Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CO.O>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CCOCC1
Solvent: O
Solvent: CO
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CCOCC1
Yield: 70 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (60 mg, 70%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=429.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O.[Na]>C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Agent: [Na]
Solvent: c1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCCl)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-Acetoxychol-5-enic acid (4.16 g; 10 mmoles) was added to 60 ml of anhydrous benzene. The solution was cooled with ice, and with stirring, 4.5 ml of thionyl chloride was gradually added dropwise. After the addition, the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and to the resulting residue was added 20 ml of anhydrous benzene which had been obtained by dehydrating benzene with sodium. The mixture was repeatedly concentrated under reduced pressure to remove the thionyl chloride contained in the residue. The resulting crude solid product, 3β-acetoxychol-5-enyl chloride, was used as a starting compound in the subsequent step without purification.
Reaction SMILES: C[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)(C)C.C(C1C=CC(CCl)=CC=1)=C.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1N1CCNCC1.CO>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:2][N:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[CH:27][CH2:28]2)=[CH:10][CH:9]=1)=[CH2:12]
Reactant: C=Cc1ccc(C(C)(C)C)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: C=Cc1ccc(CCl)cc1
Agent: Cl
Agent: c1ccc(N2CCNCC2)nc1
Solvent: CO
Product: C=Cc1ccc(CN2C=CC(N3CCNCC3)=CC2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Dye-labeled poly(4-tert-butylstyrene)-supported pyridylpiperazine catalyst for the acylation of phenols. 4-Vinylbenzylchloride was passed through neutral alumina to remove any inhibitors. 1-(4-Vinylbenzyl)-4-pyridylpiperazine was prepared by dissolving 4.32 mL of 4-vinylbenzylchloride and 10 g of N-(4-pyridyl)piperazine in 100 mL of methanol. The solution was allowed to reflux overnight. After cooling to room temperature, 20 mL of 6 N HCl was added and the solution was extracted three times with ether. The ether extracts were discarded and 20 g of NaOH in 20 mL of water was added dropwise to the aqueous solution. The resulting precipitate was recovered by filtration and purified by column chromatography using 5% triethylamine in ethyl acetate as the eluent. Removal of the solvent under reduced pressure produced the product in 72.1% yield. 1H NMR: δ 8.2 (d, 6.6 Hz, 2H), 7.3 (dd, J=6.4, 6.6 Hz, 4H), 6.7 (dd, J=10.7, 17.6 Hz, 1H), 6.6 (d, 6.4 Hz, 2H), 5.7 (d, 17.6 Hz, 1H), 5.2 (d, 10.7 Hz, 1H), 3.5 (s, 1H), 3.3 (t, 5.2 Hz, 4H), 2.5 (t, 5.1 Hz, 4H). 13C NMR: δ 155.2, 150.4, 137.6, 136.9, 136.7, 130.0, 126.4, 113.9, 108.5, 62.9, 52.7, 46.1.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[OH:17][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])[CH2:19][NH2:20].O>C1C=CC=CC=1>[OH:3][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:20][CH2:19][CH:18]([OH:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1F
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1ccccc1F
Reaction time: 2 h

