Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:17])([O-])[O:2][CH2:3][CH:4](N1C(=O)CCC1=O)[Si:5]([CH3:8])([CH3:7])[CH3:6].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][N:28]([C:1]([O:2][CH2:3][CH2:4][Si:5]([CH3:6])([CH3:7])[CH3:8])=[O:17])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)C(COC(=O)[O-])N1C(=O)CCC1=O
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2,5-Dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl) carbonate (5.44 g, 20.99 mmol) was added to a mixture of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)acetate (intermediate 126, 4.70 g, 19.08 mmol) and K2CO3 (5.80 g, 42.0 mmol) in DCM (60 ml) and water (30 ml) at room temperature. The reaction mixture was vigorously stirred for 20 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and DCM, the mixture extracted with DCM (2×), the combined organic layers dried over Na2SO4 and evaporated to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.71 (d, br, 1H), 4.16-3.93 (m, 6H), 3.30-3.21 (m, 2H), 3.09-3.00 (m, 2H), 1.37 (s, 9H), 1.19 (t, 3H), 0.99-0.94 (m, 1H), 0.90-0.85 (m, 1H), 0.05 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:25]=2)=[CH:20][CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]([NH:1][C:2]3[N:3]=[CH:4][S:5][C:6]=3[C:7]([O:9][CH3:10])=[O:8])=[O:33])[CH:25]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Reactant: COC(=O)c1scnc1N
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1scnc1NC(=O)Cc1cc(-c2ccc(Cl)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.7 %

Procedure:
1.8 g (11.38 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved in 40 acetonitrile, and 1.8 ml (22.76 mmol) of pyridine were added. After 5 min of stirring at room temperature (RT), a solution of 3.18 g (11.38 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetyl chloride (obtained from (4′-chloro-4-methylbiphenyl-3-yl)acetic acid according to WO 99/48869 A1) in 20 ml of acetonitrile was added dropwise. The mixture was stirred at RT for 12 h. The precipitate formed was filtered off, washed with water and dried under reduced pressure. The resulting mother liquor was concentrated by evaporation, dissolved in chloroform and chromatographed (ethyl acetate/n-heptane: 20/80 to 80/20). This gives a total of 1.81 g of methyl 4-{[(4′-chloro-4-methylbiphenyl-3-yl)acetyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [S:1]1[C:5]2=[C:6]([C:13]([OH:15])=O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH2:16]1[CH:25]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH:17]1[CH2:26]N.C([N:32]1CCC(CNC(C2C3C(=CC=CC=3)NC=2)=O)CC1)CCC>>[CH2:16]1[CH:25]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:19][CH2:18][CH:17]1[CH2:26][CH:2]1[S:1][C:5]2=[C:6]([C:13]([NH2:32])=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3]1
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1c2n(c3ccccc13)CCS2
Reactant: NCC1CCN2CCCCC2C1
Product: NC(=O)c1c2n(c3ccccc13)CC(CC1CCN3CCCCC3C1)S2

Procedure:
2,3-Dihydrothiazolo[3,2-a]indole-9-carboxylic acid (D15) is converted to its acid chloride and reacted with eq-quinolizidin-2-ylmethylamine (D12) using a procedure analogous to that described in Description 1b.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH:25][C:26](=[O:39])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:29]=2[F:38])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21]C(=O)C)[CH:12]=[CH:11]2)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:38][C:29]1[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([NH:25][C:9]1[C:8]([NH:7][CH2:6][CH2:5][OH:4])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]([CH2:19][CH2:20][OH:21])[C:14]2=[O:18])=[O:39]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1NC(=O)Cc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Cc1cccc(C(F)(F)F)c1F)Nc1c(NCCO)ccc2c(=O)n(CCO)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with 2-(2-(2-acetoxyethyl)-5-(2-(2-fluoro-3-(trifluoromethyl)phenyl)acetamido)-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (120 mg, 0.00022 mol), potassium carbonate (45 mg, 0.00033 mol) and methanol (3 mL, 0.07 mol) and 2 drops of water was added and the reaction stirred at room temperature for 30 minutes and was filtered over sodium sulfate and the solvent removed and the residue purified by flash chromatography to get the product as white solid. MS m/z=468.4 (M+H). 