Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:13]([N:20]=[C:21]=S)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: S=C=NCc1ccccc1
Product: Cn1c(NCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Yield: 70.8 %

Procedure:
N1-Methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and benzyl isothiocyanate (1.75 ml, 13.2 mmol) were coupled using the procedure of example one part B to give the title compound as a yellow solid (2.4 g, 71%). 1H NMR (300 MHz, d6-DMSO) δ 7.97 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.77 (t, J=5.7 Hz, 1H), 7.21-7.41 (m, 6H), 4.63 (d, J=5.7 Hz, 2H), 3.62 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C@:9]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:41])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([NH:6][C:7]([C@:9]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:41])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:29])([CH3:30])[C:18]([C:31]2[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:8])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.204 g, 0.318 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (0.040 g, 0.953 mmol) in H2O (1.000 mL). The resulting white slurry was stirred at rt overnight. After 15 h, TLC showed significant starting material left thus reaction was heated to 75° C. for 3 h. Reaction was treated with 1N HCl (1 mL) and concentrated to dryness. Material was absorpted onto silica gel, loaded onto a silica gel column (12 g cartridge) and was eluted with 0% B to 100% B for 180 mL and held 100% B for 600 mL (Solvents: A=100% DCM, B=90:10 DCM:MeOH). Obtained 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(isopentylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (182 mg, 0.281 mmol, 88% yield) as white solid. LCMS: m/e 628.6 (M−H)+, 2.45 min (method 5); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.2 Hz), 7.3 (2H, d, J=8.5 Hz), 5.6 (1H, t, J=5.6 Hz), 5.3 (1H, dd, J=6.1, 1.8 Hz), 4.8 (1H, d, J=2.1 Hz), 4.6-4.6 (1H, m), 3.3-3.4 (1H, m), 3.2-3.3 (2H, m), 2.5-2.6 (1H, m), 2.1 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.7-1.8 (2H, m), 1.7 (3H, s), 1.6-1.7 (3H, m), 1.3-1.6 (11H, m), 1.2-1.3 (2H, m), 1.0 (6H, s), 1.0 (3H, s), 1.0 (6H, s), 0.9-1.0 (6H, m) 13C NMR(CHLOROFORM-d) δ ppm 14.4, 15.6, 16.2, 19.3, 19.5, 20.8, 21.1, 22.2, 22.3, 25.5, 25.7, 29.2, 30.7, 33.4, 33.6, 36.0, 37.2, 37.7, 38.2, 38.5, 40.4, 41.5, 42.2, 46.5, 49.3, 49.9, 52.6, 55.4, 77.3, 109.0, 124.0, 126.7, 128.9, 129.9, 145.9, 149.4, 150.8, 171.1, 175.7.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl.O.C(Cl)Cl.CO>[O:11]=[CH:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]1
Reactant: CC(=O)N[C@H]1CC[C@H](CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](CC=O)CC1

Procedure:
DMSO (3.68 g, 47 mmol) in CH2Cl2 (20 ml) was added at −78° C. to a stirred solution of oxalylchloride (2.9 g, 23 mmol) in CH2Cl2 (100 ml). After 1 h stirring at −78° C. a solution of N-[trans-4-(2-hydroxy-ethyl)-cyclohexyl]-acetamide (2.18 g, 12 mmol) in CH2Cl2 (80 ml) was added followed after 2 h by Et3N (7.14 g, 71 mmol). The mixture was allowed to reach room temperature and was then diluted with H2O and extracted with CH2Cl2. The combined organic layers were dryed (Na2SO4) and the solvent was evaporated to afford the crude product. Chromatography (CH2Cl2/MeOH 95:5) yielded 1.75 g (81%, 9.5 mmol) of a light brown solid. MS (m/z): 184.3 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:11]=2[CH:13]([OH:15])[CH3:14])[C:6]([CH3:20])([CH3:19])[CH2:5][CH2:4]1)[CH3:2].[CH3:21][N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:16]([C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([CH:13]([OH:15])[CH3:14])[CH:10]=1)[N:3]([CH2:1][CH2:2][CH3:21])[CH2:4][CH2:5][C:6]2([CH3:20])[CH3:19])([CH3:18])[CH3:17]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)O)c21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)O)c21
Temperature: 0 °C

