Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][C@@H:24]([OH:31])[CH2:25][N:26]5[CH2:30]CC[CH2:27]5)[C:18]4=[O:32])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.CNC>>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][C@@H:24]([OH:31])[CH2:25][N:26]([CH3:30])[CH3:27])[C:18]4=[O:32])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:35]([F:37])([F:36])[F:38])[CH:3]=1
Reactant: O=C1SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H](O)CN1CCCC1
Agent: CNC
Product: CN(C)C[C@H](O)CN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-[(2S)-3-dimethylamino-2-hydroxypropyl]thiazolidine-2,4-dione was prepared from 5-[1-(4-chloro-2-trifluoromethyl benzyl)-1H-indazol-5-ylmethylene]-3-(R)-oxiranylmethylthiazolidine-2,4-dione (from Example 292) and dimethylamine following General Procedure X.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:18]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:33][CH2:34][CH3:35])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:26]([N:17]([C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:19])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]([CH2:33][CH2:34][CH3:35])=[N:10][C:11]=2[CH:16]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3sccc3C)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3sccc3C)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(3-methyl-thiophene-2-carbonyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.68 (d, 1H), 7.29 (m, 5H), 7.02 (m, 2H), 6.85 (d, 1H), 6.71 (d, 1H), 5.09 (s, 2H), 4.75 (s, 2H), 2.65 (t, 2H), 1.71 (m, 2H), 0.92 (t, 3H). MS calculated for C25H25N3O3S+H: 448, observed: 448.
Reaction SMILES: CN(C)[C@@H]1CCCC[C@H]1O.CNC.[H-].[Na+].CS(Cl)(=O)=O.CNCC1C=CC=CC=1.[CH3:30][N:31]([CH3:47])[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[N:38](C)[CH2:39]C1C=CC=CC=1>[Pd].CCO.C1COCC1>[CH3:30][N:31]([CH3:47])[C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[NH:38][CH3:39]
Reactant: CN(C)C1CCCCC1N(C)Cc1ccccc1
Agent: [Pd]
Agent: CN(C)[C@@H]1CCCC[C@H]1O
Agent: CNC
Solvent: CCO
Solvent: C1CCOC1
Product: CN[C@@H]1CCCC[C@H]1N(C)C
Reaction time: 18 h

Procedure:
A solution of trans-2-dimethylaminocyclohexanol (61.1 g., 0.427 mole) prepared as in Procedure I, Part A, using dimethylamine instead of methylamine in 85 ml. of THF is added during 5 min. to a suspension of NaH (17.97 g., 0.427 mole of 57% dispersion in mineral oil) in 250 ml. of THF, and the mixture is heated at 95° for 2 hrs. It is cooled to 10° and treated dropwise with methanesulfonyl chloride (48.91 g., 0.427 mole) during 40 min. keeping the temperature at 15°. N-Methylbenzylamine (103.48 g., 0.854 mole distilled) is then added, THF is evaporated and heating is continued at 95° for 18 hr. The mixture is treated with 500 ml. of 20% NaOH, heated at 95°, cooled and extracted with ether (6 × 100 ml.). The ether solution is extracted with 10% HCl (6 × 100 ml.), backwashed with ether (discard ether), cooled, basified with 20% NaOH and extracted with ether. The ether extract is washed with H2O, saturated salt solution, dried (MgSO4) and evaporated to give 48.6 g. of crude N,N,N'-trimethyl-N'-benzyl-1,2-cyclohexanediamine as an oil. A solution of this oil (46.6 g.) is hydrogenated in two portions, each in 130 ml. of EtOH, with 2.6 g. of 10% Pd-C and 28.6 g. of 70% HClO4 for 22 hrs. The mixture is filtered through Celite, the filtrate evaporated, cooled in ice, and basified with 40% KOH. The resulting thick suspension is extracted with ether (4 × 200 ml.), the ether extract dried (MgSO4) and evaporated. The product boils at 87°-88° (16 min.). Vpc-mass spectrum showed that the first peak (3.4 min.) is N,N-dimethyl-1,2-cyclohexanediamine, and the second peak (4.1 min.) the desired N,N,N'-trimethyl-1,2-cyclohexanediamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](Cl)=[O:11].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>O1CCCC1>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:11]
Reactant: Cn1c([N+](=O)[O-])cnc1C(=O)Cl
Reactant: NNC(N)=S
Solvent: C1CCOC1
Product: Cn1c([N+](=O)[O-])cnc1C(=O)NNC(N)=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1-methyl-5-nitro-2-imidazolecarboxylic acid chloride (1.1 g.) in 25 ml. of dry tetrahydrofuran is added 0.55 g. powdered thiosemicarbazide and the mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated to dryness and water is added. The solution is made basic with sodium hydroxide and the solid is filtered, washed with water and dried affording 1-(1-methyl-5-nitro-2-imidazolecarbonyl)-3-thiosemicarbazide.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[N:21]=[C:20]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:39][CH:40]=2)[N:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccncc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Phenyl chloroformate (0.029 mL, 0.23 mmol) was added to a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-4-ylsulfonylmethyl)pyrimidin-2-yl]aniline (0.097 g, 0.23 mmol) and sodium bicarbonate (0.029 g, 0.34 mmol) in dioxane at RT. The resulting slurry was stirred at RT for 2 hours. Additional phenyl chloroformate (2×0.005 mL) was added to drive the reaction to completion. Water was then added to the reaction and the solid filtered, and dried in a vacuum oven to give the desired material as an off-white solid (0.098 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Product: CN(C)c1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.41 mmol) and 4-(dimethylamino)benzylamine hydrogen chloride salt (60.9 mg, 0.49 mmol). The title compound was obtained as a solid (70 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.23 (1H, m), 8.99 (2H, s), 8.46 (1H, s), 7.1 (2H, dd), 6.7 (2H, dd), 4.26 (2H, m), 2.91 (6H, s). MS m/z: 483.05, 485.03 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][CH:22]=[N:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Product: Fc1cccc(-c2nc3[nH]cnc3nc2-c2ccncc2)c1
Temperature: 140 °C
Yield: 44 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 300 mg, 1.07 mmol) in 1,1′,1″-[methanetriyltris(oxy)]triethane (3 mL) was stirred and heated at 140° C. overnight. The solvent was removed under vacuum and the residue was triturated with diethyl ether. The resulting solid was purified by silica gel column chromatography (CH2Cl2/MeOH 9:1) to afford the title compound as a yellow solid (136 mg, 44%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-benzyl-benzenesulfonamide [CAS No. 303780-52-1] according to general procedure II. Yellow solid. MS (ISP) 618.1 [(M−H)−]; mp 227° C.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:1]([O:4][C@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([F:24])=[O:7])(=[O:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(=O)O[C@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H](Cc1ccccc1)C(=O)F
Reaction time: 1 h
Yield: 88.1 %

