Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].C(O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:10]([Cl:21])[CH:9]=1)(=O)C.[O:22]1CCC[CH2:23]1>>[Cl:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:23][OH:22])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: C1CCOC1
Reactant: COCCOCOc1ccc(COC(C)=O)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Product: COCCOCOc1ccc(CCO)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2.4 g (110 mmol) of lithium borohydride is added in portions to a solution of 10.6 g (36.7 mmol) of [3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate diluted in 110 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 2 hours. The reaction mixture is then poured into 500 ml of ice and then extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The solvents are evaporated to give 7.3 g (77%) of 2-[3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH2:27][CH2:28][CH:29]([CH:31]4[C:47]5([CH3:48])[CH:34]([CH:35]6[CH:44]([CH2:45][CH:46]5[O:49]C=O)[C:43]5([CH3:52])[CH:38]([CH2:39][CH:40]([O:53]C=O)[CH2:41][CH2:42]5)[CH2:37][CH:36]6[O:56]C=O)[CH2:33][CH2:32]4)[CH3:30])=[O:26])=[CH:20][CH:19]=3)=[C:13]([NH:59][C:60]3[C:61]4[CH:69]=[CH:68][C:67]([CH:70]([CH3:72])[CH3:71])=[N:66][C:62]=4[N:63]=[CH:64][N:65]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[CH2:27][CH2:28][CH:29]([CH:31]4[C:47]5([CH3:48])[CH:34]([CH:35]6[CH:44]([CH2:45][CH:46]5[OH:49])[C:43]5([CH3:52])[CH:38]([CH2:39][CH:40]([OH:53])[CH2:41][CH2:42]5)[CH2:37][CH:36]6[OH:56])[CH2:33][CH2:32]4)[CH3:30])=[CH:20][CH:19]=3)=[C:13]([NH:59][C:60]3[C:61]4[CH:69]=[CH:68][C:67]([CH:70]([CH3:72])[CH3:71])=[N:66][C:62]=4[N:63]=[CH:64][N:65]=3)[CH:12]=2)=[N:6][CH:7]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)CCC(C)C4CCC5C6C(OC=O)CC7CC(OC=O)CCC7(C)C6CC(OC=O)C45C)cc3)ncnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)CCC(C)C4CCC5C6C(O)CC7CC(O)CCC7(C)C6CC(O)C45C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
The product of Example 358B (162 mg, 0.1527 mmol) was suspended in methanol (2 mL) and treated with 10% sodium hydroxide in methanol (2 mL), sonicated briefly to achieve dissolution, and stirred at room temperature for one hour. The solvent was removed by rotary evaporation in vacuo and the residue taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous pH was adjusted to 5 with 1N aqueous hydrochloric acid and the layers separated. The organic phase was washed with water (50 mL) and brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography with a gradient of 8% to 10% methanol/methylene chloride afforded the title compound (137 mg, 0.140 mmol, 92%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.60 (s, 3 H) 0.81 (s, 3 H) 0.98 (d, J=5.88 Hz, 3 H) 1.12-2.52 (m, 24 H) 1.33 (d, J=6.99 Hz, 6 H) 3.12-3.31 (m, 2 H) 3.55-3.69 (m, 1 H) 3.75-3.87 (m, 1 H) 4.02 (d, J=3.31 Hz, 1 H) 4.13 (d, J=3.68 Hz, 1 H) 4.32 (d, J=4.41 Hz, 1 H) 6.89-7.05 (m, 1 H) 7.40 (d, J=8.46 Hz, 2 H) 7.57-7.66 (m, 1 H) 7.68 (d, J=8.46 Hz, 2 H) 7.81-7.95 (m, 1 H) 8.01-8.12 (m, 2 H) 8.16 (d, J=8.82 Hz, 1 H) 8.50 (d, J=2.57 Hz, 1 H) 8.53-8.67 (m, 1 H) 8.76-8.96 (m, 1 H) 10.09 (s, 1 H) 10.21 (br s, 1 H) 10.97 (br s, 1 H); MS (ESI+) m/z 977/979 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:20][CH2:19][N:18]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH2:9][CH2:8][CH2:7]2.[F:27][C:28]([F:33])([F:32])C([O-])=O.[Na+].CN1CCCC1=O.O>[Cu](I)I.C(OCC)(=O)C>[F:25][C:22]([F:24])([F:23])[C:21]([N:18]1[CH2:19][CH2:20][C:3]2[C:2]([C:28]([F:33])([F:32])[F:27])=[C:11]3[C:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:12][CH2:13][O:14][CH3:15])=[CH:5][C:4]=2[CH2:16][CH2:17]1)=[O:26]
Reactant: O=C([O-])C(F)(F)F
Reactant: COCCN1CCCc2cc3c(c(Br)c21)CCN(C(=O)C(F)(F)F)CC3
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCN1CCCc2cc3c(c(C(F)(F)F)c21)CCN(C(=O)C(F)(F)F)CC3
Temperature: 170 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
1.1946 g of 1-[11-bromo-1-(2-methoxyethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]-2,2,2-trifluoroethanone, 2.2395 g of sodium trifluoroacetate, and 1.568 g of copper iodide were added to 24 ml of N-methylpyrrolidone under an argon atmosphere, followed by stirring at 170° C. for 18 hours. To the reaction mixture were added water and ethyl acetate, and filtered through celite was performed. The filtrate was subjected to liquid separation, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: Hex-AcOEt) to obtain 239 mg of 2,2,2-trifluoro-1-[1-(2-methoxyethyl)-11-(trifluoromethyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-yl]ethanone as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].C(N(CC)CC)C.Cl.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1.CO>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1

