Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].Cl>O.CO>[CH3:3][C:4]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][C:5]1=[CH:19][C:17](=[O:18])[CH2:15][CH2:16]2
Reactant: C=CC(C)=O
Reactant: CC1C(=O)CCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC12CCC(=O)C=C1CCc1ccccc12
Temperature: -15 °C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
Potassium hydroxide in the amount of 2.25 g (40 mmol) was dissolved in 4.5 g of water in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 4.8 g (30 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution. The reaction vessel was cooled to -15° C., then, 2.1 g (30 mmol) of methyl vinyl ketone was added dropwisely to the reaction vessel and 2 ml of methanol was further added thereto. The resulted mixture was agitated under cooling with ice for 1 hour and then at room temperature for 6 hours in a stream of nitrogen-gas. Then, the mixture had been allowed to react at 70° C. for 6 hours. The reaction mixture was then poured into iced water, made acidic with hydrochloric acid and extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 5.75 g of oily yellowish orange residue. A part of this residue was crystallized and resulted crystals were recrystallized twice from cyclohexane to obtain 2.8 g of colorless plate-like crystals. The oily portion was further allowed to crystallize to obtain 1.9 g of crystals. The total yield was 4.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([O:16]CC)=[O:15])=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2([CH3:23])[C:14]([OH:16])=[O:15])=[N:4][CH:3]=1
Reactant: CCCCCC
Reactant: CCOC(=O)C1CCCCN1c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CCCCN1c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
To an ice-cold solution of ethyl 1-(5-bromopyrimidin-2-yl)piperidine-2-carboxylate (0.37 g, 1.18 mmol) in THF (25 mL) was added NaH (60% dispersion in mineral oil, 0.06 g, 1.41 mmol) portion wise. The mixture was stirred at the same temperature for 45 min followed by addition of MeI (0.52 mL, 8.26 mmol) at 0° C. The temperature of the reaction was slowly raised up to rt and left to stir for 16 h. The reaction was then cooled to 0° C., quenched by drop wise addition of ice-cold water then extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 2% EtOAc: hexane to obtain the desired product as off-white solid (0.115 g, 32% yield). MS: 300.09 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27](O)[CH2:28][OH:29]>C1(C)C=CC=CC=1>[CH2:9]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:29][CH2:28][CH2:27][O:15]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCO
Reactant: CCCCCCC(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(c2ccc(C)cc2)OCCO1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 1-(4-methylphenyl)-1-heptanone (200 mg, 0.980 mmol), p-toluenesulfonic acid (17 mg, 0.098 mmol) and ethylene glycol (0.16 mL, 2.9 mmol) in dry toluene (10 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium carbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with dichloromethane/hexane (1:2) afforded 2-hexyl-2-(4-methylphenyl)-1,3-dioxolane (19) as a tan-coloured oil (162 mg, 67%). 1H nmr (200 Mz, CDCl3) 0.80-0.92 (m, 3H, CH2CH3), 1.18-1.40 [m, 8H, (CH2)4], 1.84-1.89 (m, 2H, CCH2), 2.34 (s, 3H, ArCH3), 3.73-3.81 (m, 2H, OCH2), 3.94-4.02 (m, 2H, OCH2), 7.13 (d, J=8.2 Hz, 2H, 2×ArH), 7.32 (d, J=8.2 Hz, 2H, 2×ArH).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO.O>[NH2:2][C:3]1[C:4]([Cl:24])=[CH:5][C:6]2[C:7](=[O:23])[N:8]([CH:17]3[CH2:18][CH2:19][N:20]([CH2:25][CH3:26])[CH2:21][CH2:22]3)[C:9](=[O:16])[C:10]3[C:15]=2[C:14]=1[CH:13]=[CH:12][CH:11]=3
