Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:29](=[O:30])[NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: O=C=Nc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g, 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then 2-chloro-phenyl isocyanate was added (0.184 g., 1.2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2i; yield: 0.20 g. (50.9%), m.p. 130° C., C23H21ClN2O2; 1H NMR δ ppm (CDCl3): 1.90-2.02 (m, 2H), 2.82 (t, 2H), 3.30-3.35 (m, 2H), 4.46 (s, 2H), 6.43-6.48 (m, 1H), 6.74-6.82 (m, 2H), 7.20-7.25 (m, 5H), 7.44-7.46 (m, 4H); IR vmax (KBr) (cm−1): 534, 754, 807, 882, 1018, 1059, 1193, 1245, 1303, 1352, 1432, 1506, 1597, 1718, 1749, 2371, 2830, 2922, 3418, 3760.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g of (6-bromo-pyridin-2-yl)methanol in 50 ml of N,N-dimethylformamide were successively added 4 g of imidazole and 8.4 g of tert-butyldimethylsilyl chloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. After adding water to the reaction mixture, the mixture was extracted with n-hexane. The resulting hexane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]1)[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.Cl.[OH-:34].[NH4+]>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[C:5]([CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)=[N:4][C:3]3[C:2](=[O:34])[NH:10][CH:9]=[N:8][C:7]2=3)=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Agent: Cl
Agent: [NH4+]
Product: O=c1[nH]cnc2c1nc(CC1CCN(Cc3ccccc3)CC1)n2Cc1ccc(F)cc1
Yield: 52 %

Procedure:
A mixture of 3 parts of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purine and 50 parts of a hydrochloric acid solution 1N was stirred and refluxed for 1.5 hours. After cooling, the mixture was made alkaline with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 1.5 parts (52%) of 9-[(4-fluorophenyl)methyl]-1,9-dihydro-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-6H-purin-6-one; mp. 197.0° C. (compound 185).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=2[OH:11])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2cc(C)sc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C)sc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-methyl-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (21 g), potassium carbonate (12.2 g) and dry dimethylformamide (750 ml) was stirred at ambient temperature and iodomethane (6 ml) added. The mixture was stirred at ambient temperature for approximately 3.5 hours, then at 60° for 2 hours. The solvent was removed under reduced pressure to give a residue which on treatment with water (300 ml) gave the novel compound ethyl 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 143°-144°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N+:11]([O-:26])=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(=O)c2c[n+]([O-])ccc2c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To the stirred solution of 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (1.0 g, 4.09 mmol), prepared as described in Example 2, Part C, in DCM (20 mL) cooled to 0° C. was added m-CPBA (1.763 g, 10.22 mmol). The reaction mixture was then warmed to ambient temperature and stirred for 4 h. Reaction mixture was then diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (200 mL), brine solution (50 mL). The organics were then dried over sodium sulphate, filtered and concentrate to afford 8-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine 3-oxide (1.0 g, 3.84 mmol, 94% crude yield) as a yellow solid. The material was carried on without further purification. LC/MS (ESI) m/e 261.0, [(M+H)+, calcd for C13H10ClN2O2, 261.0]; LC/MS retention time (method C): tR=1.65 min.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([CH3:6])=[O:5].[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:11]1([CH2:17][CH2:18][CH2:3][C:4](=[O:5])[CH3:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC(=O)CCCc1ccccc1
Reaction time: 5 h

Procedure:
According to reference F. C. Montgomery, W. H. Saunders, Jr. J. Org. Chem. 1976, 41, 2368-72, 7.6 g of sodium are added to 200 ml of absolute ethanol. Once the sodium has dissolved, 43 g (0.33 mol) of ethyl acetoacetate are added dropwise within an hour, the mixture refluxed for 1 hour, 65 g of 2-phenylethyl bromide are slowly added dropwise and the mixture is refluxed again (21 hours). After cooling and filtration, the mixture is distilled. The product is first heated for 5 h to 90° C. with 350 ml of 5% sodium hydroxide, then stirred for 5 hours at the same temperature with 150 ml of 50% sulfuric acid. After cooling, the product is left to stand for 48 hours, extracted with diethyl ether, the combined extracts are dried over sodium sulfate and 3a is finally obtained in good yield by distillation (b.p.: 132-134° C., 2.3 103 Pa (17 Torr)).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:7][C:6]=1[O:19][CH3:20])[CH3:4].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH2:3]([C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:13]2[CH2:17][N:16]([CH3:21])[C:15](=[O:18])[CH2:14]2)=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4]
Reactant: CCc1c(OC)cc(C2CNC(=O)C2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1c(OC)cc(C2CC(=O)N(C)C2)cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3.12 g (78 mmol) of a sodium hydride dispersion (60% in oil) were added using a spatula and while stirring to a suspension of 8.85 g (35.5 mmol) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-pyrrolidin-2-one in 250 ml of tetrahydrofuran and 2 ml of dimethylformamide and the mixture was stirred at room temperature for a further hour. Thereafter, the reaction mixture was treated with 3.52 ml (106.5 mmol) of methyl iodide and left to stir at room temperature for a further 16 hours. Subsequently, the reaction mixture was poured on to 400 ml of ice-water and extracted twice with 600 ml of ethyl acetate each time. The combined organic phases were washed twice with 300 ml of saturated sodium chloride solution each time, dried (MgSO4) and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (methylene chloride/methanol 39:1). 8.08 g (86%) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-one were obtained as a beige solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C1C=CC=CC=1>[C:14]1([CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[C:10](=[O:12])[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ccc(CC(C)=O)cc1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CSc1ccc(C(=Cc2ccccc2)C(C)=O)cc1

