Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1.[CH2:13](N(CC)CC)C.CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine (480 mg, 2.09 mmol) and triethylamine (0.295 ml, 2.1 mmol) in DMF (4 ml) was added methyl iodide (2.1 ml of a 1.0M solution in DMF, 2.1 mmol) under an inert atmosphere. The reaction was stirred at room temperature overnight, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (260 mg), which was used without further purification. 1H NMR (400 MHz, CDCl3): 7.47 (1H, s), 7.45 (1H, s), 4.16-4.04 (1H, m), 3.09-2.92 (2H, m), 2.34 (3H, s), 2.30-2.10 (4H, m), 2.10-1.96 (2H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][CH:5]1[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>[Pd].C(O)C>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1
Reactant: CN(C)C(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)CC1CNCC(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N,N-dimethyl [1-(4-fluorobenzyl)-4-(benzyloxycarbonyl)-6-oxo-piperazin-2-yl]acetamide (0.5 g, 1.17 mmol) and 10% palladium on carbon (120 mg; 0.11 mmol) in ethanol (25 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The reaction mixture was filtered through a pad of Celite, and concentrated under vacuum to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.24-7.28 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 5.06 (d, J=14.8 Hz, 1H), 4.06 (d, J=14.8 Hz, 1H), 3.87-3.94 (m, 1H), 3.57-3.69 (m, 2H), 2.88-3.08 (m, 9H), 2.48 (d, J=16.3 Hz, 1H). ES MS (M+1)=294.3
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:12]=1[CH2:13][N:14]1[C:26]2[CH:25]=[N:24][C:23]([CH2:27][NH2:28])=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.COCCOC.C(N(CC)CC)C>ClCCCl>[Cl:10][C:11]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:12]=1[CH2:13][N:14]1[C:26]2[CH:25]=[N:24][C:23]([CH2:27][NH:28][C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:8])=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: ClCCCl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2cc3c4ccccc4n(Cc4cc(Cl)ccc4Cl)c3cn2)no1
Reaction time: 8 h

Procedure:
A solution of 5-methylisoxazole-3-carbonyl chloride in DCE (0.25M) was treated with a solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine in DME (0.25M, 1 equiv), followed by a solution of triethylamine in DME (1.0M, 1 equiv). The mixture was agitated, and allowed to stand overnight. The solvent was evaporated and the residue purified by preparative HPLC. 1H NMR (300 MHz, DMSO-d6) δ9.5 (br t, 1H), 9.40 (s, 1H), 8.74 (s, 1H), 8.60 (d,J=7.8 Hz, 1H) 7.78 (m, 1H), 7.66-7.60 (m, overlap, 2H), 7.50-7.41 (m, overlap, 2H), 6.69 (s, 1H), 6.65 (s, 1H), 5.97 (s, 1H), 4.96 (d, J=5.4Hz, 2H), 2.49 (s, overlap with DMSO peak). A peak at 13.7 ppm in the 13C NMR spectrum is consistent with the methyl group, which presumably overlaps with the solvent in the 1H NMR spectrum. Monoisotopic mass calcd for C24H18Cl2N4O2: 464.1, (M+H) found 465.4.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:33])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>C(Cl)(Cl)Cl>[OH:7][NH:8][C:9](=[O:33])[CH2:10][C:11]1([C:20]2[S:21][C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([C:38](=[O:39])[NH:37][CH:34]([CH3:36])[CH3:35])[CH2:13][CH2:12]1
Reactant: CCc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(C3(CC(=O)NO)CCN(C(=O)NC(C)C)CCS3(=O)=O)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
To a mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-ethylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (80 mg) in chloroform (3 ml) was added isopropyl isocyanate (16.6 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between water and chloroform. The organic layer was separated, washed with 5% citric acid water solution, water, saturated sodium bicarbonate solution and brine. To the reaction mixture were added 4N hydrogen chloride ethyl acetate solution (0.5 ml), chloroform (1 ml) and methanol (1.5 ml) and the reaction mixture was stirred at ambient temperature for 30 minutes. After evaporation of solvent, the residue was purified by HPLC (0.1% trifluoroacetic acid in 20% acetonitrile-water ˜0.1% trifluoroacetic acid in 80% acetonitrile-water) to give N-hydroxy-2-[7-(5-(4-ethylphenyl)-2-thienyl)-4-isopropylcarbamoyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (36 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:18](Cl)(=[O:20])[CH3:19]>>[CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)Cl
Reactant: CCCCS(=O)(=O)NC1Cc2ccccc2C1
Product: CCCCS(=O)(=O)NC1Cc2ccc(C(C)=O)cc2C1

