Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])/[CH:10]=[C:11](/[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][C:18]=1I)\[C:12]([F:15])([F:14])[F:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:1]([O:8][C:9]([C:10]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][OH:25])[CH:21]=2)[NH:16][C:11]=1[C:12]([F:15])([F:14])[F:13])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C(/Nc1ccc(CCO)cc1I)C(F)(F)F)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1c(C(F)(F)F)[nH]c2ccc(CCO)cc12
Reaction time: 8 h
Yield: 6 %

Procedure:
A mixture of (E)-4,4,4-Trifluoro-3-[4-(2-hydroxy-ethyl)-2-iodo-phenylamino]-but-2-enoic acid benzyl ester (9.5 g, 19.3 mmol, 1.0 eq), Pd(OAc)2 (433 mg, 1.93 mmol, 0.1 eq), triethylamine (3.1 mL, 23.2 mmol, 1.2 eq), triphenyphosphinc (1.52 g, 5.79 mmol, 0.3 eq) and DMF (20 mL) was heated under refluxing in a 100-mL round bottom flask under nitrogen. The reaction mixture was stirred overnight. After the stirring was stopped, the mixture was partitioned between dichloromethane (100 mL) and water (100 mL) filtered through celite. The organic layer was washed with water (3×100 mL), dried over MgSO4, and concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 420 mg of the desired indole as pale yellow gel (6.0% yield).
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.[OH-].[Na+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O.O1CCOCC1>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(NC(=O)Oc2ccccc2)cnn1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (5 g) in water (30 ml) and dioxane (15 ml) was added aqueous sodium hydroxide solution under ice-cooling to adjust the mixture to pH 7. Phenyl chloroformate (3.42 g) was added to the mixture with controlling pH at 7, and the whole mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and the extract was dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude product of phenyl [5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]carbamate as an oil, which was used for Preparation 44 without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.CS(C)=O.[CH3:34][OH:35]>N1CCOCC1>[CH3:8][N:10]([CH3:11])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([N:7]2[CH2:6][CH2:5][O:35][CH2:34][CH2:2]2)=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Reactant: CO
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: CN(C)c1ccc(N2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in morpholine (0.5 ml). The mixture was heated at 160° C. for 2 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (16 mg) as an orange solid.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[CH3:11][N:12]1[C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:19][C:1](=[O:8])[C:2]1=[O:4]
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)C(=O)OCC
Product: Cn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 25 °C