Procedure:
A solution of 1-(4-methylthiophenyl)-2-propanone [G. Y. Lesher, U.S. Pat. No. 4,517,192, May 14, 1985; L. M. Werfel et al, J. Med. Chem., 29, 924-36 (1986)] (11.2 g, 0.062 mol) and benzaldehyde (6.6 g, 0.062 mol) in benzene (75 ml) containing piperidine (200 mg) was heated at reflux for 24 hours. After cooling, the solvent was removed and the residue was purified by chromatography on silica gel using mixtures of ethyl acetate and toluene to give the ketone. This material was recrystallized from ethyl acetate and hexane to give 14 g (82%) of pure ketone as a crystalline solid: mp 91°-93° C. Anal. Calc'd. for C17H16OS (268.38): C, 76.08; H, 6.01; S, 11.95. Found: C, 76.15; H, 6.08; S, 11.79.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)=[N:12][C:11]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.OO.C(=O)([O-])[O-:32].[K+].[K+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:19]([NH2:20])=[O:32])=[CH:21][CH:22]=4)=[N:12][C:11]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-c2nc(-c3ccccn3)c(-c3ccc4c(c3)OCO4)o2)cc1
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(-c2nc(-c3ccccn3)c(-c3ccc4c(c3)OCO4)o2)cc1
Yield: 44 %

Procedure:
Prepared from 4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)-benzonitrile using hydrogen peroxide and methanolic potassium carbonate according to Example 16 and isolated in 44% yield. 1H NMR (DMSO) δ: 6.15 (2H, s), 7.08-7.16 (2H, m), 7.45-7.54 (2H, m), 7.95-7.99 (1H, m), 8.02 (1H, br. s), 8.08 (1H, br. s), 8.12-8.15 (2H, m), 8.22 (1H, dd, J=7 and 1 Hz), 8.48 (1H, d, J=8 Hz), 8.74 (1H, d, J=8 Hz); m/z (API) 386 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([C:6]([CH3:9])([CH3:8])[CH3:7])[NH2:5].[C:11](O)(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:11]([NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: C=CCCCCC(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=CCCCCC(=O)N[C@H](C(=O)OC)C(C)(C)C
Yield: 80.7 %

Procedure:
A solution of L-t-leucine methyl ester (1.00 g, 6.89 mmol), 6-heptenoic acid (1.06 g, 8.26 mmol), EDC (1.58 g, 8.26 mmol) and HOAt (1.23 g, 8.26 mmol) in DMF (10 mL) was stirred at 22° C. for 2 hours. The reaction mixture was diluted with aqueous saturated NaHCO3 (30 mL), and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×30 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 5-50% EtOAc/hexane, to give the title product (1.42 g, 81%). LRMS (ESI) m/z 256.3 [(M+H)+; calcd for C14H26NO3: 256.2].
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:43]([CH3:50])[CH:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[O:34])[CH2:10][CH2:9]1)=O)(=[O:3])[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:29]([O:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[N:8]([C:6]4[O:3][C:1]([CH3:2])=[N:4][CH:5]=4)[CH2:9][CH2:10][C:11]([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH2:42][N:43]([CH3:50])[CH:44]5[CH2:45][CH2:46][O:47][CH2:48][CH2:49]5)=[CH:40][CH:41]=4)=[O:34])=[CH:12][C:13]=3[CH:18]=2)=[CH:20][CH:21]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C(=O)CNC(C)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3c2cnc(C)o2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
In phosphorus oxychloride (25 ml) was dissolved 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g). The solution was heated to stir at room temperature for 7 hours and at 50° C. for 2 hours, and the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with basic silica gel column chromatography (ethyl acetate/hexane). The resulting crude crystals were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 44) (0.26 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH2:31][CH2:32]1)=[O:21]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CNc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Product: CNc1nc2c(cc1NC(=O)N1CCN(c3cc(C)cc(C)c3)CC1)CCC2
Yield: 48 %

Procedure:
Phenyl N-(2-methylamino-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)nc1
Product: CC(C)(C)NC(=O)c1ccc(Br)nc1

Procedure:
6-bromo-N-tert-butylnicotinamide was prepared from 6-bromonicotinoyl chloride and tert-butylamine.
Reaction SMILES: [Br:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)C>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([Br:1])([F:8])[F:7])(=[O:19])=[O:18]
Reactant: OCCCC(F)(F)Br
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCC(F)(F)Br
Temperature: 0 °C

