Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:22][C:23](O)=[O:24])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:26][C:27]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:23](=[O:24])[CH2:22][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][C:11]1=2
Reactant: Cc1cccc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4ccccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetic acid (3.38 mmol) was dissolved in THF (20 mL) and 2,3-dimethylaniline (0.43 mL, 0.43 g, 3.6 mmol, 1.05 equiv.), dimethylaminopyridine (0.415 g, 3.40 mmol, 1.01 equiv.), and diisopropylcarbodiimide (0.60 mL, 0.48 g, 3.8 mmol, 1.13 equiv.) were added. The reaction mixture was stirred at rt under N2 for 18 h. The reaction mixture was taken up in EtOAc (100 mL) and this solution was washed with 10% aqueous citric acid (2×50 mL), 5% aqueous NaHCO3 (2×50 mL), and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (1.7223 g) was chromatographed (SiO2 187 g, eluted with 10:1 toluene:acetone followed by 9:1 toluene:acetone) to give tert-butyl 6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.1066 g) in 67% yield. 1H NMR (300 MHz, CD3OD) δ 1.50, 2.01-2.03, 2.27, 2.29-3.12, 3.66-3.75, 3.75-3.83, 5.03, 7.04-7.19, 7.37, 7.49; MS (ESI+) for C27H33N3O3 m/z 448.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH:14]2[CH2:15][CH:11]([CH:12]=[CH:13]2)[C:10]1([CH2:19][CH2:20][C:21]([O:23]C)=O)[N+:16]([O-])=O>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:10]2([CH2:19][CH2:20][C:21](=[O:23])[NH:16]2)[CH:11]2[CH2:15][CH:14]1[CH2:13][CH2:12]2
Reactant: COC(=O)CCC1([N+](=O)[O-])C2C=CC(C2)C1c1ccccc1OC
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1C1C2CCC(C2)C12CCC(=O)N2
Reaction time: 24 h

Procedure:
0.2 mole of methyl β-[3-(2-methoxyphenyl)-2-nitrobicyclo[2.2.1]-hept-5-en-2-yl]-propionate is dissolved in 800 ml of ethanol and, after adding 2 spatulas of Raney nickel, is hydrogenated at 50° C. and under 70 bars for 24 hours. The catalyst is filtered off, the solvent is evaporated off in a rotary evaporator and the residue is recrystallized from isopropanol. Colorless crystals of melting point 260° C.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1.N([O:12][C:13](C)(C)[CH3:14])=O.ON1C(=O)C2=CC=CC=C2C1=O.CC1C=C(C=C(C)C=1)C=NO.[CH3:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([CH3:49])[CH:48]=1)[CH:44]=[O:45].CC1C=C(C=C(C)C=1)C#N>C(O)(=O)C>[C:13]([O:45][CH2:44][C:43]1[CH:46]=[C:47]([CH3:49])[CH:48]=[C:41]([CH3:40])[CH:42]=1)(=[O:12])[CH3:14]
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: CC(C)(C)ON=O
Agent: Cc1cc(C)cc(C#N)c1
Agent: Cc1cc(C)cc(C=NO)c1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: Cc1cc(C)cc(C)c1
Product: CC(=O)OCc1cc(C)cc(C)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Mesitylene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 60° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that 3,5-dimethylbenzaldehyde oxime, 3,5-dimethylbenzaldehyde, 3,5-dimethylbenzonitrile, and 3,5-dimethylphenylmethyl acetate were formed in yields of 61%, 3%, 4%, and less than 1%, respectively.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1([Si](C)(C)C)[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[O:22][CH2:21]1>O1CCCC1>[Br:19][C:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[O:22][CH:21]=1
Reactant: C[Si](C)(C)C1(Br)C=C(c2ccccn2)OC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1coc(-c2ccccn2)c1
Temperature: 70 °C
Yield: 80.5 %

Procedure:
Tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 25.1 mL, 25.11 mmol) was added to a solution of 3-bromo-5-(2-pyridyl)-3-(trimethylsilyl)furan (4.96 g, 16.74 mmol) in tetrahydrofuran (50 mL). The reaction mixture was heated at 70° C. (bath temperature) for six hours. The reaction mixture was evaporated, and the residue was purified by flash chromatography using hexane as the eluant to give the sub-title compound as a pale brown solid (3.02 g), m/z 224, 226 (MH+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.501 g (5.0 mmol) of 1-hexanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.77 g (87.7%, yellow oily