Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([F:31])[C:29]=1[F:30])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:26][C:23]3[CH:24]=[CH:25][N:21]([CH2:20][C:19]4[CH:18]=[C:17]([F:16])[C:29]([F:30])=[C:28]([F:31])[CH:27]=4)[N:22]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2cc(F)c(F)c(F)c2)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4cc(F)c(F)c(F)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3,4,5-trifluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a white solid (Yield=56%). MS ISP (m/e): 409.3 (100) [(M+H)+].
Reaction SMILES: [C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1>C(#N)C>[C:1]([O:4][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:25]([NH:26][C:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=2)=[O:24])(=[O:15])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CC(=O)OC(CF)c1ncccc1S(N)(=O)=O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(CF)OC(C)=O)n1

Procedure:
To a solution of 2-(1-acetoxy-2-fluoroethyl)-3-pyridinesulfonamide (2.10 g) and phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate (1.49 g) in 50 ml acetonitrile is added dropwise 0.7 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) at 15° C. After stirring for 2 hours the resultant solution is extracted with methylene chloride and 5% hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and evaporated to yield the subject compound.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:15])([CH3:5])[CH3:4]>C(O)(=O)C.[Fe]>[CH:3]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([Br:1])[C:7]=1[OH:15])([CH3:5])[CH3:4]
Reactant: CC(C)c1ccc(O)c(C(C)C)c1
Reactant: BrBr
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)c(O)c(C(C)C)c1
Temperature: 100 °C
Yield: 85.3 %

Procedure:
1 g of iron powder and then, dropwise, 101 g (32.2 ml, 0.63 mol) of bromine are added in the course of 90 minutes to a solution of 102.3 g (0.57 mol) of 2,4-diisopropylphenol in 900 ml of glacial acetic acid at 95° C. The mixture is stirred for a further hour at 100° C. and cooled, the reaction mixture is partitioned between toluene and water and the toluene phase is washed with NaHCO3 solution. It is dried, filtered and concentrated, and the residue is distilled in a high vacuum. 125 g of the title compound is obtained as a pale yellow oil, b.p. 85° C./0.15 torr.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][C:20]1[N:21]=[C:22]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:23][C:24]=1[C:25]([F:28])([F:27])[F:26]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:22]2[S:23][C:24]([C:25]([F:28])([F:26])[F:27])=[C:20]([CH3:19])[N:21]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)sc1C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white foam (yield 52%). MS (m/e): 492.0 (M+H+, 100%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])[C:16]2=[O:35])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.CO>[H][H].[C].[Pd]>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[C:16](=[O:35])[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:18]=1)#[N:34]
Reactant: [H][H]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(OCc3ccccc3)c2)c1=O
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Yield: 62.3 %

Procedure:
52 mg of 1-[3-(benzyloxy)phenyl]-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one and 20 mg of 5% palladium-carbon were added to 3 ml of methanol, followed by stirring at room temperature in hydrogen atmosphere overnight. After the resulting insoluble matters were filtered off, the filtrate was evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexane system), to give 26 mg the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:19]1[CH:24]=[C:23]2[CH:25]=[CH:26][C:27]3[C:32](=O)[O:31][C:29](=[O:30])[C:28]=3[C:22]2=[CH:21][CH:20]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:30])[C:28]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:24][C:23]=4[CH:25]=[CH:26][C:27]=3[C:32]2=[O:31])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc4ccccc4c3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.31 g, 4.79 mmol) and 1,2-naphthalic anhydride (950 mg, 4.79 mmol) in acetic acid (15 mL). The product was obtained as a yellow solid (1.65 g, 76% yield): mp, 158.0-159.5° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H, CH3), 3.03 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.03 (q, J=6.9 Hz, 2H, CH2), 4.18 (dd, J=4.3, 14.3 Hz, 1H, CHH), 4.41 (dd, J=10.7, 14.4 Hz, 1H, CHH), 5.86 (dd, J=4.2, 10.3 Hz, 1H, NCH), 6.83-6.96 (m, 1H, Ar), 7.03-7.07 (m, 1H, Ar), 7.15 (br s, 1H, Ar), 7.70-7.9 (m, 3H, Ar), 8.15 (d, J=8.0 Hz, 1H, Ar), 8.39 (d, J=8.3 Hz, 1H, Ar), 8.76 (d, J=8.2 Hz, 1H, Ar); 13C NMR (DMSO-d6) δ 19.86, 46.29, 52.48, 58.35, 60.67, 69.03, 116.96, 117.57, 123.65, 124.97, 128.97, 131.40, 132.30, 134.15, 134.36, 134.94, 135.16, 135.89, 140.85, 11.42, 153.09, 154.06, 173.09, 173.82; Anal Calcd for C24H23NO6S: C, 63.56; H, 5.11; N, 3.09. Found: C, 63.33; H, 5.06; N, 2.95.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]([C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:1][C:2]1[C:3]([CH3:23])=[C:4]([C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C(=O)c2c(C)c(O)c3ccccn23)cc1
Product: COC(=O)c1ccc(C(=O)c2c(C)c(OCc3cccc(OC)c3)c3ccccn23)cc1