Procedure:
Compound 9 (689 mg, 3 mmol) was suspended in acetonitrile (5 mL) and then triethylamine was added (1.3 mL, 9 mmol). trans-4-aminocyclohexanol hydrochloride (682 mg, 4.5 mmol) was then added and the reaction refluxed for 12 hours, 2 mL methanol was then added and the reaction further refluxed for another 24 hours. Water (100 mL) was added and the resulting precipitate filtered, washed 3 times with water and air-dried. The product was used without further characterization in the next step MS: 309.3 (M+H+).
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[C:13]([CH3:21])[CH:12]=1)([F:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C1CCC=CC=1>C1COCC1.[Ni]>[F:10][C:2]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[C:13]([CH3:21])[CH:12]=1)([F:1])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: Cc1cc(C(F)(F)CN2CCOCC2)cc([N+](=O)[O-])c1N
Agent: [Ni]
Solvent: C1CCOC1
Solvent: C1=CCCC=C1
Product: Cc1cc(C(F)(F)CN2CCOCC2)cc(N)c1N
Reaction time: 3.5 h

Procedure:
To a solution of 4-(1,1-difluoro-2-morpholin-4-yl-ethyl)-2-methyl-6-nitro-phenylamine (60 mg, 0.2 mmol) in THF (5 mL) was added Raney nickel (100 mg) and cyclohexadiene (0.5 mL). TLC indicated the formation of the product after the reaction mixture was stirred for 3.5 h). The reaction mixture was filtered over Celite and evaporated to afforded crude title product that was used for the next step reaction without purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[NH2:30])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]OC(OC)OC>C(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[C:24]5[CH:29]=[CH:28][N:27]=[CH:26][C:25]=5[N:30]=[CH:31]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC(OC)OC
Solvent: O=CO
Product: c1cc2c(cn1)ncn2CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 24 h
Yield: 65 %

