Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:10])[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])=[N:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[O:34][CH3:35]>CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:19]2[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH2:12][N:8]4[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:3]4=[O:10])=[C:16]([O:34][CH3:35])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[C:27]([F:33])[CH:28]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Reactant: O=C1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1C(=O)CCCC1=O
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Sodium hydride (55 mg of a 60% dispersion in mineral oil. 1.1 mmol) was added to a solution of glutarimide (120 mg, 1.06 mmol) in DMF (5 ml) at ambient temperature under argon and the mixture stirred for 30 minutes. 7-(2-Bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (428 mg, 1 mmol), (prepared as described for the starting material in Example 62), in DMF (2 ml) was added and the resulting pale green solution was stirred for 18 hours and then quenched with water. The volatiles were removed by evaporation, and the residue was partitioned between water and ethyl acetate. The organic phase was separated and washed with water and then dried (MgSO4). The solvent was removed by evaporation, and the residue was purified by column chromatography eluting with ethyl acetate then ethyl acetate/methanol (9/1). The purified product was recrystallised from ethyl acetate and hexane, collected by filtration and washed with ether to give 4-(4-chloro-2-fluoroanilino)-7-(2-(2,6-dioxopiperidino)ethoxy)-6-methoxyquinazoline (252 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]1([CH2:31][CH2:32][NH2:33])[CH:30]=[CH:29][N:28]=[CH:27]1.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:33][CH2:32][CH2:31][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCn1ccnc1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 4 h

Procedure:
A mixture of 1.8 g of 5-chloroindole-2-carboxylic acid in 50 ml of tetrahydrofuran was treated with 1.5 g of 1,1'-carbonyldiimidazole and allowed to stand at room temperature for 4 hours. A solution of 1.15 g of 1H-imidazole-1-ethanamine in 25 ml of tetrahydrofuran was added and the reaction mixture was heated at reflux temperature for 3 hours, treated with 10 ml of water and again heated for one hour and then concentrated to remove the solvent. The residue was shaken with 5 ml of 1N sodium hydroxide and 300 ml of dichloromethane and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated to recover the desired compound, mp 167°-169° C.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([CH2:20][C:21]([CH3:23])=[CH2:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[FH:30]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH:14]([CH2:20][C:21]([F:30])([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]2[CH2:20][C:21]([CH3:23])([CH3:22])[O:16][C:15]2=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: F
Reactant: [H][H]
Reactant: C=C(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)CC(NS(=O)(=O)c2ccc(Cl)cc2)C(=O)O1
Product: CCOC(=O)C(CC(C)(C)F)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46 %
Yield: 37 %

