:6])[CH2:16][CH2:15][Cl:18])[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: [Cl-]
Reactant: O=C1CCc2cc(OC(=O)CCCl)ccc2N1
Agent: [Al+3]
Agent: [K+]
Agent: [Na+]
Product: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 Grams of 6-(β-chloropropionyloxy)-3,4-dihydrocarbostyril, 60 g of pulverized anhydrous aluminium chloride, 6 g of sodium chloride and 6 g of potassium chloride were mixed together and the mixture was melted by heating and stirred at 150°-170° C. for 1 hour. The reaction mixture was poured into ice-water and allowed stand overnight to obtain crystalline precipitates. The precipitates were collected by filtration, washed with water and dried, then recrystallized from methanol to obtain 12 g of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals. Melting point: 205°-208° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CS(C)=O.CCOC(C)=O>[C:25]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)=[N:7][C:2]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)#[N:26]
Reactant: NC1CC1
Reactant: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(NC3CC3)n2)C1)c1ccccc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(R)-3-(1-(6-Chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (513, 100 mg) was dissolved in 4 mL DMSO in a sealed tube. To it was added cyclopropylamine (210 μL, 3 mmol) and the mixture was stirred in 70° C. bath for 16 hours. It was diluted with 60 mL EtOAc, washed with water ×2, concentrated in vacuo to afford crude (R)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methyl-1-phenylurea (514). It was dissolved in 4 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 45 min, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide (515) as HCl salt (74 mg, 67% yield). LC-MS (ESI): m/z (M+1) 410.3. UV: λ=283, 317, 369 nm.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:3].[CH3:22][I:23]>C(O)C>[I-:23].[CH2:14]([O:13][C:12]([NH:11][C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][N+:6]1([CH3:22])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CI
Reactant: CC(C)(CCN1CCCC1)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(CC[N+]1(C)CCCC1)NC(=O)OCc1ccccc1
Product: [I-]
Temperature: 50 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
Benzyl 2-methyl-4-(pyrrolidin-1-yl)butan-2-ylcarbamate (4.81 g, 16.6 mmol) was placed into a 48 mL pressure vessel. Methyl iodide (10 mL, 10 equiv, 0.16 mol) was added to the reaction in one portion. No heat was evolved during addition, absolute ethanol (5 mL) was added to the vessel then it was sealed. The reaction was left to stir at 50° C. for 16 h. The blood red solution was concentrated to a dark red oil. The crude product was dissolved into a small amount of water and filtered through a 0.45 micron PTFE frit, then this solution was purified on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. The fractions were pooled and lyophilized to give a colorless oil (5.24 g, 73.2%). 1H NMR (CDCl3, 400 MHz): δ 1.29 (s, 6H), 2.02-2.25 (m, 6H), 2.88 (s, 3H), 3.15-3.30 (m, 4H), 3.32-3.45 (m, 2H), 5.08 (s, 2H), 7.38-7.50 (m, 5H). LRMS (ESI+) for C18H29N2O2+ (305.2); Found: 305 (M+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]([N:23]([CH3:32])[C:24](N1C=C[N+](C)=C1)=[O:25])([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:24](=[O:25])[N:23]([CH:20]([CH3:22])[CH3:21])[CH3:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N(C)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane 1:5) (77%, white crystals). HPLC-MS m/z=355.1 (M+1), Rt: 4.80 min.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:13][CH2:14][CH2:15][NH:16][C:17]2[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.