Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]=[CH2:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([CH:14]=[CH2:15])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=1
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-5-vinyl-phenyl}-carbamic acid tert-butyl ester (Example M194) (273 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (127 mg, 60%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Product: COC(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from methyl 4-chloro-3-nitrobenzoate (Lancaster Synthesis Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[C:15](O)(=O)[CH3:16]>>[CH2:1]([N:5]1[C:10]2[N:11]=[C:15]([CH3:16])[NH:12][C:9]=2[C:8](=[O:13])[NH:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2[nH]c(C)nc21

Procedure:
A solution of 7.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione in 20 ml of acetic acid was refluxed for 2 hours. The solution was evaporated. The residue was refluxed in 40 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 350 ml ethanol. Yield 1.8 g (21%) (XXXXVII) NMR (see Table I).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccccc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
3.4 g of methyl 2-chloro-4-phenoxy-5-methylsulfonylbenzoate were dissolved in 40 ml of MeOH and 9.9 ml of a 2 N aqueous NaOH solution were added. The mixture was stirred at RT for 4 hours, adjusted to pH=1-2 using a 2 N aqueous HCl solution and extracted 3 times using 150 ml of EA each time. The organic phase was dried over Na2SO4, the solvent was removed in vacuo and 2.9 g of white crystals were obtained,
Reaction SMILES: Br.[C:2]1([N:8]=[N:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>>[C:2]1([N:8]=[N:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:37](=[O:38])[CH2:36][NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(Nc1ccc(N=Nc2ccccc2)c2ccccc12)[C@@H]1CCCN1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Nc1ccc(N=Nc2ccccc2)c2ccccc12

Procedure:
The L-proline 4-phenylazo-1-naphthylamide hydrobromide thus obtained and t-butyloxycarbonyl glycine (1.36 g, 0.0077 mole) were coupled by N, N'dicyclohexylcarbodimide and the reaction mixture was worked up as in Example 6. The crude product was then purified by column chromatography, and the final product was obtained as crystals. Yield 1.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@H:6]1[C:11](=[O:24])[NH:12][C@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:4].[C:25]1([C:31]2[CH:40]=[C:39](O)[C:38]3[C:33](=[CH:34][C:35]([O:42][CH3:43])=[CH:36][CH:37]=3)[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:39]2[C:38]3[C:33](=[CH:34][C:35]([O:42][CH3:43])=[CH:36][CH:37]=3)[N:32]=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:40]=2)[CH2:7][C@H:6]1[C:11](=[O:24])[NH:12][C@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Compound 42 (249 mg, 0.725 mmol), 2-phenyl-7-methoxy-4-quinolinol (310 mg, 1.23 mmol) and PPh3 (580 mg, 2.21 mmol) were dissolved in dry THF and the temperature was lowered to 0° C. DIAD (435 uL. 2.21 mmol) dissolved in 2 mL dry THF, was added to the mixture during five minutes. After two hours the temperature was raised to room temperature and the solution was stirred overnight. Evaporation and purification by flash column chromatography (toluene/EtOAc gradient 6:1 to 4:1) gave 43 (324 mg, 78%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Yield: 109.4 %

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine (40 mg, 0.112 mmol) and 8 mg of 10% palladium/carbon (Pd/C) in 20 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through celite and the filtrate was concentrated to dryness to give a dark residue (40 mg). 1H NMR (CDCl3) δ 6.88 (s, 2H), 5.97 (s, 1H), 4.32 (d, 1H), 3.28 (m, 1H), 2.27 (s, 3H), 2.26 (s, 3H), 2.18 (s, 6H), 1.45-1.75 (m, 4H), 0.93 (t, 6H) ppm. The corresponding di-HCl salt was prepared as a tan solid, mp 213-216° C., 1H NMR (DMSO-d6) δ 11.1 (s, 1H), 8.48 (s, 1H), 6.98 (s, 2H), 6.73 (brs, 1H), 6.38 (s, 1H), 3.36 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 2.08 (s, 6H), 1.54 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:13][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH2:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])C=Cc1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1ccc(F)c(F)c1
Temperature: 40 °C
Yield: 63.6 %

