Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@@H:14]([OH:17])[C@@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([NH:4][C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@@H:14]([OH:17])[C@@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: O[C@@H]1CC[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1CC[C@@H](O)[C@@H](O)C1
Temperature: 100 °C
Yield: 8 %

Procedure:
Isopropylamine (99.5 mg, 1.68 mmol) was added to (±)-(1R*,2S*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-diol (Example 49, part g, 64.0 mg, 168.4 mmol) in ethanol (3.4 ml) and the reaction was heated at 100° C. in a sealed tube for 67 hr. The reaction was cooled, saturated sodium carbonate added, extracted with ethyl acetate, dried with magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with methanol:ethyl acetate (1:19) to give the title compound (47.9 mg, 79%). Rf=0.24 (1:19 methanol:ethyl acetate); 1H-NMR (CD3OD, 300 MHz) δ7.46 (s, 1H), 7.31 (s, 1H), 4.44 (tt, 1H, J=13, 4), 4.11 (s, 1H), 4.05 (h, 1H, J=7), 3.82 (dt, 1H, J=10,4), 2.41 (dt, 1H, J=13,2), 2.26 (dq, 1H, J=13,4), 2.04-1.75 (m, 4H), 1.29 (d, 6H, J=6); MS (ES) M+H=358.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH:11](N(CC)C(C)C)(C)[CH3:12].COCCl>O1CCCC1.ClCCl>[CH3:11][CH2:12][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(O)no1
Agent: COCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.4 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamine in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.[NH2:10][C@H:11]([CH2:13][OH:14])[CH3:12].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:12][C@H:11]([NH:10][C:7]([C@@H:5]1[CH2:4][S:3][C:2](=[O:1])[NH:6]1)=[O:9])[CH2:13][OH:14]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: C[C@H](N)CO
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Yield: 66.3 %

Procedure:
In 20 ml of dry tetrahydrofuran were dissolved 1.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 0.56 g of L-alaninol, 2.8 ml of triethylamine and 1.8 ml of diphenylphosphoryl azide were added thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography employing ethyl acetate as an eluent and further purified by silica gel column chromatography employing dichloromethane-methanol (95:5) as an eluent to obtain 0.92 g of the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 568.7 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: OB(O)c1ccc2[nH]ncc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL), was added 1H-indazol-5-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere and water (3 drops). After stirring for 20 min at 90° C., the reaction mixture was dissolved in water (30 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110.0 mg, 45%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC1CCOCC1)c1ccccc1
Yield: 91.2 %

Procedure:
Following general procedure A: ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (269 mg, 1.14 mmol), tetrahydro-4H-pyran-4-one (0.12 ml, 1.3 mmol) and NaBH(OAc)3 (340 mg, 1.60 mmol) in CH2Cl2 (8.0 ml) was stirred at room temperature for 18 hours. Standard work-up and purification by flash column chromatography on silica (CH2Cl2/MeOH, 19:1) gave [(R)-1-phenyl-2-(tetrahydro-pyran-4-ylamino)-ethyl]-carbamic acid tert-butyl ester as a colorless oil (333 mg, 91%). 1H NMR (CDCl3) δ 0.80-1.36 (m, 3H), 1.41 (s, 9H), 1.68-1.82 (m, 2H), 2.61 (tt, 1H, J=10.3, 4.1 Hz), 2.93 (d, 2H, J=5.1 Hz), 3.35 (tdd, 2H, J=11.6, 5.6, 2.2 Hz), 3.88-3.96 (m, 2H), 4.74 (br s, 1H), 5.45 (br d, 1H, J=5.7 Hz), 7.22-7.35 (m, 5H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>C(O)(C)C>[N+:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc(O)cc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc(O)cc1
Yield: 94.5 %