[C:24](Cl)(=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(Cl)(Cl)Cl>[CH2:40]([C:41]1[N:16]([CH2:15][CH2:14][CH2:13][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1NCCCn1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCn1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Triethylamine (0.72 ml) was added to a solution containing N-[3-(1H-imidazol-1-yl)propyl]-1,2-benzenediamine (1.000 g) in chloroform (10.0 ml), and then stearoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (3.85 ml) was added to a solution containing the residue (2.149 g) in ethanol (22 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.273 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=60:1), thereby yielding the entitled compound (1.657 g) as yellow solid.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:23]S(C3C=CC(C)=CC=3)(=O)=O)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[C:39]([CH2:40]O)=[N:38][CH:37]=[N:36]1.[H-].[Na+].O>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:23][CH2:40][C:39]3[N:35]([CH3:34])[N:36]=[CH:37][N:38]=3)=[N:8][N:9]3[C:14]=2[C:13]([CH3:15])=[N:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2C2CCCC2)cc1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To toluene-4-sulfonic acid 3-cyclopentyl-7-(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (Example 3, step c; 230 mg, 0.494 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (67 mg, 1.2 molar eq; prepared as described in EP-A-170073) in DMF (10 ml) was added sodium hydride (22 mg of a 60% dispersion in mineral oil; 1.2 molar eq) and the mixture was stirred at room temperature for 1 h. Water (90 ml) was added then the solution was extracted with diethyl ether (4×50 ml). The combined ether layers were washed with brine (1×100 ml), dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. 3-Cyclopentyl-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under diethyl ether/isohexane (77 mg, mp=123° C.). 1H NMR (360 MHz, CDCl3) δ 1.60-1.98 (8H, m), 2.88 (3H, s), 3.42 (1H, m), 3.73 (3H, s), 5.44 (2H, s), 7.22-7.37 (2H, m), 7.56-7.71 (2H, m), 7.85 (1H, s); MS (ES+) m/e 408 [MH]+. Anal. Found C, 61.64; H, 5.31; N, 23.77%. C21H22FN7O requires C, 61.90; H, 5.44; N, 24.06%.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]([Sn](CCCC)(CCCC)CCCC)=[C:9]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:10]=1[P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])CCC.[Cu]C#N.I[C:52]1([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH:55]=[CH:54][S:53]1.Cl>>[CH2:22]([O:21][P:19]([C:9]1[C:10]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:54]2[S:53][C:52]([C:57]3[S:58][CH:59]=[CH:60][CH:61]=3)=[CH:56][CH:55]=2)[S:7][C:8]=1[C:54]1[S:53][C:52]([C:57]2[S:58][CH:59]=[CH:60][CH:61]=2)=[CH:56][CH:55]=1)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: IC1(c2cccs2)CC=CS1
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc([Sn](CCCC)(CCCC)CCCC)c(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Agent: N#C[Cu]
Agent: Cl
Product: CCOP(=O)(OCC)c1c(-c2ccc(-c3cccs3)s2)sc(-c2ccc(-c3cccs3)s2)c1P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 13 h

Procedure:
2,5-bis(tributylstannyl)-3,4-bis(diethoxyphosphoryl)-thiophene and commercially available copper(I) cyanide (2.2 equivalents) were dissolved in solvents indicated in the following Table 11, to which 2-iodobithiophene (2.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 4 to 22 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 0.6M hydrochloric acid aqueous solution was added, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance 1.