Procedure:
Hydrogen fluorideepyridine (10 mL) was added to a 0° C. solution of ethyl 2-(4-chloro-benzenesulfonylamino)-4-methyl-4-pentenoate (1.0 g, 3.0 mmol) in THF (15 mL). The reaction mixture was allowed to warm to rt. After 5 h, an additional portion (10 mL) of hydrogen fluoride-pyridine was added. The mixture was stirred for 24 h, then a third portion of hydrogen fluoride-pyridine (10 mL) was added. After a total of 53 h, the reaction was quenched with ice chips (20 mL). The crude mixture was poured into ice water (500 mL) and extracted with CH2Cl2 (2×200 mL). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and concentrated in vacuo. The crude concentrate was purified using silica gel column chromatography (10:1 to 5:1 gradient, hexanes/EtOAc) to afford 0.395 g (37% yield) of ethyl 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate and 0.425 g (46% yield) of 4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-y)-benzenesulfonamide. Data for ethyl 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate: LCMS (M+Na)+374.1; 1H NMR (500 MHz, CDCl3) 7.78 (d, 2H, J=8.9), 7.47 (d, 2H, J=8.5), 5.19 (d, 1H, J=7.9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m, 2H), 1.42 (d, 3H, J=21.6), 1.37 (d, 3H, J=21.6), 1.12 (t, 3H, J=7.0). Data for 4-chloro-N-(5, 5-dimethyl-2-oxo-tetrahydro-furan-3-y)-benzenesulfonamide: LCMS (M+Na)+326.0; 1H NMR (400 MHz, DMSO-d6) 8.41 (d, 1H, J=9.1), 7.86 (d, 2H, J=8.6), 7.67 (d, 2H, J=8.8), 4.57 (m, 1H), 2.22 (dd, 1H, J=12.4, 9.0), 1.72 (t, 1H, J=12.0), 1.33 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C)C=O>[C:12]([CH:11]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: N#CCc1cccc(F)c1F
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(C#N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2.9 g, 71.8 mmol) was slowly added to a solution of (2,3-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) and ethyl 4-bromobutanoate (12.7 g, 65.3 mmol) in N,N-dimethylformamide (100 mL) at 0° C. After 30 min, the reaction mixture was warmed to ambient temperature. After 3 h, water was added and the mixture was extracted with ethyl acetate (2×). The organic extracts were washed with saturated aqueous ammonium chloride, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 267.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].[CH:17]([O-])([O-])OCC>>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH:17]=[N:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Reactant: CCOC([O-])[O-]
Product: Brc1ccc2ocnc2c1Oc1ccccc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.075 g, 0.268 mmol) in ethyl orthoformate (0.405 mL, 2.43 mmol) was heated at 100° C. for 2.5 h. after which time the reaction mixture was cooled to RT and concentrated in vacuo to a crude residue. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (75.1 mg, 97%) as a white solid. LCMS calculated for C13H9BrNO2 (M+H)+: m/z=290.0, 292.0. found: 289.9, 291.9.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:28])[CH3:29])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 3 h
Yield: 23.3 %

Procedure:
A solution of acryloyl chloride (0.044 mL, 0.54 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 93, 258 mg, 0.54 mmol) and DIPEA (0.103 mL, 0.59 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was suspended in CH3OH and filtered to give some of the title compound (67 mg). The filtrate was then concentrated in vacuo and purified by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo to give a solid which was suspended in CH3OH and collected by filtration to give more of the title compound (64 mg). The two batches of product were combined to give the title compound (131 mg, 46%) as a yellow solid; 1H NMR: 1.68-1.83 (1H, m), 2.04-2.16 (1H, m), 2.18 (6H, s), 2.63-2.77 (1H, m), 3.15-3.29 (3H, m), 3.35-3.46 (1H, m), 3.78 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.04 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.53 (1H, s), 8.23-8.4 (3H, m), 8.48 (1H, d), 9.34 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 532.5.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[C:8]1([NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>CO>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:15][C:4]1[CH2:5][NH:1][C:2](=[O:7])[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CNC(=O)C1
Solvent: CO
Product: Nc1ccccc1NC1=CC(=O)NC1

Procedure:
A solution of pyrrolidin-2,4-dione (6.93 g, 70 mmol) produced in step 1 and 1,2-phenylenediamine (7.88 g, 70 mmol) in methanol was stirred at 60° C. for 1 hour. The reaction solution was cooled, and the crystals thus formed were taken by the filtration to synthesize 4-((2-aminophenyl)amino)-3-pyrrolin-2-one (yield: 11.6 g, 87%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:22])=[CH:6]1)(=[O:4])=[O:3].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:22])[C:8]=2[C:9](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1F)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1F)C2
Yield: 51.8 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.047 ml), water (0.047 ml) and ethanol (30 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-fluorophenyl)-4-guanidinoimino-1-methanesulfonyl-3-methyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 16) (0.2 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1.COCCOC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=3)[C:3]=2[O:15][CH2:16][O:17][CH3:18])=[CH:22][CH:21]=1
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccc(F)cc2)c(C)cc2cc(OC)ccc12
Yield: 98.5 %