Procedure:
(R)-2-acetoxy-3-phenylpropanoic acid 11.1.C (1170 mg, 5619 μmol) was azeotroped and dissolved in DCM under nitrogen. Pyridine (454 μl, 5619 μmol) was added followed by cyanuric fluoride (1423 μl, 16858 μmol) at −20° C. After 1 h, reaction was worked up with ice and DCM to afford 1.04 g (88%) crude (R)-1-fluoro-1-oxo-3-phenylpropan-2-yl acetate 11.1.D. The crude was directly used for next step.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 94.6 %

Procedure:
Using the general method of Example 239 Part B, 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) was reacted with benzenesulfonyl chloride (1.38 g, 7.79 mmol) to provide 2.83 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamide as a light red foam.
Reaction SMILES: C([C:4]([Cl:29])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[OH-].[Ba+2].[OH-].CCOCC>C(O)C>[Cl:29][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(Cl)(Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1)C(C)=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Cl)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1

Procedure:
In 3 ml of absolute ethanol, 400 mg of ethyl 2-acetyl-2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate is dissolved and with stirring under ice-cooling, 85 mg of barium hydroxide (dehydrated at 125° C for 8 hours under reduced pressure) is added. After 10 minutes stirring, ether is added and the insoluble material is filtered away. The ether layer is washed with water thoroughly, dried, and the evaporation of the solvent gives the oily product of ethyl 2-chloro-3-[4-(2-benzoyl-2-propyloxy)-phenyl]propionate. In IR and NMR, this product is in good agreement with the compound No. 1 in Example 7.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>CC(O)C.O>[F:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][NH:25]4)=[CH:21][CH:20]=3)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(F)c4)n3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cc1F
Temperature: 70 °C
Yield: 21.4 %

