Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:7].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[CH:26][C:27]([NH:30][N:31]=[C:10]([OH:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[C:6](=[O:7])[C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:21])[F:20])[CH:4]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1)c1ncccc1C(O)=NNc1ccc(C(F)(F)F)cc1
Yield: 80.7 %

Procedure:
2-(3-Trifluoromethylbenzoyl)nicotinic acid (0.5 g), 4-trifluoromethylphenylhydrazine (0.3 g) and para-toluene sulphonic acid (0.001 g) were stirred in methanol at room temperature for 22 hours. Solvent was evaporated. The residue was triturated in cold toluene then dried to yield the title compound as a beige solid (0.62 g), m.p. 127°-129° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:46])=O>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:46])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.0 g (5 mmoles) of 4-[3-(1-adamantyl)-4-methoxy benzamido] benzoic acid are dissolved in 60 ml of THF. 1.1 g (6 mmoles of dicyclohexylamine are slowly added. A white precipitate is immediately formed. The reaction mixture is then cooled to 0° C. and 0.7 g (6 mmoles) of thionyl chloride is slowly added. The reaction mixture is stirred for 3 hours at ambient temperature. The solid that forms is filtered and then the filtrate is evaporated. The resulting residue is used, as is, in the following synthesis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (2.45 g, 6.84 mmol) and ethyl acetate (280 mL, 0.024M) was treated with 10% palladium on carbon (0.24 g, 10% weight of starting material used). The flask was fitted with a hydrogen balloon, and the reaction stirred at 25° C. overnight. At this time, the reaction was filtered through a pad of Celite®, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 80 g silica gel column, 1-20% ethyl acetate/hexanes) afforded 4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (2.00 g, 81%) as an orange solid.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:39]([O:38][C:36]([NH:35][CH:4]([CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:12][CH:13]=1)[C:3]([OH:43])=[O:2])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)C(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CSCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a solution of 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid methyl ester (0.173 g, 0.281 mmol) in 4 mL of THF and 1 mL of methanol was treated with 2 N NaOH (1.5 mL, 2.81 mmol). After stirring at room temperature for 3 hours, the solution was acidified with 2 N HCl to a pH 3. The resulting solution was extracted with ethyl acetate (2×50 mL), dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (5% methanol in dichloromethane) to afford 2-tert-butoxycarbonylamino-3-[3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-ylmethylsulfanyl]-propionic acid. 1H NMR (DMSO, 300 MHz) δ 7.58-7.49 (m, 4 H), 7.44-7.36 (m, 3 H), 7.21 (d, J=7.8 Hz, 1 H), 7.09 (d, J=7.5 Hz, 1 H), 6.76-6.70 (m, 2 H), 4.62 (s, 2 H), 4.14-4.07 (m, 1 H), 3.79 (s, 2 H), 3.47 (t, J=5.4 Hz, 2 H), 2.81-2.72 (m, 3 H), 1.99-1.91 (m, 1 H), 1.40 (s, 9 H); ESI-LCMS m/z calcd for C32H35F3N2O4S: 600.7; found 601.3 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][C:14]([CH3:18])=[CH:15][CH:16]=O>C1(C)C=CC=CC=1>[CH3:18][C:14](=[CH2:13])[CH:15]=[CH:16][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CC(C)=CC=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)C=CN1CCOCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Anhydrous potassium carbonate (43.5 mmol; 6 g) and morpholine (308 mmol; 26.8 g) were introduced into a 100-ml Erlenmeyer equipped with a dropping funnel,under an inert atmosphere. When the reaction medium had been cooled to 0° C., prenal (150 mmol) in toluene (20 ml) was added dropwise. The temperature was allowed to rise to 20° C. and stirring was continued for 4 hours. The potassium carbonate was separated by filtration. The toluene was removed at atmospheric pressure, which permits cracking of the aminal. Under reduced pressure, the excess morpholine was distilled first, and then the expected dienamine (b.p. 108-110.C at 20 mm Hg) was distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]([O:23][C:24]([C:25]1[C:26](=[O:27])[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:5]2[C:6]([C:8]=1[CH3:9])=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:29])[CH3:22]
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(C)=O)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A solution of 2 (0.20 g, 1.18 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (165 μL, 0.20 g, 1.30 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting white precipitate was filtered to give 3 (0.38 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J=2.3 Hz, 1H), 7.39 (dd, J=2.3, 9 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.81 (d, j=8.6 Hz, 2H), 5.47 (br S, 2H), 4.46 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.46 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[Li].[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:17](O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)C.C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1([OH:13])[CH3:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)OCC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Methyl lithium (670 μl [1.11 mmol, 1.1 equiv] of a 1.65 M solution in diethyl ether) is added dropwise to a stirred solution of (S)-2-(tertbutyidimethylsilyloxy)-γ-butyrolactone 12 (218 mg, 1.01 mmol) in THF (4.0 ml) cooled to −78° C. is added dropwise. After stirring at −78° C. for 3 h, the reaction is quenched by the addition of glacial acetic acid (72 μl, 1.26 mmol, 1.25 equiv). Diethyl ether (20 ml) and saturated aqueous sodium bicarbonate solution (10 ml) are added. After stirring for 5 min the organic layer is separated and the aqueous layer is extracted with diethyl ether (2×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacua. Crude (3S)-3-(tertbutyidimethylsilyloxy)-2-hydroxy-2-methyl-tetrahydrofurane 13 (235 mg, 93%) is obtained as a colourless crystalline solid (mixture of diastereomers) which is used for the synthesis of (S)-3,5-di-(tert-butyldimethylsilyloxy)-pentan-2-one 14 without further purification.
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[CH:5]([OH:8])[CH2:6][NH2:7].[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([NH:7][CH2:6][CH:5]([OH:8])[C:4]([OH:3])=[O:9])=[O:21])=[CH:14]2
Reactant: COC(=O)C(O)CN
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(NCC(O)C(=O)O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(RS)-3-amino-2-hydroxypropionic acid methyl ester hydrochloride (6.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (6.6 mmol) were coupled according to Procedure A (except that acid, then base extraction was performed, and during the first acid wash a precipitate appeared so the mixture was filtered and the filtrate carried on in the usual manner of Procedure A). The crude product (920 mg) was dissolved in methanol and treated with 1N NaOH (6.6 mL) for 2 hours at 25° C. 1N NaOH was added (6.6 mL) and the mixture was concentrated, the residue dissolved in ethyl acetate, and the resulting solution washed with 2N HCl, brine, dried, and concentrated. The resulting colorless solid was stirred in chloroform and filtered giving the title substance: Yield 763 mg, 40%; HPLC (60/40) 2.86 minutes (89%); mp 214-215° C.; PBMS 283/285 (MH+, 100%); 1H NMR (DMSO-d6) δ11.78 (s, 1H), 8.62 (t, 1H), 7.70 (d, 1H, J=2 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=2, 8.7 Hz), 7.14 (d, 1H, J=2 Hz), 4.18 (dd, 1H, J=5, 8 Hz), 3.58 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28]([CH:40]=O)[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]>COC(C)(C)C.O>[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28](/[CH:40]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:17])[CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CC[C@H](C)CC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@H](C)CC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate (A) (74.7 g, 274 mmol) in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5 g, 273 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (B) (64.02 g, 160.6=1) in t-butyl methyl ether (278 ml) and water (21.7 ml) were added thereto, and the mixed solution was heat refluxed for approximately 31 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (351 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (234 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (351 ml), and dried with anhydrous magnesium sulfate (55 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2110 g; ethyl acetate:hexane=1:4 to 1:2). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:2].IC.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([Br:14])[CH:7]=1)[CH3:18])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(Br)c1
Temperature: -78 °C