Procedure:
2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14) (0.3 g, 0.964 mmol), 4-fluorobenzeneboronic acid (0.27 g, 1.93 mmol), tetrakis(triphenylphosphino)palladium (0) (0.11 g, 0.0964 mmol), 2 M sodium carbonate (5 mL) and ethylene glycol dimethyl ether (5 mL) were added in a sealed tube and reacted as described above to give 0.31 g (96%) of the title compound (203) as a white solid. 1H NMR (400 MHz, d-CDCl3): δ 2.21 (s, 3H), 3.12 (s, 3H), 3.93 (s, 3H), 4.75 (s, 2H), 7.08-7.08 (m, 1H), 7.11-7.17 (m, 3H), 7.30-7.33 (m, 2H), 7.44 (s, 1H), 8.01 (d, J=9.2 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CN1C(=O)CCC1.O>[C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:17]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:18][CH2:19][CH2:20]2)#[N:28]
Reactant: N#Cc1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(C#N)ccc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in NMP (0.5 mL) was added 1,2,3,4-tetrahydroquinoline-6-carbonitrile (597 mg, 3.77 mmol) with stirring for 1 h at 150° C. in an oil bath. The resulting solution was diluted with water (100 mL) and the solids were collected by filtration to afford methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (200 mg, 44%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CCOCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:26][NH:27][CH:28]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of dry ether under nitrogen is added from an additional funnel a mixture of 23.5 g (122 mmol) of ethyl p-chlorocinnamate and 19.4 g (122 mmol) of (p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80 mL of dimethylsulfonide. The addition time is about 20 minutes and results in gentle refluxing of the mixture. After another 10 minutes stirring, the mixture is diluted with 100 mL of water. The mixture is extracted four times with ether which is then dried over magnessium sulfate followed by concentrated in vacuo. The resulting solid is recrystallized from ethylene dichlorite to give 7.8 g of crystals, m.p. 137°-138° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)C.Cl>C(Cl)Cl.CS(C)=O>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of 2.3 ml of oxalyl chloride in 40 ml of methylene chloride cooled at -65° C. is added a solution of 4.45 g of dimethylsulfoxide in 20 ml of methylene chloride over a period of 10 minutes, and the mixture is stirred at -60° C. for 10 minutes. To the mixture is added a solution of 5 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate in 50 ml of methylene chloride over a period of 10 minutes, and the resulting mixture is stirred at -60° C. for 20 minutes. To the mixture is added 10.3 g of diethylisopropylamine over a period of 10 minutes, and the temperature is raised from -60° C. up to -30° C. To the mixture is added 80 ml of 1N hydrochloric acid, and the mixture is stirred at room temperature. The methylene chloride layer is separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane:ethyl acetate=4:1 to 2:1), to give 2.6 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:2].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O.CC(C1C=CC([F:35])=CC=1)=C.Cl([O-])(=O)(=O)=O.[Na+]>ClCCCl.ClC(Cl)C>[ClH:18].[F:35][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:1]=[O:2])=[CH:14][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1cnccc1-c1ccccc1
Reactant: C=C(C)c1ccc(F)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cl
Product: O=Cc1cnccc1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
The title compound was prepared following the method described in the literature (C. Jutz, W. Muller and E. Muller, Chem. Ber., 1966 99, 2479) for 3-formyl-4-phenylpyridine. ##STR10## Oxalyl chloride (34 ml; 0.39 moles) was added to a stirred solution of dimethylformamide (33 ml; 0.42 moles) in 1,2-dichloroethane (50 ml). To the resulting mixture was added α-methyl-p-fluorostyrene (13.6 g; 0.1 moles) in dichloroethane (20 ml) and the mixture refluxed for 3 hours. After removal of solvent by distillation under reduced pressure, water (150 ml) was added to give a dark brown solution. An aqueous solution of sodium perchlorate was added to this solution causing the di-iminium perchlorate (2) to precipitate. This was filtered off, washed with water, added to an aqueous solution of ammonium chloride (24 g in 190 ml of water) and heated at 100° C. for 1 hour. After allowing to cool, the reaction mixture was extracted with chloroform and the organic layer separated, washed with water, and ethereal HCl added causing the title compound (3) to precipitate as buff coloured crystals (18g; 76% yield based on styrene (1))
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C(O)(C)C.O.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)(=O)C>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[N:3][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N)cnc1Br
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 77.2 %

