Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:22]#N)=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[PH2]([O-])=[O:25].[Na+]>N1C=CC=CC=1.O.[Ni]>[O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:25])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: N#Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 6-((1R*,2S*)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazole-3-carbonitrile (1 g, 3.3 mmol) in pyridine (30 mL) acetic acid (8 mL) and water (8 mL) and Raney Nickel (1 g). Sodium hypophosphite (1.8 g, 21 mmol) was dissolved in water (10 mL) and added dropwise and the reaction was stirred overnight. The product was extracted into ethyl acetate (300 mL), washed with brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (300 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 10.17 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=8.5 Hz, 1H) 7.08-7.04 (m, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 3.38-3.34 (m, 1H), 2.27-2.17 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(Cl)cc21
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(Cl)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (200 mg, 0.57 mmol), copper(I) iodide (33 mg, 0.17 mmol), 2-amino-2-methyl-propionic acid (235 mg, 2.29 mmol) and potassium carbonate (240 mg, 1.7 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (127 mg, 60.0%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 373.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 2 was suspended in pyridine (5 ml), and to the suspension was added acetic anhydride (0.14 ml), and the mixture was stirred at room temperature for 2 hours. A small amount of methanol was added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with methanol and ether in succession to produce the title compound (100 mg; 46%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:6][CH2:5][C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH:23]([OH:25])[CH3:24]>CN(C=O)C.O>[OH:25][CH2:23][CH2:24][N:3]1[C:4](=[O:19])[CH2:5][CH2:6][CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:2]1=[O:1]
Reactant: CC(O)Cl
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (2.5 g) was dissolved in DMF (dry, 60 mL). 95% NaH (0.24 g) was added. The mixture was stirred for 30 minutes at room temperature. Then, chioroethanol (0.68 mL) was added, and the mixture was stirred over night at room temperature. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (3×60 mL). Organic phases were combined and washed twice with water, and once with brine, then dried over anhydrous magnesium sulfate. Rotary evaporation of solvent yielded crude product, which was purified by silica gel column chromatography (acetic ether: petroleum ether=1:1) to yield 1.1 g of pure title product. 1H NMR (CDCl3, ppm) δ 7.88-7.90 (m, 2H), 7.77-7.79 (m, 2H), 5.06 (dd, 1H, J=5.6, 12.4Hz), 4.02-4.12 (m, 2H), 3.76-3.80 (m, 2H), 2.94-3.02 (m, 1H), 2.72-2.90 (m, 2H), 2.29-2.31 (m, 1H), 2.14-2.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]=[O:14].Cl>CS(C)=O.C[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) and paraformaldehyde (6.27 g, 209 mmol) were dissolved/suspended in DMSO (400 mL) and treated with NaOMe (537 mg, 9.94 mmol). The mixture was allowed to stir at room temperature for 2 hours, at which time the reaction was complete as determined by TLC analysis of the crude. The reaction was poured into ice-cold water (700 mL; emulsion) and neutralized with the addition of 1M HCl solution. The aqueous layer was extracted with ethyl acetate (3×), and the organics were combined. The organic layer was washed with water (2×), brine (1×), separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as an oil. The residue was loaded onto a large fitted filtered with silica gel and eluted with 9:1 hexanes:ethyl acetate and then with 1:1 hexane:ethyl acetate to give Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate as an oil (39.4 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:4]=[CH:3]1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=[O:20].C(Cl)Cl>CCOCC>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:18](=[O:22])[C:19]([Cl:21])=[O:20])=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(NC(=O)C(F)(F)F)cc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(NC(=O)C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 1-methyl-6-trifluoroacetylaminoindole was taken into 5 mL ether and cooled to 0° C. It was treated with 0.485 mL 2.0 M oxalyl chloride/methylene dichloride and stirred at 0° C. for 2 h. The yellow crystals were collected and washed with ether and dried in vacuo to yield 240 mg of (6-trifluoroacetylamino-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride.
Reaction SMILES: [Cl-].[NH2:2][NH2:3].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])C>CCO>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: NN
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [Cl-]
Solvent: CCO
Product: FC(F)(F)c1cc[nH]n1
Yield: 86 %