Reactant: Nc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCNCC1)C2=O
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN1CCC(N2C(=O)c3cccc4c(N)c(Cl)cc(c34)C2=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 6-amino-5-chloro-2,3-dihydro-2-(piperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione hydrochloride (0.9 g; 2.46 mmol), prepared as in Example 10, in methanol (30 mL) and water (5 mL), was added acetaldehyde (2 mL) and sodium cyanoborohydride (approximately 0.5 g) and the reaction mixture stirred for two hours. Additional sodium cyanoborohydride (0.4 g) was added and the mixture stirred for an additional 2 hours. The solution was concentrated to a small volume, acidified with concentrated hydrochloric acid, and then digested for 16 hours. Solid potassium carbonate was added and the solution was extracted twice with methylene chloride. The extracts were combined, dried over potassium carbonate, and concentrated. Purification by column chromatography (silica gel; 3% methanol in CH2Cl2 and approximately 1% NH4OH) gave 6-amino-5-chloro-2-(1-ethylpiperidin-4-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (0.6 g; 1.68 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH:5]=O.[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1ccc(C=O)cc1O
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1O
Yield: 35.3 %

Procedure:
A mixture of 3-hydroxy-4-ethoxybenzaldehyde (0.413 g, 2.5 mmol), 3,5-dimethoxyacetophenone (0.448 mg, 2.5 mmol) and 50% w/v of aqueous sodium hydroxide (3.98 ml, 0.049 mol) in methanol (5 ml) at room temperature for 18 h. The yellow solid that precipitated was filtered and sequentially washed with cold methanol and ether and finally dried in a vacuum dessicator. Purification by column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) yielded 0.29 g (36%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.2 (m, 2H), 7.1 (d, 3H), 6.8 (d, 1H), 6.5 (t, 1H), 5.7 (s, 1H), 4.1 (q, 2H), 3.9 (s, 6H), 1.4 (t, 3H). 13C-NMR (CDCl3) δ 190.1, 160.9, 148.2, 146.1, 144.9, 140.6, 128.5, 122.7, 120.3, 113.1, 111.4, 106.3, 105.0, 64.7, 55.7, 14.8. Mass Spectrum m/e (M+1) 329. Anal. Calcd. for C19H20O5.0.5H2O: C, 69.5; H, 6.14. Found C, 69.62; H, 6.16.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:12]1([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]2[CH:10]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:47]([C:38]3[CH:39]=[CH:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:37]=3)(=[O:49])=[O:48])[N:7]=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of the product from step c (465 mg, 1.22 mmol) and triethylamine (185 μl, 1.33 mmol) in dry dichloromethane (15 ml) was added 2-naphthalenesulfonyl chloride (227 mg, 1.22 mmol). The solution was stirred for 2 h and the solvent evaporated. Flash column chromatography (silica; 5% methanol/dichloromethane) of the residue afforded the product as a colourless foam (588 mg, 84%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[F:7][C:8]1[CH:18]=[CH:17][C:11](OCC(O)=O)=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[F:7][C:8]1[CH:18]=[CH:17][C:11]([O:3][CH2:2][C:1]([Cl:6])=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COc1ccc(F)cc1
Reaction time: 22 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (60 mL, 686 mmol) and dimethylformamide (DMF) (8 drops, cat.) were added to a stirred suspension of 2-(4-fluorophenoxy)ethanoic acid (97.3 g, 572 mmol) in dichloromethane (500 mL). After 22 hours, the mixture was concentrated under vacuum to obtain 108 g of 2-(4-fluorophenoxy)ethanoic acid chloride, a compound of formula (Y), as a yellow oil in quantitative yield; 1H NMR (CDCl3) δ 4.90 (s, 2H), 6.84 (m, 2H), 6.99 (m, 2H) ppm.
