Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][S:8]([F:21])([F:20])([F:19])([F:18])[C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][CH:10]=1.CN(C)C=O>ClC(Cl)C.ClCCl.CN(C)C=O>[F:7][S:8]([F:18])([F:19])([F:20])([F:21])[C:9]1[CH:10]=[CH:11][C:1]([C:2]([Cl:4])=[O:3])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 45 °C
Yield: 100.6 %

Procedure:
Oxalyl chloride (1.53 g) was added to a stirred solution of 4-pentafluorosulphanyl- benzoic acid (0.99 g) in dichloroethane. A solution of N,N-dimethylformamide in dichloromethane (3 ml of a solution prepared by the addition of 2 drops of N,N-dimethylformamide to 10 ml of dichloromethane) was added. After 15 minutes the solution was heated for a further 15 minutes at 45° C., and evaporated to dryness to give 4-pentafluorosulphanylbenzoyl chloride as an orange oil (1.07 g). This was used directly in the subsequent reaction stage.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(#N)C>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 60° C. for 4 hr, after which the starting material was no longer detectable by HPLC. Then, acetonitrile (58 ml) was dripped into the solution over 1.5 h. Turbidity appeared in the solution which as it was allowed to cool slowly to room temperature. The mixture was stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.23 g (73%) of fluvastatin sodium Form VI.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C(#N)C.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.50 g) in 1,2-dichloroethane (30 ml) was added rhodium(II) acetate (5 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous acetonitrile (10 ml) and then evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained was dissolved in anhydrous acetonitrile (30 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added diphenyl phosphorochloridate (0.84 ml) and N,N-diisopropyl-N-ethylamine (0.74 ml) successively and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-4-mercapto-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.97 g) in acetonitrile (10 ml) and N,N-diisopropyl-N-ethylamine (0.87 ml) with stirring at 5° C., and the stirring was continued at the same temperature for 2 hours. To the reaction mixture was added ethyl acetate (50 ml) and water (20 ml) with stirring, and the organic layer was separated. This layer was washed with saturated aqueous sodium chloride solution (40 ml×3), dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(4-methylpiperazin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([O-])(O)=O.[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:18])[CH2:16][Cl:15]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C

Procedure:
2,6-dimethylaniline (9.8 g, 81.2 mmol) was dissolved in ether (100 mL) and saturated aqueous NaHCO3 (100 mL) and the reaction mixture was cooled in an ice/water bath. To the cold solution was added chloroacetyl chloride 2 (9.17 g, 81.2 mmol) dropwise over a period of 2 h. The mixture was allowed to warm to RT over 14 h. The mixture was extracted with EtOAc (3×50). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was triturated in ether and filtered to afford compound 3 as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([NH2:17])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].CCN(CC)CC.[CH:34]1([NH:38][S:39](Cl)(=[O:41])=[O:40])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][S:39]([NH:17][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:6]=3)[CH:9]=2)([CH3:16])[CH3:15])(=[O:41])=[O:40])[CH2:37][CH2:36][CH2:35]1
Reactant: O=S(=O)(Cl)NC1CCC1
Reactant: CCn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Product: CCn1nc(COc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1

Procedure:
Prepared by the procedure of Example 1 Step 3 using the amine from Step 5 (100 mg, 0.28 mmol), Et3N (114 mg, 1.1 mmol) and cyclobutylsulfamoyl chloride (192 mg, 1.1 mmol) to yield, after purification by column chromatography on silica using 70% Et2O/iso-hexanes and then by normal phase preparative HPLC, the sulfamide (17.5 mg, 12%). 1H NMR (CDCl3, 360 MHz) δ 7.60-7.52 (2H, m), 7.44 (1H, t, J=7.6 Hz), 7.30 (1H, d, J=7.6 Hz), 6.97 (4H, app. d, J=6.3 Hz), 6.37 (1H, s), 5.06 (2H, s), 4.55 (1H, s), 4.12 (2H, q, J=7.3 Hz), 3.78 (1H, app. sextet, J=8.3 Hz), 2.45-2.35 (2H, m), 1.93-1.82 (2H, m), 1.75 (6H, s), 1.72-1.60 (2H, m), 1.44 (3H, J=7.3 Hz). MS (ES+) C25H31FN4O3S requires: 486, found: 487 (M+H+, 100%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: O=c1c2ccccc2ncn1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=c1c2ccccc2ncn1C1CCNCC1
Yield: 82.2 %

