Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][S:20][C:15]2[C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[CH:35][CH:36]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(OCc4ccccc4)cc3)c2CC1
Yield: 67.3 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (706 mg, 1.84 mmol) in methanol (20 mL). Add potassium hydroxide (3.5 g, 55 mmol) and heat the mixture at reflux for 3h. Cool to ambient temperature. Pour reaction in saturated aqueous NH4Cl solution. Extract three times with EtOAc. Combine organic extracts, dry over Na2SO4 and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (602 mg, 100%). Dissolve 3-tert-butoxycarbonyl-7-chloro-6mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Cool the reaction to ambient temperature, dilute with acetone, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give 6-(4-benzyloxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (309 mg, 67%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[C:11]([C:12]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C2(C#N)CCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)O)c2Cl)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
Methyl 2-chloro-3-(1-cyanocyclobutyl)benzoate (710 mg, 2.84 mmol) was dissolved in a mixed solvent of tetrahydrofuran (9 mL)/methanol (3 mL)/water (3 mL), lithium hydroxide monohydrate (192 mg, 4.56 mmol) was added, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid (5 mL) was added dropwise to the residue. The precipitate was collected by filtration, and washed with water to give the title compound (435 mg, 65%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.CO[CH:16](OC)[CH2:17]Br.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Li+].[Cl-]>CN(C)C=O>[Br:13][C:12]1[C:2]2[N:3]([CH:16]=[CH:17][N:1]=2)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=1
Reactant: COC(CBr)OC
Reactant: CCOC(=O)c1cnc(N)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)c2nccn2c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-amino-5-bromonicotinate (5.0 g, 20.4 mmol) in N,N-dimethylformamide (204 mL) were added bromoacetaldehyde dimethylacetal (3.45 g, 20.4 mmol) and p-toluenesulfonic acid (0.53 g, 3.1 mmol). The mixture was heated to 90° C. After 18 h, additional bromoacetaldehyde dimethylacetal (3.45 g, 20.4 mmol) and 4A° molecular sieves were added. The mixture was stirred at 90° C. for another 24 h. The mixture was warmed to ambient temperature and aqueous LiCl (3.0 M) was added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. There was still some DMF in the crude product. Water was added and the mixture was extracted with t-butyl methyl ether, washed with brine, dried over sodium sulfate, filtered and concentrated. The mixture was carried on to the next step: LC-MS [M]=269.0.
Reaction SMILES: C[CH2:2][S:3]([NH2:6])(=[O:5])=[O:4].Br[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:19])[C:15]([OH:29])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.N1C=CC=C[CH:31]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:16]2[C:15]([OH:29])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[N:13]3)=[C:8]([N:6]([CH3:31])[S:3]([CH3:2])(=[O:5])=[O:4])[N:17]=2)=[O:19])=[CH:23][CH:24]=1
Reactant: c1ccncc1
Reactant: CCS(N)(=O)=O
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Product: CN(c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)S(C)(=O)=O
Temperature: 25 °C

Procedure:
To a mixture of methyl-methanesulfonamide (1.06 g, 9.65 mmol), 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (1.21 g, 3.22 mmol), and Cu2O (0.46 g, 3.22 mmol) under an atmosphere of argon was added pyridine (25 mL) and the suspension was stirred at reflux for 16 hr. The reaction was allowed to cool to room temperature and the solvent evaporated in vacuo. The residue was treated with DMF (12 mL) and TFA (0.5 mL) and filtered to remove the solids. The filtrate was purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:18]1([CH2:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)O)[CH:22]=[CH:21][N:20]=[CH:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[N:18]1([CH2:23][C@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:1][C:2]2[C:3]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: CCCOCc1c(O)ccc2c1CCCC2=O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 73.7 %