Procedure:
To a solution of 1,2-difluoro-4-(2-nitro-vinyl)benzene (1.5 g) in THF (50 mL) is added dropwise lithium aluminum hydride (23 mL, 1M in ether) and the solution is heated at 40° C. for 3 hours. The solution is cooled, diluted with ether and quenched with Na2SO4.10H2O (104 g) overnight. The solid is filtered, and the solution is evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(3,4-difluoro-phenyl)-ethylamine (0.81 g). MS: 170 (M+H); 1H NMR (300 MHz, CDCl3) □6.9-7 (3H, m); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[CH2:16][C@@H:15]([OH:17])[C@H:14](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[CH2:21][C@H:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:3]=1[S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11].P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[CH3:1][C:2]1[CH2:16][C@@H:15]([OH:17])[C@H:14](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[CH2:21][C@H:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:3]=1[S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C)C[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)O)=C(C)C[C@H]1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To methyl (11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (41 mg, 0.099 mmol) in acetone (1 mL) was added pH 8 phosphate buffer (10 mL). To this was further added esterase containing solution (derived from pig's liver, made by Sigma Co., 100 μl). This was agitated at room temperature for 15 hours. To the reaction solution was added dilute hydrochloric acid to make the solution pH 4. Further, the solution was made saturated by ammonium sulfate, then the desired product was extracted with ethyl acetate. The extract was washed with brine, then was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then subjected to thin layer chromotography for separation (development solution: ethyl acetate) to obtain (11R,12S,13E,15S,17R)-9-methyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoic acid (5.4 mg, 14%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([O:14][CH3:15])[CH:8]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([O:14][CH3:15])[CH:8]=1
Reactant: COc1cc(Br)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Br)ccc1NC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
A solution of sodium bicarbonate (3.12 g, 0.0371 mol) in water (35 mL) was added to a solution of 4-bromo-2-methoxyaniline (3.00 g, 0.0148 mol) in dioxane (50 mL). The resulting mixture was stirred for 5 minutes and benzyl chloroformate (3.8 g, 0.022 mol) was added dropwise over 3 minutes. The reaction mixture was for two hours, then dioxane was removed under reduced pressure and the water phase was extracted twice with ethyl acetate (100 mL each). The combined organic extracts were dried over magnesium sulfate and after filtration concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield benzyl N-(4-bromo-2-methoxyphenyl)carbamate (3.75 g, 0.011 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) 8.72 (s, 1H), 7.61 (d, 1H), 7.38 (m, 5H), 7.20 (s, 1H), 7.10 (d, 1H), 5.14 (s, 2H), 3.81 (s, 3H). TLC (ethyl acetate/heptane 1:9) Rf 0.21.
Reaction SMILES: S([O:5][CH2:6][C@@H:7]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)(=O)C.[N-:24]=[N+:25]=[N-:26].[Na+].[I-].[Na+]>CN(C=O)C>[C:12]([O:11][C:9]([NH:8][C@@H:7]([C:6]([N:24]=[N+:25]=[N-:26])=[O:5])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)N=[N+]=[N-]
Temperature: 50 °C
Yield: 73 %

