Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:12])[CH2:10]Br.Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[S:23][CH:24]=[C:25]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[N:26]=2)[CH2:17][CH2:16]1.O>CN(C)C=O>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([C:25]2[N:26]=[C:22]([NH:21][CH:18]3[CH2:19][CH2:20][N:15]([CH2:10][C:9]([O:8][CH3:7])=[O:12])[CH2:16][CH2:17]3)[S:23][CH:24]=2)=[CH:28][CH:29]=1)#[N:32]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(-c2csc(NC3CCNCC3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(Nc2nc(-c3ccc(C#N)cc3)cs2)CC1
Temperature: 50 °C
Yield: 86 %

Procedure:
17.75 g of potassium carbonate and 4.3 ml of methylbromoacetate are added to 14.8 g of 4-{2-[(piperid-4-yl) amino]-1,3-thiazol-4-yl}benzonitrile dihydrochloride in 150 ml of N,N-dimethylformamide and the reaction mixture is heated at 50° C. for 2 hours. It is poured over water, extracted with ethyl acetate and the organic phase is washed with water, and then dried over sodium sulphate and concentrated under vacuum. The residue crystallizes from isopropyl ether to give beige crystals which melt at 172° C.; yield 86%.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:22][OH:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:23][CH2:22][C@@H:13]2[CH2:14][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (28.8 g: 77 mmole) in dichloromethane (150 ml) under ice cooling, p-toluenesulfonyl chloride (19.11 g: 1.3 eq.), triethylamine (10.4 ml: 1.3 eq.) and dimethylaminopyridine (0.94 g: 0.1 eq.) are added. The mixture is stirred at 25° C. for 7 hours. The reaction mixture is diluted with ice water. The resultant organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from n-hexane to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (37.7 g). Yield: 93%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2
Reactant: O=C1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCC1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (50 mg, 0.23 mmol) was dissolved in 1,1′-carbonyldiimidazole (56 mg, 0.34 mmol) in THF (1.5 mL), followed by stirring for 1 hour. Then, pyrrolidone (0.03 mL, 0.34 mmol) was added thereto, followed by stirring for 6 hours. Upon completion of the reaction, the experiment was completely terminated by addition of distilled water. EtOAc was added to the reaction product to separate an oil layer and a water layer from each other, followed by washing with a saturated solution of NaCl and then drying over anhydrous Na2SO4. The solvent was distilled under reduced pressure. The residue was purified by column chromatography using hexane/ethyl acetate (1/1) to give a target compound (36.1 mg, yield: 58.1%).
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7]CC)=O)([O-:3])=[O:2].[CH3:10][C:11](=O)[CH2:12][C:13](=O)[CH3:14].[N:17]1C=CC=CC=1.C(O)(=O)C>[OH-].[NH4+]>[CH3:10][C:11]1[CH:12]=[C:13]([CH3:14])[NH:17][C:5](=[O:7])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CC(=O)CC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 104.1 %

