Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (30 mg) and Cul (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 56 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6](=[O:8])[CH:7]=1.[Na].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>[O-]CC.[Na+].C(O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:1][C:2]2[O:3][C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][C:6](=[O:8])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc(=O)cc(-c2ccccc2)o1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=c1cc(C=Cc2ccc(Cl)cc2)oc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methyl-6-phenyl-4H-pyran-4-one (3.7 g) was dissolved in sodium ethoxide solution prepared by dissolving sodium (0.46g) in ethanol (50 ml). A solution of 4-chlorobenzaldehyde (5.6 g) in ethanol (50 ml) was added and the mixture was stirred at room temperature for 24 hours. The solid which formed was recrystallised from ethanol to give the title product (mp 169°-171° C.).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:17][C:13]4([CH2:16][O:15][CH2:14]4)[CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[C:20]1([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:16]1[C:13]2([CH2:12][N:11]([CH2:10][C:9]3[CH:18]=[CH:19][C:6]([O:5][CH:3]4[CH2:4][N:1]([C:31]([C:29]5[O:30][C:26]([C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=6)=[N:27][N:28]=5)=[O:32])[CH2:2]4)=[CH:7][CH:8]=3)[CH2:17]2)[CH2:14][O:15]1
Reactant: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Solvent: CS(C)=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
3B (0.30 g, 1.15 mmol) was mixed with ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.30 g, 1.38 mmol) in a microwave vial and sealed. The solid mixture was melted in a preheated oil bath and stirred at 120° C. for 4 h. DMSO (2 mL) was added and the mixture was filtered, and then purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 25 min, 0.2% ammonia buffer). The pure fractions were combined and then evaporated. Dichloromethane was added and the solution was dried (phase separator) and concentrated in vacuo. There was obtained 0.30 g (61%) of 3 as a colorless oil. The oil gradually solidified on standing in room temperature. 1H NMR (500 MHz, CDCl3): δ 3.38 (s, 4H), 3.49 (s, 2H), 4.31 (d, 1H), 4.65 (m, 1H), 4.73 (s, 5H), 5.06 (m, 1H), 5.11 (m, 1H), 6.72 (d, 2H), 7.19 (d, 2H), 7.47-7.63 (m, 3H), 8.14 (d, 2H), MS (APCI+) m/z 433 [M+H]+, LC purity: 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: O=C(Cl)CCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-propionic acid (1.5 g, 8.15 mmol) in benzene (50 mL) is added thionyl chloride (1.18 mL, 16.3 mmol). The resulting solution is heated to reflux for twenty-four hours and then cooled to room temperature. The solvents are removed under reduced pressure to afford 1.45 g (88% yield) of the desired compound as a colorless oil. The crude product is used without further purification. 1H NMR (CDCl3 300 MHz) δ 3.01 (t, J=7.2 Hz, 2H), 3.22 (t, J=6.9 Hz, 2H), 7.12–7.20 (m, 2H), 7.26–7.35 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19](SC)[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].[CH2:43]([NH2:45])[CH3:44].C1COCC1>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:45][CH2:43][CH3:44])[N:20]=[CH:21][C:10]=3[C:9]2=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Reactant: CCN
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(C#N)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
(S)-5-(4-Cyanobenzyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.927 g, 2.54 mmol) obtained in Step 2 was dissolved in dichloromethane (10 mL), and the mixture was stirred at room temperature for 30 minutes after adding 3-chloroperbenzoic acid (65%; 1.01 g, 3.81 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was dissolved in THF (20 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ethylamine/THF solution (12.7 mL, 25.4 mmol). The reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography, and crystallized from ethanol/diethyl ether to give the title compound (Compound 1) (0.620 g, 67%).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]>>[CH3:18][C:16]([C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][C:21]=1[OH:26])[CH:9]=[O:10])([CH3:19])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CC(C)(C)c1ccccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 22.6 %