Procedure:
To a solution of 1-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethan-1-ol (Intermediate 9, 1.50 g, 6.33 mmol) in 15 ml of CH2Cl2 at 0° C. was added 4-methylmorpholine N-oxide (1.48 g, 12.7 mmol), tetrapropylammonium perruthenate (333 mg, 0.95 mmol), and 4 Å molecular sieve powder (150 mg). The mixture was stirred at 0° C. and allowed to warm gradually while being monitored carefullly. As soon as the temperature rose to 25° C., the reaction was re-cooled in an ice bath. The crude mixture was immediately loaded onto a pre-packed silica gel column. The column was first eluted with 100% hexane, and then with 5% ethyl acetate and hexane to yield the title compound as a yellow oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=2[F:20])=[C:9]([CH3:21])[N:8]=[C:7]([NH2:22])[N:6]=1>CS(C)=O.CN(C=O)C.CCOC(C)=O>[NH2:22][C:7]1[N:6]=[C:5]([Cl:4])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:1]#[N:2])=[CH:14][C:13]=2[F:20])=[C:9]([CH3:21])[N:8]=1
Reactant: [C-]#N
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CCl)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium cyanide (0.056 g) was added to a stirred solution of the product from step (ii) (0.13 g) in DMSO (imL) and DMF (1 mL). The mixture was stirred at rt for 15 h and then diluted with EtOAc (10 mL). The organic phase was washed with water and brine then dried, filtered and evaporated to give the subtitle compound, 0.12 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>CC(C)=O>[C:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.01 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g; 0.011 mole). Then acetyl chloride (0.86 g; 0.011 mole) was added, dropwise, during 5 minutes at -10°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:52])([CH3:51])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:39]([CH3:50])[CH:38]=1)[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])=[O:12]>ClCCl>[CH3:51][C:9]([CH3:8])([CH3:52])[C@H:10]([NH:22][C:23]([C@H:25]([CH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:39]([CH3:50])[CH:38]=1)[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:11]([NH:13][C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:12]
Reactant: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CCC[C@H](CC(=O)O)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 127.3 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added dropwise over 5 min to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-methyl-4-phenoxyphenyl)hexanoate (550 mg, 0.9 mmol) in anhydrous dichloromethane (5 mL) under nitrogen at 20° C. The solution was stirred for 1 h and concentrated under reduced pressure. The residue was diluted with hydrochloric acid (2M) and extracted with three portions of ethyl acetate. The combined organic solutions were washed with saturated aqueous sodium chloride, dried (MgSO4) and concentrated under reduced pressure. Two portions of toluene were added and evaporated to give the title compound as a yellow gum (640 mg), contaminated with toluene and trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.N#N.[H-].[Na+].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[O:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:32]([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)=[O:33])[C:5]([CH3:26])=[CH:4]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc4c(cc(C)n4C(=O)Oc4ccc([N+](=O)[O-])cc4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Compound 11 (300 mg, 0.85 mmol) in dry THF was sparged with N2, then NaH (68 mg of 60% dispersion, 1.7 mmol) was added in a single portion. While still sparging with N2, 4-nitrophenyl chloroformate (341 mg, 1.7 mmol) was added and the reaction stirred at room temperature for 1 hour. Solvent was evaporated by rotary evaporator and the product precipitated from ethyl acetate/diethyl ether and filtered. The crude solid was washed with methanol (20 mL) to yield Compound 12 as crude yellow solid, which was taken directly to the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]([OH:15])[CH3:14].N1C=CC=CC=1.C(O)(=O)C>C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:15][CH:13]([CH3:14])[CH3:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)O
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)OS(=O)(=O)c1ccccc1Br