Procedure:
6.0 g of p-aminophenol was dissolved in 60 ml of isopropyl alcohol. To the solution was added 6.0 g of 4-chloro-3-nitro-benzotrifluoride and the resulting solution was heated under reflux for 12 hours. After the reaction, the solvent was removed by distillation and the residue was dissolved in benzene. The resulting solution was filtered and the solvent was removed from the filtrate by distillation. Thus, 7.5 g of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccccc1CC(=O)O
Product: Cc1c(Sc2ccccc2CC(=O)O)c2ccc(Cl)cc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1>>[CH3:31][O:30][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][N:11]([C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]([NH:32][C:33]2[CH:37]=[CH:36][O:35][N:34]=2)=[O:7])[C:20]3=[O:21])[CH2:23][CH2:24]1
Reactant: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)O)ccc4C)c(=O)c3c2)CC1
Reactant: Nc1ccon1
Product: COCCN1CCN(c2ccc3ncn(-c4cc(C(=O)Nc5ccon5)ccc4C)c(=O)c3c2)CC1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 4-methyl-3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid was reacted with 3-aminoisoxazole to give 3-[6-(4-(2-methoxyethyl)piperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]-N-isoxazol-3-yl-4-methylbenzamide; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 2.58 (m, 6H), 3.26 (m, 7H), 3.47 (t, 2H), 7.05 (s, 1H), 7.50 (s, 1H), 7.66 (m, 3H), 8.10 (m, 2H), 8.13 (s, 1H), 8.87 (s, 1H), 11.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7]([CH3:9])(O)[CH:6]2[CH2:10][CH:3]1[CH2:4][CH:5]2[OH:11].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:7](=[CH2:9])[C@H:6]2[C@H:5]([OH:11])[CH2:4][C@@H:3]1[CH2:10]2
Reactant: CC1(C)C2CC(O)C(C2)C1(C)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: C=C1[C@@H]2C[C@@H](C[C@H]2O)C1(C)C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
In 5.0 ml of pyridine was dissolved 1.7 g of 2,2,3-trimethylbicyclo[2.2.1]heptan-3,5-diol and, then, 1.2 g of thionyl chloride was added dropwise to the solution at a temperature of -5° C. to 0° C. The mixture was stirred for 2 hours, after which it was poured into water and extracted with n-hexane. The extract was washed with dilute hydrochloric acid and an aqueous solution of sodium hydrogen carbonate in that order, dried over anhydrous magnesium sulfate, and distilled to remove the hexane. The residue was subjected to silica gel column chromatography to give 0.10 g of nojigiku alcohol. The physical properties of this product were in agreement with those of the nojigiku alcohol obtained in Example 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH2:15]([C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH:23]=1)[OH:22])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([O:24][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:20]=[C:21]([OH:22])[CH:23]=1)[CH3:16]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCc1cc(O)cc(O)c1
Product: CCc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield from 2-methylsulfonylbenzenesulfonyl chloride and 5-ethylresorcinol in a manner analogous to step a of Eg. 1. 1H-NMR (300 MHz, CDCl3) δ8.43 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.87 (t, J=7.8 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 6.56 (s, 2H), 6.52 (s, 1H), 5.59 (br s, 1H), 3.45 (s, 3H), 2.49 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C(NCC)(C)C.CCCCCC.[C:25]([O:28][CH2:29]C)(=O)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.COCCl>[CH3:25][O:28][CH2:29][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CCOC(C)=O
Agent: CCNC(C)C
Agent: COCCl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCOc1ccc2ccc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an atmosphere of argon, to a solution of 7-hydroxycoumarine (100 g), isopropylethylamine (161 mL) in anhydrous DMF (500 mL), methoxymethyl chloride (70.3 mL) was dropped at 0° C. The mixture was stirred for 4 hours at room temperature. To the reaction mixture, a mixture of hexane/ethyl acetate (2/1), and a saturated aqueous solution of sodium bicarbonate were added, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (74.1 g) having the following physical data.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[N:19]2[CH2:22][CH:21]([CH:23]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=3)[CH:24]([OH:26])[CH3:25])[CH2:20]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:18]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=2)[N:19]2[CH2:22][CH:21]([CH:23]([C:27]3[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=3)[C:24]([CH3:25])=[O:26])[CH2:20]2)=[CH:36][CH:37]=1
Reactant: CC(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 0.33 h