1H NMR (400 MHz ) δ 9.45 (s, 1H), 7.98 (d, J=8.95 Hz, 1H), 7.79 (t, J=7.45 Hz, 1H), 7.70 (t, J=7.09 Hz, 1H), 7.40 (t, J=7.83 Hz, 1H), 7.22 (d, J=7.83 Hz, 1H), 6.91 (d, J=9.08 Hz, 1H), 6.16 (d, J=7.73 Hz, 1H), 5.64 (t, J=5.72 Hz, 1H), 4.84 (t, J=5.33 Hz, 1H), 4.76 (t, J=5.48 Hz, 1H), 3.96 (s, 2H), 3.91 (t, J=5.27 Hz, 2H), 3.62-3.53 (m, 4H), 3.27 (q, J=6.15 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#N)[CH:5]=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:3]=1.[OH-:17].[Na+].Cl.[O:20]1CCOCC1>CO.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:20])=[O:17])[CH:5]=[C:4]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:3]=1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: Cc1cc(Oc2cncnc2)cc(C#N)n1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Oc2cncnc2)cc(C(=O)O)n1
Yield: 99 %

Procedure:
6-methyl-4-(pyrimidin-5-yloxy)picolinonitrile (4.31 g, 20.3 mmol, 1.00 eq) was dissolved in dioxane (90 mL), and 2N NaOH (45 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 2N HCl (45 mL). The water and solvent were removed in vacuo and the crude reaction was dissolved in 10% MeOH/CH2Cl2. The undissolved salt was filtered off and the solvents were removed in vacuo to afford 4.65 g (99%) of the title compound as a white solid which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6](O)[N:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]1[S:4](=[C:12]=[O:13])[C:5]([O:9][CH2:10][CH3:11])=[C:6]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC1=C(O)N=C(CBr)S1=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC1=C(S(=O)(=O)c2ccc(C)cc2)N=C(CBr)S1=C=O
Yield: 70.1 %

Procedure:
2-Bromomethyl-5-ethoxy-carbonyl-4-hydroxy-thiazole (8 g, 0.03 mol) was dissolved in 80 ml of chloroform. The solution was then cooled down to 0° C. p-Toluenesulfonyl chloride (5.7 g, 0.03 mol) was added, followed by slow addition of triethylamine (3.64 g, 0.036 mol) at 0° C. The reaction was monitored by TLC and LCMS. After the reaction was done, solvent was evaporated and the crude product was then purified by column chromatography to give 8.5 g of title product (yield 67%; LC: Retention Time=2.05 min; MS: M+1=421).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C.CN(C)C=O>O1CCCC1>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)nc2nc[nH]c12
Temperature: 85 °C
Reaction time: 12 h

Procedure:
A mixture of 6-chloro-2-trifluoromethylpurine (45 mg, 0.20 mmol), dimethylamine (0.2 mL of a 2.0 M solution in tetrahydrofuran), triethylamine (60 mg, 0.6 mmol) and N,N-dimethylformamide (2 mL) was stirred at 85° C. for 12 hours. The solvent was removed under vacuum and the residue was dissolved in 25 mL of ethyl acetate, washed with 5% aqueous sodium bicarbonate (25 mL) and water (25 mL). The organic layer was concentrated and dried under vacuum to give crude 6-dimethylamino-2-trifluoromethylpurine (51 mg), which was used as such for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[CH:26][NH:25][C:24]1=O.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=CN(C2C=CC(F)=CC=2F)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:24]2[N:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])[CH:27]=[CH:26][N:25]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(F)cc1F