Procedure:
Into 101.5 g of N-methylformanilide was added dropwise with cooling 107 g of phosphoryl chloride over a period of 15 minutes. The mixture was allowed to warm to room temperature and stirred for 70 minutes. 67.5 g of ortho-t-butylphenol was added and stirred for about 45 minutes after which the mixture was heated to about 50-60° C. and allowed to stir for 4.5 hours. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 ml of a 5% potassium hydroxide solution. The aqueous potassium hydroxide layer was separated and added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to 3 with concentrated hydrochloric acid with stirring. The resultant layers were separated and the aqueous layer was again extracted with chloroform and dried over sodium sulfate overnight to give 18.1 g of the desired subtitled intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C(OCC)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[O:29]1)([CH2:17][CH2:18][CH:19]=[CH2:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: C=CCCC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
While under an atmosphere of argon, a solution of tert-butyl 2-(tert-butoxycarbonylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate (1.35 g, 2.89 mmol) in freshly distilled (THF 5 mL) was cooled to 0° C. and treated with sodium bis(trimethylsilyl)amide (6 mL, 1.0 M in THF) under argon. After stirring for 10 min, iodomethane (2.04 g, 14.4 mmol) was added and the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl ether and washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 8 CV) gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)hex-5-enoate as a colorless oil (1.27 g, 91%). Rf 0.35 (20% ethyl acetate in heptane). ESI MS found for C26H48BNO6 m/z [482.3 (M+1)].
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18].CON(C)[C:23](=[O:39])[CH:24]([O:37][CH3:38])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[F:19][CH:2]([F:1])[O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][C:14]([C:23](=[O:39])[CH:24]([O:37][CH3:38])[C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC(F)F
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1OC(F)F
Yield: 6 %

Procedure:
2-(4-(Difluoromethoxy)-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide following the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) provided 1-(5-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)-ethanone as a brown oil (0.021 g, 6% yield). MS: m/z 504.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[OH:20][C:21]1[C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7](=[O:8])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:20][C:21]2[C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23][CH:24]=[CH:25][N:26]=2)[N:14]=1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: COC(=O)c1nccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1nccnc1OCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 8 h