Procedure:
To a solution of 100 mg of 3-(1-benzyl-piperidin-4-yl)-3-H-quinazolin-4-one (from Step B) in 6 mL of MeOH was added 100 mg of ammonium formate followed by 100 mg of 10% palladium on carbon. After refluxing for 5 hours, the mixture was filtered through celite. Concentration under reduced pressure afforded 59 mg of the title compound as a foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[N:15]=[N:14]1)[C:9]([O:11]C)=[O:10].[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:13]1[CH:17]=[C:16]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[N:20]2)[N:15]=[N:14]1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
49 mg (0.09 mmol) of the compound from Example 103 were dissolved in 2 ml of methanol, and 193 μl (0.19 mmol) of a 1 N aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 30 min. The solvent was then removed under reduced pressure, the residue was dissolved in 5 ml of water and the solution was extracted once with 5 ml of ethyl acetate. The organic phase was discarded. The aqueous phase was acidified with 0.2 ml of 1 N hydrochloric acid and extracted twice with in each case 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 40 mg (83% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][CH:13]=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Li].[Cl:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.O>C1COCC1.C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]([CH2:12][C:4]23[CH2:5][CH:6]4[CH2:7][CH:8]([CH2:9][C:2]([CH3:1])([CH2:11]4)[CH2:3]2)[CH2:10]3)[OH:14])[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cccc(Cn2ccnc2)c1
Reactant: CC12CC3CC(C1)CC(CC=O)(C3)C2
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC12CC3CC(C1)CC(CC(O)C(c1cccc(Cl)c1)n1ccnc1)(C3)C2
Temperature: -60 °C
Reaction time: 1.75 h
Yield: 24.7 %

Procedure:
A solution of 4.05 g (20 mmol) of 2-(3-methyl-1-adamant-yl)-acetaldehyde (95% pure) in 40 ml of absolute THF was added, at about -60° C., to a solution of 20 mmol of lithium-N-(3-chlorobenzyl)-imidazole in THF/hexane, the said solution being prepared analogously to Example 105, and the mixture was stirred for 45 minutes at about -60° C. and for 1.75 hours at -60° C. to room temperature. After about 200 ml of water had been added, the mixture was extracted with ether. The residue (8.8 g) from the ether extract was crystallized from diisopropyl ether, and the product obtained was then recrystallized from acetonitrile. After isolation, 1.90 g (=24.7% of theory) of 2-(3-chlorophenyl)-2-(1-imidazolyl)-1-(3-methyladamant-1-ylmethyl)-ethanol of melting point 126° C. were obtained as a diastereomer which was pure according to thin layer chromatography. According to thin layer chromatography, the mother liquor contained further amounts of the same diastereomer, and the other diastereomer as the principal component.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:32]([O:34]C)=[O:33])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:32]([OH:34])=[O:33])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
In THF (4.5 ml)/ethanol (4.5 ml) was dissolved methyl 1-(allyloxycarbonyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.30 g). To the solution was added 1N sodium hydroxide (3.0 ml), and the mixture was stirred at room temperature for 4 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=8/1) to give 1-(allyloxycarbonyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.25 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:19][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Sc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-fluorobenzotrifluoride (9.85 g) and 4-aminothiophenol (7.51 g) in DMSO (60 mL), cooled in an ice bath, was added in one portion potassium t-butoxide (6.73 g). The resulting mixture was stirred at 0° C. for 10 minutes, then at 60° C. overnight. After cooling, the mixture was poured into water (600 mL) and the resulting mixture extracted with ether (2×200 mL). The organic phase was washed with 2N sodium hydroxide (50 mL), then with water (50 mL). After drying (MgSO4), the solvent was evaporated to give a brown solid. Recrystallization from hexane gave the title aniline as a yellow solid, m.p. 97-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.[C:25]([O:28][CH2:29]C)(=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:25][O:28][CH3:29])=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C(=O)O)cc12
Reactant: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1COC

Procedure:
3-ethoxycarbonyl-β-carboline-6-carboxylic acid, mp 313°-314° C. (decomposition; ethanol/ethyl acetate); and
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17](O)=[O:18])[CH2:14][N:15]=1)=[CH:7]2.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[S:12][CH:13]([CH2:16][C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:18])[CH2:14][N:15]=1)=[CH:7]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12
Reaction time: 15 h
Yield: 83 %