substance) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[C:14]([Cl:20])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[K+].Cl>C(O)C>[Cl:20][C:14]1[CH:13]=[C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:4]([OH:21])=[O:3])[CH:17]=[CH:16][C:15]=1[S:18][CH3:19]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (0.45 g, 1.39 mmol) in ethanol (3 mL) was treated with a 10% aqueous potassium hydroxide solution (2 mL). The reaction mixture was stirred under nitrogen at 25° C. for 16 h. The reaction mixture was then acidified with a 1N aqueous hydrochloric acid solution (5 mL). The reaction mixture was then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29 g, 70%) as a white solid: EI-HRMS m/e calcd for C15H19ClO2S (M+) 298.0794, found 298.0798.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(CC(C)C)c1ccc(O)c(Br)c1
Solvent: CC(=O)O
Product: CC(C)CC(C(=O)O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate (16 g) was taken in acetic acid (100 ml) and to it added drop wise 70% nitric acid (10 ml) below 15° C. The reaction mixture was stirred for 2 h. After completion of the reaction; it was poured into 300 ml of ice water and extracted with ethyl acetate (300 ml×3). The ethyl acetate layer was washed with bicarbonate solution, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (2:3) as eluent provided 12 g of 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoic acid. The acid was taken in 50 ml of absolute ethanol and 2 ml of concentrated sulfuric acid and refluxed for 1 h. The ethanol layer was distilled off, washed it with water and dried gave 13 g of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate intermediate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.90 (bs,1H),4.15 (q, 2H), 3.60 (t, 1H),1.95-2.00(m,1H), 1.75-1.80(m,1H), 1.45-1.50(m,1H), 1.20(t,3H), 1.00 (m,6H). Mass: (360, M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.OS(O)(=O)=O.[CH3:34][C:35]([CH3:37])=O.[OH-].[NH4+]>C(O)(=O)C.O>[CH2:17]([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[CH:34][C:35]([CH3:37])=[N:1]2)=[CH:4][CH:5]=1)[CH3:16])[CH:18]=[CH2:19]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)cc(C)nc2c1
Temperature: 0 °C

Procedure:
A solution of 360 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone in 1.6 ml of acetic acid is treated with 0.01 ml of H2SO4 and 0.4 ml of acetone and boiled at 95° C. for 21 hrs., with a further 0.4 ml of acetone being added after 6 hrs. At 0° C. the reaction is poured into an ice-cold solution of 1.2 ml of 25% ammonium hydroxide solution in 3.5 ml of water and the mixture is subsequently extracted with methylene chloride. After drying the organic phase is evaporated and the residue is purified over silica gel with methylene chloride/methanol (95:5). The title compound obtained (200 mg) is crystallized with 24.6 mg of fumaric acid from methylene chloride/methanol/ether. There are obtained 56 mg of allyl-[6-[4-(4-bromo-phenyl)-2-methyl-quinolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:2), m.p. 88°-93° C., MS: m/e 467 (M+H+, 1 Br).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11](ON1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=[O:12])[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)(=[O:45])[OH:46])=[O:12])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:39])[CH3:1]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: NCCCP(=O)(O)CC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(=O)(O)CC1CCCCC1)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added compound (25) (100 mmol), 3-aminopropyl(cyclohexylmethyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the product (99) as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].[Cl-].[NH4+].C(OCC)C>O1CCCC1>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([C:15]3[C:14]([C:13]([F:23])([F:22])[F:12])=[CH:21][CH:20]=[CH:19][C:16]=3[CH2:17][OH:18])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: BrC1CCC2(CC1)OCCO2