Procedure:
A mixture of 1-(4-carbomethoxymethoxyphenyl)propan-2-one (2.22 g) and 2-hydroxy-2-(2-fluorophenyl)ethanamine (1.55 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water using a Dean and Stark trap, for 2 hours. The solution was cooled, evaporated to dryness, the residue dissolved in methanol and sodium borohydride (500 mg) added. After 30 minutes, the methanol was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was dried (magnesium sulphate) and evaporated to leave an oil which was chromatographed on silica gel 60 eluting with 2% methanol/chloroform. N-[2-(4-(2-hydroxyethoxy)phenyl-1-methylethyl]-2-hydroxy-2-(2-fluorophenyl)ethanamine (300 mg) crystallised from hexane, m.p. 80°-95°, as a 55:45 mixture of diastereoisomers.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].[CH3:20][CH:21]([CH3:36])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)=[O:23].O>O1CCCC1>[CH3:19][O:18][C:8]1[C:9]([CH3:17])=[C:10]([CH3:16])[C:11]([O:14][CH3:15])=[C:12]([CH3:13])[C:7]=1[C:22]([C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:28][CH:29]=1)([OH:23])[CH:21]([CH3:36])[CH3:20]
Reactant: CC(C)C(=O)c1ccc(N2CCOCC2)cc1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(N3CCOCC3)cc2)C(C)C)c1C
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
n-Butyllithium (1.6 M, 18.1 mL, 29.0 mmol) was added to a solution of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene (7.52 g, 29.0 mmol) in tetrahydrofuran (50 mL) at −78° C., and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 2-methyl-1-[4-(4-morpholinyl)phenyl] propan-1-one (6.15 g, 26.4 mmol), and the mixture was stirred for 30 minutes at room temperature. Water (40 mL) was poured into the reaction mixture, which was then extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain the title compound (8.40 g, yield 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[NH:19]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[Cu]Br>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[C:18]([C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[O:23])[N:19]2[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Br)cc1OC
Reactant: O=C(c1cc2ccc(Cl)cc2[nH]1)N1CCOCC1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-n2c(C(=O)N3CCOCC3)cc3ccc(Cl)cc32)cc1OC
Temperature: 140 °C
Reaction time: 14 h

Procedure:
4-Bromoveratrole (5.7 g, 26 mmol), 6-chloroindole-2-carboxylic acid morpholide (1.7 g, 6.5 mmol), potassium carbonate (1.7 g), copper(I) bromide (0.2 g) in a mixture of pyridine (2 ml) and nitrobenzene was stirred at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture was applied onto a flash chromatography column (silica gel, 140 g), Elution with toluene, toluene/acetone [9:1] and toluene/acetone [8:2] (500 ml each) gave 6-chloro-1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid morpholide as brown oil. Yield: 2.1 g (81% of theoretical) Rf : 0.54 (toluene/acetone, 7:3). The H-NMR spectra was consistent with the assigned structure.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.C(#N)C>[C:20]([C:16]1[O:15][C:19]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:22]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)c1ccco1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Reaction time: 0.75 h
Yield: 18 %

Procedure:
A mixture of 50 g (0.42 mole) of p-aminobenzonitrile, 146 ml of concentrated hydrochloric acid, and 106 ml of H2O was heated at 80° for for 20 minutes and then cooled to 0°. A solution of 29 g (0.42 mole) of sodium nitrite in 105 ml of H2O was added dropwise while maintaining the temperature at 0°-5° by means of an ice bath. The reaction was kept at 0° for 45 minutes. A solution of 47 g (0.42 mole) of methyl 2-furyl ketone in 43 ml of acetonitrile was added followed by a solution of 10 g of CuCl2 .2H2O in 50 ml of water. The reaction became exothermic and was controlled below 40°. The reaction was allowed to stand overnight. The aqueous layer was decanted and the residual semisolid was extracted with 6000 ml of refluxing hexane. The hexane was cooled and the resulting precipitate was filtered and air dried to yield 16 g (18%) of p-(5-acetyl-2-furyl)benzonitrile. An analytical sample was prepared by recrystallizing a sample from hexane/charcoal, m.p. 115°-116°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[O:23][CH3:24].[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:36][C:34]2[CH:33]=[CH:32][C:29]3[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=3[N:35]=2)[C@H:3]([O:23][CH3:24])[CH2:4]1
Reactant: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1NCc1ccc2c(n1)NC(=O)CO2
Yield: 57.2 %