Procedure:
According to step 2 in the method of example 19a, 6-Hydroxy-5-propoxymethyl-3,4-dihydro-2H-naphthalen-1-one (0.123 g, 0.53 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol), triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, Argonaut Technologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, Aldrich Chemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical) were combined in a 2 dram screw topped vial with a teflon lined cap. After mixing on an inverting mixer at 25° C. for 16 hrs., the resin was removed by gravity filtration and mixture concentrated in vacuo to a yellow-brown syrup. The residue was dissolved in methanol (5 ml) and macroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5 mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C., the resin was collected by gravity filtration, washed with methanol (2×5 ml). Elution of product from the resin with 2.0 M ammonia in methanol (5 ml, Aldrich) and concentration in vacuo yielded 158 mg yellow glass compound. Low resolution mass spectroscopy m/z (APCI) 405 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[OH:21][C:20]1[N:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:28])=[CH:24][N:23]=2)[N:18]=[CH:17][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[CH:11][C:12]=1[CH3:31]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCNCC1
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using 1-methylpiperazine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (22 mg, 0.055 mmol, 43.8%) as a white solid. MS: 403 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H) 2.43 (s, 3 H) 3.28-3.70 (m, 8H) 7.62 (d, J=8.1 Hz, 1 H) 7.68 (s, 1 H) 7.90 (d, J=8.1 Hz, 1 H) 8.02 (dd, J=8.6, 2.3 Hz, 1 H) 8.08 (s, 1 H) 8.43 (d, J=8.6 Hz, 1 H) 8.52 (d, J=2.0 Hz, 1 H) 12.74 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[N:14]([C:15]=1[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][O:11]2.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>C(OCC)(=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:17][C:16]([C:15]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)C=CC(=O)c1c(-c2ccccc2Cl)nc2occn12
Temperature: 25 °C
Yield: 52 %