Procedure:
This compound is obtained according to the same procedure as that of Example 86, by O-alkylation of methyl 4-[(1-hydroxy-2-methylindolizin-3-yl)carbonyl]benzoate with 3-methoxybenzyl bromide. A yellow powder is obtained which melts at 106° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20](=[O:22])(=[O:21])[N:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18](=[O:27])[CH:17]=2)=[CH:12][CH:11]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20](=[O:22])(=[O:21])[N:19]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:18](=[O:27])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CCN)cc2)S1(=O)=O
Yield: 100 %

Procedure:
2-[4-(2-tert-Butyl-1,1,3-trioxo-2,3-dihydro-1H-1λ6-isothiazol-5-yl)-phenyl]-ethyl-carbamic acid tert-butyl ester (200 mg, 0.490 mmol) was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (2 mL) and the reaction was stirred for 2 h. The reaction was chromatographed on a 21 mm Luna C18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 15 minute period. The major fraction was lyophilized to give a white powder (207 mg, 100%). 1H NMR (500 MHz, CDCl3): δ 7.90 (m, 2H), 7.52 (m, 2H), 3.25 (t, J=6.5 Hz, 2H), 3.06 (t, J=7.4 Hz, 2H), 1.73 (s, 9H); LCMS found for C17H22F3N2O5S (M+H)+: m/z=309.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+]>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[S:26][CH2:25][CH2:24][N:23]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C2CCNCCS2)cc1
Reactant: ClCCCCc1ccncc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2CCN(CCCCc3ccncc3)CCS2)cc1
Yield: 37.6 %

Procedure:
To 25 mL of acetonitrile is added 1-(4-pyridinyl)-4-chlorobutane (2.00 g, 11.8 mmol), hexahydro-7-(4 methoxyphenyl)-1,4-thiazepine (Example 1) (2.63 g, 11.8 mmol), and anhydrous potassium bicarbonate (2.65 g, 47.2 mmol). The reaction mixture is heated to reflux under an atmosphere of nitrogen for 24 hours. The reaction mixture is then filtered, the filtrate concentrated, and the resulting residue is purified by column chromatography on silica eluting with 98% chloroform, 2% methanol, and 0.1% anhydrous ammonia to yield 1.58 g of the desired product; m/z 356.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])C(Cl)=O>C1COCC1.CCCCCC.Cl>[Cl:12][C:13]1[CH:14]=[C:15]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: N#CCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of cyanoacetic acid (4.07 g, 47.8 mmol) in THF (240 mL) cooled to −78° C. under an atmosphere of argon was added 1.6 M n-butyllithium in hexane (59.8 mL). The reaction mixture was stirred for 10 min at −78° C. and was then allowed to warm to 0° C. The reaction mixture was recooled to −78° C. To the mixture was added dropwise 3,4-dichlorobenzoyl chloride (5.01 g, 23.9 mmol) in THF (30 mL). The reaction mixture was allowed to warm to rt. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 3-(3,4-dichlorophenyl)-3-oxopropanenitrile (3.9 g, 76%). LCMS: (FA) ES− 212.0. 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H) and 4.05 (s, 2H).
Reaction SMILES: N1C2C3C(CNCC=3C=CC=2)=[CH:2]1.[CH2:13]([N:16]1[C:26]2[C:27]3[C:18]([CH2:19][NH:20][CH2:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)=[CH:17]1)[CH2:14][CH3:15]>>[CH3:2][N:20]1[CH2:19][C:18]2=[CH:17][N:16]([CH2:13][CH2:14][CH3:15])[C:26]3[C:27]2=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH2:21]1
Reactant: CCCn1cc2c3c(cccc31)CNC2
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Product: CCCn1cc2c3c(cccc31)CN(C)C2