Reaction SMILES: C(Br)C1C=CC=CC=1.I[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:30]2=[O:34])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: ICCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)nc1C
Yield: 35 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with (2-iodoethyl)benzene to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 35% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.20 (m, 5H), 4.25 (q, 1=7.2 Hz, 2H), 4.02 (t, J=7.8 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.8 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.2 Hz, 3H): MS (ES+) m/z 360.2 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[C:12]([CH:14]=[C:15]3[CH2:20][C@@H:19](O)[CH2:18][CH2:17][C@:16]3([CH3:22])[C@H:5]1[CH2:4][CH2:3]2)=[O:13].[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25]>O1CCCC1.N1C=CC=CC=1>[C:27]([C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:22])[C:15](=[CH:14][C:12](=[O:13])[C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:20]1)([O:26][CH2:23][CH:24]=[CH2:25])=[O:28]
Reactant: C=CCOC(=O)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reaction time: 6 h
Yield: 78 %

Procedure:
Compound 43 was prepared from 7-oxo-DHEA (2) (1.0 mmol) and allylchloroformate (4.0 mmol) in tetrahydrofuran-pyridine mixture at 0-5° C. After stirring 6 hours only 30% conversion had occurred; from the mixture the product was isolated in 78% yield (based on 30% conversion) by column chromatography. M.p. 159-61° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:31]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C>[NH2:31][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(=O)O
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-(phenylsulfonyl)phenyl)propanoic acid (675 mg) was dissolved in DMF (8 mL) and to the solution was added N-ethylmorpholine (0.316 mL) followed by TBTU (802 mg). The reaction mixture was stirred at room temperature for 20 min then it was cooled to 0° C. Aqueous ammonia (0.379 mL) was added and the mixture was allowed to reach room temperature over 1 h. The reaction mixture was left to stir for a further 2 h. LCMS showed little change so further TBTU (400 mg) and ammonia (0.3 mL) were added, and the mixture stirred for a further 2 h. The reaction mixture was partitioned between ethyl acetate and diluted brine, and the aqueous phase was extracted into ethyl acetate twice more. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to yield a pale gum. This was purified by flash silica chromatography, eluting with ethyl acetate to give the subtitle compound (450 mg) as a colourless gum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[Se:24][C:23]([C:25]([NH2:27])=[O:26])=[C:22]([OH:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:22]1[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[Se:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
As shown in scheme R, 4-chloro-6,7-dimethoxyquinazoline is reacted with 5-tert-butyl-3-hydroxyselenophene-2-carboxamide in presence of NaOH and DMF to give 3-(6,7-dimethoxyquinazolin-4-yloxy)-5-tert-butylselenophene-2-carboxamide. The 5-tert-butyl-3-hydroxyselenophene-2-carboxamide is prepared in five steps from pinacolone and is described in examples.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>C(O)C>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: OC1CCNCC1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cncc(N2CCC(O)CC2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of ethanol, 1.52 g of 4-hydroxypiperidine was added, and the mixture was refluxed for 6 hours. The reaction mixture was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.00 g of the desired compound as pale yellow crystals, m.p. 259.5°-261° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][N:5]([CH3:7])[CH:6]=1.[Br:10]P(Br)Br>ClCCl>[Br:10][CH2:8][C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: Cn1cc(Cl)c(CO)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cn1cc(Cl)c(CBr)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-chloro-1-methyl-1H-pyrazol-3-yl)methanol (680 mg, 4.7 mmol) in anhydrous dichloromethane (25 mL) was added dropwise a solution of tribromophosphane (450 μL, 4.7 mmol) in anhydrous dichloromethane (5 mL) at 0° C. The mixture was stirred for 1 hour at room temperature and then was evaporated to yield 3-(bromomethyl)-4-chloro-1-methyl-1H-pyrazole, which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:9][CH2:8][S:5](=[O:7])(=[O:6])[CH2:4]1)#[N:2].[C-:10]#[N:11].[Na+:12]>>[C:1]([CH:3]([CH2:4][C:10]#[N:11])[CH2:9][CH2:8][S:5]([O-:7])=[O:6])#[N:2].[Na+:12]
Reactant: [C-]#N
Reactant: N#CC1CCS(=O)(=O)C1
Agent: [Na+]
Product: N#CCC(C#N)CCS(=O)[O-]

Procedure:
The following runs demonstrate the reaction of 3-cyanosulfolane with sodium cyanide to give sodium 3,4-dicyanobutane-1-sulfinate which was then either oxidized to sodium 3,4-dicyanobutane-1-sulfonate or converted by reaction with methyl iodide to the corresponding methylsulfone, i.e., 2-(2-methylsulfonylethyl)succinonitrile.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][N+:17]([O-])=O)=[C:11]([Cl:20])[CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[C:11]([Cl:20])[CH:10]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.1 %

Procedure:
To a stirred suspension of lithium borohydride (0.29 g, 13 mmol) in tetrahydrofuran (20 mL) at ambient temperature was added chlorotrimethylsilane (3.4 mL, 27 mmol), dropwise over 2 minutes. After stirring at ambient temperature for 20 minutes, argon gas was bubbled through the mixture for 2 minutes to remove the remaining trimethylsilane that had formed. A solution of 4-bromo-2-chloro-1-(2-nitrovinyl)benzene (0.88 g, 3.4 mmol) in tetrahydrofuran (15 mL) was added dropwise over 4 minutes with stirring at ambient temperature. The resulting mixture was stirred and heated to reflux for 1 hour. The mixture was cooled in an ice bath and carefully quenched with methanol (20 mL). The solvent was evaporated, and the residue was partitioned between 20% potassium hydroxide (40 mL) and dichloromethane (20 mL) The organic layer was dried over sodium sulfate and concentrated to afford 2-(4-bromo-2-chlorophenyl)ethanamine as a light yellow oil (0.75 g, 95% yield).