Procedure:
A 50 ml round bottom flask is charged with the 1-[6-(2-chlorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]ethanone (952 mg, 3.65 mmol) and dimethylformamide dimethylacetal (22 ml). The mixture is refluxed for 5 hours and then cooled to room temperature. The mixture is diluted with ethyl acetate (150 ml) and washed three times with 100 ml each of a saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown oil. The product is purified by flash chromatography on silica gel (ethyl acetate), yielding 604 mg of a pale brown solid (52%). M.p.=187-189° C.; 300 MHz 1H NMR (CDCl3) δ: 8.07 (d, J=1.6 Hz, 1H), 7.62-7.35 (m, 6H), 4.78 (d, J=12.5 Hz), 1H), 3.04-3.01 (m, 3H), 2.4-2.32 (m, 3H). LCMS: 316[M+H]; calc. for C16H14ClN3O2: C, 60.76; H, 4.49; N, 13.28; found. C, 60.81; H, 4.39; N, 13.35.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][C:18]#[CH:19].Cl[CH2:21][CH:22]=[N:23][OH:24].C(N(CC)CC)C>O1CCCC1>[CH3:21][C:22]1[CH:19]=[C:18]([CH2:17][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])[O:24][N:23]=1
Reactant: C#CCn1c(=O)c(C(=O)OCC)nc2ccccc21
Reactant: ON=CCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2ccccc2n(Cc2cc(C)no2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
3.0 g (11.7 mmol) of ethyl 2-oxo-1-(2-propynyl)-1,2-dihydroquinoxaline-3-carboxylate and 3.28 g (35.1 mmol) of chloroacetaldoxime were dissolved in tetrahydrofuran (30 mL), and 3.55 g (35.1 mmol) of triethylamine was added dropwise at a temperature in the range of 0° C. to 5° C. The mixture was stirred for 3 days at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid, dried over anhydrous sodium sulfate, and concentrated. The solid matter thus obtained was washed with diisopropyl ether, to obtain 3.4 g (yield: 93%) of ethyl 1-[(3-methylisoxazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35])([CH3:28])([CH3:27])[CH3:26]>CCCCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: CC(C)(C)c1ccccc1S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccccc4C(C)(C)C)cc23)CC1
Temperature: 110 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 2-t-butyl-thiophenol (0.216 g, 1.3 mmol), Nat-BuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in n-BuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-heptane: ethyl acetate 8:2) to give 440 mg of the title compound as colorless oil (yield 71%). 1H NMR (CDCl3) δ 8.00-8.10 (m, 2H), 7.15-7.65 (m, 7H), 3.60-3.70 (m, 1H), 3.30-3.45 (m, 4H), 3.05-3.20 (m, 3H), 1.55 (s, 9H), 1.50 (s, 9H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.CS(C)=O>C(OCC)C>[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BrH:1]
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOCC
Product: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 70 ml of a 25% hydrogen bromide-acetic acid solution was suspended 8.02 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 2.96 g of dimethyl sulfoxide was added to the suspension under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Then, 140 ml of diethyl ether was added to the reaction mixture, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 8.55 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide.
Reaction SMILES: O[CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[OH-].[Na+].[C:22](=O)([O-])O.[Na+]>Cl.O>[OH:9][CH:7]([CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:11]1[NH:19][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]=1
Reactant: O=C([O-])O
Reactant: COC(=O)CCCCC(C)O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CCCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
3.28 g of methyl 6-hydroxyheptanoate and 2.16 g of phenylenediamine were dissolved in a mixed solvent of 10 ml of concentrated hydrochloric acid and 20 ml of water, and the mixture was refluxed with stirring under heating for 24 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 8 with about 100 ml of 1 N sodium hydroxide solution and saturated aqueous sodium hydrogencarbonate. The reaction mixture was extracted three times with 150 ml of ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate—ethyl acetate:methanol=95:5) to obtain 3.03 g of the title compound as pale brown solid (yield: 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[N:8][C:9]=1[S:10][CH3:11].Cl[CH:14]([F:16])[F:15]>O1CCOCC1.O.CCOCC>[F:15][CH:14]([F:16])[O:12][C:6]1[CH:5]=[C:4]([CH3:3])[C:9]([S:10][CH3:11])=[N:8][CH:7]=1
Reactant: CSc1ncc(O)cc1C
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc(OC(F)F)cc1C
Temperature: 25 °C
Yield: 61 %

Procedure:
Solid sodium hydroxide (9.3 g, 232 mmol) were added in one portion to a stirred solution of 5-methyl-6-methylsulfanylpyridine-3-ol (7.2 g, 46.4 mmol) in 1,4-dioxane (75 mL) and water (25 mL) causing an exotherm to 50° C. Chlorodifluoromethane (13 g, 150 mmol) was then rapidly bubbled into the reaction over 9 minutes, causing a gradual exotherm to 75° C. After the reaction had cooled to room temperature, it was diluted with ether (100 mL) and water (100 mL) and the layers separated. The organic phase was extracted with water (6×100 mL), brine and dried (Na2SO4). Filtration and removal of solvent left a brown oil, 8.3 g, that was purified by chromatography on silica, eluting with 1:1 methylene chloride/hexanes to give product, as an orange liquid, 5.8 g, 28.3 mmol, 61 percent yield.
Reaction SMILES: ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:13]1[C:18]([NH2:19])=[C:17](Cl)[C:16]([Cl:21])=[C:15](Cl)[C:14]=1[Cl:23].C1(O)C=CC=CC=1.II>[Ta].O>[Cl:21][C:16]1[CH:17]=[C:18]([CH:13]=[C:14]([Cl:23])[CH:15]=1)[NH2:19]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: II
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Temperature: 165 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
131 parts of tetrachloroaniline/pentachloroaniline mixture corresponding to the data in Example 3, 200 parts of phenol, 5.7 parts of iodine and 33 parts of a 5% strength ruthenium-on-charcoal catalyst which is moist with water (23 parts dry) are brought to reaction in a tantalum autoclave, whilst stirring, during the course of 4 hours, at 165° C. and under a maximum hydrogen pressure of 50 bars. After the usual working up, 87 parts of 98% strength 3,5-dichloroaniline are obtained (93% yield).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[C:13](OC=C)(=[O:15])[CH3:14]>C(O)(C)(C)C>[C:13]([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6])(=[O:15])[CH3:14]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C=COC(C)=O
Solvent: CC(C)(C)O
Product: CC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Reaction time: 20 h
Yield: 96.9 %

