Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:10])[S:8][C:4]=2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:26]=[CH:25][C:5]4[N:6]=[C:7]([C:9]([NH:11][CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]5)=[O:10])[S:8][C:4]=4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3s2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a stirred solution of tert-butyl 4-(6-hydroxybenzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate (0.20 g, 0.54 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.13 g, 0.64 mmol), 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.13 g, 0.54 mmol), and triphenylphosphine (0.17 g, 0.64 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=3/7) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamido)piperidine-1-carboxylate (compound 14) as a white solid (0.28 g, 86%). 1H-NMR (CDCl3, 300 MHz): δ 7.95 (m, 1H), 7.48 (m, 3H), 7.27 (m, 1H), 7.17 (m, 1H), 6.97 (m, 2H), 4.62 (m, 1H), 4.12 (m, 3H), 3.61 (m, 2H), 3.29 (m, 2H), 2.95 (m, 2H), 2.06 (m, 6H), 1.56 (m, 2H), 1.41 (s, 9H) ppm; MS (ESI): 605.5 (M+1).
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:40])[CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:30](=[O:40])[CH2:31][C@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH2:33])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H](CC(=O)NCc1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@H](CC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Yield: 81.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-β-phenylalanine N-benzylamide (286 mg, 1.06 mmol, 2.0 eq) and dichloromethane (1.5 mL), was treated with triethylamine (442 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (673 uL, 2.0 eq), to provide 229 mg (81%) of L-β-phenylalanine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:21]=[C:20]([CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:19]=[CH:18][CH:17]=3)=[O:15])=[C:9]([C:37]3[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=4)[CH:40]=[CH:39][N:38]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[N:23]1([CH2:22][C:20]2[N:21]=[C:16]([C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][C:9]=3[C:37]3[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:53])([F:55])[F:54])[CH:47]=4)[CH:40]=[CH:39][N:38]=3)=[O:15])[CH:17]=[CH:18][CH:19]=2)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-((6-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)pyridin-2-yl)methyl)-1,4-diazepane-1-carboxylate (150 mg, 0.18 mmol, 1.00 equiv, 95%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The solution was adjusted to pH 9 with aqueous sodium bicarbonate. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 120 mg (97%) of a yellow solid.
Reaction SMILES: CN1C(=O)CCC1.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].[CH3:30][C@:31]1([CH2:39][N:40]2[C:44]3[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=3[N:42]=[CH:41]2)CCC[C@:33]2(OC2)[CH2:32]1>CC#N>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[CH2:21][C@@:19]3([CH2:20][CH2:33][CH2:32][C@@:31]([CH2:39][N:40]4[C:44]5[CH:45]=[C:46]([C:49]#[N:50])[CH:47]=[CH:48][C:43]=5[N:42]=[CH:41]4)([CH3:30])[CH2:22]3)[O:18][C:17]2=[O:23])=[CH:12][CH:11]=1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: COc1ccc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 33.6 %

Procedure:
To a 4 mL vial was added NMP (1997 μL), tert-butyl (6-methoxypyridin-3-yl)carbamate (448 mg, 1.997 mmol) and potassium tert-butoxide (213 mg, 1.898 mmol) at RT. After stirring for ˜1 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (281 mg, 0.999 mmol) was added. The solution was then heated to 55° C. and stirred for 17 h. The resulting solution was cooled to RT, diluted with 2 mL of MeCN, then purified on HPLC: 20-60% MeCN/Water over 14 min, Sunfire C-18 column, 0.1% TFA. Fractions containing product were added to a separatory funnel, diluted with DCM and saturated NaHCO3. DCM layer was separated, passed over a phase separator and concentrated to give 1-(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (145 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=4, 12 Hz, 2H), 8.06 (s, 1H), 7.91 (d, J=4 Hz, 1H), 7.76 (s, 1H), 7.58 (dd, J=4 Hz, 1H), 6.80 (d, J=12 Hz, 1H), 4.02 (s, 2H), 3.94 (s, 3H), 3.66 (q, J=8 Hz, 2H), 2.14-2.18 (m, 1H), 1.94-2.00 (m, 2H), 1.66-1.77 (m, 2H), 1.51 (d, J=16 Hz, 1H), 1.36-1.44 (m, 2H), 1.33 (s, 3H). MS (m/z) 432.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]2[O:20][CH2:21][CH2:22][O:23][C:17]2=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[Cl:24][CH2:25][C:26](=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:28]([C:27]1[C:26]([CH2:25][Cl:24])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]1[O:23][CH2:22][CH2:21][O:20][C:18]=1[CH:19]=2)=[O:29])[CH3:32]
Reactant: COc1ccc(C(=O)c2cc3c(cc2N)OCCO3)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc3c(cc2c1-c1ccc(OC)c(OC)c1)OCCO3
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a mixture of 2-amino-3',4'-dimethoxy-4,5-ethylenedioxybenzo-phenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml), concentrated sulfuric acid (0.3 ml) was added, followed by stirring at 100° C. for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured over water and alkalinized with 2 N NaOH and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to yield 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-ethylenedioxyquinoline-3-carboxylic acid ethyl ester (5.5 g, 60%), which was then recrystallized from acetone to yield a colorless prismatic crystal having a melting point of 197 to 198° C.
Reaction SMILES: C(OC(NC1C=C([C:15]2[C:24]3[NH:23][C:22](=[O:25])[C:21](=[O:26])[NH:20][C:19]=3[C:18]3[CH2:27][CH2:28][CH2:29][CH2:30][C:17]=3[CH:16]=2)C=CC=1)=O)(C)(C)C.F[C:32](F)(F)[C:33](O)=O>ClCCl>[NH2:20][C:19]1[CH:18]=[C:17]([N:23]2[C:24]3[CH:15]=[CH:16][C:17]4[CH2:30][CH2:29][CH2:28][CH2:27][C:18]=4[C:19]=3[NH:20][C:21](=[O:26])[C:22]2=[O:25])[CH:16]=[CH:32][CH:33]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cc3c(c4[nH]c(=O)c(=O)[nH]c24)CCCC3)c1
Solvent: ClCCl
Product: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reaction time: 1 h