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@@H:5]2[CH2:6][C@H:7]([CH3:23])[C:8](=[O:22])[CH2:9]3)#N.[ClH:24]>>[ClH:24].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@H:4]3[NH:3][CH2:21][CH2:20][C@@:10]4([C:11]=2[CH:12]=1)[C@H:5]3[CH2:6][C@H:7]([CH3:23])[C:8](=[O:22])[CH2:9]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Agent: Cl
Product: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
A suspension of 10 (7.2 g, 23 mmol) in 2 N HCl was refluxed for 5 hours. The clear solution was evaporated to give 7.4 g of 13 as a foam, homogeneous by thin layer chromatography, which was used without further purification in the alkylation reactions as described below.
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+].O>C(O)CO>[CH2:1]([C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc2ccccc2cn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1ccc(Cc2cc3ccccc3cn2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
303 mg of 3-benzoyl isoquinoline and 9.75 g of hydrazine hydrate were dissolved in 10 mL of ethylene glycol at room temperature, followed by stirring at 150° C. After 10 minutes, to the reaction liquid was added 3.65 g of pulverized potassium hydroxide, followed by warming to 180° C. and continuously reacting for additional 2 hours. After completion of the reaction, the reaction liquid was left to be cooled, and water was added thereto, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (diethyl ether:n-hexane=1:1) to obtain 280 mg (yield 95%) of a title compound as a light yellow solid.
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3](OCC)=[O:4].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].[Na]>C(O)(C)C>[OH:4][C:3]1[C:2]([Cl:1])=[C:8]([CH3:10])[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CC(C)O
Product: COC(=O)c1sc(C)c(Cl)c1O

Procedure:
Prepared by the method described in Example 1 from ethyl α-chloroacetoacetate (59 g, 0.35 moles), methyl thioglycolate (102 g, 0.70 moles) and sodium (19.7 g, 0.86 moles). The product is obtained from the crystalline precipitate by fractional recrystallization from isopropanol to give 2.8 g; mp 105°-107° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1>>[C:1]1([CH2:7][O:8][C:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:31]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:30]=3[N:21]=[CH:22][CH:23]=[CH:24]4)(=[O:32])=[O:33])=[CH:17][CH:18]=2)=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Product: O=C(NCCc1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1)OCc1ccccc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Cbz amine from Example 3 and 8quinolinesulfonyl chloride: 1H NMR (400 MHz, d6 -DMSO) 9.94 (s, H), 9.12 (m, 1H), 8.49 (dd, 1H), 8.31 (dd, 1H), 8.24 (dd, 1H), 7.70 (m, 2H), 7.2-7.4 (m, 4H), 6.94 (d, 2H), 6.88 (d, 2H), 4.94 (s, 2H), 3.04 (m, 2H), 2.48 (t, 2H). FAB MS m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]2([CH3:25])[O:35][CH2:24]2)[C:3]=1[OH:26]
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2CC2(C)CO2)c1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.4 %

Procedure:
First, 50 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved in 500 ml of chloroform, to which 30.0 g of m-chloroperbenzoic acid was added, and the reaction was allowed to proceed at 60° C. for 4.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and subjected to phase separation with chloroform and aqueous sodium sulfite solution. The organic layer was successively washed with saturated aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was recrystallized to afford 46 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2,3-epoxy-2-methylpropyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.