Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[Br:19][C:20]1[C:21]([CH3:27])=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(Cl)Cl.CN(C=O)C>[Br:19][C:20]1[C:21]([CH3:27])=[C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:3]=2[CH2:2][Br:1])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cc(F)ccc1CBr
Reactant: Cc1c(N)cccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Step 2 A solution of crude 2-(bromomethyl)-5-fluorobenzoic acid (3.05 g, 13.1 mmol) in DCM (50 mL) was treated with oxalyl chloride (1.66 g, 13.1 mmol) and 6 drops of DMF. The mixture was stirred at rt for 1 h, then was concentrated. The residue was redissolved in DCM (50 mL) and treated with 3-bromo-2-methylaniline (1.705 g, 9.16 mmol). The mixture was stirred at rt for 1 h, then TEA (2.19 mL, 15.7 mmol) was added in portions. The mixture was stirred at rt for 2 h, then was diluted with DCM (100 mL), washed with NaHCO3 (aq) and water, dried and concentrated. The residue was triturated with DCM to provide N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide as a white solid (0.9 g). The mother liquor was concentrated and the residue was again triturated with DCM to provide additional N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide as a white solid (0.46 g). The mother liquor was concentrated and the residue was purified by column chromatography (eluting with a gradient from hexane to 70:30 EtOAc-hexane) to provide additional N-(3-bromo-2-methylphenyl)-2-(bromomethyl)-5-fluorobenzamide as a pink solid (1.18 g) for a total of 2.54 g (48%). Mass spectrum m/z 400, 402, 404 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([C:13](=[O:33])[NH:14][CH:15]1[CH2:21][CH:20]([CH3:22])[CH2:19][N:18]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17][CH:16]1[OH:32])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[CH3:43][O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51](C(O)=O)=[CH:50][C:49]=2[CH:56]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:32][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:51]2[O:52][C:48]3[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:56][C:49]=3[CH:50]=2)=[O:5])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:33])[CH2:21][CH:20]([CH3:22])[CH2:19][N:18]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)CN(S(=O)(=O)c2ccccn2)CC1O
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COc1ccc2oc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CC(C)CN(S(=O)(=O)c4ccccn4)CC3O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To {(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester (0.13 g, 0.28 mmol) was added HCl/dioxane (4M, 2.8 ml, 11.2 mmol). The mixture was stirred at RT for 2 h before solvents and excess amount of HCl was removed on rotavapor. The result white solid was dissolved in 5 ml DMF. To the solution was added 5-methoxy-benzofuran-2-carboxylic acid (63.4 mg, 0.33 mmol), HBTU (125 g, 0.33 mmol) and NMM (0.14 g, 1.34 mmol). The mixture was stirred at RT overnight. DMF was then removed and the residue was re-dissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). The combined organics were concentrated by rotary evaporation. Purification by column chromatograghy gave the title compound (110 mg in 69% yield, 2 steps): MS (M+H+):573.4; 1H-NMR (400 Hz, CDCl3): d=8.74-8.66(dd, 1H), 7.96-6.97(m, 9H), 4.72(m, 1H), 4.18-3.21(m, 7H), 2.81(m, 1H), 2.04-1.74(m, 6H), 1.25(m, 2H), 0.99-0.87(m, 9H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (5 mL, 43.6 mmol), ethyl 2-aminobenzoate (7.6 g, 46.0 mmol), di-isopropyl-ethylamine (8.3 mL, 48.0 mmol) and ethanol (60 mL). The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to room temperature, and the solid was filtered off and washed with ethanol (100 mL), ethanol/hexane (1:1, 200 mL) and hexane (200 mL) to afford the product (10.2 g, 32.7 mmol, 75% yield) as a white solid. MS: M(C13H11Cl2N3O2)=312.15, (M+H)+=312.0 and 314.0.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:5]=1.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10]([OH:14])=[C:11]2[C:15]([O:16][CH3:17])=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(O)CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a refluxing stirred suspension of sodium hydride (5.6 g of 80% in oil, 187 mmoles) in dry dimethyl carbonate (120 ml) under a nitrogen atmosphere was added a solution of 7-bromo-2-tetralone (14 g, 61 mmoles) in dry dimethyl carbonate (60 ml) dropwise over 40 minutes. Refluxing was continued for an additional 45 minutes and then cooled to room temperature. The reaction was carefully quenched with glacial acetic acid, diluted with one volume of water and extracted with ethyl acetate (150 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to leave a residue which was purified using silica gel column chromatography eluting with ethyl acetate:hexane (39:7) to give methyl 7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate as a white solid. (15.2 g. 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[Li]CCCC>C1COCC1>[CH3:8][C:6]1[CH:7]=[C:2]([B:10]([OH:15])[OH:11])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)cc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc(C)n1
Reaction time: 3 h