Procedure:
Cis(±)1-[2-(4-amino-3-methoxypiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 167, 140 mg, 0.42 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride (250 mg, 1.20 mmol) were reacted as described according to Example 69. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.50% ammonium hydroxide gave 120 mg (57%) of the free base of the product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](OC(=O)C)(=[O:15])[CH3:14].Cl>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
An amount of 4-hydroxybenzoic acid (92.1 grams (g), 0.67 mole) was dissolved in a solution of sodium hydroxide (NaOH) (53.4 g, 1.33 moles) and 1.33 liters (L) of water in a 4 L beaker. The solution was stirred and cooled to a temperature of 0° C. by adding crushed ice, then acetic anhydride (102.1 g, 1.00 mole) was added. The temperature was maintained at -2° C. for 1 hour by adding one kilogram (Kg) of crushed ice. A solution of concentrated hydrochloric acid (HCl) (144.7 g, 1.42 moles) in 267 milliliters (ml) of water was added. The slurry was stirred briefly and filtered. The product was washed twice by stirring it with 2 L portions of fresh water then filtered and dried in a vacuum oven at 80° C. for 16 hours. After recrystallization from methyl isobutyl ketone, the product consisted of 111 g of white crystals with a melting point (m.p.) of 192.0° C. to 192.5° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H]3CCN(CCC)C3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH3:30][O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36](C2C=CC=C(N)C=2)[CH2:35]1)=[O:33].FC(F)(F)OC1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:30][O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:28])([F:1])[F:29])[CH:5]=3)(=[O:11])=[O:12])[CH:15]=2)[CH2:35]1)=[O:33]
Reactant: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)cc2)C1
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Agent: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)C1

Procedure:
This compound was obtained following the same synthetic procedure as described for 3-trifluoromethoxy-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide by reacting 1-(Methoxycarbonyl)-3-(3-aminophenyl)-pyrrolidine as obtained in example b.1 with commercially available 3-trifluoromethoxy-benzenesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>CN(C=O)C>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.8 %

Procedure:
To a solution of 5-hydroxyindole (7.45 g) in 100 ml of DMF was added K2CO3 (10.4 g). This mixture was stirred for 10 minutes at room temperature and then a solution of 4-chloro-3-nitropyridine (11.89 g) in 50 ml DMF was added dropwise. The reaction was allowed to proceed for 24 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution and dried over MgSO4. After filtration, the solvent was evaporated to yield an oil (15.4 g). This material was eluted with 5% ethyl acetate/DCM on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid, 1.35 g, m.p. 182°-184° C.
Reaction SMILES: [CH3:1][C:2](=O)[C:3](=[N:7]O)[C:4](=[O:6])[CH3:5].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1>C(#N)C>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:18][C:2]([CH3:1])=[C:3]([C:4](=[O:6])[CH3:5])[N:7]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: NCc1ccc(Cl)nc1
Solvent: CC#N
Product: CC(=O)c1nc(-c2ccc(Cl)nc2)[nH]c1C
Temperature: -10 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
A mixture of 4.5 g (0.035 mole) of 2,3,4-pentanetrione 3-oxime and 5.3 g (0.037 mole) of 6-chloro-3-pyridylmethylamine in 100 ml of acetonitrile was stirred at the reflux temperature for 18 hours. The reacted mixture was cooled at -10° C. with formation of a precipitate. The precipitate was washed, dried and recrystallized as for Example 24 to give 2.6 g of the desired product as a pale yellow solid, mp 239°-240° C.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].[C:7](=O)([O-:9])[O-:8].[Na+].[Na+].S(=O)=O>>[S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+:5].[C:7](=[O:9])=[O:8]
Reactant: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: O=S=O
Agent: [Na+]
Product: O=C=O

