Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([CH3:10])[CH2:4]1.[CH:18]1[CH:19]=[CH:20][C:21]2[NH:26][CH:25]=[C:24]([CH2:27][CH2:28]O)[C:22]=2[CH:23]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.C(O)C.O>[CH3:17][N:2]([CH3:1])[C:3]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6]2([C:25]3[NH:26][C:21]4[C:22]([C:24]=3[CH2:27][CH2:28][O:9]2)=[CH:23][CH:18]=[CH:19][CH:20]=4)[CH:5]([CH3:10])[CH2:4]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC1CC(c2ccccc2)(N(C)C)CCC1=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC1CC(c2ccccc2)(N(C)C)CCC12OCCc1c2[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(±)-4-dimethylamino-2-methyl-4-phenylcyclohexanone (461 mg, 2 mmol) together with tryptophol (322 mg, 2 mmol) was dissolved in DCM (100 ml) and mixed with trifluoromethane sulphonic acid (0.19 ml, 2.14 mmol). The mixture was stirred at RT for 20 h. The reaction mixture was mixed with 2N NaOH (2 ml) and H2O (2 ml) and stirred for 20 min. The organic residue was firstly washed with 2N NaOH (5 ml), then with H2O (5 ml) and dried over Na2SO4. The solvent was then removed in vacuum. The semisolid residue obtained was taken up in 10 ml of ethanol and cooled to 5° C. for 2 h. The solid precipitated out during this was discarded. The residue remaining in the mother liquor was purified by column chromatography on silica gel (50 g, EE/ethanol=4:1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15]CC)=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:15])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(Cl)c(Cl)ccc2c1O
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(Cl)c(Cl)ccc2c1O
Temperature: 180 °C

Procedure:
2,3-Dichloroaniline (7.83 g) and diethyl ethoxymethylenemalonate (9.76 g) are heated at 130° C. for 1.5 hours. The reaction is cooled to 60° C. and the solution poured into hexanes. The intermediate enamine is collected and dried. The solid is added to 70 mL diphenyl ether and heated to 250° C. for 1.5 hours with removal of ethanol with a Dean-Stark trap. The reaction is cooled to room temperature. The product is collected by filtration, washed thoroughly with hexanes, and dried to yield 11.32 g of ethyl 7,8-dichloro-4-hydroxyquinoline-3-carboxylate. A mixture of this ester (0.48 g) and 4-chlorobenzylamine (1.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diethyl ether is added. The resulting solid is filtered, washed twice with diethyl ether, and dried. The solid is adsorbed onto silica and purified by Biotage Flash 40S chromatography (eluent 2% MeOH:CH2Cl2). The product-containing fractions are evaporated to give a white solid (0.12 g).
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([CH:26]([C:28]2[CH:32]=[N:31][N:30]([CH3:33])[N:29]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](N[C@@H](C2C=CC(OC)=C(F)C=2)C2C=NN(C)C=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:64][C@H:65]1[CH2:70][CH2:69][O:68][CH2:67][C@H:66]1F)=[N:40]2.FC1C=C(C(N)=O)C=C2C=1C=NC(N[C@H]1CCOC[C@H]1F)=N2.O1C=CC(N)=CC1.F[C@H]1[C@@H](N)CCOC1>>[F:34][C:35]1[CH:44]=[C:43]([C:45]([NH:27][C@@H:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)[C:28]2[CH:32]=[N:31][N:30]([CH3:33])[N:29]=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:64][CH:65]1[CH2:66][CH2:67][O:68][CH2:69][CH2:70]1)=[N:40]2
Reactant: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(N[C@H]4CCOC[C@H]4F)nc3c2)c2cnn(C)c2)cc1F
Reactant: COc1ccc(C(N)c2cnn(C)n2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Agent: NC(=O)c1cc(F)c2cnc(N[C@H]3CCOC[C@H]3F)nc2c1
Agent: NC1=CCOC=C1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NC4CCOCC4)nc3c2)c2cnn(C)n2)cc1F

