Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH2:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5])#[N:2].[CH2:15]([NH:18][CH2:19][CH:20]=[CH2:21])[CH:16]=[CH2:17]>ClCCl>[CH2:15]([N:18]([CH2:19][CH:20]=[CH2:21])[C:4](=[O:5])[C:3]([C:1]#[N:2])([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:16]=[CH2:17]
Reactant: C=CCNCC=C
Reactant: CCC(C#N)(C(=O)Cl)c1ccccc1
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)C(C#N)(CC)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 327.6 %

Procedure:
10.5 g (0.05 mole) of 2-cyano-2-ethyl-2-phenylacetyl chloride are dissolved in 50 ml of dichloromethane, the solution is cooled to 5° C., and 9.7 g (0.01 mole) of diallyl amine are added to it under maintaining the temperature of the mixture below 10° C. The reaction mixture is stirred at room temperature for 2 hours, then washed with water, dried over anhydrous magnesium sulfate, and the solvent is removed. 8.79 g (65.5%) of N,N-diallyl-2-cyano-2-ethyl-2-phenylacetic acid amide are obtained; m.p.: 33°-35° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1
Reactant: Sc1ncccn1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCSc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a mixture of 523 mg 2-mercaptopyrimidine and 25 ml anhydrous N,N-diemthylformamide, were added 640 mg anhydrous potassium carbonate and 2 g ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate, and the resulting mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water and dried. The chloroform was distilled off, and the residue was purified by silica gel column chromatography (chloroform), affording 740 mg ethyl 6-[p-[5-(2-pyrimidylthio)pentyloxy]phenoxy]-2,2-dimethylhexanoate as oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[N:9][CH:8]=2)=[N:4][CH:3]=1.[CH3:14][N:15](C=O)C>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:10]1[N:11]=[N:12][C:7]([C:5]2[S:6][C:2]([C:14]#[N:15])=[CH:3][N:4]=2)=[CH:8][N:9]=1
Reactant: CN(C)C=O
Reactant: Nc1ncc(-c2ncc(Br)s2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cnc(-c2cnc(N)nn2)s1
Temperature: 160 °C