Procedure:
4-Bromo-2,6-dimethyl-pyridine (910 mg, 4.9 mmol) and triisopropyl borate (2.3 mL, 10 mmol) in THF (10 mL) were cooled in a −78° C. bath. BuLi (2.7 M, 7 mL) was added in drop wise. After 3 hrs, the bath was removed. The reaction was acidified with 1N HCl till pH=1. The separated aqueous layer was neutralized with NaOH and subsequently extracted with ethyl acetate. A crude white solid was obtained (800 mg) as the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Treat a solution of (4-hydroxy-piperidin-1-yl)-acetic acid methyl ester (10.0 g, 57.7 mmol) and imidazole (4.71 g, 69.2 mmol) in DMF (100 mL) with t-butyl-diphenylsilyl chloride (19.04 g, 69.3 mmol) and stir for 16 hours at room temperature. Dilute the reaction with diethyl ether and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 2% methanol in CH2Cl2 to afford 17.38 g (73%) of the titled product. Rf=0.71 (9/1 CH2Cl2/methanol). ES MS (m/z): 412 (M+).
Reaction SMILES: [C:1]([S:4][CH:5]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])[C:6]([NH2:8])=[O:7])(=[NH:3])[NH2:2]>C(O)C>[NH2:2][C:1]1[S:4][C:5]([C:6]([NH2:8])=[O:7])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:3]=1
Reactant: N=C(N)SC(C(N)=O)C(=O)c1ccccc1C(F)(F)F
Solvent: CCO
Product: NC(=O)c1sc(N)nc1-c1ccccc1C(F)(F)F
Yield: 69.6 %

Procedure:
A mixture of 2.00 g (0.0066 mole) of 2-carbamimidoylsulfanyl-3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide in 80 mL of ethanol was heated to 60 degrees for overnight. The mixture was concentrated under reduce pressure. Purification of the residue by chromatography on C18-reverse phase silica gel, eluting with water-acetonitrile (gradient 100:0-50:50) gave 1.32 g of 2-amino-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.17) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([NH2:14])[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[N+:17]([C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22](O)=[O:23])([O-:19])=[O:18].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[N+:17]([C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([NH:14][C:12]1[N:11]=[CH:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH:13]=1)=[O:23])([O-:19])=[O:18]
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: Nc1cn(-c2cccc(C(F)(F)F)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cn(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 28 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-amine (1.2 g, 4.49 mmol, 1.00 equiv, 85%) in dichloromethane (30 mL), 2-nitro-5-(piperidin-1-yl)benzoic acid (1.32 g, 5.07 mmol, 1.00 equiv, 96%), EDC.HCl (2 g, 10.42 mmol, 2.00 equiv), and 4-dimethylaminopyridine (1.29 g, 10.57 mmol, 2.00 equiv). The resulting solution was stirred overnight at 28° C. The resulting solution was diluted with 200 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1) to give 600 mg (22%) of product as brown oil.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2.CO>C(Cl)(Cl)Cl>[CH2:1]([NH:5][C:20]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 83 %