Procedure:
N*4*-{4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-ylmethyl}-pyridine-3,4-diamine (280 mg, 0.68 mmol), trimethylorthoformate (5 mL) and formic acid (0.5 mL) were stirred at 40° C. for 18 hours then at 60° C. for 24 hours, then at 80° C. for 24 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1 by volume) to provide the title compound as a clear viscous oil (185 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 4H), 1.91-2.03 (m, 4H), 2.15-2.20 (m, 2H), 2.52 (m, 4H), 2.61 (t, 2H), 3.44 (m, 2H), 3.82 (m, 2H), 4.00 (t, 2H), 4.19 (s, 2H), 6.82 (d, 2H), 6.86-6.93 (m, 3H), 7.08 (s, 1H), 8.30 (d, 1H), 9.01 (s, 1H). HRMS ESI+ m/z 421.2590 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[F:11][C:12]([F:19])([F:18])[C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH:14]=[C:13]([C:12]([F:19])([F:18])[F:11])[CH:17]=[N:16]2)=[C:3]([CH3:10])[CH:4]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: COc1ccc(Br)c(C)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2cc(C(F)(F)F)cn2)c(C)c1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
To a mixture of 1-bromo-4-methoxy-2-methylbenzene (1.5 g, 7.5 mmol) in N,N-dimethylformamide (15 mL) was added 4-(trifluoromethyl)-1H-pyrazole (1.12 g, 8.21 mmol), copper(II) oxide (107 mg, 0.746 mmol), and cesium carbonate (4.86 g, 14.9 mmol). The mixture was heated in a microwave to 120° C. for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 1-(4-methoxy-2-methylphenyl)-4-(trifluoromethyl)-1H-pyrazole (550 mg, 29%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 7.81 (s, 1H), 7.74 (s, 1H), 7.16 (m, 1H), 6.74 (m, 2H), 3.77 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: C(N[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(CC)C.[N+](C1C=CC=C[C:26]=1[OH:31])([O-])=O.[N+](C1C=C(C(C)(C)C)C=C([N+]([O-])=O)C=1O)([O-])=O.CI.C(=O)([O-])[O-].[K+].[K+]>>[C:15]([C:9]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]([O:31][CH3:26])=[C:7]([N+:19]([O-:21])=[O:20])[CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
An alternative synthesis for N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is set forth in U.S. Pat. Nos. 4,289,907 and 4,395,572 to Chan. The starting material in this synthesis is a nitrophenol such as 2,6-dinitro-4-tert-butylphenol. The nitrophenol is methylated by reaction with methyl iodide/potassium carbonate to produce 4-tert-butyl-2,6-dinitroanisole. The 4-tert-butyl-2,6-dinitroanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline. While effective in producing the desired product, this process also suffers from a number of distinct disadvantages.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[N+:19]([C:22]1[CH:52]=[CH:51][C:25]([CH2:26][O:27][C:28]([N:30]=[C:31]([NH:37][C:38](=[O:50])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)N2C=CC=N2)=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]([N:30]=[C:31]([NH:37][C:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:50])[NH:1][C@H:2]([CH3:18])[C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])=[O:29])=[CH:51][CH:52]=1)([O-:21])=[O:20]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](N)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 100.6 %

Procedure:
To a solution of tert-butyl (3S)-3-[(2R)-2-amino-2-methylacetylamino]-1-pyrrolidinecarboxylate (448 mg) in anhydrous tetrahydrofuran (20 ml), 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (776 mg) was added under ice cooling. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(1), whereby the title compound (1.096 g) was obtained as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCCO
Reactant: O=Cc1ccnc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Brc1cc(C2OCCO2)ccn1
Yield: 80.9 %

Procedure:
60 g of 2-bromo-4-pyridinecarboxaldehyde was dissolved in 600 ml of benzene, and 40 g of ethylene glycol and 6 g of p-toluenesulfonic acid were put in the solution. The mixture was heated under reflux for 18 hours while water was removed by using a Dean-Stark trap. After the reaction, the reaction mixture was made basic by adding ice and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with water and dried. The solvent was evaporated. The residue was distilled to give 60 g (yield 82%) of 2-bromo-4-(1,3-dioxolan-2-yl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](OC(C)(C)C)=[O:19])=[N:9][N:10]([CH3:12])[CH:11]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=1)=C=O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:47])[F:48])=[CH:41][CH:40]=3)=[O:19])=[N:9][N:10]([CH3:12])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1cc(Cc2ccc(Cl)cc2)c([C@H]2CCCN2C(=O)OC(C)(C)C)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2ccc(Cl)cc2)c([C@H]2CCCN2C(=O)Nc2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1-methyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (39 mg, 0.1 mmol) was dissolved in 4M HCl in 1,4-dioxane (2 mL), stirred for 2 hr and then concentrated in vacuo. The resulting residue was then suspended in dichloromethane (2 mL) and DIEA (34 μL, 0.2 mmol) before 1-isocyanato-4-(trifluoromethyl)benzene (28 μL, 0.15 mmol) was added. After 16 h of stirring, the reaction mixture was concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-2-(4-(4-chlorobenzyl)-1-methyl-1H-pyrazol-3-yl)-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamide (12 mg, 26%).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH2:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][NH:28][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:32][CH:33]=1
Reactant: NCc1cccc(COc2ccc(Cl)cc2)c1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCc2cccc(COc3ccc(Cl)cc3)c2)c(Nc2cccnc2)c1=O
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 3-(4-chlorophenoxy-methyl)-benzylamine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5]([Cl:16])=[O:6]
Reactant: CCCCC(CC(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Product: CCCCC(CC(=O)Cl)C(F)(F)F
Yield: 83.1 %