Procedure:
2-Bromobenzenesulfonyl chloride (50 g, 0.19 mol) was suspended in 2-propanol (45 mL, 3 equiv.) and the slurry was cooled to less than 10° C. Pyridine (32 mL, 2 equiv.) was added in portions while maintaining the reaction temperature below 10° C. After reaction completion (ca. 3 hours), 11 mL of glacial acetic acid followed by 250 mL of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125 mL of iN aqueous hydrochloric acid and 150 mL of saturated sodium bicarbonate solutions. The rich MTBE solution was solvent exchanged into hexane (i.e., the addition of hexane with concurrent distillation of MTBE) to induce crystallization. The crystal slurry was filtered, washed and dried in vacuo at no more than 25° C., to give 48 g (87 M %, HPLC area % >99) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:4](I)[CH:3]=1.[C:24](=[O:26])=[O:25]>C1COCC1.C(OCC)(=O)C>[C:13]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:24]([OH:26])=[O:25])=[O:10])[CH:12]=1
Reactant: O=C(Nc1ccc(Cl)cc1I)c1cccc(-c2ccccc2)c1
Reactant: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1cccc(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
433 mg (1.0 mmol) of N-(4-chloro-2-iodophenyl)biphenyl-3-carboxamide was dissolved in 5 mL of THF solution, and 1.6M n-butyllithium(n-BuLi)hexane solution (1.25 mL) was added dropwise under an Ar atmosphere at −78° C. The mixture was stirred for 0.5 hours. Dry ice was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and dried over anhydrous sodium sulfate. The resultant was separated and purified by silica gel column chromatography, thereby giving 48.2 mg of the target 2-[(biphenyl-3-ylcarbonyl)amino]-5-chlorobenzoic acid (yield: 14%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([NH:28]C(=O)OC(C)(C)C)[CH:18]=[N:19][C:20]=2[O:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([NH2:28])[CH:18]=[N:19][C:20]=2[O:21][C@@H:22]([CH3:27])[C:23]([F:24])([F:25])[F:26])=[CH:13][CH:14]=1
Reactant: C[C@H](Oc1ncc(NC(=O)OC(C)(C)C)cc1-c1ccc(Cl)cc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid (2.74 g, 1.85 ml, 24.0 mmol) was added to (S)-tert-butyl 5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)pyridin-3-ylcarbamate (0.350 g, 840 μmol). The resulting yellow solution was stirred at RT for 1 h. The solvent was evaporated. The residue was partitioned between ethyl acetate and 1M Na2CO3 solution, the organic phase was dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 5 to 50% EtOAc in heptane) to give 0.22 g (82%) of the title compound as light brown oil; MS (EI) 317.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([N:21]([CH3:25])[CH2:22][CH2:23][OH:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1[C:31](O)=[CH:30][CH:29]=[C:28]([CH3:33])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:31]3[CH:30]=[CH:29][C:28]([CH3:33])=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)cc1
Reactant: CN(CCO)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCN(C)[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of trans-2-{[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-amino}-ethanol (0.3 g, 0.88 mmol), p-cresol (96 mg, 0.88 mmol), triphenylphosphine (232 mg, 0.88 mmol), diethyl-azodicarboxylate (154 mg, 0.88 mmol) and THF was stirred at rt for 3h. The solvent was evaporated and the rsidue was treated with MeOH/H2O (3:1, 50 ml) and hexane (50 ml). The aq. layer was extracted with hexane (30 ml). The combined hexane extracts were dried and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2—MeOH 95:5) to give trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-methyl-(2-p-tolyloxy-ethyl)-amine (135 mg, 69%, white solid, MS: m/e=430.5 (M+H+)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH:18]=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc3ccccc3s2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2sc3ccccc3c2C=O)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-methylphenyl)benzo[b]thiophene (896 mg) in freshly distillated tetrahydrofuran (15 ml) was added n-butyllithium (2.75 ml, 1.6 mol solution in n-hexane) through a syringe at -78° C. The solution was stirred at -78° C. for 10 minutes and then at ambient temperature for half an hour. To the deep red colored solution was added N,N-dimethylformamide (365mg) at 5° C. The mixture was stirred at ambient temperature for one hour, quenched with aqueous saturated ammonium chloride solution, and extracted with diethyl ether. The organic layer was washed with aqueous saturated ammonium chloride solution, dried, and concentrated in vacuo to give a yellow residue, which was purified by flash column chromatography on silica gel eluted with 50% n-hexane in dichloromethane to yield 2-(4-methylphenyl)benzo[b]thiophene-3-carbaldehyde (285 mg) as white crystals.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.[CH3:23][C:24]([CH:27]=O)([CH3:26])[CH3:25].C(=O)CC>>[CH2:23]([NH:22][CH2:21][C:18]1[S:19][CH:20]=[C:16]([C:3]2[CH:4]=[CH:5][C:6]3[S:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:14][C:15]=3[CH:2]=2)[N:17]=1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: CC(C)(C)C=O
Agent: Cl
Solvent: CCC=O
Product: CC(C)(C)CNCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Yield: 40.6 %