Procedure:
A stirred solution of 4-bromo4,4-difluorobutanol (0.57 g) in dry diethylether (5 cm3) was cooled to 0° C. Maintaining this temperature, triethylamine (1.7 cm3) was added. After ten minutes methanesulfonyl chloride (0.3 cm3) was added and the mixture stirred for a further hour at 0° C. The reaction mixture was poured into 2M hydrochloric acid (2 cm3) and diethylether (20 cm3). The organic phase was separated, washed with saturated brine, then passed through a plug of silica gel eluting with further diethylether. The diethylether fractions were evaporated under reduced pressure to give a light yellow oil (0.705 g). 1H NMR: δ 2.04-2.18(2H,m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:30][CH:31]3[CH2:33][CH:32]3[C:34]([O:36]CC)=[O:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:30][CH:31]3[CH2:33][CH:32]3[C:34]([OH:36])=[O:35])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3C(=O)OCC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3C(=O)O)c3ccc(F)c(C(=O)O)c3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 73.1 %

Procedure:
To a solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}{[2-(ethoxycarbonyl)cyclopropyl]methyl}amino)-2-fluorobenzoate (340 mg; 0.63 mmol) in anhydrous THF (5 mL) were added lithium hydroxide monohydrate (64 mg; 1.54 mmol) and water (7 mL). The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl (1N) was added, the residue was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (60 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure to give 230 mg (73%) of the title compound as a white solid. HPLC, Rt: 4.99 min (purity 99.5%). LC/MS: M−(ESI): 498.2, 1H NMR (MeOD) δ: 7.46 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.29 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 4.66 (s, 2H), 3.44 (m, 1H), 2.65 (t, J=7.5 Hz, 2H), 1.65 (m, 3H), 1.35 (m, 3H), 1.15 (m, 1H), 0.95 (m, 4H), 3.59 (m, 1H), 7.05 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][NH:8][CH2:9][C:10]#[CH:11].[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14]>C(O)C.CCOCC>[C:12]([OH:17])(=[O:16])[C:13]([OH:15])=[O:14].[CH2:2]([N:8]([CH2:9][C:10]#[CH:11])[CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCNC
Reactant: CCCCCBr
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: C#CCN(C)CCCCC
Yield: 60 %

Procedure:
1-Bromopentane (12.1 g, 80 mmoles) and N-methylpropargylamine (11.1 g, 160 mmoles) were refluxed in absolute ethanol (75 mL) for 72 h. to give (after addition to 80 mmoles of oxalic acid in ether) the title compound in 60% yield after recrystallization from methanol-ether, m.p.=101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+].O.Cl>O1CCCC1>[Cl:29][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Cl:1])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Yield: 79.7 %

Procedure:
A mixture of methyl 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)benzoate, (30 mg, 0.06 mmol) and sodium hydroxide (27 mg, 0.06 mmol) were stirred in tetrahydrofuran and water (1:1, 6 mL) solution for about 2 hours, followed by slowly addition of aqueous hydrochloric acid till pH 4-5. The precipitated product was filtered and dried under vacuum to afford 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)benzoic acid (20 mg, 62.5%).
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][NH:24][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)(C)(C)C.C(N(C(C)C)CC)(C)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>CN(C)C=O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:39]([NH:38][CH2:36][CH3:37])=[O:40])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc21
Temperature: 60 °C
Reaction time: 48 h
Yield: 9 %

Procedure:
4-(3-t-Butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.056 mmol) was dissolved in dimethylformamide (1 mL), and diisopropylethylamine (29 μL, 3 equivalents) and ethyl isocyanate (13 μL, 3 equivalents) were added, followed by stirring at 60° C. for 2 days. The reaction mixture was poured onto water, followed by extraction with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtering off the drying agent, concentration was carried out under reduced pressure, and the resulting residue was stirred at room temperature for 30 minutes in trifluoroacetic acid. Concentration was carried out under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), to obtain the desired compound (colorless powder, 1.7 mg, 9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[CH2:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]ncc2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-aminoindazol and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone according to the method described in Example 142b. Melting Point: 153-155° C. (diethylether)
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][C:12]=2[N:19]2[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]2)[CH2:5][CH2:4]1.[F:29][C:30]1[C:43]([N:44]=[C:45]=S)=[C:42]([F:47])[CH:41]=[CH:40][C:31]=1[CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].CC(C)N=C=NC(C)C>CN(C=O)C>[F:28][C:2]([F:27])([F:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:19]3[CH2:24][CH2:23][CH:22]([F:25])[CH2:21][CH2:20]3)=[CH:13][C:14]3[NH:18][C:45]([NH:44][C:43]4[C:42]([F:47])=[CH:41][CH:40]=[C:31]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])[C:30]=4[F:29])=[N:17][C:15]=3[CH:16]=2)=[O:26])[CH2:7][CH2:8]1
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CCC(F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(F)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(N4CCC(F)CC4)cc3[nH]2)c1F

Procedure:
The title compound is prepared in analogy to 2c from N-(trans-4-trifluoromethyl-cyclohexyl)-2-(4-fluoro-piperidinyl)-4,5-diamino-benzoic acid amide (50 mg, 0.12 mmol), and N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (70 mg, 0.24 mmol), DIC (30 μL) and DMF (2.0 mL).