Agent: C[C@@H](n1ccn(-c2ccc(F)cc2F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1nccn1-c1ccc(F)cc1F)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 27.4 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.06 g of 1-(2,4-difluorophenyl)-2(1H,3H)-imidazolone, 0.53 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(2,4-difluorophenyl)-2(1H,3H)-imidazolone and 0.56 g of (2R)-2-(2,4-difluorophenyl)- 2-[(1R)-1-[1-(2,4-difluorophenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([C:9]([CH2:20][CH2:21][CH3:22])(C(OCC)=O)[C:10]([O:12]CC)=[O:11])[CH2:7][CH3:8].C(O)C>O>[C:10]([OH:12])(=[O:11])[CH:9]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(CCC)(C(=O)OCC)C(=O)OCC
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: O
Product: CCCC(CCC)C(=O)O
Reaction time: 1.5 h
Yield: 123.9 %

Procedure:
A mixture of 38.6 ml of 70% methanesulfonic acid and 352.2 g of diethyl dipropylmalonate was heated to 135°-145° C. in a flask equipped with a distillation column packed with Raschig rings. After 1.5 hour, ethanol began to reflux in the distillation head. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-145° C. by periodic addition of water to the pot. After 5 hours, additional ester (133 g) was added to the pot and the distillation of ethanol was continued. After 24 hours, the distillation of ethanol had ceased. The mixture then was cooled and treated with 50 ml of water. The layers were separated and the organic layer was washed with 100 ml of 5% sodium chloride solution to afford 257.6 g (90% yield) of valproic acid as a light brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1.S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([Cl:26])=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)O)cc1Cl
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)Cl)cc1Cl
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-chloro-2-methylthiopyrimidine 10.50 g and thionyl chloride 25 ml is stirred for 20 minutes at 75° C. After reaction thionyl chloride is distilled off and the solvent is removed by azeotrope with methylene chloride to give 4-(3-chloro-4-methoxybenzylamino)-5-chloroformyl-6-chloro-2-methylthiopyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:24][C:22]1[N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[N:21]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
38 mg (0.17 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 50 mg (0.17 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.57 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 80° C. Then another 15 mg (0.069 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one were added and the mixture was further stirred overnight at RT. The reaction mixture was diluted with water, the precipitate formed was suction filtered and dried i. vac.
Reaction SMILES: [CH2:1]([S:5]C1C=CC(Br)=CC=1)[CH2:2][CH2:3]C.[Li][CH2:14][CH2:15][CH2:16][CH3:17].CN(C=O)C.O.[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[CH2:14]([C:24]1[CH:28]=[CH:3][C:2]([CH:1]=[S:5])=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCSc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ccc(C=S)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromophenyl n-butyl sulfide (1.5 g, 6.12 mmol) in 60 ml of dry THF was added nBuLi (4.1 ml, 1.6 M in hexanes) at −78° C. under nitrogen. The mixture was stirred for 1 hour at −78° C. and then DMF (2.0 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. Then 40 ml of water was added to this mixture, the product was extracted three times by ether (3×50 ml) and the combined organic layer was dried over magnesium sulfate. After removal of solvent under reduced pressure, the product was purified by flash chromatography column using 10% of ethyl acetate in hexanes as eluant and isolated in 66.7% (0.88 g) yield.1H NMR (CDCl3, 500 MHz) δppm: 9.98 (s, 1H, CHO), 7.77 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H,), 7.11 (s, 2H), 3.02 (t, J=7.2 Hz, 2H, CH2), 1.71 (m, 2H, CH2), 1.50 (m, 2H, CH2), 0.97 (t, J=7.5 Hz, 6H, CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].