Procedure:
To a solution of 110 uL (1.26 mmol) of oxalyl chloride in 10 mL of methylene chloride was slowly added 180 uL (2.52 mmol) of DMSO at −78° C., followed by stirring for 20 minutes. Then a solution of 292 mg (0.63 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)propan-2-ol in 2 mL of methylene chloride was added into the reaction mixture, followed by stirring for 30 minutes at −78° C. Then 435 uL (3.15 mmol) of triethylamine was added at −78° C. and the mixture was stirred for 1 h while it warmed from −78° C. to rt. The mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford the title compound. NMR (CDCl3) δ 2.09 (s, 3H), 2.65 (m, 1H), 2.78 (m, 1H), 3.08 (m, 2H), 3.45 (m, 1H), 3.90 (d, J=10.5 Hz, 1H), 4.28 (s, 1H), 6.73-6.77 (m, 3H), 7.24-7.33 (m, 8H); Mass Spectrum: m/e=460 (M+1 35Cl, 35Cl) and 462 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[C:46](O)[CH:45]=[CH:44][C:43]=2[CH2:49][CH2:50][NH:51][C:52](=[O:54])[CH3:53])[CH:39]=[CH:40][CH:41]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:46]2[CH:45]=[CH:44][C:43]([CH2:49][CH2:50][NH:51][C:52](=[O:54])[CH3:53])=[C:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=3)[CH:47]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1C=CC(OCc2ccccc2)CC1
Reactant: CC(=O)NCCc1ccc(O)cc1-c1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCCc1ccc(OC2C=CC(OCc3ccccc3)CC2)cc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 35 (70 mg, 0.34 mmol) in freshly distilled THF (3 mL) at 0° C. was added triphenyl phosphine (180 mg, 0.68 mmol) and 23 (90 mg, 0.34 mmol). DIAD (0.135 mL, 0.68 mmol) was added to the mixture dropwise. The reaction was warmed to room temperature and stirred for 4 h. The reaction mixture was treated with saturated aqueous NaHCO3 solution (2 mL), washed with water, followed by brine, dried over Na2SO4, and concentrated to give a crude mixture that was purified by column chromatography (30% 50% EtOAc in hexane) to give 36 as an oil.
Reaction SMILES: C(S([C:5]1[CH:25]=[C:24](N(CC)CC)[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH:22]=[O:23])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=1)=O)C.OC[C:33]([NH:35][NH2:36])=O>C(O)CCC>[CH:22]([NH:21][C:17]1[CH:16]=[C:15]([C:9]2[C:8]3[CH:24]=[CH:25][CH:5]=[CH:6][C:7]=3[N:13]3[CH:33]=[N:35][N:36]=[C:12]3[CH2:11][N:10]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: NNC(=O)CO
Reactant: CCN(CC)c1cc(S(=O)CC)cc2c1C(c1cccc(NC=O)c1)=NCC(=S)N2
Solvent: CCCCO
Product: O=CNc1cccc(C2=NCc3nncn3-c3ccccc32)c1

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-8-(ethylsulfinyl)-6-(diethylamino)-5-(m-formamidophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalcohol was refluxed to give 9-(ethylsulfinyl)-7-(diethylamino)-1-hydroxymethyl)-6-(m-formamidophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH+:11]([O-:36])[C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:2]=1
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(c1ccccc1NCc1ccncc1)[NH+]([O-])c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
212 mg (0.6 mmol) of N-(isoquinolin-3-yl)-2-(4-pyridylmethyl)aminobenzoic acid amide is mixed in 10 ml of dichloromethane with 103 mg (0.6 mmol) of m-chloroperbenzoic acid, and it is stirred for 6 hours at room temperature in a moisture-free environment and under argon. The batch is then washed with 15 ml of saturated sodium bicarbonate solution and with saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1 as an eluant. 68 mg (30% of theory) of N-(isoquinolin-3-yl)-2-(4-pyridylmethyl)aminobenzoic acid amide-N-oxide with a melting point of 212.2° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[OH:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccc1O

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2, 2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-hydroxy-benzoic acid (CAN 69-72-7) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 421.5080 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].CO>C1COCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:6])=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)cc1N
Reaction time: 2 h

Procedure:
A solution of 4,5-difluoro-2-nitroaniline (6)(1.0 g) in 30 mL of THF was treated with a solution comprised of 6 g of Na2S2O4 and 3 g NaHCO3 in 30 mL of water. Methanol (10 mL) was added after the addition of the aqueous solution so that the mixture remained homogeneous. The mixture was stirred for two hours and then diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was separated and the aqueous layer was extracted again with 100 mL of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the crude intermediate 4,5-difluorobenzene-1,2-diamine (7). The intermediate was refluxed with (ethoxymethylene)malononitrile (1.1 g) in 25 mL of isopropyl alcohol for 16 h. The mixture was concentrated in vacuo and the resulting crude product was suspended in water and filtered. The precipitate was washed with water and air-dried to provide 380 mg of 5,6-difluoro-1H-benzo[d]imidazole (8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].C(=O)(O)[O-].[K+]>C(#N)C.O>[Cl:24][CH2:25][C:26]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:27]
Reactant: Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CCl)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To 7.7 g (25 mmol) of 3,4-dibenzyloxyaniline in 50 ml of 1:1 acetonitrile/water at 0° C. was added chloroacetyl chloride (3.0 ml) while keeping the pH at 6.5 with saturated aqueous potassium bicarbonate. When the pH remained constant for 15 minutes, an additional 3 ml of chloroacetyl chloride was added in small portions while maintaining the pH at 6.5. When the pH remained constant for 15 minutes, the acetonitrile was evaporated, and the resulting aqueous solution was filtered. The precipitate was washed thoroughly with water to yield, upon drying in vacuo, 8.98 g of the title compound.