Procedure:
To a stirred solution of hydrazine monochloride (6.62 g, 1.6 eq.) in EtOH (300 mL) was added dropwise compound 84 (10.16 g, 1 eq.) in EtOH (200 mL). The reaction mixture was refluxed for 6 hrs and evaporated to dryness. Water and EtOAc were added to the residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 86a as a brown solid in 86% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>O1CCCC1>[N:11]1([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C)nc(Cl)n1
Solvent: C1CCOC1
Product: COc1cc(C)nc(-n2ccnc2)n1
Yield: 51.1 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 2-chloro-4-methoxy-6-methylpyrimidine was substituted with 68 mg of imidazole. The reaction mixture was treated according to the Procedure of Example 5 to yield 97 mg of 2-(1-imidazolyl)-4-methoxy-6-methylpyrimidine, recrystallized from n-hexane, having a melting point of 53°-54° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH3:12])[C:8](=[O:11])[CH2:9][CH3:10])[CH2:3][CH2:2]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(O)C>[CH2:18]([O:17][C:13]([CH2:14][CH2:15][N:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH3:12])[C:8](=[O:11])[CH2:9][CH3:10])[CH2:3][CH2:2]1)=[O:16])[CH3:19]
Reactant: CCC(=O)N(C)C1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N(C)C(=O)CC)CC1

Procedure:
7.4 g of the compound obtained in Stage C of Example 1 are dissolved in 10 ml of ethanol, then 4.73 ml of ethyl acrylate dissolved in 12 ml of ethanol are poured onto the solution. The mixture is left at room temperature for one night, and then concentrated in a rotary evaporator and distilled in a Kugelrohr to yield the compound in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:12][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(C)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COc1cc(CBr)ccc1C#N
Yield: 35.3 %

Procedure:
4.6 g (31.3 mmol) of 4-methyl-2-methoxybenzonitrile were brominated with 34.7 mmol of N-bromosuccinimide in the presence of catalytic amounts of azobisisobutyronitrile in 60 ml of 1,2-dichloroethane under reflux. 2.5 g of the product were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:39])[C:15]2[C:16]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200.0 mg, 0.42 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (50.0 mg, 2.08 mmol) at 0° C. and stirred for 30 minutes at room temperature. Subsequently, iodomethane (350.0 mg, 2.47 mmol) was added and stirred overnight at room temperature. The reaction mixture was then quenched by the addition of NH4Cl solution (100 mL), extracted with dichloromethane (3×15 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (210 mg, crude).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH:29]1[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH:29]3[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 86 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl 3-amino-1-azetidinecarboxylate gave tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-azetidinecarboxylate in 86% yield: mp (CH2Cl2/hexanes) 201-203° C.; 1H NMR (DMSO-d6) (rotamers) δ8.50 and 8.45 (2d, J=6.3, 6.5 Hz, 1H), 8.01 and 7.93 (2d, J=8.2, 8.3 Hz, 1H), 7.83 and 7.44 (2t, JHF=53.1, 52.9 Hz, 1H), 7.44-7.37 (m, 1H), 6.96 and 6.95 (2d, J=8.1, 8.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.78 (t, J=7.8 Hz, 2H), 3.97 (s, 3H), 3.87-3.82 (m, 2H), 3.78 (m, 4H), 3.69, (m, 4H), 1 40 and 1.39 (2s, 9H); Anal. Calcd. for C24H30F2N8O4: C, 54.1; H, 5.7; N, 21.0. Found: C, 54.0; 5.8; N, 21.0%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([O:12][CH3:18])=[O:11]
Reactant: O=C([O-])O
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1Cc2ccccc2C1

Procedure:
A solution of 50 g. of indan-2-carboxylic acid (prepared according to the procedure reported by E. D. Bergmann and E. Hoffman, J. Org. Chem., 26, 3555 (1961)) and 5 ml. of con d sulfuric acid in 500 ml. of methanol is heated at reflux for 3.0 hours then is cooled in ice. The cooled solution is neutralized (pH~5) with saturated sodium bicarbonate, is concentrated, and the aqueous layer is extracted with methylene chloride. The combined organic extracts are washed with saturated bicarbonate, with saturated brine, are dried (anhydrous magnesium sulfate), and are concentrated. Distillation of the crude residue in vacuo provides the desired methyl indan-2-carboxylate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O>CO>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4scnc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of methyl 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (120 mg, 0.31 mmol) in MeOH (10 mL) was added sodium hydroxide (49 mg, 1.2 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with HCl (1 N). The solids were collected by filtration to afford 2-(benzo[d]thiazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (99 mg, 86%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: N#Cc1ccc(F)cc1
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1