[NH4+].[OH-]>OS(O)(=O)=O>[CH2:18]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([N+:25]([O-:27])=[O:26])=[C:8]([C:6]3[CH:5]=[C:4]([CH3:24])[N:3]=[C:2]([CH3:1])[CH:7]=3)[CH:17]=2)[C:12](=[O:23])[C:13]([C:20]([OH:22])=[O:21])=[CH:14]1)[CH3:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3cc(C)nc(C)c3)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cc([N+](=O)[O-])c(-c3cc(C)nc(C)c3)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 200 g. of 7-(2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 440 ml of 95-98% H2SO4 was added a solution of 80 ml of 90% HNO3 in 80 ml of 95-98% H2SO4 over a period of one hour. The resulting solution was stirred at room temperature for an additional 20 minutes, then heated on a steam bath for 8 hours. The reaction mixture was allowed to stand at room temperature overnight and then poured into 6000 ml of ice water. The precipitate was collected and slurried in approximately 2000 ml water. Concentrated NH4OH was added to reach a pH of 5.5-6.0. The solid was collected and washed with a small amount of ethanol and ether. Additional material was obtained by treating the original filtrate with NH4OH as described above. Recrystallization from dimethylformamide gave several crops totalling 135 g (59%) and melting from 274° C. to 298° C. A 2.8 g sample was recrystallized from 20 ml of dimethylformamide, washed with ether and dried at 120° C. for 16 hours at 0.02 mm to produce 1.54 g of 1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-6-nitro-4-oxo-3-quinolinecarboxylic acid, m.p. 289°-291° C.
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[CH3:23][C:5]1[NH:4][C:3](=[O:2])[N:8]([C:30](=[O:33])[CH2:31][CH3:32])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)CC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (750 mg., 2.35 mmole) and dry pyridine (0.57 ml., 7.05 mmole) in dichloromethane (5.0 ml.) at -20° (methanol/ice bath) under argon is treated dropwise via gas-tight syringe with propionyl chloride (0.26 ml., 2.82 mmole). The reaction mixture is stirred for 2.0 hours and evaporated. The solid yellow residue is dissolved in methanol (25 ml.) and tetrahydrofuran (15 ml.) and treated with 5N hydrochloric acid (6.0 ml.). After stirring at room temperature for 1.0 hour, the reaction mixture is evaporated. The residue is partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is flash chromatographed to give the title compound as a white foam (567 mg.). This foam is combined with material from another batch (290 mg.) and recrystallized from dichloromethane/isopropyl ether to give large shiny white crystals (784 mg., m. p. 152°-154°). TLC(silica gel; 50% ethyl acetate:hexanes) Rf =0.57.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][C:23]1=[O:32]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][C:23]2=[O:32])[CH2:13][CH2:12]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C1CCc2ccccc2N1CCCCBr
Product: Cl
Product: O=C1CCc2ccccc2N1CCCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
from 5-chloro-3-(piperidin-4-yl)-1H-indole and 1-(4-bromobutan-1-yl)-3,4-dihydroquinolin-2(1h)-one. Mp 229-231° C. 1H NMR (DMSO-d6): 1.55-1.65 (m, 2H); 1.70-1.80 (m, 2H); 2.00-2.15 (m, 4H); 2.55 (t, 2H); 2.85 (t, 2H); 2.95-3.15 (m, 5H); 2.55 (d, 2H); 3.95 (t, 2H); 7.00 (t, 1H); 7.05 (d, 1H); 7.15 (d, 1H); 7.20-7.30 (m, 3H); 7.40 (d, 1H); 7.75 (s, 1H); 10.05 (broad s, 1H); 11.10 (s, 1H). MS m/z: 436 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:14])[C:6]([Cl:13])=[CH:7][C:8]=2[Cl:12])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]([Cl:13])[C:5]([OH:14])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[N:3]2
Reactant: CN
Reactant: Oc1c(Cl)cc(Cl)c2ccc(Cl)nc12
Solvent: CCO
Product: CNc1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
