Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[CH2:2]C.[C:6]([C:10]1[O:11][C:12]([CH2:36]C)=[C:13]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:27]3[CH:26]=[CH:25]S[C:23]=3[C:22]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[C:30]([OH:32])=[O:31])=[CH:21][CH:20]=2)[N:14]=1)(C)([CH3:8])C>O=[Os](=O)(=O)=O.[BH4-].[Na+]>[CH2:34]([O:33][CH:29]([CH2:28][C:22]1[C:23]2[C:27](=[CH:26][CH:25]=[CH:1][CH:2]=2)[C:19]([O:18][CH2:17][CH2:16][CH2:15][C:13]2[N:14]=[C:10]([CH2:6][CH3:8])[O:11][C:12]=2[CH3:36])=[CH:20][CH:21]=1)[C:30]([OH:32])=[O:31])[CH3:35]
Reactant: CCOC(Cc1ccc(OCCCc2nc(C(C)(C)C)oc2CC)c2ccsc12)C(=O)O
Reactant: CCC(=O)Cl
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(Cc1ccc(OCCCc2nc(CC)oc2C)c2ccccc12)C(=O)O

Procedure:
was prepared in analogy to example 59, but starting the reaction sequence with propionyl chloride instead of isobutyryl chloride, and elaborating the terminal double bond via hydroboration with 9-BBN (as described in example 53) into a primary hydroxy group instead of oxidative cleavage with OsO4/NaBH4, as off-white solid of mp. 113–17°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]C)=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a suspension of 7-chloro-5-hydroxy-1-[6-(2-methoxycarbonylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (4 ml) is added 5% aqueous sodium hydroxide solution (1.5 ml), and the mixture is stirred at room temperature for one hour. To the reaction solution are added water and diluted aqueous hydrochloric acid solution in order to make the mixture weak acidic. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane-methanol to give 7-chloro-5-hydroxy-1-[6-(2-carboxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (150 mg) as white powder.
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@@H:12]2[C@H:17]3[CH2:18][O:19][C@H:15]([O:16]3)[C@H:14]([O:20][S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C@H:13]2[OH:31])=[CH:7][CH:6]=1>CN(C)C=O.[Ag]=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@@H:12]2[C@H:17]3[CH2:18][O:19][C@H:15]([O:16]3)[C@H:14]([O:20][S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C@H:13]2[O:31][CH3:1])=[CH:7][CH:6]=1
Reactant: CI
Reactant: COc1ccc(O[C@H]2[C@H](O)[C@@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]3OC[C@H]2O3)cc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COc1ccc(O[C@H]2[C@H](OC)[C@@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]3OC[C@H]2O3)cc1
Reaction time: 16 h
Yield: 93.1 %

Procedure:
Methyl iodide (54 ml, 954 mmol) and silver oxide (18.4 g, 79.5 mmol) are added to a solution of compound 88 (3.36 g, 7.95 mmol) in dry N,N-dimethylformamide (8 ml). After stirring for 16 h, the mixture is filtered (Celite), diluted with ethyl acetate (300 ml), washed with water (3×100 ml), dried (sodium sulphate), filtered, concentrated and purified by chromatography on silica to give the derivative 89 (3.23 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCc2ccccc2N1
Temperature: -10 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and as a catalyst, 6.7 mg (0.2 mol %) of a crystalline (R)-chloro[(1,2,3,4,5-η)-pentamethyl-2,4-cyclopentadien-1-yl](2-pyrrolidinecarboxamidato-κN1, κN2)iridium(III) complex (Cp*Ir(Cl−)(R-PA-H+)) was added. After cooling to −10° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was stirred at the same temperature for 2 days to give 2-methyl-1,2,3,4-tetrahydroquinoline (degree of conversion: 73%). The R-enantiomer was in excess and the optical purity was 90.2% ee.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].[O-]CC.[Na+:16].C(OCC)C>CC(OC)(C)C>[Cl:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O-:9].[Na+:16]
Reactant: CCOC=O
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CCOC(=O)C(Cl)C[O-]
Reaction time: 16 h

Procedure:
89.31 g (728 mmol) of ethyl chloroacetate and 63.7 g (859.9 mmol) of ethyl formate were dissolved in 500 ml of MTBE. 259.77 g (801 mmol) of an ethanolic solution of sodium ethoxide were added dropwise while stirring. After 16 hours, the supernatant was decanted off from the precipitate formed, the residue was stirred with approx. 500 ml of diethyl ether and filtered with suction, and the solid was washed with a further 500 ml of diethyl ether and dried.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1nnc(-c2cccc(C=O)c2)n1