Procedure:
reacting methyl isobutyrylacetate with 4-fluoro-benzonitrile to produce methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanate; and
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[H][H]>C(O)C.C1COCC1.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(N)cccc2cn1
Yield: 94 %

Procedure:
To a solution of Example 35A (1.60 g, 8.82 mmol) in ethanol (45 mL) and THF (45 mL) was added 10% Pd/C (100 mg). The solution was hydrogenated under 1 atmosphere of hydrogen for 16 hours at ambient temperature. The mixture was filtered through a plug of Celite and the volatiles were evaporated in vacuo. The resulting solid was triturated with 1:1 CH2Cl2-hexanes and air-dried to provide the title compound (1.31 g, 8.29 mmol, 94% yield) as a light green solid. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.78 (d, J=0.6 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.80 (dd, J=7.4, 1.2 Hz, 1H), 5.84 (s, 2H), 2.58 (s, 3H); MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]2[CH3:45])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[C:42]([CH3:44])[N:41]=[C:40]2[CH3:45])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccccc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (231 mg, 0.75 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (140 mg).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:10][CH:11]=1)=[O:21]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Methyl 2-{2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethoxy}benzoate (0.400 g, 1.0351 mmol) was dissolved in DCM and trifluoracetic acid (0.8 ml, 8.281 mmol) was added. The mixture was stirred at room temperature for 3 h. The solvent was evaporated to give 325 mg of a white powder.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[CH:9]1[C:16](=C)C[C@H:14]2[C@@H:10]1[CH2:11][C@@H:12]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:5]([O:4][CH:1]1[C:9](=[CH2:16])[CH2:10][C@H:14]2[C@@H:2]1[CH2:11][C@@H:12]([O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[C@H:13]2/[CH:18]=[CH:19]/[C@@H:20]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:7])[CH3:6]
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2C1O
Reactant: CC(=O)OC(C)=O
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2C1OC(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 97 %

Procedure:
Acetic anhydride (5.0 ml) and pyrdine (5.0 g) were added to the (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane (928 mg, 2.00 mmoles) obtained in Example 65, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and subjected to column chromatography (silica gel 200 g; hexane/ethyl acetate=19/1) to give (1S,2RS,5S,6S,7R)-2-acetoxy-3-methylene-6-[(E,3S)-3-(2-tetrahydropyranyloxy)-1-octenyl]-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane (982 mg, 1.94 mmoles, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24]>N1C=CC=CC=1>[NH2:25][C:23]([NH:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1)=[O:24]
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(NC(N)=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
1.00 g (3.7 mmol) of ethyl 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were dissolved in 50 mL of pyridine and 1 mL (8.0 mmol) of trichloroacetylisocyanate were added. The mixture was stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residue was treated with 50 mL of methanol. After 2 hours under stirring the solvent was removed, the residue redissolved with dichloromethane and washed with a diluted solution of ammonium hydrate. After drying over anhydrous Na2SO4 the organic layer was evaporated to dryness and the residue purified by chromatography on a silica gel column (eluant: dichloromethane/acetone 4/1) leading 0.40 g (34% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][CH2:33][S:34]([N:37]1[CH2:40][CH2:39][CH2:38]1)(=[O:36])=[O:35].[I-].[Na+]>CN1C(=O)CCC1>[N:37]1([S:34]([CH2:33][CH2:32][CH2:31][N:19]2[CH2:20][CH2:21][CH:16]([C:12]3[C:13]([CH3:15])=[CH:14][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:23][C:24]5[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=5)[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([CH3:22])[CH:11]=3)[CH2:17][CH2:18]2)(=[O:36])=[O:35])[CH2:40][CH2:39][CH2:38]1
Reactant: O=S(=O)(CCCCl)N1CCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCCS(=O)(=O)N5CCC5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (42 mg, 0.1 mmol), 1-(3-chloropropylsulfonyl) azetidine (Step 1, 0.1 mmol), TEA (70 μL) and sodium iodide (150 mg) in NMP (1 mL) was placed in a sealed vial which was heated in a microwave for 30 min at 150° C. The reaction was purified by RP-HPLC to give N2-(4-(1-(3-(azetidin-1-ylsulfonyl)propyl)piperidin-4-yl)-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white powder; ESMS m/z 573.3 (M+H+).