Procedure:
A mixture of ethyl nitroacetate (80.0 g, 601 mmol) in ammonium hydroxide (25% NH3 in water, 400 mL) was stirred at room temperature for 3 days, and then the solution was concentrated by air-drying. The residue was dissolved in water (450 mL). To the solution was added 2,4-pentanedione (73.1 g, 730 mmol), pyridine (16.2 mL, 200 mmol) and acetic acid (11.4 mL, 200 mmol), and the mixture was stirred for an additional 7 days. The resulting precipitates were collected by filtration and dried under reduced pressure to give 35.0 g (35%) of the title compound as yellow solids: 1H-NMR (DMSO-d6) δ 12.44 (1H, br.s), 6.06 (1H, s), 2.19 (3H, s), 2.13 (3H, s).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]2([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]2([C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:8]4[CH2:9][CH2:10][C:5]5[CH:4]=[CH:3][O:2][C:6]=5[CH2:7]4)=[O:25])=[CH:27][CH:28]=3)[CH2:18][CH2:19]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C2(c3ccccc3)CC2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(C2(c3ccccc3)CC2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.209 g (7.575 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 1.80 g (7.58 mmol) of 4-(1-phenylcyclopropyl)benzoic acid and 4.22 ml (30.3 mmol) of triethylamine in 50 ml of N,N-dimethylformamide, 1.38 ml (9.09 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: O=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Br[C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:2]1[C:3]([OH:5])=[O:4]
Reactant: CC(=O)C(=O)O
Reactant: Nc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc2ncccc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.22 mL 2-oxo-propionic acid, 0.26 g palladium acetate and 3.20 mL triethylamine were added to a solution of 1.00 g 2-bromo-pyridin-3-yl amine and 1.21 g triphenyl-phosphine in 10 mL N,N-dimethylformamide. The reaction mixture was stirred for 4 hours at 100° C. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel with dichloromethane/methanol as eluent. Yield: 260 mg MS(ES+): m/e=163.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2cccnc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(3-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (657 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:11][N:10]1[C@H:9]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:4][C:3]([C:2]4[CH:3]=[CH:4][CH:5]=[C:6]5[C:11]=4[N:10]=[CH:9][CH:8]=[CH:7]5)=[CH:2][C:19]=3[CH2:20][CH2:8]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1cccc2cccnc12
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5cccnc45)cc3CC[C@@H]12
Yield: 38 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 8-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 88 mg (38%) of the title compound as a tan solid. mp 205°-207°. FDMS: m/e=356 α[D]589 =+76.28 (c=0.47, chloroform).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a mixture of 4-nitro-1H-imidazole (2.0 g, 17.7 mmol) and K2CO3 (3.67 g, 26.5 mmol) in acetonitrile (20 mL) was added iodomethane (1.3 mL, 3.0 g, 21.2 mmol) dropwise while stirring at room temperature. The resulting mixture was stirred at 60° C. overnight. It was then evaporated under reduced pressure and the residue was diluted with water (20 mL). The mixture was extracted with dichloromethane (2×20 mL). The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 268a as a yellow solid (1.8 g, 82%). MS-ESI: [M+H]+ 128.1. 1H NMR (500 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.82 (s, 1H), 3.76 (s, 3H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and pyrrolidine are converted to the named compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=S1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCS(=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine-1-oxide in DMSO at ambient temperature.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25](Cl)=[O:26].O>ClCCl>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:25]([C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)=[O:26]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc2ccccc2c1
Temperature: 2 °C
Yield: 9560.7 %

Procedure:
Dichloromethane (66 mL) and then triethylamine (14.6 mL, 105 mmol, 2.0 eq.) were added to glycine methyl ester hydrochloride (6.61 g, 52.5 mmol, 1.0 eq.). A white precipitate appeared on the addition of the triethylamine, and the solution became a lot thicker. The mixture was stirred and cooled to 2° C. using an ice/water bath. A solution of 2-naphthoyl chloride (10.07 g, 52.5 mmol, 1.0 eq.) in dichloromethane (33 mL) was added over 15 minutes. The pale brown mixture was stirred for 25 hours at 5° C. Water (100 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with sodium hydroxide (1 M, 100 mL) and then evaporated to dryness using a rotary evaporator to give an off-white solid (1221 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CC)CC)C.[O-][Si]([O-])=O.[Mg+2]>CCCCCC.C(OCC)(=O)C.CCCCCC>[CH3:17][C:18]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:19]=1[C:20]([C:6]1[N:2]([CH3:1])[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:5]=1)=[O:21]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3)n2C)c(C)c1
Reaction time: 48 h
Yield: 42.3 %

Procedure:
4-(1-Methylpyrrol-2-ylmethyl)nitrobenzene (1.2 g, 5.5 mmol) [prepared as in Example 7, Step (b)], 2,4-dimethylbenzoyl chloride (1.6 g, 9.5 mmol), and triethylamine (1.3 ml, 9.3 mmol) were dissolved in xylenes (50 ml), and the reaction mixture was heated at reflux under argon. After 48 h, the reaction mixture was passed through a Florisil® column (hexane followed by hexane-ethyl acetate, 95:5) to give 4-{5-(2,4-dimethylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl}nitrobenzene (0.81 g, 42%) as a solid. ##STR41##
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reaction time: 2 h

Procedure:
The 2,4 difluoro aniline (5.06 ml, 49.6 mmole) put into a solution of 10% NaOH (76 ml). Cooled in an ice bath and added benzyl chloroformate (7.85 ml, 55 mmole). After stirring for 2 hours the product was filtered, stirred with hexane, dried. Yield 9.4 g
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([N:17]=[C:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:10]([N:17]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][C:19]2[CH2:20][CH2:21][CH2:22][C:18]1=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: c1ccc(CN=C2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2
Reaction time: 2 h

