Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([Li])CCC.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[F:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(C(=O)c3ccccc3F)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.22 mmol) dissolved in THF (25 ml) was cooled to -78° C., and 2.5 ml of n-butyllithium (1.27M in hexane) were added. After one hour, o-fluorobenzoyl chloride (0.38 ml, 3.22 mmol) was added. The mixture was stirred for 10 minutes at -78° C. after which the reaction was quenched by addition of water at -78° C. The reaction was made basic with NaOH and extracted three times with methylene chloride. The basic extract was dried (Na2SO4) and concentrated to give 2.0 g of crude residue. Purification of this material by flash silica gel chromatography using 1:1 ether:hexane containing a trace of ammonium hydroxide as solvent provided 2-di-n-propylamino-8-(2'-fluorobenzoyl)-1,2,3,4-tetrahydronaphthalene (340 mg).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ccccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmole) in dimethylacetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmol) dropwise. The resulting solution was stirred at -10° C. for approximately 30 min. 4-(2-Pyridylsulfonyl)aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A brown colored precipitate was formed. The solid was filtered, washed with water, and dried. Crystallization and decoloration (charcoal) from ethyl acetate/methanol/hexane gave the title compound (0.42 g, 43%) as off-white leaves; mp 200°-202° C. 1H-NMR(300 MHz, d6-DMSO): 6.45 (t, J=54.09 Hz, 2H, HCF2), 7.68(t, J=6.24 Hz, 1H, ArH), 7.92-8.03 (m, 5H, ArH, OH), 8.11-8.21 (m, 2H, ArH), 8.68 (d, J=4.47 Hz, 1H, ArH), 10.54 (s, 1H, NH). MS(CI,CH4): 393 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29]([O:13][C:12]([C@@H:10]1[CH2:11][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1([CH3:16])[CH3:15])=[O:14])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OC(=O)c2c(Cl)cc(Cl)cc2Cl)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (about 0.450 g, 1.97 mmol) and DIPEA (about 1.01 ml, 5.92 mmol) in THF (about 4 ml) and 2,4,6-trichloro benzoyl chloride (0.35 ml, 2.17 mmol) were added at 0° C. and the reaction mixture was allowed to stir at room temperature for about 6 hours, after completion of the reaction (monitored by TLC), the solvent was evaporated and crude product proceeded as such for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]1[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]2=1.N1C=CC=CC=1.[Cl-].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][NH:41][CH:42]=[S:43])=[CH:39][C:34]=2[O:33][CH2:32]1.CO>ClCCl>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][NH:41][C:42]([N:21]3[CH2:20][CH2:19][N:18]([C:17]4[C:6]5[C:5]6[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=6)[NH:8][C:7]=5[N:14]=[CH:15][N:16]=4)[CH2:23][CH2:22]3)=[S:43])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: COc1cc2[nH]c3ncnc(N4CCNCC4)c3c2cc1OC
Reactant: S=CNCc1ccc2c(c1)OCO2
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc2[nH]c3ncnc(N4CCN(C(=S)NCc5ccc6c(c5)OCO6)CC4)c3c2cc1OC
Reaction time: 8 h

Procedure:
To a solution of 6,7-dimethoxy-4-piperazino-9H-pyrimido[4,5-b]indole (200 mg, 0.64 mmol) and pyridine (0.5 mL, 6.4 mmol) in dichloromethane (20 mL) was added the solution of product 1c in dichloromethane (20 mL) and the mixture was stirred overnight. Methanol was added to quench excess thiophosgene, and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 130 mg (40%).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:50][CH3:51])=[C:22]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([N:7]([C:5]4[S:6][C:2]([F:1])=[CH:3][N:4]=4)[CH2:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[C:27](=[O:49])[NH:26][N:25]=2)[CH:23]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2ncc(F)s2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.9 %

Procedure:
A vial was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (67.1 mg, 0.282 mmol), perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol), and THF (938 μl). The resulting solution was cooled to 0° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. LCMS after 15 min showed incomplete conversion of SM. Additional LHMDS (400 μL, 1M in THF) was added. After 15 min, TLC showed complete conversion of PFP-sulfonate to a lower spot. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 59.0% yield) as a brown solid. m/z (ESI) 587.0 (M+H)+, 609.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (65 mg, 0.105 mmol) was dissolved in DCM (1053 μl, 0.105 mmol) and then TFA (40.6 μl, 0.527 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford impure product. The product was purified further by RPLC on the acidic Gilson. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 1-(5-chloro-2-methoxyphenyl)-N-(5-fluorothiazol-2-yl)-4-oxo-3,4-dihydrophthalazine-6-sulfonamide (1.3 mg, 2.64% yield) as off-white solid. m/z (ESI) 467.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41][CH2:42][OH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:43][CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccccc2)cc1
Reaction time: 18 h
Yield: 19.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-phenylethanol (26.1 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-phenethoxyphenyl)pyridin-3-yl)acetic acid (4.6 mg, 8.44 μmol, 19.79% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.29 (m, 4H), 7.27-7.17 (m, 2H), 7.08-6.93 (m, 3H), 5.70 (br. s., 1H), 4.32-4.18 (m, 2H), 3.51-3.42 (m, 2H), 3.06 (d, J=7.0 Hz, 1H), 2.81-2.68 (m, 1H), 2.43 (s, 3H), 2.17 (d, J=13.2 Hz, 1H), 2.05 (s, 3H), 1.96-1.90 (m, 1H), 1.50 (br. s., 1H), 1.29 (br. s., 1H), 1.15 (d, J=11.7 Hz, 1H), 1.11 (s, 9H), 1.01 (d, J=11.0 Hz, 1H), 0.85 (br. s., 3H), 0.62 (br. s., 3H). LCMS (M+H)=545.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)=[O:12]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(Oc2ccc(N)c(F)c2)cc1

Procedure:
This compound is prepared according to a method analogous to that described in Example 1.1 using 4-amino-3-fluorophenol (7.68 g, 0.06 mol) and 4-fluoroacetophenone (8.34 g, 0.06 mol) as starting compounds. After treatment, a white-coloured powder is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4](O)[CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][N:24]4[CH2:29][C:30]([NH2:32])=[O:31])[N:16]=2)[CH:11]=[CH:12][C:13]=1F.[NH4+].[Cl-]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][N:24]4[CH2:29][C:30]([NH2:32])=[O:31])[N:16]=2)[CH:11]=[CH:12][C:13]=1[CH:4]([CH3:5])[CH3:3]
Reactant: CC(C)O
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(F)c(Cl)c4)n3)cccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8.2 %

Procedure:
To a suspension of 60% NaH (43 mg) in DMF (4 ml) was added 2-propanol (65 mg) at 0° C., followed by stirring at room temperature for 20 min. After cooling to 0° C. again, 2-{4-[5-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl-acetamide (200 mg) was added thereto. The reaction mixture was radiated with a microwave at 60° C. for 50 min. The reaction solution was added to an aqueous NH4Cl solution, followed by stirring, and then the solvent was evaporated. After adding a mixed solvent (4:1) of chloroform-CH3OH, and suspending, the solid was removed, silica gel was added thereto, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 98:2; n-hexane:EtOAc=0:100) to obtain 2-{4-[5-(3-chloro-4-isopropylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (17.5 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11]Cl>>[CH3:9][O:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Product: COCOc1ccc(Br)cc1
Yield: 104.2 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 48.84 g (282.3 mmol) of 4-bromophenol with 25.0 ml (310.5 mmol) of chloromethyl methyl ether, 63.85 g (100%) of the expected product are obtained in the form of a beige-coloured oil.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)C=1.[NH:15]1C=CN=N1>>[N:4]1[N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[N:15]=[CH:2][CH:3]=1
Reactant: c1c[nH]nn1
Reactant: CCOC(=N)C1(n2cc(F)cn2)CC1