Procedure:
1-(3-fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate XXIII, 1.0 mmol) and methyl 3-hydroxypyrazine-2-carboxylate (1.0 mmol) were dissolved in N-methylpyrrolidinone (3 ml) and K2CO3 (1.1 eq) was added. The mixture was stirred overnight. 20 ml water was added and the product was extracted three times with dichloromethane. The organic was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography using 0-70% gradient of saturated ammonia/MeOH and dichloromethane. 1H NMR (400 MHz, DMSO-d6): 10.73 (s, 1H), 7.89 (d, 1H), 7.40 (d, 1H), 7.35 (m, 1H), 6.95-7.10 (m, 3H), 6.94 (m, 2H), 5.04 (s, 2H), 4.31 (d, 2H), 3.79 (s, 3H). MS (ES+): M/Z 418 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.C(O)(=O)C.[N:23]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1nccnc1Cl)C1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.7 mmol, 1 g) was dissolved in dichloromethane (10 mL) and acetic acid (0.1 mL) was added. To this solution benzyl 1-piperazinecarboxylate (11.2 mmol, 2.16 mL) and sodium cyanoborohydride (7.47 mmol, 0.47 g) were added subsequently. The mixture was stirred overnight at room temperature. Reaction was quenched with an aqueous sodium hydrogencarbonate solution and extracted twice with dichloromethane. The combined organic layers were dried over phase separation filter, concentrated under reduced pressure and purified using column chromatography (silica gel; dichloromethane/methanol) to yield 2.35 g of the title compound as a mixture of cis and trans isomers which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(=O)C.C=O.[CH3:10][N:11]1[C:16]2[C:17]([CH3:20])=[CH:18][NH:19][C:15]=2[C:14](=[O:21])[N:13]([CH3:22])[C:12]1=[O:23]>O>[CH3:1][N:2]([CH2:20][C:17]1[C:16]2[N:11]([CH3:10])[C:12](=[O:23])[N:13]([CH3:22])[C:14](=[O:21])[C:15]=2[NH:19][CH:18]=1)[CH3:3]
Reactant: CNC
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 50% dimethyl amine (0.4 mL), acetic acid (0.4 mL) and 38% formaldehyde (0.4 mL) were added, after which Intermediate 1 (0.4 g, 2.232 mmol) was added. The reaction mixture was refluxed for 10 min and then held for 20 min at 90° C. Reaction mixture was cooled to room temperature and diluted with water (25 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (25 mL), dried (Na2SO4) and filtered. The filtrate was evaporated to give a crude product which was recrystallised from acetonitrile to give 97 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.08 (s, 6H), 3.23 (s, 3H), 3.30 (s, 2H), 3.69 (s, 3H), 7.13 (s, 1H), 11.93 (br s, 1H); APCI-MS (m/z) 237.00 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:4]([C:5]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[C:3]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCCOC(=O)CC(=O)OCCCC
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C(=O)OCCCC)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
A 0.5-liter three-neck flask equipped with a stirrer was purged with nitrogen gas, and 7.2 g (0.3mols) of sodium hydride and 250 ml of dewatered tetrahydrofuran were put thereinto in a nitrogen stream atmosphere. With stirring, the mixture was cooled to 0° C., and, while its temperature was kept cooled, 66 ml (0.3 mols) of di-n-butyl malonate was dropwise added thereto over a period of 30 minutes. After the addition, the mixture was heated up to room temperature, and 32 ml of cyclopentyl bromide was dropwise added thereto, and refluxed for 5 hours. After this was cooled to room temperature, 10 g of sodium hydride and 32 ml of cyclopentyl bromide were added thereto, and refluxed further for 8 hours. The resulting reaction mixture was washed with 200 ml of water, and subjected to distillation under reduced pressure to obtain 20 g of di-n-butyl cyclopentylmalonate. The yield was 23.5%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([NH:20][CH2:21][CH2:22][OH:23])[C:11]=2[Cl:24])[CH:5]=[N:4]1)[CH3:2].[CH:26]([CH:28]=[O:29])=O>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([N:20]3[CH2:26][CH2:28][O:29][C:22](=[O:23])[CH2:21]3)[C:11]=2[Cl:24])[CH:5]=[N:4]1)[CH3:2]
Reactant: O=CC=O
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(NCCO)c2Cl)c1O
Solvent: Cc1ccccc1
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOC(=O)C3)c2Cl)c1O
Reaction time: 24 h

Procedure:
A solution of 0.50 g (1.3 mmol) of 1-ethyl-4-(2-chloro-3-(2-hydroxyethylamino)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 20 mL of toluene was heated to 90° C. and treated with 2 mL of 40 percent aqueous glyoxal solution with stirring. The progress of the reaction was monitored by HPLC analysis and additional aliquots of 40 percent aqueous glyoxal solution were added every few hours until the starting material was consumed. After 24 hours, the reaction was complete and the dark solution was decanted from a gummy residue. The residue was extracted with several portions of hot toluene and the organic solutions were combined. The volatiles were removed by evaporation under reduced pressure and the resulting residue was purified by adding a small amount of diethyl ether and collecting the solids present by filtration. More solids were obtained when the diethyl ether solution was concentrated by evaporation. These solids were collected by filtration as well. The solids were combined to obtain 0.39 g (71 percent of theory) of the title compound as a tan powder melting at 198°-202° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2].[C:17](O)(=[O:19])[CH3:18].C(OC(=O)C)(=O)C>[Fe]>[C:8]([C:7]1[CH:10]=[C:11]([NH:14][C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][C:6]=1[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])#[N:9]
Reactant: CC(=O)O
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)c1ccc(NC(C)=O)cc1C#N
Temperature: 100 °C
Yield: 83 %