Procedure:
n-Butyl amine (0.66 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.60 mmol) were coupled according to procedure A (0-25° C. reaction temperature). The crude product was dissolved in chloroform and methanol and the resulting solution stirred 18 hours with 50 mg dimethylaminopyridine-polystyrene resin (Fluka Chemical Co.), the solution filtered, concentrated and the solids triturated with ether: Yield 83%; HPLC (60/40) 8.88 minutes (92%); mp 192-193° C.; TSPMS 398/400 (MH+,100%);
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=1.[F:13][CH:14]([F:17])[CH2:15][OH:16].Cl>CS(C)=O.O>[F:13][CH:14]([F:17])[CH2:15][O:16][C:4]1[N:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: OCC(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCC(F)F)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.3 %

Procedure:
Powdered potassium hydroxide (712 mg, 12.7 mmol) was added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol) and 2,2-difluoroethanol (520 mg, 6.35 mmol) in DMSO (15 mL) and the mixture was stirred at 120 C for 14 h. An additional two equivalents of 2,2-difluoroethanol and potassium hydroxide were added and the mixture was heated for 24 h. The mixture was cooled to room temperature, diluted with water (5 mL), acidified with 1N aq. HCl (to pH 1) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×25 mL) then brine (50 mL) and concentrated under reduced pressure to provide title compound as a beige solid (620 mg, 96%). Method B HPLC-MS: MH+ requires m/z=204. Found: m/z=204, Rt=1.54 min (90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](O)(=O)[CH3:14].Cl.[OH-].[NH4+]>O>[CH3:13][C:14]1[NH:1][C:2]2[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Reactant: CC(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2ccc([N+](=O)[O-])c(C)c2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 668 mg of 2,3-diamino-6-nitrotoluene, 20 mL of glacial acetic acid and 2 mL of 12N hydrochloric acid is heated to reflux for 3 hours. The resulting mixture is cooled to room temperature and rotary evaporated. The residue is diluted with 20 mL of water, and basified with ammonium hydroxide (28-30%). The resulting suspension is extracted with ethyl acetate and the extracts are dried over magnesium sulfate, filtered and rotary evaporated to provide 720 mg of 2,4-dimethyl-5-nitrobenzimidazole as a tan solid.
Reaction SMILES: [CH:1]([NH:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>>[CH2:29]([N:3]([CH:1]=[O:2])[N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]1)[CH3:30]
Reactant: CCOC(=O)c1cn(NC=O)c2cc3c(cc2c1=O)OCO3
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cn(N(C=O)CC)c2cc3c(cc2c1=O)OCO3

Procedure:
Ethyl 5-[ethyl(formyl)amino]-5,8-dihydro-8-oxo-1,3-dioxolo-[4,5-g]quinoline-7-carboxylate [V; R and R" are C2H5 ] was prepared from 5 g of ethyl 5-(formylamino)-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (Example 3), 4.5 g of potassium carbonate and 3.7 ml of ethyl iodide according to the procedure of Example 6. There was obtained 3.2 g of ethyl 5-[ethyl(formyl)amino]-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]-quinoline-7-carboxylate, colorless granules, m.p. 218°-221° C. when recrystallized from ethanol.
Reaction SMILES: O1CCCC1.C[Si](C)(C(C)(C)C)[O:8][CH2:9][C@@H:10]1[C@@H:18]2[C@@H:13]([S:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:17]2)[CH2:12][C@H:11]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(OCC)(=O)C>[OH:8][CH2:9][C@@H:10]1[C@@H:18]2[C@@H:13]([S:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:17]2)[CH2:12][C@H:11]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2S1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a tetrahydrofuran (74 mL) solution of the compound 9 (7.3 g) was added a 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (27 mL), and the mixture was stirred for 3 hours. The reaction liquid was diluted with ethyl acetate (380 mL), washed with water (740 mL) and a saturated saline (380 mL). Further the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, dried with anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). The resulting compound was purified again by silica gel column chromatography (dichloromethane:ethyl acetate=4:1→ethyl acetate) to obtain a titled compound (3.24 g) having the following physical property values.
Reaction SMILES: [C:1]1([C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=O)[S:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>C(O)COCCO>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:6][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)CCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)CCCCc1cccs1
Temperature: 120 °C