Procedure:
This compound is prepared according to a protocol identical to that described for Stage 399.1 of Example 399, with the compound of Example 362 and pivaldehyde respectively replacing intermediate 355.2 and the propionaldehyde. The expected product is obtained in the form of an off-white solid with a yield of 40.6%. Melting point: 172.0-174.0° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:50].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([I:50])=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:25])([F:24])[F:26])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:6][N:7]=1
Reactant: [IH2+]
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)ccc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)c(I)cc12
Reaction time: 48 h

Procedure:
To a stirred slurry of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (60 mg, 0.14 mmol) and bis(pyridine)iodonium tetrafluoroborate (152 mg, 0.41 mmol) in DCM (2.5 mL) was added trifluoromethanesulfonic acid (0.11 mL, 1.2 mmol). The reaction mixture was left to stir for 2 d, treated with additional bis(pyridine)iodonium tetrafluoroborate (152 mg, 0.41 mmol) and trifluoromethanesulfonic acid (0.07 mL, 0.8 mmol), and left to stir for 6 h. The mixture was diluted with DCM and treated with sodium bicarbonate solution. The mixture was extracted with EtOAc, and the combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.78 (s, 1H); 9.02 (s, 1H), 8.51 (s, 1H); 8.23 (s, 2H); 7.92 (br s, 1H); 7.70 (s, 1H); 7.78 (br s, 1H); 7.77 (d, 1H); 6.80 (s, 2H); 4.87 (m, 1H); 1.58 (m, 1H); 0.73 (m, 1H); 0.62 (m, 1H); 0.54 (m, 1H); 0.32 (m, 1H). LRMS (APCI) calc'd for (C21H17IF3N7O) [M+H]+, 568.0. found 568.0.
Reaction SMILES: [Na:1].C(O)C.[NH2:5][C:6]1[S:10][N:9]=[N:8][C:7]=1[C:11]([O:13]CC)=[O:12]>O>[Na:1].[Na:1].[Na:1].[C:11]([C:7]1[N:8]=[N:9][NH:5][C:6]=1[SH:10])([OH:13])=[O:12]
Reactant: CCOC(=O)c1nnsc1N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nn[nH]c1S
Reaction time: 1 h

Procedure:
To a solution of 4.6 g. (0.20 mol.) of sodium and 250 ml. of absolute ethanol was added under a nitrogen atmosphere 8.65 g. (0.05 mol.) of 5-amino-4-carbethoxy-1,2,3-thiadiazole. The reaction mixture was stirred 1 hour, 5 ml. of water was added and the mixture was refluxed for 12 hours. After cooling, the mixture was filtered and the solid product was washed with ethanol and ether and dried to give 4-carboxy-1,2,3-triazole-5-thiol trisodium salt.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])=[C:12]([Cl:23])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:24][C:25]([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:26]([O:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][CH3:36])[CH2:31][CH2:30]1)=[O:27]>C(Cl)Cl>[OH:24][C:25]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[C:26]([O:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([N:35]([CH2:21][CH2:20][C:19]([NH:18][C:13]2[CH:14]=[C:15]([O:16][CH3:17])[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:11][C:12]=2[Cl:23])=[O:22])[CH3:36])[CH2:33][CH2:34]1)=[O:27]
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Reactant: C=CC(=O)Nc1cc(OC)c(CO[Si](C)(C)C(C)(C)C)cc1Cl
Solvent: ClCCl
Product: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 64 h

Procedure:
A mixture of N-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyphenyl]-acrylamide (intermediate 40; 0.9 g, 0.002 mol) and trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 0.7 g, 0.002 mol) in methylene chloride (20 mL) was stirred at 75° C. in a closed vessel for 64 hours. The solvent was evaporated and the crude obtained was purified by column chromatography with silica gel, eluting with chloroform/methanol (from 50/1 to 25/1) to give the title compound as a white-yellow solid (49%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:35][CH3:36]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][N:37]([CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCCN1CCNCC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-propylpiperazine. A yellow solid 135 was obtained (0.033 g, 64%). 1H-NMR (CDCl3, 400 MHz) δ 1.03 (t, J=7.3 Hz, 3H), 1.84–1.92 (m, 2H), 2.30–2.52 (br, 8H), 2.98–3.03 (m, 2H), 4.28–4.34 (m, 4H), 6.87 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.01 (d, J=5.8 Hz, 1H), 7.04 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.82 (s, 1H), 8.26 (d, J=5.9 Hz, 1H); MS (APCI) m/z 516 (M+H)+.