Procedure:
To 5B (3.60 g, 15.0 mmol) in 1:1 acetic acid/acetic anhydride (150 mL), Fe (4.20 g, 75.2 mmol) was added. The reaction mixture was heated to 100° C. for 2 h then poured into ice. After the ice melted, the product was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated to provide 5C (3.14 g, 83%). LC-MS: 241.18 (M+H)+.
Reaction SMILES: [H-].[Na+].CO.[C:5](/[C:8](=[C:13](\[C:15]1[C:24]([NH:25][C:26]([O:28]CC)=O)=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)/[OH:14])/C(OC)=O)(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([C:8]1[C:26](=[O:28])[NH:25][C:24]2[C:15]([C:13]=1[OH:14])=[CH:16][C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=1[CH:23]=2)(=[O:7])[CH3:6]
Reactant: CCOC(=O)Nc1cc2c(cc1/C(O)=C(\C(C)=O)C(=O)OC)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)c1c(O)c2cc3c(cc2[nH]c1=O)CCCC3
Temperature: 72 °C
Reaction time: 0.08 h

Procedure:
To a mixture of sodium hydride (95%) (0.70 g, 29 mmol, 2.6 equiv) in benzene (100 mL) at 23° C. under nitrogen was added methanol (2.5 mL, 2.0 g, 62 mmol, 5.4 equiv) dropwise over 10 min. After stirring for an additional 5 min, methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-3-hydroxyprop-2-enoate (1-4) (4.1 g, 11 mmol, 1 equiv) was added and the resulting mixture was heated at 72° C. for 20 h. The solvent was evaporated under reduced pressure and the solid residue was suspended in water (50 mL) for 30 min followed by 1 N aqueous hydrochloric acid solution (100 mL) for an additional 30 min with stirring. The solid was filtered, washed with water (100 mL) and hexanes (100 mL), and dried to yield 3-acetyl-4-hydroxy-6,7,8,9-tetrahydrobenzo[g]quinolin-2(1H)-one (1-5) as an off-white solid. LRMS m/z (M+H) 258.4 found, 258.1 required.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C=O)C>[Br:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)CNc1ccnc(Cl)n1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(CBr)cc1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (2.0 g, 10.0 mmoles) and 1,4-bis-bromomethyl-benzene (4.0 g, 15.0 mmoles) are dissolved in 50 ml of DMF and NaH (0.8 g, 21.0 mmoles, 60% oil suspension) is added at 0° C. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 0.9 g of desired (4-bromomethyl-benzyl)-(2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 24% yield.
Reaction SMILES: C(OC)(=[O:3])C.Cl.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:16]#[N:17].CO>>[ClH:24].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:16]([NH2:17])=[O:3]
Reactant: N#CC(NCCc1cccs1)c1ccccc1Cl
Reactant: COC(C)=O
Agent: Cl
Solvent: CO
Product: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Temperature: 22.5 °C
Reaction time: 6 h

Procedure:
Into 1200 ml of methyl acetate 204 g (5.6 mol) of hydrogen chloride gas is introduced at 15-25° C., and to the solution are added 221.4 g (0.8 mol) of the [2-(2-thienyl)ethylamino](2-chorophenyl)acetonitrile, prepared as described in Example 1., and 48 ml (1.2 mol) of methanol. The mixture is stirred at 20-25° C. for 6 hours. In the course of the reaction first the hydrochloride of the starting “nitrile”, then gradually the hydrochloride of the resulting “acid amide” precipitates, in the form of white crystals. The crystals are collected by filtration, washed with methyl acetate and dried. Weight: 249 g (94%) mp.: 231-232° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])/[CH:5]=[CH:6]/[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[Br:12])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[Br:12])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccsc1Br
Solvent: CCO
Product: CCOC(=O)CCc1ccsc1Br
Reaction time: 23 h
Yield: 85.5 %

Procedure:
A mixture of the ester of Example 23(d) (5.217 g, 20.0 mmol) and (PPh3)3RhCl (1.56 g, 1.69 mmol, Aldrich) in ethanol (60 mL) was stirred under a balloon of H2 for 23 h. The mixture was then filtered through celite and evaporated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes→10%) to give 3-(2-Bromo-thiophen-3-yl)-propionic acid ethyl ester (4.507 g, 17.1 mmol, 85%).