Reaction SMILES: [NH2:1][C:2]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:44])[C@@H:17]([CH2:34][CH2:35][CH2:36][NH:37][C:38]([NH2:43])=[N:39][N+]([O-])=O)[NH:18][C:19](=[O:33])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)=[N:3][C:4]#[N:5].C[OH:46]>[Pd]>[NH2:1][C:2]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:44])[C@@H:17]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:43])[NH:18][C:19](=[O:33])[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)=[N:3][C:4]#[N:5].[C:19]([O-:33])(=[O:46])[CH3:20]
Reactant: N#CN=C(N)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CO
Agent: [Pd]
Product: CC(=O)[O-]
Product: N#CN=C(N)NCc1ccc(CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 5.9 %

Procedure:
Prepared analogously to Example 1d) from (R)-N-[[4-[[[amino-(cyanoimino)methyl]amino]methyl]phenyl]methyl]-N5 -[amino(nitroimino)methyl]-N2 -(diphenylacetyl)-ornithinamide by catalytic hydrogenation in the presence of palladium/activated charcoal and using methanol as solvent. After final purification by column chromatography on silica gel (Macherey-Nagel, 0.063-0.2 mm) using n-butanol/glacial acetic acid/water=4/1/1 (v/v/v) as eluant, the desired compound is obtained as a colourless, amorphous-glassy substance in a yield of 5.9% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][NH:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[H-].[Na+]>>[CH2:8]([N:7]([CH2:6][CH2:24][CH2:2][Cl:1])[CH2:17][CH2:18][CH3:19])[CH2:9][CH3:10].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([CH2:4][CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH3:10])[NH:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: O=C1NNC2=CC(=O)N(c3ccccc3Cl)c3cc(Cl)ccc3N12
Agent: [H-]
Agent: [Na+]
Product: CCCN(CCC)CCCCl
Product: CCCN(CCC)CCCN1NC2=CC(=O)N(c3ccccc3Cl)c3cc(Cl)ccc3N2C1=O

Procedure:
In the manner given in Example 21, 8-chloro-6-(o-chlorophenyl)-1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5-(2H,6H)-dione can be reacted with sodium hydride and then with dipropylamino propyl chloride to give 8-chloro-2-[(dipropylamino)propyl]-6-(o-chlorophenyl)-1H-s-triazolo[4,3-a][1,5]benzodiazepin-1,5-(2H,6H)-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1)([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O.C(OCC)(=O)C>[C:11]([O:15][C:16](=[O:26])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:19]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Temperature: 0 °C
Yield: 46.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 595 mg, 5.26 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL) and a 60% dispersion of sodium hydride in mineral oil (211 mg, 5.28 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and (3-bromomethyl-phenyl)-carbamic acid tert-butyl ester (1.50 g, 5.26 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The reaction was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column (Merck silica gel 60, 40-63 μm; 15% ethyl acetate/hexanes) followed by recrystallization from methylene chloride afforded [3-(3-nitro-pyrazol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (782 mg, 47%) as a beige solid: H1-NMR (400 MHz, DMSO-d6) δ 1.45 (9H, s), 5.39 (2H, s), 6.88 (1H, d, J=7.6 Hz), 7.06 (1H, d, J=2.4 Hz), 7.22 (1H, t, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.40 (1H, s), 8.11 (1H, d, J=2.8 Hz), 9.36 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCl.[CH3:50][C:51]([CH3:53])=O>C(O)(=O)C>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH:51]([CH3:53])[CH3:50])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 60 %

Procedure:
To a suspension of 7-cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.23 mmol) in dichloromethane/acetone is added NaBH(OAc)3 (488 mg, 2.3 mmol) followed by 3 drops of glacial acetic acid. After reaction is completed and concentrated. Diluted with 100 mL of H2O and basified to pH12 with 50% NaOH solution dropwise (2 mL). Extracted with dichloromethane (3×100 mL) and concentrated to give 7-cyclopentyl-2-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (65 mg, 60%). MS (ESI) m/z 476.3 (M+H)+
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH2:13][Cl:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:12]([OH:15])[CH2:13][Cl:14])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)CCl)cc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)[C@@H](O)CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(3S)-3-(p-Toluenesulfonyl)amino-1-chloro-4-phenyl-2-butanone (175.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=500) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-(p-toluenesulfonyl)amino-1-chloro-2-hydroxy-4-phenylbutane (173.5 mg; yield: 98.3%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 10.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:20]([NH:19][CH2:18][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:28])(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccccc1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol) in CH2Cl3 (1 mL) was treated with hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (38 μL, 0.27 mmol). The reaction mixture was stirred for 16 h at 25° C., diluted with 1 mL of CH2Cl2, washed with 2 N aqueous NaOH solution (2×0.75 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 6 to 8% CH3OH/CH3Cl2 gradient elution) afforded 4-{(N-benzoylglycyl)amino}methyl-1-(4-chlorobenzyl)piperidine (compound No. 458) which was treated with TFA to give a TFA salt (105 mg, 97%): The purity was determined by RPLC/MS (85%); ESI/MS m/e 400 (M++H, C22H26ClN3O2).