Procedure:
4-(2-thenoyl)butyric acid (9.2 g) was dissolved in 60 ml of diethylene glycol and 30 ml of hydrazine hydrate added. After heating the mixture to 120° C. gradual addition of potassium hydroxide (13.6 g) was begun. Low boiling components were distilled out of the reaction mixture until the reaction mixture temperature reached 210° C. After cooling to room temperature water was added to the reaction mixture followed by 6N hydrochloric acid. This mixture was extracted with benzene, the benzene dried over sodium sulfate, filtered through a pad of charcoal, and concentrated under vacuum. A solid residue was obtained after trituration with ligroine, cooling and scratching. Yield 5.5 g. N.M.R. (CDCl3)δ1.76 (m, 4H), 2.42 (m, 2H), 2.88 (m, 2H), 6.80 (m, 1H), 6.90 (m, 1H), 7.12 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1cccc(O)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(O)c3)ccn2c1=O

Procedure:
Methyl 8-(3-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (3-hydroxyphenyl)-boronic acid (56.6 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][C:9]#[CH:10])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:39])([F:38])[CH:31]([S:36][CH3:37])[CH2:32][C:33](O)=[O:34]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][C:9]#[CH:10])[C:33](=[O:34])[CH2:32][CH:31]([S:36][CH3:37])[C:30]([F:39])([F:38])[F:29])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CSC(CC(=O)O)C(F)(F)F
Reactant: C#CCNc1cn(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: C#CCN(C(=O)CC(SC)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a 7 mL vial was added 3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (140 mg, 0.6 mmol), N,N-dimethylpyridin-4-amine (249 mg, 2.040 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (276 mg, 1.440 mmol) followed by 4,4,4-trifluoro-3-(methylthio)butanoic acid (158 mg, 0.840 mmol) and DCE (1.2 mL). The solution was stirred at 25° C. for 18 hours, the crude reaction mixture was concentrated and purified with silica gel chromatography (0-100% EtOAc/hexane) to give the title compound as a brown oil (237 mg, 0.588 mmol, 98%): (IR thin film) 1674 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.13 (s, 1H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.48 (ddd, J=8.3, 4.8, 0.5 Hz, 1H), 4.39 (s, 2H), 3.76 (dqd, J=17.2, 8.6, 3.6 Hz, 1H), 2.67 (dd, J=16.6, 3.6 Hz, 1H), 2.46 (dd, J=16.5, 9.9 Hz, 1H), 2.29 (d, J=2.5 Hz, 4H); ESIMS m/z 403 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:4]=1.[S:15]([CH2:25][N+:26]#[C-:27])([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[C-]#N.[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C@H:7]2[O:8][CH:27]=[N:26][C@@H:25]2[S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:5]([O:11][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COCOc1cc(OC)ccc1C=O
Agent: [C-]#N
Agent: [Na+]
Product: COCOc1cc(OC)ccc1[C@H]1OC=N[C@@H]1S(=O)(=O)c1ccc(C)cc1

Procedure:
In a manner analogous to Preparation 1, 4-methoxy-2-methoxymethoxybenzaldehyde (0.12 g, 0.63 mmol), tosylmethylisocyanide (0.12 g, 0.60 mmol) and NaCN (3 mg, 0.06 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 392.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Cl:7][C:8]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:9]=1[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.O.Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:8]=2[Cl:7])=[CH:17][CH:16]=1)=[O:4]
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 80.8 %

Procedure:
13 g (0.14 mole) of dimethylcarbamic acid chloride were added dropwise to 29 g (0.1 mole) of 4-(2-chloro-4-trifluoromethyl-phenoxy)-aniline, dissolved in 50 ml of pyridine, at 0° C. The mixture was warmed to 70°-75° C for half an hour, the bulk of the pyridine was stripped off in vacuo and the residue was poured into water and acidified with dilute hydrochloric acid. The precipitate was filtered off, dried and recrystallized from toluene. 29 g (89% of theory) of N,N-dimethyl-N'-[4-(2-chloro-4-trifluoromethylphenoxy)-phenyl]-urea were obtained as pink crystals of melting point 140° C.