Procedure:
By following the procedure of Example 7 but replacing 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline with an equivalent amount of 1,3,4,5-tetrahydro-1-propylpyrrolo[4,3,2-de]isoquinoline, described in Example 6, 1,3,4,5-tetrahydro-4-methyl-1-propylpyrrolo[4,3,2-de]isoquinoline is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[CH2:26]1[O:35][C:34]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:27]1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][NH:31][C:30]1[CH:32]=[CH:33][C:34]2[O:35][CH2:26][O:27][C:28]=2[CH:29]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CNc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A mixture of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (2.1 g, 5.0 mmol) and 3,4-methylenedioxyaniline (1.5 g, 11 mmol) in acetonitrile (100 ml) was stirred at 80° C. for 3 h and overnight at 25° C. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1). The purified product was washed with acetone to afford 1.55 g (65%) of the title compound. M.p. >250° C.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6](O)[C:5]=1[CH3:11])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]([CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(O)ncnc1C(C)C
Product: Cc1c(Cl)ncnc1C(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To 6-isopropyl-5-methylpyrimidin-4-ol (0.25 g, 1.6 mmol) was added neat phosphorous oxychloride (5 mL) and the mixture stirred at 70° C. for 3 h. After cooling to room temperature the solution was concentrated, diluted with water then neutralized by portionwise addition of saturated sodium carbonate solution. The aqueous mixture was extracted with ethyl acetate and the organic solution washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration provided 4-chloro-6-isopropyl-5-methylpyrimidine (30 mg, 11% yield) as a brown oil that was used without further purification. MS (EI) for C8H11ClN2: 170 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=1>>[C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:11](=[O:13])[CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:19]([F:20])([F:22])[F:21])[CH:5]=2)[CH2:14][C:15]([F:16])([F:17])[F:18])=[CH:25][CH:26]=1)(=[O:33])[CH3:32]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(N)cc1
Product: CC(=O)Nc1ccc(NC(=O)CN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and N-(4-aminophenyl)acetamide: MS (APCI) m/z 459 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[S:18][C:19]([C:22](Cl)=[O:23])=[CH:20][N:21]=1)([CH3:13])([CH3:12])[CH3:11].C(NC(C)C)(C)C>ClCCl>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[S:18][C:19]([C:22](=[O:23])[NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[CH:20][N:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)Cl)s1
Reactant: Cc1cccc(Cl)c1N
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The fourth step involves adding 2-chloro-6-methylaniline to a stirred solution of tert-butyl[5-(chlorocarbonyl)-1,3-thiazol-2-yl]carbamate in dichloromethane at 0° C. Diisopropylamine was added to the reaction mixture, warmed to room temperature, stirred for 24 hours, diluted with dichloromethane, and washed with 2N hydrochloric acid. The organic extract thus obtained was dried, filtered, and concentrated to obtain a residue. The residue was diluted with ethyl acetate-ether, filtered, washed with ether, and dried in vacuo to obtain tert-butyl{5-[(2-chloro-6-methylphenyl)carbamoyl]-1,3-thiazol-2-yl}carbamate (Formula 1b) in an overall yield of 48%.
Reaction SMILES: [C:1]1([C@H:7]([NH2:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>C(O)C>[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:16][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C[C@@H](N)c2ccccc2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C[C@@H](NCc2ccc(O)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
21.13 g (0.1 mole) of (R)-(-)-α-phenyl-β-p-tolylethylamine (optical purity: 100%) and 12.82 g (0.105 mole) of p-hydroxybenzaldehyde were dissolved in 750 ml of ethyl alcohol. The reaction solution thus obtained was stirred at room temperature for 3 hours, and then stirred under reflux for 1 hour. Thereafter, the reaction solution was admixed at room temperature with 1.89 g (0.05 mole) of sodium borohydride, stirred for 3 hours, and then stirred under reflux for 1 hour. The reaction mixture was admixed with 75 ml of a 10% hydrochloric acid, and then concentrated under reduced pressure to give a crude (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine.HCl salt, which was thereafter neutralized with an aqueous sodium hydroxide solution. The resultant solution was concentrated under reduced pressure to obtain the crystals, which were then recrystallized from ethyl alcohol, so that 20.47 g of (R)-(+)-N-p-hydroxybenzyl-α-phenyl-β-p-tolylethylamine were obtained as colorless crystals. Yield: 64.5%. m.p. 129.5°-130° C.; α!D25 +21.2° (C 1.0, CHCl3) NMR-spectral data (δ ppm, CDCl3) 2.29 (s) 3H; 2.94 (d) 2H; 3.49 (d) 2H; 3.89 (t) 1H; 3.37 (s) 2H; 6.35-6.90 (m) 4H; 6.99 (s) 4H; 7.30 (s) 5H
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=2[C:9]=1[CH2:19][CH2:20][CH3:21].C([O:24][C:25](=[O:48])[CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=2)=[O:35])[CH:31]=[CH:30][C:29]=1[OH:47])C>CCCCCC.C(OCC)(=O)C>[C:42]([C:38]1[CH:37]=[C:36]([C:34]([C:32]2[CH:31]=[CH:30][C:29]([O:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:18]=[CH:17][C:11]4[C:12](=[O:16])[CH2:13][CH2:14][O:15][C:10]=4[C:9]=3[CH2:19][CH2:20][CH3:21])=[C:28]([CH2:27][CH2:26][C:25]([OH:48])=[O:24])[CH:33]=2)=[O:35])[CH:41]=[CH:40][CH:39]=1)([OH:44])=[O:43]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Reactant: CCCc1c(OCCCCCBr)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 36 %