Procedure:
To (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (12.2 mmol) in THF was added iodomethane (0.75 mL, 12.2 mmol), and the mixture was cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 12.2 mL, 12.2 mmol) was added, and subsequent work-up gave the title compound.
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.Br[CH2:15][C:16]([C:18]1C=CC=[CH:20][CH:19]=1)=O.C(O)C>[Pt](=O)=O.CO>[C:2]1([C:3]2[N:4]=[C:5]3[CH2:10][NH:9][CH2:8][CH2:7][N:6]3[CH:11]=2)[CH:20]=[CH:19][CH:18]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: c1ccc(-c2cn3c(n2)CNCC3)cc1

Procedure:
2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 2-bromo-1-phenylethanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: Br.[CH2:2]([C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[CH2:7][CH:6]=1)[CH2:3][CH3:4].C(C1C=CC(C2CCC(=[O:35])CC2)=CC=1)CC.C([Mg]Br)CC>C(Cl)Cl>[CH2:17]([C:14]1([OH:35])[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)[CH2:18][CH3:19]
Reactant: CCCc1ccc(C2CCC(=O)CC2)cc1
Reactant: CCCC1=CCC(c2ccc(CCC)cc2)CC1
Agent: Br
Agent: CCC[Mg]Br
Solvent: ClCCl
Product: CCCc1ccc(C2CCC(O)(CCC)CC2)cc1

Procedure:
HBr is passed, at 0°, into a solution in 50 ml of CH2Cl2 of 2.42 g of 1-propyl-4-p-propylphenylcyclohexene (obtainable by reacting 4-p-propylphenylcyclohexanone with C3H7MgBr, hydrolysing the product to give 1-propyl-4-p-propylphenylcyclohexan-1-ol and dehydrating the latter), the mixture is allowed to stand overnight and is worked up in the customary manner to give r-1-bromo-1-propyl-cis-4-p-propylphenylcyclohexane.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)([O-:22])=[O:21].[Cl-].[Na+]>O1CCCC1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccccn1
Yield: 24 %