Procedure:
(S)-5-Fluoro-N-((3-fluoro-4-methoxyphenyl)(2-methyl-2H-1,2,3-triazol-4-yl)methyl)-2-(tetrahydro-2H-pyran-4-ylamino)quinazoline-7-carboxamide (I-51) was prepared analogously except 32b was replaced with 34c, and 5-fluoro-N-((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)quinazoline-7-carboxamide (I-52) was prepared analogously except 84b was replaced with 5-fluoro-2-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-ylamino)quinazoline-7-carboxamide which can be prepared in accord with the procedure in example 3 except in step 3, 2H-pyran-4-amine was replaced with 60c.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[C:11](=[S:16])(OCC)[S-:12].[K+].Cl>CN(C=O)C.O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[S:12][C:11]([SH:16])=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: CCOC(=S)[S-]
Reactant: N#Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 76.1 %

Procedure:
A mixture of 3-amino-4-chloro benzonitrile (13, 0.50 g, 3.28 mmol) and potassium O-ethyl dithiocarbonate (1.05 g, 6.55 mmol) in DMF (15 mL) was heated overnight at 110-120° C. under N2. After cooling, the reaction mixture was diluted with water and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield 14 (0.48 g, 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21]C)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:23])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate (Compound E18, 300.0 mg, 0.926 mmol) in 4.0 mL of EtOH and 2.0 mL TBH was added NaOH (200.0 mg, 5.00 mmol; 5.0 nmL of a 1N aqueous solution). After stirring overnight at room temperature the reaction was quenched by the addition of 10% aqueous HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous NaCl before being dried over Na2SO4. Removal of the solvents under pressure afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:8][NH2:9])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(C#N)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(CN)(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of 1-methyl-4-phenylpiperidine-4-carbonitrile (1.0 g, 4.99 mmol) in THF (25 mL) was slowly added to a suspension of LAH (0.379, 9.99 mmol) in THF (10 mL). The reaction was stirred for 2 hours and then quenched with sodium sulfate decahydrate. This was stirred for 30 minutes, and then ethyl acetate was added. The mixture was stirred 10 minutes, and then filtered on celite. The filtrate was concentrated on rotovap to give the desired compound (0.916 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm: 1.79-1.89 24H, m), 2.18-2.28 (7H, m), 2.55-2.65 (2H, m), 2.77 (2H, s), 7.21-7.27 (1H, m), 7.28-7.39 (4H, m).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:24])[CH:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30].Cl>C1COCC1.O>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:30])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:24])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(CC(=O)c1ccc(Br)cc1)(Cc1cccc(C(F)(F)F)c1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Diallyl-2-(3-trifluoromethylbenzyl)malonate (1.03 g, 3.01 mmol) in anhyd THF (20 mL) was added dropwise to a stirred suspension of sodium hydride (95%, 84 mg, 3.31 mmol) in anhyd THF (20 mL) at room temperature. The clear solution was stirred at room temperature for 30 min and then a solution of 2,4′-dibromoacetophenone (1.0 g, 3.61 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to 50° C. for 3 h (TLC control), cooled to room temperature and then water (10 mL) was added cautiously. The reaction mixture was acidified to pH 3 with 2 N hydrochloric acid and then extracted with ethyl acetate (3×30 mL). The combined extract was washed with water, sat'd aq NaCl, dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10% ethyl acetate in heptane) afforded the title compound as a colorless oil (1.23 g)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([O:17][CH3:18])(=[O:16])[C:12](OC)=[O:13]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([NH:10][C:12](=[O:13])[C:11]([O:17][CH3:18])=[O:16])=[CH:9][C:2]=1[NH:1][C:12](=[O:13])[C:11]([O:17][CH3:18])=[O:16])#[N:5]
Reactant: N#Cc1ccc(N)cc1N
Reactant: COC(=O)C(=O)OC
Product: COC(=O)C(=O)Nc1ccc(C#N)c(NC(=O)C(=O)OC)c1
Yield: 80.7 %