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc(C(F)(F)F)c1C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 6, using 22.1 grams (0.09 mole) of the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane and 17.4 grams (0.10 mole) of 3-trifluoromethylbenzaldehyde in tetrahydrofuran. Upon completion of the reaction, the reaction mixture is poured into a mixture of 100 grams of ice, 100 mL of an aqueous solution saturated with ammonium chloride, and 200 mL of diethyl ether. This mixture is filtered and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding [(1,4-dioxaspiro[4.5]decan-8-yl) (3-trifluoromethylphenyl)]methanol. Step D Synthesis of phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether as an intermediate
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(N2CCN(C)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) in CH2Cl2 (5 mL) was treated with a 37% aqueous formaldehyde solution (16.4 uL, 0.22 mmol) and stirred for 5 min after which time solid sodium triacetoxyborohydride (64 mg, 0.3 mmol) was added. The suspension was then stirred for 3 hr then quenched with a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 5% MeOH/CH2Cl2 as eluant to afford product as a burgundy oil (69 mg, 91%). 1H NMR (CDCl3) 1.54-1.61 (m, 2H), 1.77-1.85 (m, 6H), 2.57 (s, 3H), 2.60-2.67 (m, 3H), 3.02-3.13 (m, 3H), 3.22-3.32 (m, 2H), 3.76 (s, 3H), 4.59-4.62 (m, 1H), 3.76 (s, 3H), 4.59-4.62 (M, 1H), 6.30 (dd, J=8.6, 2.9, 1H), 6.35 (d, J=8.6, 1H), 7.20-7.33 (m, 5H). 13C NMR 24.2 (CH2), 33.0 (CH2), 36.3 (CH2), 42.9 (CH3), 50.2 (CH2), 55.0 (CH2), 55.1 (CH2), 56.8 (CH3), 63.7 (CH), 80.4 (CH), 106.2 (CH), 107.8 (CH), 113.2 (CH), 126.4 (CH) 128.6, 129.5 (CH), 139.0 (CH), 144.5, 146.1, 148.4. LC/MS 5.10 min, [M+1]+ 381.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To 2-methyl-4-nitrobenzoic acid (10.5 g, 58.0 mmol) in CH2Cl2 (80 ml) was added 2.0 M oxalyl chloride in methylene chloride (39.9 ml, 80 mmol), followed by DMF (0.224 ml, 2.90 mmol). The mixture was stirred at 40° C. for 1.5 h and then at rt for 0.5 h. Solvent was removed and the residue was put on high vacuum for 0.5 h. The acyl chloride prepared was then dissolved in methylene chloride (40 mL) and cooled at 0° C., MeOH (40 mL) was added and the mixture was stirred at 0° C. for 0.5 h. Solvent was removed, the crude was diluted with EtOAc, washed with sat. sodium bicarbonate, brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (11.35 g, 58.2 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.98-8.11 (m, 3H) 3.93 (s, 3H) 2.67 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Cl)[C:11]=1O)[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.[OH-].[Li+].Cl>CO.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(O)c(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
A solution of the ester from Step 2 (0.20 g, 0.56 mmole) was dissolved in 3 mL mixture of MeOH/ACN/H2O=1/1/1, treated with lithium hydroxide (81 mg, 3.36 mmole) and stirred at room temperature for 2 days. The reaction mixture was acidified with 1.0 N HCl to pH=1 and was extracted with EtOAc. The organic layer was washed with water,dried over anhydrous MgSO4, and filtered. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.11 g, 60%): ESHRMS m/z 326.9438 (M−H, C11H4O4F3Cl2, Calc'd 326.9433). 1H NMR (acetone-d6/400 MHz) 7.82 (s, 1H), 7.46(s, 1H), 6.00 (q, 1H, J=7.0 Hz).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([OH:10])=[N:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1>COCCOC>[CH2:14]([O:13][C:11]([C:6]1[N:7]=[C:8]([OH:10])[S:9][C:5]=1[C:3]1[N:16]=[C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:12])[CH3:15]
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1nc(O)sc1C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)c1nc(O)sc1-c1cn2cccc(C)c2n1
Yield: 58 %

Procedure:
A solution of ethyl 5-(2-bromoacetyl)-2-hydroxy-4-thiazolecarboxylate (2.94 g) and 2-amino-3-methylpyridine (3.24 g) in 1,2-dimethoxyethane (100 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water, and the resulting mixture was acidified to pH 0.8 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated and diethyl ether and recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 2-(4-ethoxycarbonyl-2-hydroxy-5-thiazolyl)-8-methylimidazo[1,2-a]pyridine (1.76 g). mp 240°-242° C. (dec.)