Procedure:
N-Methyl-1,4-dihydro-2,3-quinoxalinedione was prepared using an adaptation of the method of Cheeseman (J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.23 g, 22.1 mmol) and N-methyl-1,2-diaminobenzene (332 mg, 2.72 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH. The gray brown solid was further dried under vacuum (0.1 torr, 25° C.) to give 274.3 mg (57.2%). A portion of this solid was further purified by recrystallization from 50 mL EtOH and treatment with activated charcoal to give fluffy pale yellow crystals which were collected by vacuum filtration and rinsed with cold EtOH to yield 104.9 mg. 1H NMR (d6 -DMSO) δ3.50 (s, 3H, CH3), 7.16 (m, 3H, ArH), 7.36 (m, 1H, ArH), 12.01 (s, 1H, NH). EIMS 176 (M+, 52), 148 (33), 119 (100, bp).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[CH:12]([CH3:16])[C:13]([OH:15])=[O:14])([O-:19])=[O:18]
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(C(=O)O)c1cc(=O)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
α-(1,2-Dihydro-2-oxo-quinol-4-yl)propionic acid (15g.) was added in portions to stirred fuming nitric acid cooled to 5° C. The rate of addition was such that the reaction temperature remained between 5° and 10° C. After the addition was complete, the mixture was stirred at ambient temperature for 40 minutes and was then poured into water (1.2 l.). The resultant solid was separated by filtration, washed with water and dried in vacuo to give α-(6-nitro-1,2-dihydro-2-oxo-quinol-4-yl)propionic acid as a white solid (90% yield), with m.p. 276°-278° C. (decomposition).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1([CH3:40])[O:28][C@@H:27]([C@@H:29]2[C@@H:33]3[O:34][C:35]([CH3:38])([CH3:37])[O:36][C@@H:32]3[CH:31]([OH:39])[O:30]2)[CH2:26][O:25]1.CC(O)(C)C>C(Cl)Cl>[CH3:23][C:24]1([CH3:40])[O:28][C@@H:27]([C@@H:29]2[C@@H:33]3[O:34][C:35]([CH3:38])([CH3:37])[O:36][C@@H:32]3[C:31](=[O:39])[O:30]2)[CH2:26][O:25]1
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(O)[C@H]2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
In a 1000 mL round bottom flask, Dess-Martin periodinane (110 g, 261.62 mmol, Spectrochem, India) was added to a solution of (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (45 g, 174 mmol) in anhydrous DCM (900 mL) at rt. The resulting mixture was stirred for 15 minutes and treated with t-BuOH (14.16 g, 191.4 mmol, Rankem, India) at rt. The resulting reaction mixture was stirred at rt for 3 days under an argon atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf, 0.55), the reaction mixture was quenched with aqueous Na2S2O3 (1000 mL) and extracted with DCM (4×250 mL). The combined organic extracts were washed with saturated NaHCO3 (500 mL), brine (200 mL), and then dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure, and the residue obtained was washed with n-pentane to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one as a colorless solid (35 g, 78%): 1H NMR (400 MHz, CDCl3) δ 4.87 (dd, J=3.2, 5.2 Hz, 1H), 4.83 (d, J=5.2 Hz, 1H), 4.43-4.31 (m, 1H), 4.38-4.37 (m, 1H), 4.13 (dd, J=5.7, 9.2 Hz, 1H), 4.06 (dd, J=5.6, 9.2 Hz, 1H), 1.48 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:34])[F:33])#[N:13].N1C=CC=CC=1>ClCCl>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][N:29]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:33])[F:34])#[N:13]
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
3-Chloro-benzenesulphonyl chloride (55 mg, 0.26 mmol, 1.1 equiv.) was added to a mixture of crude 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (70 mg, 0.24 mmol, 1 equiv.) in dichloromethane (2 ml) and pyridine (0.15 mL, 1.9 mmol, 8 equiv.) and the mixture stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). Fractions were combined to afford 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 81 mg (67% yield). LC @215 nm; Rt 1.74: 94%, m/z (ES+): 547 (M+H+.), δH (400 MHz; d6-DMSO) 11.04 (1H, s), 8.55 (1H, s), 8.36 (1H, d), 8.12-8.26 (5H, m), 7.92 (1H, t), 7.79 (1H, d), 7.45 (1H, d), 4.15 (2H, t), 3.07 (2H, t).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH2:22])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:14][C:13]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:32](=[O:34])[CH3:33])[CH3:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)N)s3)s2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(-c2nnc(Oc3ccc(OC(C)C)cc3)s2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of Example 24G (0.044 g, 0.122 mmol) in CH2Cl2 (2 mL) was treated with triethyl amine (0.051 mL, 0.366 mmol) followed by acetyl chloride (0.0173 mL, 0.244 mmol). The reaction was stirred at 25° C. for 1 hour and was concentrated under reduced pressure on a rotary evaporator. The residual white solids (0.075 g) were purified by flash chromatography on silica gel eluting with a solvent gradient of 30% to 50% ethyl acetate in hexanes to provide 0.035 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (d, J=8.09 Hz, 1H) 7.49 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.99 (dd, J=3.68, 0.74 Hz, 1H) 5.09-5.20 (m, 1 H) 4.63 (heptet, J=5.88 Hz, 1H) 1.85 (s, 3H) 1.45 (d, J=6.99 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=4[C:2]([F:17])([F:16])[F:1])[CH2:34][CH2:33]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,4-bis-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (29% yield). 1H NMR (400 MHz, CDCl3) δ 8.08, 8.02-7.98, 7.91, 7.54, 7.03, 3.97-3.86, 3.85-3.72, 3.57, 3.36, 1.52, 0.77-0.74, 0.49-0.46, 0.12-0.09.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH:27]3[CH2:32][O:31]C(C)(C)[O:29][CH2:28]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[Na+].[I-].CO>CC#N>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH:27]([CH2:32][OH:31])[CH2:28][OH:29])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C3COC(C)(C)OC3)no2)cc1OCC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(CO)CO)no2)cc1OCC
Yield: 60.1 %

Procedure:
To a solution of the product of Step A (0.0346 g; 0.0743 mmol) and NaI (0.033 g; 0.22 mmol) in anhydrous CH3CN (1 ml) Me3SiCl (0.1 ml) was added at room temperature under N2. After stirring for 30 min at room temperature MeOH (2 ml) was added and the resulting mixture was evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc (5 ml) and 1% NaHCO3 (5 ml). The precipitate formed was filtered off, washed with H2O (5 ml), fresh EtOAc (5 ml) and dried to give the title compound (0.019 g; 61%) as creamy solid. 1H-NMR (DMSO-d6) 1.28-1.41 (m, 6H): 3.2-3.4 (m, 2H+H2O); 3.5-4.02 (m, 7H); 4.07-4.18 (m, 4H); 4.6 (broad s, 2H); 6.52 (d, 1H, J=6 Hz); 7.06-7.19 (m, 3H); 7.58 (d, 1H, J=3 Hz); 7.72 (dd, 1H, J=9 Hz).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: CC1(C)Cc2c(Cl)ccc(C(=O)O)c2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2c(Cl)c([N+](=O)[O-])cc(C(=O)O)c2O1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooled to 5° C. by means of an external ice bath were added 10 g of 4-chloro-2,2-di-methyl-2,3-dihydro-7-benzofurancarboxylic acid over a period of 28 minutes. After stirring at 5° C. for 10 minutes, the mixture was added to ice with stirring. The resulting solid was collected by filtration and washed with water. After air drying, the residue was crystallized twice from ethyl acetate/hexane to provide 3.5 g of the desired subtitle intermediate, m.p. 260°-262° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[OH:21][CH2:22][CH2:23][NH:24][C@@H:25]([CH3:31])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:24]([CH2:23][CH2:22][OH:21])[C@@H:25]([CH3:31])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: C[C@H](NCCO)C(=O)N(C)C
Product: COc1ccccc1C1(N(CCO)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.17 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 79-3 (4.18 mmol, crude form) as starting materials, respectively 0.92 g (Isomer A, colorless solid) and 0.66 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1>O.NN.CO>[CH3:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:21])=[CH:4][N:3]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.5 %