Procedure:
2.0 g (10 mmol) of 3-trifluoromethylheptanoic acid and 6 ml (about 80 mmol) of thionyl chloride were reacted for 2 hours under heat-refluxing, followed by distillation to obtain 1.8 g of 3-trifluoromethylheptanoic acid chloride (b.p.: 72.2-75.0° C./25 mmHg). The acid chloride was dissolved in 10 ml of diethyl ether and added dropwise to a preliminarily ice-cooled ether solution of diazomethane, followed by stirring overnight at room temperature. After distilling off the solvent, the remainder was suspended in 15 ml of dioxane and then added to an aqueous solution at 70° C. of 1.1 g of silver oxide and 2.7 g of sodium thiosulfate (penta-hydrate), followed by stirring for 70 min. After the reaction, potassium hydroxide aqueous solution was added thereto and the mixture was filtered. 5N-nitric acid was added to the filtrate to provide an acidity as judged by Congo Red, followed by extraction with diethyl ether. The resultant ether layer was dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and distillation of the product to obtain 0.42 g of objective 4-trifluoromethyloctanoic acid (b.p.: 130-135° C./26 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH:19]([Mg]Br)=[CH2:20].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:20]=[CH:19]2
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2[nH]ccc2c1
Temperature: -45 °C
Reaction time: 0.75 h

Procedure:
Combine 3-bromo-4-nitro-1-tert-butyldimethylsilyloxybenzene and dry THF. Cool to about −45° C. and then treat with vinylmagnesium bromide (1.2 eq.) over a few minutes. After about 45 minutes, pour the reaction mixture into saturated aq. NH4Cl, extract with ether, combined the organic extracts and extract with water, dry over Na2SO4 and concentrate. Purify to give 7-bromo-5-(tert-butyldimethylsilanyloxy)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@H:18]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])[CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.58 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (176 mg, 0.54 mmol) [prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (336 mg, 0.72 mmol) in chloroform (6 mL). DIEA (520 μL, 2.98 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (336 mg, 0.61 mmol, quant.): LC-MS (ES) m/z=526 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[N:6][CH:7]=[N+:8]([O-:15])[CH:9]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1cnc[n+]([O-])c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of 5-ethoxypyrimidine (2.00 g, 16.1 mmol) in CH2Cl2 (100 mL) was added 3-chloroperoxybenzoic acid, 50-60% tech. grade, (6.13 g, 17.7 mmol) and the reaction stirred at 23° C. for 18 h. The reaction was extracted with water (2 mL) containing Na2CO3 (1.71 g, 16.1 mmol). The organic phase was dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure to afford the N-oxide (1.75 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.CC(C)([O-])C.[K+].P(Cl)(OCC)(OCC)=O.[C:36]([NH:39][NH2:40])(=O)[CH3:37]>O1CCCC1.C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:36]([CH3:37])=[N:39][N:40]=[C:11]2[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(I)ccc2N1
Reactant: CC(=O)NN
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: CCCCO
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of 15.7 g (0.04 mol) of 5-(2-chlorophenyl)-7-iodo-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 350 ml of tetrahydrofuran was cooled to -30° C. potassium t-butoxide. 4.9 g (0.044 mol) was added and stirring under nitrogen was continued for 30 minutes at -10° to -5° C. Diethyl chlorophosphate, 6.6 ml, was then added and the mixture was stirred at this temperature for another 30 minutes. Following the addition of 3.4 g of acetyl hydrazine, stirring without cooling was continued for 1 hour and 150 ml of n-butanol was added. The tetrahydrofuran was distilled out of the reaction mixture over a period of 45 minutes. The residue was partitioned between water and toluene. The organic phase was washed with brine, dried over sodium sulfate and evaporated down to a small volume. The precipitated crystals were collected to leave 14 g of crude product which was purified by chromatography over 250 g of silica gel using 5% ethanol (V/V) in methylene chloride. The clean fractions were combined and evaporated. Crystallization from tetrahydrofuran/ethanol gave 8.5 g (49%) of 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with m.p. 290°-292° C.