Procedure:
The reaction of 8.0 g (0.022 mole) of 2-tributylstannylpyridine with 4.92 g (0.020 mole) of ortho-nitroiodobenzene was carried out in the presence of 0.70 g (0.001 mole) of dichlorobis(triphenlylphosphine)palladium in 100 ml of tetrahydrofuran at 110° C. After 24 hours from the start of the reaction, a saturated aqueous sodium chloride solution was added to the reaction mixture and the reaction product was extracted with ether. The ether layer was then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The resulting liquid was purified by column chromatography and concentrated to give 0.96 g (0.0048 mole, 24.9%) of ortho-(2-pyridyl)nitrobenzene as brown liquid.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3]C1C=CC=CC=1.[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>>[NH2:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:3][CH2:2][C:10](=[O:11])[OH:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCC(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.07 His: 1.00 Phe: 2.10 Gly: 2.03
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=2[N+:27]([O-:29])=[O:28])=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(F)cc2[N+](=O)[O-])cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.32 g, 3.2 mmol) and ethyl isocyanate (0.23 g, 3.2 mmol) were added to a solution of 3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole (0.69 g, 2.9 mmol) in ethyl acetate (10 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow solid of N-ethyl-3-(4-fluoro-2-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (0.72 g, yield: 79.7%). mp: 81-84° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.34 (dq, J=1.4 and 7.2 Hz, 2H), 5.78 (q, J=0.8 Hz, 1H), 6.71 (br s, 1H), 7.34-7.37 (m, 2H), 7.73 (ddd, J=1.2, 2.2 and 7.7 Hz, 1H).
Reaction SMILES: O[Li].O.[C:4]1([C:14]([NH:16][C@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([C:14]([NH:16][C@H:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1cccc3ccccc13)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
LiOH.H2O (0.272 g, 3.62 mmol, 5 eq) dissolved in water (0.6 ml) was added dropwise to a cooled (0° C.) solution of (R)-methyl 3-(1-naphthamido)-2,3-dihydro-1H-indene-5-carboxylate (B-36) (0.25 g, 0.724 mmol, 1 eq) in MeOH (3 ml), and the resulting mixture was stirred for 16 h at RT. After monitoring by TLC, further LiOH.H2O (0.272 g, 3.62 mmol, 5 eq) was metered in, and the reaction mixture was heated to 40° C. and stirred for 1 hour. Then the reaction solution was concentrated under reduced pressure, the residue was taken up in water and diethyl ether, and the phases were separated. The aqueous phase was acidified with 1 M HCl and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Yield: 96% (0.23 g)
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O1CCCC1>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 60 °C
Yield: 33.9 %

Procedure:
Phenyl isocyanate (15.5 g) is added to a solution of 2-amino-7-chloro-1,8-naphthyridine (17.9 g) in anhydrous tetrahydrofuran (600 cc) and the mixture is heated for 15 hours at approximately 60° C. After cooling the mixture, the crystallized solid is separated by filtration, washed with ethyl ether (3×50 cc) and air-dried. A crude product (25.2 g), m.p. 270° C., is obtained. This product (15 g) is purified under the following conditions: the product is dissolved in a mixture of dimethylformamide (200 cc) and acetonitrile (125 cc). After cooling for 5 hours at 20° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×50 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-N'-phenylurea (10.1 g), m.p. 276° C., is obtained.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)([CH3:9])([CH3:8])[CH3:7]>CCO>[C:6]([O:10][C:11]([NH:12][C@H:13]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:3][C:1](=[O:4])[CH3:2])=[O:29])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCCBr)C(=O)Nc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Potassium thioacetate (9.7 mmol) was added to a solution of ((S)-6-bromo-1-phenylcarbamoyl-hexyl)-carbamic acid tert-butyl ester (6.5 mmol) in EtOH (40 ml). The reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the resulting precipitate was poured into water and extracted twice with AcOEt. The organic layer was washed with brine and dried over Na2SO4 before being evaporated to afford the desired adduct.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[CH2:15](O)[CH3:16]>O>[CH2:15]([O:13][C:12]([C:11]1[C:3]([O:2][CH3:1])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)=[O:14])[CH3:16]
Reactant: COc1c(C(=O)O)ccc2[nH]ncc12
Reactant: CCO
Solvent: O
Product: CCOC(=O)c1ccc2[nH]ncc2c1OC
Temperature: 95 °C
Reaction time: 11 h

Procedure:
2 g of 4-methoxy-1H-indazole-5-carboxylic acid was added to a mixed solvent of 40 mL ethanol/2.2 mL concentrated sulfuric acid, and stirred at 95° C. for 11 hours. After cooling the reaction solution on ice, water was slowly added under ice cooling, and the precipitated crystals were collected by filtration and washed with water. Thereafter, the crystals were dried under reduced pressure, to afford 1.52 g of the title compound as pale brown crude crystals.