Procedure:
A mixture of 29.0 grams (0.218 mole) of 2,4-diaminobenzonitrile and 255 grams of dimethyl oxalate is refluxed for 3 hours. The excess dimethyl oxalate is distilled off in vacuo. The residue is boiled with 150 ml. of methanol and filtered. The filtrate is poured into 900 ml. of water and the tan precipitate removed by filtration. There is obtained 53.7 grams (81%) of tan needles melting at 155°-160°. The product is boiled in 1800 ml. of methanol and the insoluble material removed by filtration. The filtrate is poured into 2 liters of water, refrigerated, and the precipitate removed by filtration. There is obtained 23.8 grams of fine yellow needles melting at 160°-163°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(OC(F)(F)F)cc4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-trifluoromethoxyphenylboronic acid (177 mg, 0.86 mmol) the subtitle compound was obtained, (119 mg, 48%). 1H NMR (DMSO) δ 8.70(s, 1H), 8.52(d, 1H), 8.16(s, 1H), 7.93(d, 3H), 7.81(d, 2H), 7.68(d, 1H), 7.55(d, 1H), 4.12(s, 3H). MS 431 m/z (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:24][C:25]1[C:30]2[CH2:31][CH2:32][CH2:33][CH:34]([C:36](OC)=[O:37])[CH2:35][C:29]=2[CH:28]=[CH:27][CH:26]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[Si:7]([O:24][C:25]1[C:30]2[CH2:31][CH2:32][CH2:33][CH:34]([CH2:36][OH:37])[CH2:35][C:29]=2[CH:28]=[CH:27][CH:26]=1)([C:20]([CH3:21])([CH3:22])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CCCc2c(cccc2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CCCC(CO)C2)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a suspension of lithium aluminum hydride (66 mg) in THF (20 ml) was added dropwise a solution of methyl 1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H- benzocycloheptene -6-carboxylate (800 mg) in THF (4 ml) at 5° C. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. The mixture was added with 1N-hydrochloric acid under ice cooling and extracted with EtOAc. The organic layer was washed with water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 2:1) to give [1-(tert-butyldiphenylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]methanol (715 mg) as an oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([C:63]5[O:67][CH:66]=[N:65][CH:64]=5)=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([C:63]5[O:67][CH:66]=[N:65][CH:64]=5)=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cnco5)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cnco5)cc4)cc3)cc2C1=O
Yield: 73 %

Procedure:
The compound of example 622 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 621.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:14]#[N:15])[C:11]([OH:13])=O)[CH:3]=1.S(Cl)(Cl)=O.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>Cl>[CH2:20]([NH:24][C:11](=[O:13])[C:10](=[C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:1])=[CH:3]1)[C:14]#[N:15])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CC1=CC(=C(C#N)C(=O)O)CC(C)(C)C1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCNC(=O)C(C#N)=C1C=C(C)CC(C)(C)C1