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]([O:8][C:9](=[O:22])[N:10]([C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:11])([CH3:7])([CH3:6])[CH3:5].CN(C=O)C>O1CCCC1>[C:4]([O:8][C:9](=[O:22])[N:10]([C:12]1[CH:17]=[C:16]([S:2][CH3:1])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[S-]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a suspension of sodium thiomethoxide (1.47 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise a solution of N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (6.0 g) in anhydrous tetrahydrofuran (120 ml) while cooling at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. At the end of this time anhydrous DMF (30 ml) was added and the resulting mixture stirred at room temperature for 1 hour. DMF (20 ml) was added and then sodium thiomethoxide (0.73 g) and further DMF (50 ml) were added. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to afford the desired compound (6.15 g).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][C@H:14]1[C@@H:18]([C:19]([F:22])([F:21])[F:20])[CH2:17][C:16](=N)[NH:15]1)CC1OC=C(C(O)=O)N=1.Cl.C[OH:26]>>[O:26]=[C:16]1[NH:15][CH:14]([CH2:13][CH:3]=[O:2])[CH:18]([C:19]([F:22])([F:21])[F:20])[CH2:17]1
Reactant: N=C1C[C@H](C(F)(F)F)[C@H](CC(O)Cc2nc(C(=O)O)co2)N1
Reactant: CO
Agent: Cl
Product: O=CCC1NC(=O)CC1C(F)(F)F

Procedure:
Isomer B: (±) (cis) 2-[2-hydroxy-3-[5-imino-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylic acid, monohydrochloride ##STR229## 224 A) The product of Example 223 B in MeOH is treated with HCl (1N) to yield 5-oxo-3-(trifluoromethyl)pyrrolidine-2-acetaldehyde which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH:23](=O)[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:23][C:24]4[O:28][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccco1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccco4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of furfural to form 4-(3-chloro-phenylamino)-3-[(fur-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]-pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino-3-[(fur-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100) 8.4; MS (M)+=340.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[SH:10].[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15](O)=O>C(Cl)Cl.CO>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:14]=1[C:15]1[S:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(N)c(S)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3OC)sc2c1
Temperature: 150 °C
Yield: 84.2 %

Procedure:
A thoroughly mixed paste of 2-amino-5-methoxybenzenethiol (2.0 g, 12.88 mmol) and 2-methoxy-4-nitrobenzoic acid (2.54 g, 12.88 mmol) in trimethylsilylpolyphosphate (10 ml) was stirred and heated at 150° C. under an atmosphere of argon for 30 min. On cooling to room temperature, the reaction mixture was suspended in DCM/MeOH and an orange solid was collected by filtration. The filtrate was washed with 1 M HCl (2×50 ml), sat. NaHCO3 (2×50 ml), brine (70 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was combined with that collected and recrystallised from AcOH to give the title compound (3.43 g, 83%) as a yellow solid.