Procedure:
To a dichloromethane (15 mL) solution of 5-(3-tert-butoxycarbonylaminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (180 mg, 0.440 mmol) was added dropwise a dichloromethane (3 mL) solution of trifluoroacetic acid (2 mL) under cooling in an ice-bath. The mixture was stirred for one hour under cooling in ice-bath. The solvent was removed by evaporation under reduced pressure. The obtained solid was washed with ethyl acetate and water, and dried to obtain 4-(3-aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (93 mg). The obtained compound was dissolved in dichloromethane (5 mL) and methanol (2 mL). To the solution, a 2M hydrogen chloride/methanol solution (0.15 mL) was added. The solvent was removed by evaporation under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was stirred at room temperature for 18 hours, filtered, and dried to obtain the titled compound as a white crystal (80 mg, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4'-chloropropiophenone (39.6 g) and anhydrous aluminum chlorid (0.1 g) were dissolved in 100 ml of chloroform. To the resulting solution was protionwise added bromine (37.6 g) at a temperature of 30° to 35° C. The reaction mixture was stirred at room temperature for 30 minutes. Then nitrogen was blown into the reaction mixture to remove the formed hydrogen bromide therefrom. Thereafter, the solvent was distilled off under reduced pressure to give 2-bromo-4'-chloropropiophenone (58.1 g). mp 77.5°-79.5° C.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:22][CH2:21]2)=[O:19])[CH:9]=1.C(N(CC)CC)C.[CH3:62][CH:63]([NH2:65])[CH3:64]>C(Cl)Cl>[CH:63]([NH:65][CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][NH:41][C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:24][CH2:25]2)=[O:19])[CH:9]=1)([CH3:64])[CH3:62]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reactant: CC(C)N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride (2.8 0.036 mmol) in methylene chloride (0.20 mL) was added to a mixture of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (21 mg, 0.030 mmol, prepared as in Example 376, Step E) and triethylamine (8.4 μL, 0.060 mmol) in methylene chloride (1.0 mL) at 0° C. After 15 minutes, 2-propanamine (20 μL, 0.3 mmol) was added. The mixture was then heated to 40° C. After 1.5 hours, additional 2-Propanamine (20 μL, 0.3 mmol, Aldrich) was added and the reaction heated for a total of 3 hours at this temperature. The mixture was concentrated in vacuo. The residue was stirred for 1 hour in a 1:1 mixture of TFA/DCM, then concentrated again. The residue was redissolved in MeOH (1.0 mL) and ethylenediamine (0.2 mL) was added. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 11.6 mg (63%); LC-MS: 608.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.61 (d, 1H), 7.07 (d, 1H), 41.2-4.02 (m, 1H), 3.94 (s, 2H), 3.75 (dd, 2H), 3.63-3.45 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.75 (septet, 1H), 2.61-2.53 (m, 1H), 1.84-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.36-1.19 (m, 2H), 1.01 (d, 6H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[N:23][O:24][C:25]=3[CH3:26])=[N:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of cyclopropylmethylamine (85 mg, 103 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (78 mg, 68%) which was obtained as an off white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:13]2[NH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10][C:9]=2[CH:8]=[C:7]([N+:18]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C:5]1[C:13]2[NH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[N:10][C:9]=2[CH:8]=[C:7]([NH2:18])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2nc(C(F)(F)F)[nH]c12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc2nc(C(F)(F)F)[nH]c12
Yield: 160 %