Procedure:
Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask containing 3.46 gm of benzyliminocyclopentane and 2.0 g of triethylamine in 50 ml of ethanol at 0° C., stir for 2 hours, then heat to reflux for 2 hours. Concentrate the reaction mixture and partition between 1N HCl and ether. Dry the ether extract over magnesium sulfate, filter, ooncentrate under high vacuum to obtain a brown oil and distill in a kugelrohr at 190°-210°/0.1 mm to obtain the title compound of Part A as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11]>>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CNc1cccc(Br)c1
Product: CNc1cccc(-c2ccc(C=O)cc2)c1
Yield: 59.2 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 4.3 g (23.2 mmol) of (3-bromophenyl)-methylamine with 5.2 g (34.8 mmol) of 4-formylbenzene-boronic acid, 2.9 g (60%) of the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:21][C:22]([N:24]([CH:34]1[CH2:36][CH2:35]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][O:17][CH2:18][O:19][CH3:20])[CH2:9][CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].CO.[Cl-].[NH4+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:34]1([N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])[C:22]([CH:21]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:15]2[CH2:16][O:17][CH2:18][O:19][CH3:20])=[O:23])[CH2:36][CH2:35]1
Reactant: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C(=O)CCN1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 62 %

Procedure:
Into a 100 mL round bottom flask was added 4E and toluene (42 mL) under nitrogen. Sodium metal (392 mg, 17.1 mmol, 1.3 eq) was added at once followed by methanol (160 μL, 3.9 mmol, 0.3 eq). The reaction was allowed to stir under nitrogen over 48 hours. After sodium metal had dissolved, saturated ammonium chloride (50 mL) was added to quench the reaction. Ethyl acetate (50 mL) was added and the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate and filtered. Solvent was removed under vacuum to leave a residue which was purified by column chromatography (20% ethyl acetate/hexanes) to give 4F (4.17 g, 62%). ESI-MS:m/z 459.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>C(O)C(C)C>[C:1]([CH2:3][C:4]([O:6][CH2:8][CH:7]([CH3:17])[CH3:12])=[O:5])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#CCC(=O)O
Solvent: CC(C)CO
Product: CC(C)COC(=O)CC#N
Reaction time: 14 h
Yield: 90 %

Procedure:
495.2 g of 68.7 wt % strength aqueous cyanoacetic acid, 1500 mL of isobutanol and 5 g of p-toluenesulfonic acid were heated to 80° C. in 3 h under a pressure of ca 270 mbar, and the water/isobutanol azeotrope was removed completely. Stirring was then continued for a further 14 h at a ratio of withdrawn to recycled material of 11:99, to give a transition temperature of 67° C. and a final temperature of 88° C. at 200 mbar. Excess isobutanol was distilled off after filtration and 529 g of crude isobutyl cyanoacetate (purity as measured by GC analysis: 90%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12].[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[N:7]([CH3:21])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSCC(C)C(=O)N(C)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a dry 50 ml round bottom flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 1.0 g (3.05 mmoles) of N-(4-chloro-2-(pyridin-3-yl)-1,3-thiazol-5-yl)-2-methyl-3-(methylthio)propanamide and 10 mLs of anhydrous N,N-dimethyl formamide. To the resulting solution was then added 1.1 g (3.36 mmoles) of cesium carbonate powder in one portion, followed by the dropwise addition of 0.476 g (3.36 mmoles) of iodomethane in 5 mLs of anhydrous N,N-dimethylformamide. The heterogeneous mixture was stirred at ambient temperature for 12 hours, and then poured into 200 mLs of water and extracted with methylene chloride (3×100 mLs). The combined organic extracts were washed with water (100 mLs), saturated aqueous sodium chloride solution (100 mLs) dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes to yield a yellow oil (0.93 g, 89%): 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.4 Hz, 1H), 8.73 (d, J=3.8 Hz, 1H), 8.34-8.09 (m, 1H), 7.43 (dd, J=7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06-2.70 (m, 2H), 2.49 (d, J=7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 175.22, 162.37, 151.91, 146.53, 136.46, 134.64, 133.35, 127.98, 124.27, 37.47, 36.71, 36.47, 17.56, 15.44.