Procedure:
6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine (300 mg, 1.15 mmol), zinc cyanide (340 mg, 2.30 mmol), Pd(PPh3)4 (133 mg, 0.13 mmol), and DMF (5 mL) were combined and heated to 160° C. for 12 h. The reaction mixture was cooled, diluted with CH2Cl2 (30 mL), filtered through silica gel, eluted with EtOAc, and concentrated. The crude product was then purified using silica gel chromatography to afford 30 mg of 2-(3-amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.
Reaction SMILES: Cl[CH:2]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=1>>[CH:13]1([CH:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccccc12
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccccc12
Yield: 37.4 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran (433 mg) synthesized in Example A16(3) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (390 mg) synthesized in Example 1(2) and in the same manner as, in Example A7(3), the title object compound (268 mg, 37%) was obtained as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:35][CH2:36][CH:37](CO)[OH:38]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH:37]([OH:38])[CH2:36][OH:35])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCBr)cc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(11-bromoundecylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(11-bromoundecylamino)benzoate.
Reaction SMILES: C([O:8][N:9]=[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[C:20]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)C1C=CC=CC=1.Cl.[H][H].C(O)CCC>CO.[OH-].[Pd+2].[OH-]>[CH3:24][N:22]1[CH:23]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:10](=[N:9][OH:8])[CH2:11][CH2:12]3)[C:20]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:21]1
Reactant: [H][H]
Reactant: Cn1cc(-c2ccc3c(c2)CCC3=NOCc2ccccc2)c(-c2ccncc2)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: Cn1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To 5-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one O-benzyl oxime (2.50 g; Example 3, Step 4) in 60 mL methanol was added 0.89 g palladium hydroxide (20% by weight on carbon) and 6.3 mL 6M hydrochloric acid. A hydrogen-filled balloon was attached to the reaction vessel and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered through celite and the celite was washed with methanol. The filtrate was concentrated under vacuum and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with brine and evaporated to yield 1.0 g of crude product as a white solid. The aqueous layer was reextracted with two portions of n-butanol. The n-butanol was evaporated under vacuum to afford an additional 0.4 g crude product as a white solid. The solids were combined and washed with two 15 mL portions of water, dissolved in a 1:1 mixture of dichloromethane-methanol, filtered, and the filtrate evaporated under vacuum. The residue was triturated with ethyl acetate and dried to afford 0.98 g (51% yield) of product as a white solid. 1H NMR (CDCl3) was consistent with the desired structure 113. LC/MS showed a peak with a M+1 molecular ion of m/z 305.4 by positive ESI.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[CH2:15]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: C1CCOC1
Product: CC(C)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 50.Og (0.24 mole) of 4-chloro-3-nitroquinoline in 300 ml of tetrahydrofuran was added, in small portions, 52.7g (0.72 mole) of isobutylamine. The mixture was heated at its reflux temperature for one hour, and was then evaporated in vacuo. Water was added to the residue and the solid was separated by filtration. The solid was suspended in one liter of water, and was dissolved by the gradual addition of concentrated hydrochloric acid (to pH 3 to 4), at which time the solution was filtered. The filtrate was basified (to pH 9 to 10) by the addition of concentrated ammonium hydroxide to provide bright yellow 4-(isobutylamino)-3-nitroquinoline, m.p. 119°-121° C. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [CH:1]([CH:5]([N:34]([CH3:51])[C:35]([CH:37]([NH:41][C:42](=[O:50])[CH:43]([N:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:38]([CH3:40])[CH3:39])=[O:36])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([C:18](=[O:29])[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH3:17])=[O:9])([CH2:3][CH3:4])[CH3:2].[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:49][N:47]([CH3:48])[CH:43]([CH:44]([CH3:46])[CH3:45])[C:42]([NH:41][CH:37]([CH:38]([CH3:39])[CH3:40])[C:35]([N:34]([CH3:51])[CH:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:6]([O:32][CH3:33])[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH:15]([S:30][CH3:31])[CH:16]([CH3:17])[C:18]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([O:28][C:55](=[O:56])[NH:54][CH2:52][CH3:53])[CH:25]=[CH:26][CH:27]=1)=[O:29])=[O:9])=[O:36])=[O:50]
Reactant: CCC(C)C(C(CC(=O)N1CCCC1C(SC)C(C)C(=O)NCCc1cccc(O)c1)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Oc1cccc(CCNC(=O)C(C)C(SC)C2CCCN2C(=O)CC(OC)C(C(C)CC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a stirred solution of N-(1-{[1-sec-butyl-4-(2-{2-[2-(3-hydroxy-phenyl)-ethylcarbamoyl]-1-methylsulfanyl-propyl}-pyrrolidin-1-yl)-2-methoxy-4-oxo-butyl]-methyl-carbamoyl}-2-methyl-propyl)-2-dimethylamino-3-methyl-butyramide (30 mg, 0.035 mmol) in CH2Cl2 (0.5 mL) were added ethyl isocyanate (0.042 mL, 0.53 mmol) and diisopropylethylamine (0.062 mL, 0.35 mmol) at room temperature. After being stirred at room temperature for 13hr, the mixture was concentrated in vacuo to give a crude oil (58 mg), which was purified by preparative HPLC (column:ODS-8OTs, eluent: 35/35 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to give the title compound as a white amorphous powder (13 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C1C(=O)N([Br:32])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([Br:32])=[CH:4][C:5]([CH3:19])=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: Cc1cc(Br)c(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 3-[(6-amino-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (7.422 g, 26.8 mmol) and ammonium acetate (0.207 g, 2.68 mmol) in acetonitrile (150 ml) was added NBS (5.01 g, 28.2 mmol) and the reaction mixture was stirred for two hours at rt. The solvent was removed and the crude material was purified via silica gel chromatography to give 3-[(2-amino-3-bromo-6-fluoro-5-methylphenyl)oxy]-5-chlorobenzonitrile (8.379 g, 23.56 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 1H), 7.33 (s, 1H), 7.23-7.30 (m, 2H), 5.31 (s, 2H), 2.08 (s, 3 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Br:37]C(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][Br:37])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
Under nitrogen atmosphere, a solution of triphenylphosphine (0.94 g) in THF (4 ml) was added slowly to a mixture of 4-(3-hydroxy-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g) and tetrabromomethane (1.19 g) in THF (15 ml). The mixture was stirred at room temperature for 16 hours, then ethyl acetate (100 ml) and a saturated solution of sodium carbonate (30 ml) were added and the organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 8/2) to afford 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.66 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].OS(O)(=O)=O.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 120 °C
Yield: 40 %

Procedure:
To a suspension of 2,6-dichloro-9H-purine (8.00 g, 40 mmol, 1.00 eq) and Na2SO4 (96.2 g, 677 mmol, 16.0 eq) in tert-butanol (380 mL) was added concentrated H2SO4 (11.3 mL, 211 mmol, 5 eq). The reaction mixture was heated at 120° C. with vigorous stirring under a reflux condenser [Caution: Gas evolution]. During the following 10 hr, additional H2SO4 (26 mL), Na2SO4 (75 g), and tert-butanol (350 mL) were added to the reaction mixture in several portions. After a further 6 hr of heating, the reaction mixture was cooled to ambient temperature, quenched with NaHCO3(s) added portionwise [Caution: Gas evolution], and diluted with water (300 mL) and EtOAc (300 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×300 mL). The combined organics were washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified via flash chromatography eluting with a gradient of 0-50% EtOAc in heptane to give the title compound (4.09 g, 40% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H) 1.73 (s, 9H). m/z (APCI+) for C9H10Cl2N4 245.1/247.1 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:18][CH2:19][O:20][CH:21]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=O)=O>CN(C)C=O.O>[CH:21]1([O:20][CH2:19][CH2:18][S:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)c1ccc(S)cc1
Reactant: CS(=O)(=O)OCCOC1CCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(SCCOC2CCCCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 70.6 %