Procedure:
4-tert-Butyl-6-nitro-2-trifluoromethylbenzimidazole (6.0 grams of crude) was dissolved in 100 milliliters of ethanol and a small amount of platinum oxide was added. The reaction mixture was then placed in a pressure container and hydrogenated until hydrogen uptake ceased. The reaction mixture was filtered and solvent removed to yield 8.6 grams of crude 4-tert-butyl-6-amino-2-trifluoromethylbenzimidazole, as a brown oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[F-].[K+].Cl>C(Cl)Cl>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cc1
Temperature: 180 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
A mixture of 2-fluoro-nitrobenzene (33.7 g), 4-chloroaniline (61.0 g) and anhydrous potassium fluoride (13.9 g) was stirred at 180° C. for 10 h. After being cooled to rt, 3 M HCl was added and the mixture was stirred at 100° C. for 30 min. Then cooled to rt, filtered by suction, washed with water to give a brown solid. The solid was dissolved in CH2Cl2 and filtered through a thin pad of silica gel, washed with CH2Cl2. The filtrate was concentrated to dryness, and the residue was recrystallized with 95% ethanol to give 57.0 g of orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:22]([NH:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=3)=[O:23])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2c(N)cccc12
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: Cc1nccc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc12

Procedure:
Prepared from 1-methylisoquinolin-5-amine (Description 68) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 376 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:22]=[C:21]4[C:17]([C:18]([C:23]5[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=5)=[CH:19][NH:20]4)=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]2[C:17]3[C:21](=[CH:22][C:14]([NH:13][C:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[CH:3]=[CH:4]5)=[O:12])=[CH:15][CH:16]=3)[NH:20][CH:19]=2)=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc([N+](=O)[O-])cc5)c[nH]c4c3)ccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccc2cc(C(=O)Nc3ccc4c(-c5ccc(N)cc5)c[nH]c4c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a slurry of 1-methyl-N-(3-(4-nitrophenyl)-1H-indol-6-yl)-1H-indole-5-carboxamide (59.0 mg, 0.14 mmol) in ethanol (1.50 mL) under an atmosphere of nitrogen was added 20 wt % palladium hydroxide on carbon (5.9 mg, 10 wt %), followed by a balloon of hydrogen. The reaction was stirred overnight at room temperature and was then filtered through a pad of Celite, rinsing with excess methanol and methylene chloride. The filtrate was concentrated to give a grey-pink solid for N-(3-(4-aminophenyl)-1H-indol-6-yl)-1-methyl-1H-indole-5-carboxamide (56.9 mg, 0.14 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([S:31]([OH:34])(=[O:33])=[O:32])[CH:16]=[C:17]3[C:22]=2[C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][C:19]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:18]3)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:86][C:87](=O)[C:88]2[CH:93]=[CH:92][C:91]([N+:94]([O-:96])=[O:95])=[CH:90][C:89]=2[S:97]([OH:100])(=[O:99])=[O:98])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[N+:94]([C:91]1[CH:92]=[CH:93][C:88]([C:87]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([NH:12][C:13]3[CH:14]=[C:15]([S:31]([OH:34])(=[O:33])=[O:32])[CH:16]=[C:17]4[C:22]=3[C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:20][C:19]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:18]4)(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[O:86])=[C:89]([S:97]([OH:100])(=[O:98])=[O:99])[CH:90]=1)([O-:96])=[O:95]
Reactant: Cc1cc(N)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2S(=O)(=O)O)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Temperature: 0 °C
Yield: 166.9 %

Procedure:
To a stirred solution of 9.0 g of 8-(5-amino-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt, and 3.34 g of sodium acetate trihydrate in 47.0 ml of water chilled to 0° C. in an ice bath is added 4.29 g of 4-nitro-2-sulfobenzoic acid anhydride in one portion. The mixture is stirred for a total of 10 minutes in the ice bath and the undissolved material is separated. The solution, at 0° C., is acidified with 1.38 ml of concentrated hydrochloric acid, then is added dropwise, with vigorous stirring, to 750 ml of absolute ethanol. The product is collected, washed with 85% aqueous ethanol, ethanol and ether and is dried to yield 11.75 g of 8-[5-(4-nitro-2-sulfobenzamido)-o-toluenesulfonamido]-1,3,6-naphthalenetrisulfonic acid, tetrasodium salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1
Reaction time: 0.67 h
Yield: 86.3 %

Procedure:
A stirred solution of 4-bromoanisole (639 mg) in THF (15 ml) under argon was cooled to −78° C. A solution of n-butyllithium (2.07 ml, 1.6 M in hexane) was added slowly while keeping the temperature below −70° C. After stirring for 40 min, a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (400 mg, example 74, step 4) in THF (15 ml) was added while keeping the temperature below −70° C. The mixture was stirred at this temperature for 1 hour. The reaction was stopped by addition of saturated aqueous ammonium chloride solution (15 ml). Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phase was washed with water and brine, dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (390 mg) as a light yellow oil, MS (ESI+): m/z=409.2 [M+H]+.