Procedure:
The product from (B) (12.6 mmol) was dissolved in DMF (25 mL) and sodium azide (NaN3) (50 mmol) and sodium iodide (NaI) (50 mmol) were added. This solution was warmed at 50° C. for 24 hr then cooled to room temperature, washed with H2O (3×50 mL), extracted with EtOAc (2×50 mL) and washed with brine (1×25 mL). The organic layer was dried over Na2SO4, filtered dried to give the title compound (2.8 g, 77%) as an oil.
Reaction SMILES: C(O[C:4](=[O:26])[C:5](=[N:11][N:12]([C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)C.[O-]CC.[Na+].Cl>CCO>[CH2:23]([O:22][C:20]([C:19]1[C:18](=[O:25])[N:12]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:11]=[C:5]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[C:4]=1[OH:26])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)N(CCC(C)C)N=C(C(=O)OCC)c1cccs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c(-c2cccs2)nn(CCC(C)C)c1=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To a solution of [(2-Ethoxycarbonyl-acetyl)-(3-methyl-butyl)-hydrazono]-thiophen-2-yl-acetic acid ethyl ester (12a) (380 mg, 1.0 mmol) in EtOH (6 mL) at room temperature, sodium ethoxide (Aldrich) (21 wt % in ethanol, 0.4 mL, 1.1 mmol) was added, and the resulting mixture was stirred for 30 min. Aqueous HCl (5%, 0.75 mL) was added slowly, and then followed by liquid-liquid extraction with H2O/EtOAc. The combined organic layer was washed with brine, dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel to give the desired product (13a) (280 mg, 83%) as yellow solid. LC-MS (ESI+): m/e=337.30 [M+1]+(exact ms: 336.11); 1H NMR (400 MHz, CDCl3): δ 7.89 (dd, 1H, J=3.6, 1.2 Hz), 7.39 (dd, 1H, J=5.2, 1.2 Hz), 7.10 (dd, 1H, J=5.2, 3.6 Hz), 4.53 (q, 2H, J=7.2 Hz), 4.22 (m, 2H), 1.73 (m, 2H), 1.68 (m, 1H), 1.50 (t, 3H, J=7.2 Hz), 0.99 (d, 6H, J=6.4 Hz).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:14][P:15](=[O:22])([O:19]CC)[O:16]CC)=O)C1C=CC=CC=1.I[Si](C)(C)C>C(Cl)Cl>[NH2:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:13][CH2:14][P:15](=[O:16])([OH:22])[OH:19]
Reactant: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CCCCCCCCCCCCC(N)CCP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.6 %

Procedure:
A solution of 100 mg (0.2 mmol) of (±)-diethyl 3-(benzyloxycarbonylamino)pentadecylphosphate (from Example 27, Step C) in 1 mL of CH2Cl2 was treated with 0.11 mL (0.8 mmol) of iodotrimethylsilane then stirred at rt for 1 h. The reaction was quenched with 1 mL of methanol, stirred at rt for 15 min then concentrated. The resulting oil was dissolved in 0.5 mL of EtOAc, diluted with 5 mL of hexanes and. sonicated for 1 min. The suspension was filtered and dried to give 68 mg of the title compound: 1H NMR (500 MHz) δ 3.22-3.30 (m, 1H), 1.76-2.01 (m, 4H), 1.56-1.70 (m, 2H), 1.26-1.46 (m, 20H), 0.89 (t, J=6.9 Hz, 3H); ESI-MS 308.2 (M+H).
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.O>C(O)C>[CH:1]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCCCCCCCCCC1
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: OC1CCCCCCCCCCCCCC1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
5.0 g of cyclopentadecanone (MW 224, 22.3 mmol) were dissolved in 5.0 ml of ethanol, and hydrogenated sodium borate (MW 37.8, 2.5 g) was added thereto over 30 minutes. During this period, the temperature of the reaction mixture increased from 20° C. to 50° C. After reaction for one hour at 50° C., 50 ml of hexane and 50 ml of water were successively added, and the reaction was terminated. The reaction mixture was separated into an aqueous phase and an organic phase. The organic phase was washed twice with water and the solvent was removed under reduced pressure to yield a crude product. 4.57 g of crude product were purified on a silica gel column chromatograph (internal diameter 25 mm×height 190 mm, silica gel 60 manufactured by Nakalai Tesque Co. Ltd.) using hexane:ethyl acetate (9:1, v/v), to give 2.35 g of cyclopentadecanol having a purity of 99.3%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:18][CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:9]=[C:4]2[NH:3]1.[H-].[Na+].[N:21]1[C:29]2[CH2:28][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[N:21]1[C:29]2[CH2:28][C@H:27]([CH2:30][N:3]3[C:4]4=[N:9][C:8]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][CH2:18][CH:2]3[CH3:1])[CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)OC[C@@H]1Cc2cccnc2C1
Reactant: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1C[C@@H]1Cc2cccnc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 0.15 g (0.62 mmol) of 8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous dimethylformamide was added 0.032 g (0.81 mmol) of sodium hydride (60% suspension in mineral oil). The mixture was allowed to stir at 50° C. for 30 min. 0.184 g (0.81 mmol) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl ester was added and the stirring continued at 85° C. for 18 h. Water was added and the mixture extracted with trichloromethane/methanol 90/10. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel, eluting with a mixture of ethyl acetate/ethanol in the proportions 100/0 to 74/26, gives 0.14 g (60%) of the compound in the form of free base. Mp.: 164-166° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][N:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]2=[O:26])=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][N:12]([CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[C:13](=[O:26])[CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CCn2ccc(OCc3ccccc3)cc2=O)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCn2ccc(OCc3ccccc3)cc2=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 540 mg (1.46 mmol) 5-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-thiophene-2-carboxylic acid methyl ester (preparation 11b) in 8.0 mL MeOH is added 5.5 mL (5.50 mmol) 1M aqueous sodium hydroxide-solution. The reaction is stirred overnight at RT and additional 3.0 mL (3.00 mmol) 1M aqueous sodium hydroxide-solution is added. The reaction mixture is stirred 4 days at RT and the solvent is evaporated. The residue is acidified with 1M aqueous HCl, the precipitate is collected, washed with water and dried.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][N:37]2[CH3:40])=[CH:33][CH:32]=1)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][N:37]4[CH3:40])=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cn1ccc2ccc(C=O)cc21
Product: Cn1ccc2ccc(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc21