Procedure:
A stirred mixture of 1-(4-mercaptophenyl)ethanone (0.76 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.218 g), stirred for 20 minutes and treated with 2-(cyclooctyloxy)ethyl methanesulfonate (1.25 g). The mixture was heated at 60° C. overnight, cooled, diluted with water, extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude material which was purified by HPLC (dichloromethane-hexane-ethyl acetate; 48:48:4) to provide 1.08 g of 1-[4-[[2-(cyclooctyloxy)ethyl]thio]phenyl]ethanone as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 21.8 %

Procedure:
In 100 ml of acetonitrile are dissolved 2.0 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 3.0 g of ethyl 2-bromo-9-phthalimidononanoate, and 0.85 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1-2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])=[O:14].Cl>O.CO>[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[O:14]
Reactant: COC(=O)/C=C/c1cccc(NC(=O)c2cccn2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: Cn1cccc1C(=O)Nc1cccc(/C=C/C(=O)O)c1
Yield: 91.3 %

Procedure:
A solution of Cs2CO3 (3.26 g) in H2O (2 mL) was diluted with MeOH (8 mL) and ester 10 (0.91 g, 3.2 mmol) was added. The mixture was heated under reflux for 2.5 h then cooled and acidified with 0.5N HCl. The precipitated solid was collected, dried and dissolved in warm EtOAc. The solution was concentrated to a small volume under reduced pressure below 40° C. and then diluted with i-Pr2O to provide (E) -3- (1-methylpyrrole-2-carboxamido)cinnamic acid (11) (0.79 g, 91%) mp 202-204° C. 1H NMR [(CD3)2SO] δ12.44 (br s, 1 H, CO2H), 9.82 (s, 1 H, NH), 7.99 (s, 1 H, H-2), 7.79-7.73 (m, 1 H, H-4), 7.56 (d, J=16.0 Hz, 1 H, PhCH═CH), 7.40-7.34 (m, 2 H, H-5,6), 7.05 (dd, J=4.0, 1.7 Hz, 1 H, H-pyrrole), 7.02 (t, J=2.0 Hz, 1 H, H-pyrrole), 6.44 (d, J=16.0 Hz, 1 H, PhCH═CH), 6.11 (dd, J=3.8,2.6 Hz, 1 H, H-pyrrole), 3.89 (s, 3 H, NCH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(OC=1C1C=CC=CC=1)=[C:44]1[N:54](C)[N:55]=[CH:56]C1=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:55]([CH3:56])[N:54]=[CH:44][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 98 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a gummy solid (70 mg, 98%). LCMS (Method B): RT=4.44 min, [M+H]+=522.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[C:12](#[N:16])[CH2:13][C:14]#[N:15].[BH4-].[Na+]>CC(O)C>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([CH:13]([C:12]#[N:16])[C:14]#[N:15])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N#CCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: N#CC(C#N)C1CCC2(CC1)OCCO2
Reaction time: 2 h

Procedure:
The title compound was prepared by the method of Dunham et al. (Synthesis 2006 (4), 680). 1,4-Cyclohexanedione monoethylene ketal (3.15 g, 20.0 mmol) was dissolved in anhydrous 2-propanol (20 mL), treated with warm malononitrile (Aldrich, 0.70 mL, 11.1 mmol) via syringe, and the reaction was cooled in ice and treated with powdered sodium borohydride (Aldrich, 0.42 g, 11.1 mmol). After stirring for 2 h in ice, the reaction was quenched with water and acidified to pH 6 with 1N aqueous HCl, and the resulting suspension was extracted thrice with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil, which was purified by flash column chromatography on silica gel (gradient elution, 30 to 80% EtOAc in hexanes) giving the title compound as a pale yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
4-Bromo-4'-hydroxybiphenyl (2.49 g) was added over 30 minutes to a stirred suspension of sodium hydride (0.42 g of 60% dispersion in mineral oil) in dimethylformamide (10 ml) whilst keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at a temperature below 10° C. for a futher 5 minutes. Ethyl iodide (1.87 g) was added over 10 minutes and stirring continued at room temperature for 2 hours. Water (200 ml) was added to the mixture and the mixture extracted with diethyl ether (3×50 ml). The ether extracts were combined, washed with 1M sodium hydroxide solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to give a residue which was crystallised from hexane to give, as a colourless solid, 4-bromo-4'-ethoxybiphenyl (2.15 g), m.p. 139° C.; NMR (CDCl3): 1.4(3H, t), 4.0-4.1(2H, q), 6.9(2H, d) and 7.35-7.55(6H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=Cc1ccc(O)cc1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-chloro-6-(trifluoromethyl)pyridine and 4-hydroxybenzaldehyde.