Procedure:
Starting with 0.275 g (0.78 mmol) of 7-[(5-bromopentyl)oxy]-2,3-dihydro-8-propyl-4H-1-benzopyran-4-one, and 0.286 g (0.77 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, 5-[(3-carboxyphenyl)carbonyl]-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid (0.163 g; 52% overall yield) was obtained, as a white solid, mp 122°-128° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 19.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[N+]=[N-]>C(OCC)(=O)C.CO.[C].[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2
Reactant: [N-]=[N+]=NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCOc1ccc2[nH]c(=O)ccc2c1
Yield: 94 %

Procedure:
To a solution of 6-(3-azidopropoxy)carbostyril (17.5 g) in a mixture of ethyl acetate-methanol (1:1, 700 ml) is added 10% palladium-carbon (1.75 g), and the mixture is subjected to hydrogenation at room temperature under atmospheric pressure. After the reaction is complete, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. The resulting residue is washed with diethyl ether to give 6-(3-aminopropoxy)carbostyril (14.7 g) as a white powder.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]#[N:11].[H][H].C([O-])(=O)C.[K+].CO>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[C:4]([NH2:9])[C:3]([C:10]#[N:11])=[CH:2][N:7]=1
Reactant: [H][H]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(N)cc1N
Reaction time: 2 h

Procedure:
A suspension of 21.3 g of 6-bromo-2,4-diamino-5-cyanopyridine (JACS, 80:2838-2840 (1958)) and 1 g of 20% palladium on charcoal in 250 mL of tetrahydrofuran was shaken in a Parr apparatus under an atmosphere hydrogen. After 2 hours, the reaction was stopped and 10 g of potassium acetate and 50 mL of methanol added. The reaction was recharged with hydrogen and shaken for 18 hours. The solvents were removed under reduced pressure and the residue crystallized from isopropyl alcohol to afford the title compound 2,4-diamino-5-cyanopyridine, mp 201°-202° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[O:3]1.Br[CH2:15][C:16]1[C:28]([Cl:29])=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:30])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:29][C:28]1[C:16]([CH2:15][O:12][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][CH2:11][C:2]([CH3:13])([CH3:1])[O:3]3)=[CH:8][CH:7]=2)=[CH:17][C:18]([F:30])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC1(C)CCc2ccc(O)cc2O1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2,2-dimethylchroman-7-ol (100 mg, 0.561 mmol), tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (191 mg, 0.590 mmol) and potassium carbonate (194 mg, 1.40 mmol) in acetone (30 mL) was stirred at 50° C. for 16 hrs. After cooling to room temperature, the mixture was extracted with EtOAc (150×5 mL). The combined orgaic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was used in next step without further purification (290 mg, crude). LCMS (ESI) m/z: 420.8 [M+H].
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:35]([NH:40][NH2:41])(=[O:39])[CH:36]([CH3:38])[CH3:37]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([NH:41][NH:40][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[O:15])=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C(=O)NN
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(=O)C(C)C)cnc21
Reaction time: 0.25 h

Procedure:
Intermediate 3 (0.060 g), EDC (0.06 g) and HOBT (0.035 g) were suspended in DMF (2 ml) and stirred under nitrogen for 15 minutes. Isobutyric acid hydrazide (0.027 g) was then added and the mixture stirred under nitrogen for 18 h. Solvents were removed in vacuo and the residue partitioned between DCM and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then concentrated in vacuo and applied to an SPE cartridge (aminopropyl, 1 g) which was eluted with methanol. Concentration in vacuo afforded Intermediate 10. LCMS showed MH+=359; TRET=2.70 min.