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-formy-1-methylindole to the procedure of step 1, Example 66. MS (ESI) m/z 522.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[N:10]=1)[C:5]([NH2:7])=[O:6].[Br:18][C:19]1[CH:20]=[C:21]([C:25](O)=[O:26])[NH:22][C:23]=1[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:18][C:19]1[CH:20]=[C:21]([C:25]([O:17][CH:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=[C:2]([Cl:1])[N:10]=3)[CH2:12][CH2:13]2)=[O:26])[NH:22][C:23]=1[CH3:24]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(O)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Br
Temperature: 0 °C
Reaction time: 18 h
Yield: 5.2 %

Procedure:
2-chloro-6-(4-hydroxypiperidin-1-yl)isonicotinamide (Intermediate 62; 123 mg, 0.48 mmol), 4-bromo-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 18) (98 mg, 0.48 mmol) and triphenylphosphine (138 mg, 0.53 mmol) were stirred in anhydrous THF and cooled to 0° C. DEAD (83 μl, 0.53 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was filtered, diluted with EtOAc and washed with water and dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/hexane (4:1) to afford the title compound (11 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[C:23](O)(=[O:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Reactant: CC(=O)O
Product: CC(=O)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and acetic acid; MS: m/e=334.4 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:5]1[C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c2occc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c2ccoc12
Yield: 51.6 %

Procedure:
A mixture of 7-chloro-4-methyl-benzofuran (CAS-number 79444-976; 51.9 g), N-bromosuccinimide (61.4 g), benzoyl peroxide (0.52 g) and carbon tetrachloride (1200 ml) was heated under reflux under the illumination of an 80 W flood lamp for 20 h. The mixture was cooled, and filtered and the filtrate evaporated to dryness. The residue was absorbed onto silica and purified by chromatography on silica using ethyl acetate and hexane (1:20) to give the title compound (39.50 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:11]>O1CCCC1>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: N#Cc1c(F)cccc1F
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1F
Temperature: 25 °C
Yield: 99 %

Procedure:
1,000 parts of 2,6-difluorobenzonitrile, 1,500 parts by volume of tetrahydrofuran and 800 parts by volume of ammonia are stirred for 10 hours at 100° C. in a closed vessel. The mixture is cooled to room temperature, the solid is filtered off and washed with tetrahydrofuran, and the organic phase is freed from solvent under reduced pressure. The residue is dried under reduced pressure. 972 parts (99% of theory) of 2-amino-6-fluorobenzonitrile, of solidification point 127° C., are obtained.