Procedure:
In an autoclave, 3.2 g (18.4 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (see Step 59.1) in 22 ml of toluene are heated at 110° C. for 1.5 hours with ≈1.5 g of isobutene and 0.216 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 200 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=3:1) and crystallization from diethyl ether/hexane (−15° C.) yield 3-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.41 (hexane/ethyl acetate=3:1); FAB-MS: (M+H)+=231.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:14][C:15]3[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:6]2
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)[nH]c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-(6-methoxy-2-naphthyl)-3-pentyl-1H-indole (0.915 g, 2.66 mmol) in CH2Cl2 (30 mL) cooled to −78° C. was added BBr3 (9.86 mL, 1.0 M in CH2Cl2, 9.86 mmol) dropwise. The reaction was stirred at this temperature for 0.5 h and then warmed to rt for 2 h. The reaction mixture was quenched with MeOH (˜5 mL) followed by dilution with H2O (20 mL) and EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) to afford the product (0.677 g, 77%) as a foamy solid; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.23-1.42 (m, 4H), 1.58-1.76 (m, 2H), 2.89 (t, J=8.2 Hz, 2H), 7.00 (t, J=8.2 Hz, 1H), 7.06-7.19 (m, 3H), 7.35 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.2, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.74-7.88 (m, 2H), 7.98 (s, 1H), 9.83 (s, 1H), 11.14 (s, 1H); mass spectrum [(+) ESI], m/z 330 (M+H)+ and [(−) ESI], m/z 328 (M−H)−.
Reaction SMILES: [NH:1]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:70]([O:77][C:78](=[O:84])[N:79]([CH2:81][CH2:82][NH2:83])[CH3:80])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.Cl>CN(C=O)C.CCOC(C)=O>[C:33]([O:32][C:30](=[O:31])[NH:1][C@H:2]([C:27](=[O:28])[NH:83][CH2:82][CH2:81][N:79]([C:78]([O:77][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:84])[CH3:80])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]1[C:24]([CH3:25])=[C:23]([CH3:22])[C:17]2[O:18][C:19]([CH3:21])([CH3:20])[CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11])([CH3:35])([CH3:34])[CH3:36]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c2c1OC(C)(C)C2
Reactant: CN(CCN)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCN(C)C(=O)OCc2ccccc2)c(C)c2c1OC(C)(C)C2
Reaction time: 1 h

Procedure:
A solution of Boc-Arg(Pbf)-OH (3.33 g, 6.32 mmol), HATU (2.88 g, 7.58 mmol) and DIEA (7.4 ml, 31.6 mmol) in DMF (40 ml) was maintained at room temperature for 20 min, followed by the addition of compound C hydrochloride (1.45 g, 6.95 mmol). Stirring was continued for additional 1 h. The reaction mixture was diluted with EtOAc (500 ml) and extracted with water (3×75 ml) and brine (75 ml). The organic layer was dried over MgSO4 and then evaporated to provide compound D (4.14 g, 5.77 mmol) as yellowish amorphous solid. LC-MS [M+H] 717.6 (C35H52N6O8S+H, calc: 717.9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH2:34][CH3:35].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH2:33][CH2:34][CH3:35])=[N:8][C:7]=2[N:26]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: CCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (153 mg), 1M aqueous sodium hydrogen carbonate solution (439 μl), 1-iodopropane (117 μl) and N,N-dimethylformamide (3 ml) was stirred at 80° C. for 10 min. The reaction mixture was allowed to be cooled, and water (20 ml) was added thereto. The white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (10 ml). The solution was diluted with ethyl acetate (20 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethyl acetate/heptane to give the title compound (114 mg) as cotton-like needle crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:18])[CH:12]2[C:13]3([CH3:17])[O:16][CH:14]3[CH2:15][CH:10]1[CH2:11]2.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH3:11][C:12]1[C:9]([CH3:8])([CH3:18])[CH:10]([CH2:15][CH:14]=[O:16])[CH2:17][CH:13]=1
Reactant: CC1(C)C2CC3OC3(C)C1C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=CCC(CC=O)C1(C)C
Reaction time: 2 h