Procedure:
2-n-Butylsulfonylaminoindane and acetyl chloride were treated in the same manner as in Example 31-(2) to obtain 2-n-butylsulfonylamino-5-acetylindane.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>CO.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2cnccn2)cc2c1[C@@H](CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-[1-hydroxy-4-methyl-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]-oxaborol-3-yl]-acetic acid ethyl ester (0.90 g, 2.74 mmol, 1st peak) in methanol (15 mL) was added a solution of LiOH (0.328 g, 13.7 mmol) in water (12 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with dilute hydrochloric acid and extracted with EtOAc (2×30 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.681 g, 82.8%). 1HNMR (400 MHz, DMSO-d δ 9.20 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.19 (dd, J=2.63, 1.46 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.51 (dd, J=9.51, 2.20 Hz, 1H), 3.07 (dd, J=15.52, 2.63 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:17]([O:20][C@@H:21]([C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)[CH3:22])(=[O:19])[CH3:18].C(N(CC)CC)C>C(O)(C)C>[C:17]([O:20][C@@H:21]([C:23]1[N:24]=[C:25]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=3)[CH2:13]2)[CH:26]=[CH:27][N:28]=1)[CH3:22])(=[O:19])[CH3:18]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 92 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mixture was stirred at room temperature for 1.75 h then heated to reflux for 1.5 h, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.68-7.58 (c, 2H), 7.47 (d, 1H), 6.44 (d, 1H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d, 3H); MS (TS) 431 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[CH3:22][C@@H:23]1[CH2:28][NH:27][C@@H:26]([CH3:29])[CH2:25][NH:24]1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:24]2[CH2:25][C@@H:26]([CH3:29])[NH:27][CH2:28][C@@H:23]2[CH3:22])=[C:4]2[CH:9]=[N:10][CH:11]=[CH:12][C:3]=12
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: Clc1nnc(Cl)c2cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2nnc(Cl)c3ccncc23)[C@@H](C)CN1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 1,4-dichloropyrido[3,4-d]pyridazine 3 (4.80 g, 24.0 mmol) and Hünig's Base (14.7 ml, 84.0 mmol) in NMP (10 ml) was added (2R,5S)-2,5-dimethylpiperazine (4.11 g, 36.0 mmol). The reaction was stirred at 100° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (10× volume) and extracted with dichloromethane (4×50 mL). Silica gel chromatography (gradient 0 to 2.5% MeOH in 30% EtOAc in CH2Cl2 with 2.5% TEA additive) provided 1.4 g of 1-chloro-4-(rac-2,5-trans-dimethylpiperazine-1-yl)pyrido[3,4-d]pyridazine 43. 1H NMR (500 MHz, CDCl3) δ ppm 9.66 (s, 1H) 9.08 (d, J=5.6 Hz, 1H) 7.97 (d, J=5.6 Hz, 1H) 3.77 (tdd, J=11.8, 5.9, 3.4 Hz, 1H) 3.43 (dd, J=12.1, 2.6 Hz, 1H) 3.17-3.32 (m, 2H) 2.91 (dd, J=10.5, 2.0 Hz, 1H) 2.74 (dd, J=11.7, 10.3 Hz, 1H) 1.13 (d, J=6.1 Hz, 3H) 1.12 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C[Si](Cl)(C)C.C(N(C(C)C)C(C)C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-azetidine carboxylic acid (0.50 g, 4.9 mmol), trimethylsilyl chloride (1.25 ml, 9.8 mmol) and N-ethyldiisopropylamine (2.20 ml, 12.6 mmol) was heated under reflux in dichloromethane (20 ml) for 20 minutes. The reaction mixture was cooled in an ice bath and benzyl chloroformate (0.92 ml, 6.4 mmol) added. The mixture was stirred at room temperature for 72 hours before quenching with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase was acidified to pH2 with 2N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a brown oil, 1.01 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28](B(O)O)=[CH:27][N:26]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:3][C:2]=1[C:28]1[CH:27]=[N:26][C:25]([Cl:24])=[CH:30][C:29]=1[Cl:31]
Reactant: O=S(=O)(c1ccc(Cl)c(Br)c1)N1CCCCc2ccccc21
Reactant: OB(O)c1cnc(Cl)cc1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)c(-c2cnc(Cl)cc2Cl)c1)N1CCCCc2ccccc21
Temperature: 50 °C
Yield: 8.7 %