Procedure:
2(3,5,5-trimethyl-2-cyclohexenylidene) cyanoacetic acid (0.2 mol) and thionyl chloride (50 mls) were refluxed together for 1 hr. The acid chloride was then added dropwise with stirring to n-butylamine (0.4 mol) in petroleum ether (340 mls). The flask may have to be cooled with an ice bath. After addition, 1N HCl (150 mls) was added and the mixture stirred. The mixture was allowed to separate and the upper layer was washed until acid free. It was then treated with 1.4 g activated carbon, then n-butyl (3,5,5-trimethyl-2-cyclohexenylidene) cyanoacetamide was isolated. Ref. J. Am. Chem. Soc., 1949, 71, 2215.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(F)cc3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 17.9 g. (0.077 mole) of 2-(p-fluorophenacyl)cyclohexanone, 11.8 g. (0.077 mole) of 5-aminosalicylic acid, and 90 ml. of glacial acetic acid was heated under reflux under nitrogen for 43/4 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetic acid to provide 10.0 g. (37%) of yellow crystals, m.p. 239°-240°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2.[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]1[CH2:25][O:24]1)([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]([OH:24])[CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2)([CH3:17])([CH3:16])[CH3:18]
Reactant: CCN1C(=O)Cc2cc(N)cc(F)c21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (2.25 g, 11.6 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (2.00 g, 11.6 mmol) and lithium trifluoromethanesulfonate (1.80 g, 11.6 mmol) in acetonitrile (12 ml) are heated at 90° C. for 20 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.95 min; MS for C 18H26FN3O4 m/z 368.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[N+:8]([C:7]1[C:2]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2ncccc2[N+](=O)[O-])c(C)c1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (24.05 g, 152 mmol), 2,4,6-trimethylaniline (60 ml, 427 mmol), and Cs2CO3 (59.4 g, 182.4 mmol) was heated at 100° C. for 24 h. Flash chromatography using 1) methylene chloride/Hexanes (1:4) and 2) methylene chloride, followed by recrystallization from 95% ethanol. The title compound was obtained as an orange-yellow crystals (17.0 g, 44% yield). 1H NMR (CDCl3, 5 MHz) δ 9.38 (s, 1H), 8.51 (d, J=5.8 Hz, 1H), 8.38 (s, 1H), 7.00 (s, 2H), 6.73 (s, 1H), 2.34 (s, 3H), 2.18(s, 6H); 13C NMR (CDCl3, 100 MHz) δ 156.2, 152.1, 137.2, 135.7, 135.4, 132.3, 129.1, 128.3, 112.8, 21.1, 18.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:23])[CH:17]=[C:18]([NH2:22])[O:19][CH2:20][CH3:21])[CH3:14]>C(O)(C)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:23])[C:18]([O:19][CH2:20][CH3:21])=[N:22][C:18]=1[NH2:22])=[O:23])[CH3:14]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Upon heating a solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 136°-37°C (isopropanol) is obtained.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH:17][C@H:18]([C:30]2[NH:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH2:19][C:20]([O:22]CC2C=CC=CC=2)=O)=[CH:8]1>C1COCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][N:17]2[C@H:18]([C:30]3[NH:31][CH:32]=[C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:34]=3)[CH2:19][C:20](=[O:22])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[S:6])=[CH:8]1
Reactant: O=C(C[C@H](NCc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)OCc1ccccc1
Reactant: CCCN=C=S
Solvent: C1CCOC1
Product: CCCN1C(=O)C[C@@H](c2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C1=S
Temperature: 40 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
Propylisothiocyanate (25 μl, 1.2 eq.) is added to a solution of benzyl (3S)-3-[(1H-indol-3-ylmethyl)amino]-3(4phenyl-1H-imidazol-2-yl)propanoate (90 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then diluted with 2 ml of THF. An aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added. The mixture is stirred for 5 hours at a temperature of approximately 20° C. then filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. 1 ml of THF and 1 ml of triethylamine are added to the residue. The mixture is stirred for 15 hours at a temperature of approximately 40° C. then concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: ethyl acetate/heptane 8:2)-yields the expected compound (72 mg, yield 82%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-(N-t-Butoxycarbonylamino)-3-(4-fluoro-phenyl)-1-morpholin-4-yl-propan-1-one (3.1 mmol) was dissolved in 4M HCl-dioxane at 0° C. and the resulting suspension stirred at 25° C. for 1 hour. The mixture was concentrated and the residue triturated with ether. Yield, 776 mg, 88%; HPLC (60/40) 2.31 minutes (99%).
Reaction SMILES: [CH:1]12[CH2:8][CH:7]=[CH:6][CH:5]1[CH:4]1[C:9]([O:11][C:12](=[O:13])[CH:2]2[CH2:3]1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=2)[CH2:21][CH2:20]1>>[Cl:31][C:27]1[N:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:9](=[O:11])[CH:4]4[CH2:3][CH:2]([CH:1]5[CH2:8][CH:7]=[CH:6][CH:5]54)[C:12]3=[O:13])[CH2:24][CH2:23]2)[CH:30]=[N:29][CH:28]=1
Reactant: O=C1OC(=O)C2CC1C1C=CCC21
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3cncc(Cl)n3)CC1)C1CC=CC21

Procedure:
The title compound was prepared from 2.1 g (12 mmoles) of bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic anhydride and 3.2 g (12 mmoles) of 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine following the procedure in Example 4. 620 mg of the hydrochloride salt was isolated as the hemihydrate, m.p. 222°-224° C., after two recrystallizations from isopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([Br:23])=[C:13]([CH:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([Br:23])=[C:13]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Br)c(C(O)C2CCCCC2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(Br)c(C(=O)C2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of (5-benzyloxy-2-bromo-4-methoxyphenyl)-cyclohexylmethanol (Reference example 9-2) (580 mg), triethylamine (0.797 mL) and dimethylsulfoxide (21 mL) was added pyridine sulfur trioxide complex (684 mg) under ice-bath cooling. After stirring at room temperature for an hour, water and ethyl acetate were added to the mixture. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (348 mg).