2,5,7-Trichloro-8-hydroxyquinoline 10 (200 mg, 0.805 mmol) and a solution of methylamine in ethanol (12 mL of a 33% solution) were heated in a sealed vessel at 90° C. for 26 h, and cooled. The precipitate was then isolated via filtration and washed with diethyl ether. This provided pure 5,7-dichloro-2-methylamino-8-hydroxyquinoline (PBT 1047) as a pale yellow solid (186 mg, 95%). 1H NMR (DMSO-d6, 400 MHz): δ 8.80 (br, 1 H), 7.98 (d, J=9.1, 1 H), 7.48 (br, 1 H), 7.25 (s, 1 H), 6.90 (d, J=9.1, 1H), 2.98 (d, J=4.8, 3 H); mass spectrum: m/z 243, 245 (M++1, 100 and 66%, respectively).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=O)[NH:3][C:2]1=O.CO.[ClH:16]>C(OCC)C>[ClH:16].[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][NH:3][CH2:4]1
Reactant: O=C1Cc2ccccc2CC(=O)N1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc2c(c1)CCNCC2
Temperature: 25 °C
Yield: 78 %

Procedure:
To a suspension of 1,5-dihydro-benzo[d]azepine-2,4-dione (9.3 g) in toluene (250 ml) borane-methylsulfide complex (20 ml) was added dropwise under nitrogen atmosphere, then the mixture was heated at reflux for 4 h. MeOH (20 ml) was added dropwise and the mixture refluxed for additional 1 h, then cooled to room temperature. A 10% solution of anidrous HCl in ethyl ether (50 ml) was added and the solid precipitate was filtered off, washed with ethyl ether and desiccated under reduced pressure to afford the title compound as a white solid (7.6 g, 78% yield).
Reaction SMILES: [CH:1](Cl)(Cl)[C:2]([F:8])([F:7])[C:3]([F:6])([F:5])[F:4].FC(F)(C(F)(F)F)CO.[Cl-].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:7][C:2]([F:8])([C:3]([F:6])([F:5])[F:4])[CH2:1][O:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: FC(F)(F)C(F)(F)C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: OCC(F)(F)C(F)(F)F
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1

Procedure:
Until HCFC-225ca becomes available in commercial quantities, HCFC-225ca may be prepared by a standard and well-known organic synthesis technique. For example, to prepare 1,1-dichloro-2,2,3,3,3-pentafluoropropane, 2,2,3,3,3-pentafluoro-1-propanol and p-toluenesulfonate chloride are reacted together to form 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,3-pentafluoropropyl-p-toluenesulfonate are reacted together to form 1-chloro-2,2,3,3,3-pentafluoropropane. Chlorine and the 1-chloro-2,2,3,3,3-pentafluoropropane are then reacted together to form 1,1-dichloro-2,2,3,3,3-pentafluoropropane. A detailed synthesis is set forth below.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1)=[O:7])C.O[Li].O>CO.O>[C:14]1([C:11]2[N:10]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:20])=[O:3])[S:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)Nc1nc(-c2ccccc2)ns1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CC(=O)Nc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a stirred solution of 3-phenyl-[1,2,4]thiadiazol-5-ylamine (0.25 g, 0.00141 mol) in chloroform (2.5 mL) was added mono ethylmalonylchloride (0.233 g, 0.00155 mol) dropwise, the resulting mixture was stirred for 3 hours. The mixture was then concentrated and the residue was stirred in ethyl acetate. The filtrate was removed and concentrated to afford 0.26 g (63%) of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid ethyl ester. LC-MS purity: 292.07 (M+1)+, 67%. To a solution of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid ethyl ester (0.26 g, 0.00089 mol) in a mixture of methanol (3 mL) and H2O (1 mL) was added LiOH.H2O (0.112 g, 0.00267 mol). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The resulting residue was diluted with cold water, acidified with 2NHCl and the product was extracted with ethyl acetate. The ethyl acetate layer washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.105 g (45%) of N-(3-phenyl-[1,2,4]thiadiazol-5-yl)-malonamic acid. LCMS: 264.27 (M+1)+: 97.64%.