Procedure:
To a solution of [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg) and morpholine (0.088 mL) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole (137 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (194 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio), and the obtained pale-yellow oil was crystallized from ethyl acetate-diethyl ether to give the title compound (286 mg, yield 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.C([N:27](CC)CC)C.CS(Cl)(=O)=O.[I-].[K+].N>O1CCCC1.C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:27]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CCN(CC)CC
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Agent: N
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 0.363 g. (1.00 mmol.) of 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone in 5.0 ml. of methylene chloride was cooled to -20° C. in a Dry Ice/acetone bath and treated with 0.206 ml. (0.150 g., 1.50 mmol.) of triethylamine, followed by dropwise addition of 0.106 ml. (1.3 mmol.) of methanesulfonyl chloride. (Most of the starting material dissolved during the addition of the methanesulfonyl chloride.) During 15 minutes the temperature was gradually raised to 0°. The reaction mixture was quenched on ice and extracted with methylene chloride. The organic extracts were treated with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an oil. The oil was dissolved in 5 ml. of freshly distilled tetrahydrofuran in a dry flask and treated first with 0.332 g. (2.00 mmol.) of potassium iodide, then ammonia (gas). After saturating the reaction mixture with ammonia, the mixture was warmed to room temperature (22°-24° C.) and stirred for 24 hours. The mixture was quenched in a saturated aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an oil. Crystallization from ethyl acetate and methanol/ethyl acetate yielded 25 mg. of a tan solid of melting point 210°-221° C. Recrystallization from ethyl acetate gave pure 8-chloro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 223°-225° C.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C.Cl>>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[NH:18][CH:9]([P:10]([OH:15])(=[O:11])[OH:14])[P:4]([OH:8])(=[O:3])[OH:5]
Reactant: CCOP(=O)(OCC)C(Nc1nc2ccccc2s1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Nc1nc2ccccc2s1)P(=O)(O)O
Temperature: 25 °C

Procedure:
4.36 g (10 mmol) of 1-(benzothiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated in 40 ml of N hydrochloric acid at 110°-120° for 6 hours. In the course of the reaction, the product separates out in the form of a white precipitate. After cooling to room temperature, filtration is carried out and the product is washed with aqueous methanol. 3.09 g (95% of the theoretical yield) of 1-(benzothiazol-2-yl-amino)methane-1,1-diphosphonic acid of m.p. 290° (decomposition) are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH:19]([C:18]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:17]=2[F:16])[OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CCN(Cc2ccccc2)C1
Reactant: O=Cc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)C1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A solution containing 0.38 mol of 1-benzyl-3-chloromethylpyrrolidine in 200 ml of tetrahydrofuran (THF) is added, at 65° C., to a suspension containing 9.3 g of magnesium in 100 ml of THF. The mixture is maintained at reflux and, after disappearance of the metal, followed by cooling, this solution is added to a solution containing 0.38 mol of 2,4-difluorobenzaldehyde in 300 ml of THF. The mixture is maintained at room temperature for 12 hours and is then hydrolyzed with 220 ml of saturated ammonium chloride solution. After extraction with dichloromethane and then evaporation, the residual oil is purified by chromatography on a column of silica, using a dichloromethane/methanol/aqueous ammonia (98/2/0.2) mixture as eluent, and gives the expected product.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([OH:27])=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].FC(F)(F)C(O)=O.[NH2:35][C@@H:36]1[C:43](=[O:44])[N:42]2[C@@H:37]1[S:38][CH2:39][C:40](/[CH:48]=[C:49]1/[C:50](=[O:62])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=3)[CH2:52][CH2:53]/1)=[C:41]2[C:45]([OH:47])=[O:46]>CN(C)C(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([NH:35][C@@H:36]2[C:43](=[O:44])[N:42]3[C@@H:37]2[S:38][CH2:39][C:40](/[CH:48]=[C:49]2/[C:50](=[O:62])[N:51]([CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=4)[CH2:52][CH2:53]/2)=[C:41]3[C:45]([OH:47])=[O:46])=[O:27])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(SCC(=O)O)cc1OC
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cccc(O)c4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(SCC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(Cc5cccc(O)c5)C4=O)CS[C@H]23)cc1OC

Procedure:
With 121.1 mg (0.75 mmol) 1,1,-carbonyldiimidazole, 170.6 mg (0.75 mmol) 2-(3,4-dimethoxyphenylthio)acetic acid and 250.0 mg (0.62 mmol) (E)-(6R,7R)-7-amino-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene2-carboxylic acid trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:44]=[CH:43][C:28]([C:29]([NH:31][CH2:32][C:33]5([CH2:36][NH:37][C:38](=[O:42])[C:39](O)=[O:40])[CH2:35][CH2:34]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:67][C:68]1[CH:74]=[CH:73][C:71]([NH2:72])=[CH:70][CH:69]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:44]=[CH:43][C:28]([C:29]([NH:31][CH2:32][C:33]5([CH2:36][NH:37][C:38](=[O:42])[C:39]([NH:72][C:71]6[CH:73]=[CH:74][C:68]([F:67])=[CH:69][CH:70]=6)=[O:40])[CH2:34][CH2:35]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)NCC1(CNC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCC1(CNC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(((1-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopropyl)methyl)amino)-2-oxoacetic acid (17 mg) and TBTU (10.33 mg) in DMF (2 mL) was added 4-fluoroaniline (3.58 mg). The mixture was stirred at room temperature for 16 hours, before being purified by preparative HPLC.