Procedure:
A mixture of (2-methyl-5-nitro-pyridin-3-yl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine (450 mg, 11.84 mmol), catalytic ferric chloride (50 mg) in hydrazine hydrate (20 mL) and methanol (20 mL) was refluxed for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure and the crude residue was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was stirred with hexane (20 mL) for 5 min, the hexane layer was decanted and the residue was dried to give 280 mg of product as a pale yellow solid (Yield: 68%). Mp: 135° C.; 1H NMR (200 MHz, CDCl3): δ 2.51 (s, 3H), 3.65 (bs, 2H), 6.99 (s, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.78 (d, J=10.0 Hz, 1H), 8.05 (d, J=2 Hz, 1H), 8.36-8.31 (m, 1H), 8.51 (d, J=4.0 Hz, 1H), 8.75-8.72 (m, 1H), 9.27 (d, J=2.0 Hz, 1H); Mass [M+H]+: 279.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[O:13][CH3:14].[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][NH2:1])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (12 mL) and a solution of sodium nitrite (1.7 g, 24.4 mmol) in water (8 mL) were added to a solution of 4-chloro-3-methoxy aniline (3.86 g, 24.4 mmol) in water (8 mL), at −10° C. The mixture was stirred for 30 minutes and was then added to solution of tin chloride (14.89 g, 66 mmol) in concentrated hydrochloric acid (24 mL) and water (24 mL), cooled to 0° C. The reaction mixture was stirred for 18 hours, allowing the temperature to rise to 25° C. The resulting precipitate was filtered off and the solid was re-crystallised from heptanes/ethyl acetate (33:66) to afford the title compound the title compound as white solid in 72% yield, 3 g
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc(OC)c1OC

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3,4,5-trimethoxybenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:25][CH2:26]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1

Procedure:
The title compound, off-white solid (76 mg, 65%), MS (ISP) m/z=471.4 [(M+H)+], mp 187.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(7-fluoro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate C) (104 mg, 0.25 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[C:14]2[O:15][CH2:16][C:17](=[O:19])[NH:18][C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:9]1[C:14]2[O:15][CH2:16][C:17](=[O:19])[N:18]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:13]=2[N:12]=[C:11]([CH3:20])[N:10]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CN1C(=O)COc2c(Cl)nc(C)nc21
Yield: 68.7 %

Procedure:
A solution of 0.41 g of ethyl chloroacetate in 5 ml of methyl ethyl ketone is dropped to a mixture containing 0.6 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 0.5 g of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone within 15 minutes under refluxing and stirring. Then the mixture is refluxed under stirring for 8 hours, filtered as hot and washed with methyl ethyl ketone. The filtrate is evaporated to 10 ml, cooled and the unchanged starting material is filtered out. The mother liquor is evaporated, the residue is triturated with n-hexane, the solid precipitate is filtered, washed with n-hexane and dried to give 0.59 g (68%) of product, m.p.: 69°-70° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24](=[O:37])[N:25]([CH2:34][CH2:35][CH3:36])[C:26](=[O:33])[N:27]([CH2:30][CH2:31][CH3:32])[C:28]=1[NH2:29]>C(Cl)Cl>[CH2:34]([N:25]1[C:24](=[O:37])[C:23]2[NH:22][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:29][C:28]=2[N:27]([CH2:30][CH2:31][CH3:32])[C:26]1=[O:33])[CH2:35][CH3:36]
Reactant: O=C(O)C1CCOCC1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCOCC3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
3.2 g (0.025 mol) of tetrahydropyran-4-carboxylic acid, 4.0 g (0.025 mol) of carbonyldiimidazole and 85 ml of absolute methylene chloride are stirred for 30 minutes at ambient temperature. After the addition of 5.7 g (0.025 mol) of 5,6-diamino-1,3-dipropyluracil, the mixture is stirred for 4 hours at ambient temperature and then evaporated down in vacuo. The residue is combined with 130 ml of water and 11.6 g of calcium hydroxide, stirred for 30 minutes at 80° C. and, after cooling, acidified with conc. HCl whilst cooling with ice. The mixture is extracted with ethyl acetate and the organic phase is dried and evaporated. Chromatography of the crystalline residue on silica gel (CH2Cl2 /CH3OH 99:1) yields 1.7 g of the title compound in the form of white crystals (15% of theory), m.p. 171°-172° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.