Procedure:
The reaction mass is then transferred to a 5 liter flask and 2145 grams of toluene are added. Alpha-pinene epoxide (1086 grams, 7.1 moles) is then added over a period of 1 hour while maintaining the reaction mass temperature below 53° C. using dry-ice/isopropanol bath in order to control exotherm. The reaction mass is then stirred for an additional 2 hours after addition is complete. The reaction mass is then intimately admixed with a 10% acetic acid solution to a pH of 4.3 followed by neutralization with sodium bicarbonate and sodium chloride solutions. The toluene is then recovered and the reaction mass crude material is "rush over" distilled whereby 785.3 grams of product is collected. (Chemical yield=74%). The rush over distillation fractions are collected using a 2 inch rush over column packed with saddle stones yielding the following fractions:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:23].C(N(CC)CC)C>C(O)(C)C>[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[N:6]3[CH3:11])[CH2:36][CH2:37]1)=[O:23]
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: Cc1cccc(C(=O)NCc2ccccc2N2CCNCC2)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NCc2ccccc2N2CCN(c3ncnc4c3nc(-c3cnn(C)c3)n4C)CC2)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 3-methyl-N-(2-(piperazin-1-yl)benzyl)benzamide (46.4 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 31.5 mg (50% yield) of the title compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]1([NH:21][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)ccc1F
Yield: 95 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.508 g, 0.0021 mol), Cyclohexylamine (G, 0.211 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclohexylsulfamoyl-2-fluoro-benzoic acid (H, 0.6 g, 95%). After drying overnight under vacuum, H (0.22 g, 0.737 mmol) in SOC12 (5 mL) was heated at 80° C. for 2 hours after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 95 mg, 0.737 mmol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.192 g (63%) of 5-cyclohexylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-45) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15](F)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[C:1]([C:3]1[C:4](=[O:20])[C:5]2[CH:6]=[C:7]3[CH:17]=[C:16]([F:18])[C:15]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[CH:14][C:8]3=[N:9][C:10]=2[N:11]([CH3:13])[CH:12]=1)#[N:2]
Reactant: CN1CCNCC1
Reactant: Cn1cc(C#N)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C#N)cn4C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A suspension of 2.1 g of 3-cyano-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 100 cm3 of dimethyl sulphoxide is heated to 80° C. in the presence of 2 cm3 of N-methylpiperazine. The reaction mixture is maintained at this temperature for 8 hours. The solution obtained is cooled to room temperature and stirred at this temperature for 15 hours. The precipitate formed is filtered off, washed with 3 times 20 cm3 of water and dried under vacuum (20 kPa) at 50° C. 2.6 g of 3-cyano-7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4oxobenzo[b][1,8]naphthyridine are obtained in the form of a yellow precipitate, melting point 335° C.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@:13]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C(F)(F)F>[CH3:16][C@:13]1([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:11]2[C@@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Solvent: OCC(F)(F)F
Product: C[C@@]1(NC(=O)c2ccccc2)CC[C@@H]2CNC[C@@H]21

Procedure:
N-[(3aR,4R,6aS)-2-benzyl-4-methyloctahydrocyclopenta[c]pyrrol-4-yl]benzamide from Example 2 (250 mg, 0.747 mmol) and trifluoroethanol (10 mL) were added to 20% Pd(OH)2—C, wet (50.0 mg, 0.356 mmol) in a 50 mL pressure bottle and stirred for 2 hours under 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane and the solvent removed in vacuo to give the title compound as a white solid: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.40 (s, 1H), 8.22-8.15 (m, 2H), 7.46-7.38 (m, 3H), 3.15 (dd, J=10.2, 1.3, 1H), 2.91-2.86 (m, 1H), 2.83-2.77 (m, 1H), 2.75-2.66 (m, 2H), 2.54 (qd, J=9.1, 2.0, 1H), 2.38 (dd, J=11.8, 4.4, 1H), 1.92-1.84 (m, 1H), 1.75 (s, 3H), 1.49-1.41 (m, 1H), 1.32 (ddt, J=13.0, 10.5, 6.6, 1H); MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH:48]3[CH2:50][CH2:49]3)[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH:48]3[CH2:49][CH2:50]3)[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K36) (264 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (347 mg, 71%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]>O>[CH:1]([NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:3]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: O=CNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (50 ml) was added to 98% formic acid (85 ml). The mixture was stirred at room temperature for 30 mins, then 3-aminobenzoic acid (10 g, 73 mmol) was added and the mixture was stirred for one hour at room temperature. Water (850 ml) was added and the mixture was stirred overnight at room temperature. The resultant white precipitate was collected (10.66 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33]>C(Cl)(Cl)Cl.CN(C=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: NCc1ccccn1
Reactant: COC(=O)c1ccc(C)nc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CNCc2ccccn2)nc1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
Commercially available methyl 6-methylnicotinate (2.5116 g) was dissolved in chloroform (50 ml), and N-bromosuccinimide (3.5682 g) and azoisobutylonitrile (290.4 mg) were added to the solution. The mixture was stirred for 22 hours at 70° C. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (100 g, hexane/ethyl acetate=4/1) to obtain a crude product (1.0883 g) as a pale yellow solid. 280.7 mg of the solid (280.7 mg) was dissolved in DMF (5.6 ml), and potassium carbonate (168.5 mg) and 2-picolylamine (0.370 ml) were added. The mixture was stirred for 12 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with distilled water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and then the residue was purified by silica gel column chromatography (25 g, chloroform/methanol 25/1) to obtain the title compound (298.3 mg) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:10]1([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1])[CH3:32]
Reactant: O=C1C(Cc2cnccn2)c2ccccc2N1c1ccccc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCC1(Cc2cnccn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 80 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(2-pyrazinylmethyl)-1H-indole and ethyl 4-bromobutyrate in Example 1, the desired product was obtained in 80% yield as an oil.