Product: CCOC(=N)C1(n2nccn2)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 64, but using 1,2,3-triazole as the starting material.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].Cl[CH2:15][C:16]1[N:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[N:4]([CH2:15][C:16]2[N:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: ClCc1cccnn1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1Cc1cccnn1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (15.7 g, 85.6 mmol, prepared using procedure in WO9849166), 3-(chloromethyl)pyridazine (11.0 g, 85.6 mmol, prepared using procedure in WO0023449) and cesium carbonate (27.8 g, 85.6 mmol) in N,N-dimethylformamide (200 ml) was stirred at 20° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (200 ml) and 10% aqueous Na2CO3 (100 ml). The phases were separated, and the aqueous layer extracted with further DCM (6×50 ml). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc/MeOH, 95:5-9010) to afford the title compound of preparation 43 (Note, the regioisomers were assigned on the basis of nOe experiments) (4.09 g, 14.8 mmol, 17%):
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure BD above, and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:21][NH:20][C:19](=O)[CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9](=O)[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>COCCOC>[CH:1]1([CH:7]2[CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CC(=O)NCC(C3CCCCC3)NC(=O)CN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: C1CCC(C2CNCCNCCNCCNCCN2)CC1
Temperature: 25 °C
Reaction time: 39.5 h
Yield: 42 %

Procedure:
5-Cyclohexyl-1,10,13-tris(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecan-3,8-dione prepared as in Example 30D (4.841 g, 6.386 mmol) was placed in a 2-necked flask under argon. Dry 1,2-dimethoxyethane (dme, 100 ml) was added, giving a suspension. After placing the reaction flask in a cold water bath, lithium aluminum hydride in dme (0.5M, 100 ml, 50 mmol) was added over a 10 min period giving an almost clear solution. Additional dme (50 ml) was added and the flask was removed from the water bath and heating with a mantle was started. After a few minutes of heating, more lithium aluminum hydride solution (40 ml, 20 mmol) was added, and heating to reflux was continued. The solution quickly became yellow and opaque. Overnight the refluxed solution became mostly white and heterogeneous. After 39.5 h, the reaction mixture appeared milky with a slight tint of yellow. Heating was stopped and the reaction mixture was cooled to room temperature. It was quenched, after placing the reaction flask in a Water bath, by careful addition of water (2.2 ml) over a 10 min period. The reaction was exothermic with gas evolution. Next, 15% aqueous sodium hydroxide solution (2.2 ml) was rapidly added, then water (6.5 ml). After stirring for 1 h, tetrahydrofuran (135 ml) was added with continued stirring. The mixture was thick with a white precipitate. Fifty min later the mixture was filtered under an inverted funnel through which N2 was flowing, and the filtrate was removed on the rotary evaporator to give a viscous liquid. After pumping on the vacuum line, this residue was recrystallized under argon from acetonitrile with cooling to -20° C. Three successive batches of a slightly sticky white solid were obtained which were combined and recrystallized from hexanes under argon with cooling to -20° C. to give 0.796 g (42% yield): mp 67°-69.5° C. (under nitrogen); 1H NMR (CDCl3) δ 0.84-1.32 (several m, 5 H), 1.40-2.0 (several m, 11 H), 2.28-2.46 (m, 2 H), 2.50-2.97 (several m, 17 H); Exact mass (M+H)+ : calcd, 298.2971; Found, 298.2973 (C16H36N5).