Procedure:
Four grams of the immobilized Lipase PS prepared by the same procedure as in Example 2 was added to 40 ml of a dry t-butanol solution containing 4 g of ascorbic acid and 3 g of vinyl acetate. The reaction was continued for 20 hours at 50° C. The reaction mixture was filtered and concentrated to yield 4.8 g of a crude ascorbic acid-6-acetate. Recrystallization from acetone-benzene gave a crystal with purity of 93%. The water content of the reaction system was 650 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:14]([SH:16])[S:15][C:3]=2[C:2]=1[Cl:1]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(Cl)c(Cl)c1F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2ccc(Cl)c(Cl)c2s1
Temperature: 95 °C
Yield: 91.5 %

Procedure:
A mixture of 1.5 g (8.33 mmol) 3.4-dichloro-2-fluoroaniline and 1.64 g (10.00 mmol) potassium ethylxanthogenate in 8 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 5 h. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 1.8 g (92%) of the title compound as a white solid. MS(m/e): 233.8 (M−H+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:26])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=2)[O:6][C:5]1=[O:25])[CH:2]=[CH2:3].[NH2:27][C@@H:28]([CH:31]1[CH2:33][CH2:32]1)[CH2:29][OH:30]>C(OCC)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH:7]([OH:6])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:9][C@:4]([CH3:26])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:27][C@@H:28]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][OH:30])=[O:25])=[CH:18][C:19]=1[F:24]
Reactant: N[C@H](CO)C1CC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)c(F)c2)OC1=O
Solvent: CCOC(C)=O
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)C(O)c1ccc(Cl)c(F)c1)C(=O)N[C@H](CO)C1CC1
Temperature: 100 °C

Procedure:
(3S,5R,6R)-3-Allyl-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (32 g, 81 mmol, Example 4, Step E) was combined with (S)-2-amino-2-cyclopropylethanol (26.7 g, 265 mmol) and the suspension was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with 1 N hydrochloric acid (2×), water, and brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.I[CH3:11]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(O)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ncc(C)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-bromo-5-methylpyridin-2-ol (500 mg, 2.7 mmol) and silver carbonate (2.6 g, 9.6 mmol) suspended in dichloromethane (10 mL) was added iodomethane (0.83 mL, 13 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered through a pad of celite and the volatiles were evaporated to yield 3-bromo-2-methoxy-5-methylpyridine, which was used directly in the next step. ESI-MS m/z calc. 201.0. found 202.3 (M+1)+. Retention time 1.51 minutes.
Reaction SMILES: Cl.Cl.[CH2:3]([C:9]1[NH:10][NH:11][C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:26]([Cl:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(#N)C>[ClH:34].[CH2:3]([C:9]1[NH:10][N:11]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]2[N:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCC1=Nc2cccnc2NN1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCC1=Nc2cccnc2N(C(=O)c2ccccc2)N1

Procedure:
3 g (0.01 mole) of 3-hexyl-1,2-dihydropyrido-[3,2-e]-as-triazine dihydrochloride are reacted with 2 g (0.02 mole) of triethylamine in 60 ml of anhydrous acetonitrile under argon, thereafter 2.9 g (0.02 mole) of benzoylchloride are added to the reaction mixture which is boiled for an hour. Then the mixture is cooled, poured into water, neutralized and extracted with chloroform. The solvent is evaporated and the residue is reacted with anhydrous hydrochloric ethanol to form a salt.