Procedure:
In a brief overview, sodium sulfite may be manufactured commercially by preparing a sodium sulfite liquor by the reaction of sodium carbonate with sulfur dioxide in a reactor. The reaction produces sodium sulfite with carbon dioxide (CO2) as a by-product. The reactor liquor is then fed to a crystallization system, which includes a crystallizer and a crystallizer heater in a heater circulation loop connected to the crystallizer. The liquor is moved by the help of a circulating pump in the heater circulation.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[NH:8][C:9](=[O:16])[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:5]=[N:4]1)[CH3:2].[H][H]>[Rh].C(O)C>[CH2:1]([N:3]1[C:7]2[NH:8][C:9](=[O:16])[CH2:10][CH:11]([C:12]([F:13])([F:15])[F:14])[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(C(F)(F)F)cc(=O)[nH]c21
Reactant: [H][H]
Agent: [Rh]
Solvent: CCO
Product: CCn1ncc2c1NC(=O)CC2C(F)(F)F

Procedure:
16.2 G. of 1-ethyl-1,7-dihydro-4-(trifluoromethyl)-6H-pyrazolo[3,4-b]pyridin-6-one, dissolved in 250 ml. of absolute ethanol, are catalytically hydrogenated by means of rhodium on charcoal catalyst (5%) at a temperature of 90°-100°. The reaction is performed in an autoclave at a hydrogen pressure of 10 atm. for 14 hours. After cooling, the catalyst is filtered off and the solution evaporated to dryness. The residual 1-ethyl-1,4,5,7-tetrahydro-4-(trifluoromethyl)-6H-pyrazolo[3,4-b]pyridin-6-one is treated with hot hexane providing 13.3 g. (81.5%) of the compound, m.p. 129°-130°. Recrystallization from a mixture of benzene/petroleum ether (1:2) raises the melting point at 130°-132°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)[N:5]=2.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:27]1([C:30]([NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([F:26])=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)[N:5]=3)=[O:31])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)ccc1F
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}carbamate (1.13 g, 3.0 mmol) and N,N-dimethylpyridin-4-amine (1.22 g, 10 mmol) in pyridine (10 mL) was added dropwise cyclopropanecarbonyl chloride (1.05 g, 10 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (0.78 g, 59%) as a pale-yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:14][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (413 mg, 2.85 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (171 mg of 60% dispersion in oil, 4.27 mmol). The mixture was stirred for 40 min at room temperature. Methyl iodide (0.36 mL, 5.78 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (25 mL) and the mixture was extracted with ethyl acetate (3×25 mL). Combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. Purification by column chromatography (silica gel, CH2Cl2) gave 1-methyl-1H-indole-4-carbaldehyde (452 mg g, 99%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.38-7.34 (m, 1H), 7.08 (d, J=3.2 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 10.99 (s, 1H), 8.95-8.94 (m, 1H), 8.36-8.33 (m, 1H), 8.02-7.99 (m, 1H), 7.80-7.69 (m, 3H), 7.48-7.42 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].CS(C)=O.C[C:21](C)([O-:23])C.[K+]>CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:23][CH3:21])[C:3]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15]
Reactant: O=C1NC(=O)C(c2c(F)cccc2F)O1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cccc(F)c1C1OC(=O)NC1=O
Temperature: 155 °C

Procedure:
5-(2,6-Difluorophenyl)oxazolidine-2,4-dione (2.0 g., 9.4 mmoles) was dissolved in 50 ml. of dimethylsulfoxide. Methanol (5 ml.) and then potassium tert-butoxide (2.11 g., 18.8 mmoles) were then added and the reaction mixture heated in an oil bath maintained at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 200 ml. of 1 N hydrochloric acid and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. The solids were taken up in 1 N sodium hydroxide, and the solution washed with three portions of ethyl acetate and then acidified with 1 N hydrochloric acid to precipitate purified 5-(2-fluoro-6-methoxyphenyl)oxazolidine-2,4-dione (1.32 g., 62%; m.p. 138°-142° C.). For analysis, the product was recrystallized from toluene (930 mg. recovered; m.p. 139°-141° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:28][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCCc1ccccc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCc1ccccc1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with phenethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).