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([N:5]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC(=O)NNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-t-butyl-2-valerylhydrazine (4 g, 0.023M) in toluene (40 ml) at 5° C. was added benzoyl chloride (3.4 g, 0.024M) and 50% aq. sodium hydroxide (0.98 g, 0.024M). After addition, the mixture was warmed to room temperature and stirred 2.5 hr. The mixture was diluted with ethyl acetate (50 ml) and washed with water (2×25 ml) and brine (1×25 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford N'-t-butyl-N-valeryl-N'-benzoyl-hydrazine as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([NH:13][C@@H:14]([CH2:29][C:30]3[N:31]=[CH:32][S:33][CH:34]=3)[C:15]([N:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)=[O:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:38].O>CN(C=O)C>[CH2:25]([N:17]([CH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1)[C:15](=[O:16])[C@@H:14]([N:13]([CH3:38])[S:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)(=[O:11])=[O:12])[CH2:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)NS(=O)(=O)c2ccc3occc3c2)cs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(CN(CC(C)C)C(=O)[C@H](Cc2cscn2)N(C)S(=O)(=O)c2ccc3occc3c2)cs1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of compound 58 (76 mg, 0.15 mmol) in DMF (1 ml) were added sodium hydride (12 mg, 0.30 mmol) and iodomethane (14 μl, 0.23 mmol). After 1 hr, water (7 ml) was added to quench the reaction. The aqueous phase was extracted with EtOAc (10 ml) and the organic layer was washed with brine (5 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by preparative TLC (EtOAc) to provide compound 80 (49 mg, 61%) as an oil. [M+H]+ 533.0, HPLC purity: >99%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]([CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[C:20]2=[N:21][CH:22]=1>>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:6]=[CH:7][C:2]=1[NH:1][C:26]([C:24]1[N:23]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[C:20]2=[N:21][CH:22]=[C:17]([C:16]([F:15])([F:36])[F:37])[CH:18]=[C:19]2[CH:25]=1)=[O:27]
Reactant: COc1cc(N2CCCC2)ncc1N
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1
Product: COc1cc(N2CCCC2)ncc1NC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1

Procedure:
The method described in Example 12.3 is followed, starting from 5-amino-4-methoxy-2-(pyrrolidin-1-yl)pyridine, prepared in the preceding stage, and 5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid prepared in Stage 9.2.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[OH:5][CH:6]([CH3:31])[CH2:7][N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[NH:10][CH2:11][CH2:12][Cl:13]>C(O)C.C(O)(=O)C>[OH:5][CH:6]([CH3:31])[CH2:7][N:8]([CH:15]([OH:30])[C@H:16]1[O:22][C@:20]([CH2:23][CH:24]([CH3:25])[CH3:26])([OH:21])[C@H:19]([OH:27])[C@@H:18]([OH:28])[C@@H:17]1[OH:29])[C:9](=[O:14])[N:10]([CH2:11][CH2:12][Cl:13])[N:1]=[O:3]
Reactant: CC(C)CC1(O)O[C@H](C(O)N(CC(C)O)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C[C@]1(O)O[C@H](C(O)N(CC(C)O)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
Sodium nitrite (2 g) was added to a solution of the above fractionated α,β-mixed form of 3-(2-hydroxy-n-propyl)-3-(isobutyl D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (4.48 g, 11.7 mmol) in a mixture of ethanol (60 ml) and 80% aqueous acetic acid (30 ml) with well stirring at 0° to 5° C. spending 30 minutes. This reaction mixture was allowed to stand in a refrigerator at 0° to 5° C. for 18 hours to complete reaction, which was confirmed by TLC. An ion exchange resin (H+ form, registered trade mark: Amberlite IR-120) (20 ml) was added to the reaction mixture and the mixture was stirred at 0° to 5° C. for 1 hour. The ion exchange resin was filtered off, and the filtrate was vacuum-concentrated at 25° C. and fractionated by column chromatography (packing: Kiesel gel 60; eluent: chloroform/ethanol 9:1) to separate the α- and β-forms. Each fractionated solution was vacuum-concentrated at 25° C. and crystallized from ether and petroleum ether. Thus, there were obtained 1.43 g of 3-(2-hydroxy-n-propyl)-3-(isobutyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 28.5%, m.p. 62°-64° C., [α]D20 +66.9° (C 1.0, methanol); and 1.14 g of 3-(2-hydroxy-n-propyl)-3-(isobutyl β-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 22.7%, m.p. 80°-82° C., [α]D20 -12.5° (C 1.0, methanol).