Procedure:
Sodium hydroxide (8 mg) was added to a solution of ethyl 3-[6-(5-{5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D110) (60 mg) in iPrOH (5 mL) and water (5 mL). The resulting mixture was heated at 70° C. for 40 mins. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[6-(5-{5-fluoro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E84) (12 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.61 (2H, t), 2.96 (2H, t), 5.47 (1H, m), 7.35 (1H, d), 7.72 (2H, d), 8.11 (1H, t), 8.37 (1H, dd), 8.81 (1H, d), 11.23 (1H, d), 12.11 (1H, br s). MS (ES): C21H19FN4O4 requires 410; found 411.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>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.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:4]2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[C:3]=2[CH:14]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Reactant: COc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude (E)-5,7-dichloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (30 g, 0.124 mol) was dissolved into 300 mL of DME. To this was added a solution of Na2CO3 (21 g, 0.2 mol in 200 mL of H2O) followed by addition of 4-methoxyphenyl boronic acid (22 g, 0.145 mol) and Pd(PPh3)4 (1.2 g, 8.3 mmol). The reaction mixture was heated in a 85° C. oil bath, under N2, for 2 h and then cool to room temp. To this was added 200 mL of EtOAc and the mixture stirred for 5 min. The organic layer was separated and washed with H2O (200 mL) and brine (200 mL). Organic layer was dried over MgSO4 and then concentrated to dryness to give 53 g of crude product. This was subjected to silica chromatography using 210 g of silica gel and EtOAc/hepatene (12:88 to 30:70 to 50:50 to 70:30; total of 8 L mobile phase). Fractions containing pure product were combined and concentrated to dryness to give 42.7 g of pure product (quantitative). 1H NMR (300 MHz, CDCl3) δ 3.38 (s, 3H), 3.73 (d, 1H), 3.85 (s, 3H), 4.75 (d, 1H), 6.9 (m, 2H), 7.31 (m, 2H), 7.48-7.58 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[C:17]([CH2:26][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:15][C:16]1[C:17]([CH:26]=[CH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[N:5]=2)=[N:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1
Reactant: Cn1nc(N2CCCC2)nc1C=O
Reactant: Cc1nc2ccccc2nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: Cc1nc2ccccc2nc1C=Cc1nc(N2CCCC2)nn1C
Yield: 56.3 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (50 mg, 277 μmol, Eq: 1.00) and ((3-methylquinoxalin-2-yl)methyl)triphenylphosphonium chloride (126 mg, 277 μmol, Eq: 1.00) as starting materials. Chromatography afforded 2-Methyl-3-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-quinoxaline (50 mg, 56.2%) as light yellow solid. MS: m/z=321.4 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:16][C:14]([F:17])([F:15])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 84 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and piperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 84%; MS: m/z=417 (M+H).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
Triethylsilane (1.13 mL, 7.08 mmol) was added to a stirring, room temperature solution of 4-[2-(4-chlorophenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (37) (0.6662 g, 2.28 mmol) in trifluoroacetic acid (TFA) (5.54 mL, 0.42 M) under N2. After stirring at room temperature for 4 hours, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O:CH3CN. 12-13 min, 35:65 to 0:100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 137 mg/mL, 1.0 mL/injection. 0.2704 g (42.6%) of 38 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.055 min by HPLC.) 1H (CDCl3, 400 MHz): δ 8.99 (1H, broad s), 7.23 (2H, d, J=8.3 Hz), 7.09 (2H, d, J=8.3 Hz), 6.76 (1H, s), 6.64 (1H, s), 4.30 (2H, q, J=7.0 Hz), 2.84 (2H, t, J=7.6 Hz), 2.75 (2H, t, J=7.6 Hz), 1.35 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.14, 140.25, 131.52, 129.80, 128.32, 125.17, 122.62, 120.66, 114.73, 60.25, 36.62, 28.53, 14.43 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.43; CH2 carbons: 60.25, 36.62, 28.53; CH carbons: 129.80, 128.32, 120.66, 114.73 ppm. HPLC: 11.049 min.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: Ic1ccccc1
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1,1-Dimethylethyl (2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 55) (150 mg, 0.351 mmol), iodobenzene (0.078 mL, 0.702 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (27.6 mg, 0.070 mmol), tris(dibenzylideneacetone)dipalladium(0) (32.1 mg, 0.035 mmol) and sodium tert-butoxide (67.4 mg, 0.702 mmol) were dissolved in 1,4-dioxane (4 mL). The resulting mixture was stirred at 100° C. under nitrogen for 20 h, at 120° C. for 16 h then cooled to room temperature and partitioned between DCM and a saturated NaHCO3 aqueous solution. The layers were separated using an hydrophobic frit and the organic phase concentrated in vacuovacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient:20 to 100% AcOEt in hexanes) gave 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (104 mg, 0.206 mmol, 58.9% yield) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=[CH:2]1.C1C2C(C3CC2CC3NC(=O)OC(C)(C)C)CC=1.C(O)(=O)C>CO.[Pd]>[CH2:1]1[CH:9]2[CH:4]([CH:5]3[CH2:10][CH:8]2[CH2:7][CH:6]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CC2CC1C1C=CCC21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)NC1CC2CC1C1CC=CC21
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CC2CC1C1CCCC21

Procedure:
500 mg of a mixture of tert-butyl (3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)carbamate and tert-butyl (3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)carbamate were dissolved in 20 ml of methanol and 2 ml of acetic acid and hydrogenated under an atmosphere of hydrogen (1 bar) for 6 hours, with the aid of 200 mg of Pd/C 10% (50% water). The catalyst was filtered off and the volatile components were removed under reduced pressure. This gave 470 mg of a resin-like amorphous solid.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[OH:15])([CH3:3])[CH3:2].I[CH2:17][C:18]#[N:19]>>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][CH2:17][C:18]#[N:19])([CH3:3])[CH3:2]
Reactant: N#CCI
Reactant: Cc1cn(C)c2cc(C(C)C)c(O)cc12
Product: Cc1cn(C)c2cc(C(C)C)c(OCC#N)cc12

Procedure:
(6-Isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-acetonitrile was prepared from 6-isopropyl-1,3-dimethyl-1H-indol-5-ol by treatment with iodoacetonitrile using the procedure of step 5 of Example 2 above.