Procedure:
To a suspension of 1-(3-bromo-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, 2,4-dichloropyridine-5-boronic acid hydrate, tri-t-butylphosphonium tetrafluoroborate and tris(dibenzylideneacetone)dipalladium(0) in THF (0.73 mL) was added potassium hydroxide aqueous solution (0.05 g in 0.18 mL water). The suspension was bubbled with N2 for 5 min and then heated at 50° C. for 12 hrs. This mixture was cooled to it and concentrated. The residue was purified by silica gel column chromatography eluting with (hexanes/ethyl acetate, 20/1) to yield 1-[4-chloro-3-(4,6-dichloro-pyridin-3-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepine 5-1 (9 mg, 8.7% yield). MS: 467 (M+H)+; tR=9.95 min (method 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.O1CCOCC1.[Cl:19][C:20]1[C:32](I)=[CH:31][C:23]2[NH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:19][C:20]1[C:32]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[CH:31][C:23]2[NH:24][C:25]([C:27]([F:29])([F:30])[F:28])=[N:26][C:22]=2[CH:21]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3cc(Cl)cc(Cl)c3Cl)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Compound number 261 (i.e., 6-chloro-5-(2,3,5-trichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen. (2,3,5-trichlorophenyl)boronic acid (284 mg, 1.26 mmol, 2.00 equiv), dioxane (30 mL), 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.58 mmol, 1.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed in the flask. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 22.3 mg (10%) of 6-chloro-5-(2,3,5-trichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[N:8]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:7](=[O:15])[CH:6]1[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:32]C(OCC1C=CC=CC=1)=O)=[N:21]C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2].[ClH:43]>[Pd].CO.C(OCC)(=O)C>[ClH:43].[C:1]([O:4][CH:5]1[N:8]([C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[C:7](=[O:15])[CH:6]1[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH2:32])=[NH:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(=O)C(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1C(CCCNC(=N)N)C(=O)N1C(=O)C(C)(C)C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A methanol/ethyl acetate solution of compound 41 (300 mg, 0.5 mmol) and 1N HCl (0.52 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere for 30 min. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 0.1 g (64%) of the title product as a mixture of trans and cis (3:2) isomers.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[NH2:32]>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)=[CH:34][CH:35]=1
Reactant: Cc1ccc(C(N)=NO)cc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1ccc(-c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)cc1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-4-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 68 mg (66% of theory)
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17](C(=O)C)[CH:16]=1)(=[O:14])[CH3:13].[OH-].[Li+].[OH-].[Na+]>ClCCl>[C:21]([C:19]1[CH:20]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=[C:17]([OH:9])[CH:18]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)c1cc(C(C)=O)cc(C(C)(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
m-Chloroperbenzoic acid (382 g, 2.21 mol) was added to a solution of 1,3-bisacetyl-5-tert-butylbenzene (O4.106; 169 g, 776 mmol) in dichloromethane (1.7 l). The resulting suspension was heated to reflux temperature for 24 h. Once the suspension had cooled, the solids were filtered off and the filtrate was admixed with saturated aqueous NaHSO3 solution (500 ml). The phases were separated, the organic phase was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in THF (500 ml) and admixed with lithium hydroxide (34.9 g, 1.46 mol). After 4 h at RT, aqueous sodium hydroxide solution (1 M, 500 ml) was added and the mixture was washed with MtB ether (3×500 ml). The aqueous phase was acidified (pH 3) with HCl (1 M), and extracted with EA (3×500 ml). The combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (met. C). The product was obtained as a colorless oil which crystallized slowly (36.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(Cn3cncn3)c2nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cn3cncn3)c2[nH]c1=O
Yield: 66.3 %

Procedure:
6,7-Dichloro-2,3-dimethoxy-5-(1,2,4-triazol-1-ylmethyl)-quinoxaline (99 mg, 0.29 mmol) was heated in a mixture of 2M hydrochloric acid (2 mL) and dioxane (2 mL) at reflux for 3 hours. The solvent was removed under reduced pressure and the solid residue was suspended in water and filtered to give 1,4-dihydro-6,7dichloro-5-(1,2,4-triazol-1-ylmethyl)-quinoxalin-2,3-dione (60 mg, 62%) as a white solid, mp>320° C. Found: C, 39.47; H 2.49; N, 20.54. C11H7Cl2N5O2.1.25.H2O requires C, 39.48; H 2.86; N, 20.93%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1COCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30](=[O:31])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (121.0 mL of a 2.0 M solution, 0.243 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. 2,6-Dimethyl-7-octen-2-yl acetate (22.66 g, 0.114 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 4-nitrobenzoyl chloride (20.00 g, 0.108 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (70 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].[H-].[Na+]>C1COCC1>[CH2:8]([C@H:5]1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:3]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:2]=2[O:7][CH2:6]1)[CH3:9]
Reactant: CC[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Yield: 75.3 %

Procedure:
This compound was prepared according to General Method 20 from (2R )-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol (5.4 g, 17.3 mmol) in 45 mL THF and NaH (1.4 g, 35 mmol) in 10 mL THF heated at reflux for 1 hr to afford 3.78 g (75%) of (3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, after flash chromatography (gradient elution, hexanes:ethyl acetate 95:5 to 50:50). Data for (3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: 1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J=8.8, 2.4, 1H), 7.73 (d, J=2.9, 1H), 6.72 (d, J=8.8, 1H), 4.34 (dd, J=11.2, 1.5, 1H), 4.13 (m, 1H), 4.03 (dd, J=11.2, 2.4, 1H), 3.8 (m, 1H), 3.37 (m, 1H), 1.67 (m, 1H), 1.01 (t, J=7.3, 3H).