Procedure:
To a suspension of 2-bromo-3-methyl-5-nitropyridine (10.01 g), isopropanol (130 ml), water (26 ml) and iron (12.9 g) was added acetic acid (5.27 ml), and stirred at 80° C. for 3.5 hours. To the reaction solution was added potassium carbonate (13.37 g), filtered through Celite, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The precipitated solid was collected by filtration to give 5-amino-2-bromo-3-methylpyridine (6.66 g) as a gray solid. MS (ESI) m/z: 187, 189 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1csc(Nc2ccncc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(Nc2ccncc2)n1

Procedure:
2-(Pyridin-4-ylamino)-thiazole-4-carboxylic acid (160 mg) was prepared according to General Procedure C using 2-(pyridin-4-ylamino)-thiazole-4-carboxylic acid ethyl ester in methanol:tetrahydrofuran:2N NaOH (1:1:1, 1.5 mL). The solvents were evaporated and the compound was dried. The crude product was used without further purification.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]1)[CH2:20][CH2:19]2.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([NH:11][C:12]([NH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH2:22][C:21]2([C:29](=[O:30])[NH:28][C:27](=[O:31])[NH:26]2)[CH2:20][CH2:19]3)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Reactant: O=C=Nc1cccc2ccccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O)Nc1cccc2ccccc12

Procedure:
A mixture of 1-naphthyl isocyanate (9.5 mg, 0.056 mmol), (±)-6′-amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione hydrochloride (described in Intermediate 2) (15 mg, 0.056 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.056 mmol) was stirred in THF (0.5 mL) at ambient temperature for 18 h. The crude mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=401 (M+1). HRMS: m/z=401.1638; calculated m/z=401.1608 for C23H21N4O3.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1.C(O)(=O)C(C)O>CCCCCCCCCC1C=CC(O)=CC=1.[OH-].[Na+]>[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:1][CH2:2][OH:3])=[CH:17][CH:18]=1
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C1CO1
Agent: CC(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCc1ccc(OCCO)cc1

Procedure:
In a stainless steel reactor having an inner volume of 1,000 ml and provided with a thermometer, a pressure gauge, and a stirrer, 376 g of nonylphenol (molecular weight 221), 0.6 g of sodium hydroxide as a catalyst, and 224 g of ethylene oxide were heated at 150° C. under pressure of 6.0 kg/cm2G for reaction. The resultant averagely 3.0-mole ethylene oxide adduct of nonylphenol and 2.7 g of an aqueous 50 wt% lactic acid solution added thereto were thoroughly stirred. The nonylphenol ethoxylate obtained as the result was tested for the effect of aging. the results are shown in Table 28.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].C(OCC)(=O)C.[CH3:11][C:12]([CH3:15])=[C:13]=[O:14].C(Cl)(Cl)(Cl)[Cl:17]>>[CH3:11][C:12]([CH3:15])([C:13]([Cl:17])=[O:14])[C:1]([Cl:4])=[S:2]
Reactant: CC(C)=C=O
Reactant: S=C(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)Cl)C(=S)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7.2 ml (9.2 grams, 0.08 mole; 85% in carbon tetrachloride) of thiophosgene in 50 ml of carbon tetrachloride under an argon atmosphere was added dropwise 70.0 grams of an ethyl acetate solution containing 5.6 grams (0.08 mole) of dimethylketene. The addition required five minutes during which time the reaction mixture temperature rose from 25° C. to 32° C. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a semi-solid residue. The residue was slurried in petroleum ether and a solid collected by filtration. The solid, mp 112°-114° C., was the dimethylketene dimer. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to give 2.2 grams of dimethylthiomalonyl dichloride; bp 62°-67° C./8-8.5mm. The nmr spectrum was consistent with the assigned structure.