Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH3:1][O:2][CH:3]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:43]([CH3:42])(=[O:45])=[O:44])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCCCO)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCCCCCOS(C)(=O)=O)OC
Temperature: 25 °C

Procedure:
In 30 ml of dichloromethane are dissolved 1.77 g of 6-hydroxyhexyl 2-methoxy-3-octadecyloxypropyl sulfone and 0.64 ml of triethylamine, to which 0.35 ml of methanesulfonyl chloride is added dropwise with stirring at room temperature. Thereafter, the mixture is stirred at room temperature for 2 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution and water. After drying, the solvent is distilled off to leave 1.98 g of the captioned compound.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:11]Br>CC(O)=O.O>[Br:11][C:2]1[S:1][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1NCCc2ccsc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1NCCc2cc(Br)sc21
Temperature: 0 °C
Yield: 85.1 %

Procedure:
Dissolve 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (4.80 g, 31.37 mmol) in HOAc (40 mL) and water (30 mL). Cool to 0° C. and add Br2 (1.8 mL, 34.51 mmol) dropwise. Stir the reaction at 0° C. for 1 h. Dilute the reaction mixture with water (100 mL) and extract with EtOAc (3×100 mL). Wash the combined organic layers with 5% Na2SO3 (2×50 mL), saturated NaHCO3 (2×100 mL), dry over Na2SO4, filter, and concentrate to give 6.198 g (85%) of the title compound. MS/ES m/z (81Br) 233.9 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 2.87 (t, J=6.9 Hz, 2H), 3.59 (t, J=6.9 Hz, 2H), 6.21 (bs, 1H), 6.93 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[N:23]=3)[N:20]=2)[N:15](COCC[Si](C)(C)C)[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[N:23]=3)[N:20]=2)[NH:15][CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(Cc1ccccn1)NC(=O)c1c[nH]c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 43.4 %

Procedure:
2-[6-Fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)amide (75 mg, 0.117 mmol) was combined with dichloromethane (1 mL) then trifluoroacetic acid (0.26 ml, 3.50 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.23 ml, 3.50 mmol) was added and the reaction was stirred at room temperature for 20 min. The reaction mixture was concentrated in vacuo and the residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to afford 26 mg (41%) of 2-[6-fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (26 mg, 41%) as a yellow solid. MS: (M+H)+=513; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.32-8.44 (m, 2H), 8.22 (d, J=8.3 Hz, 1H), 7.73 (d, J=9.8 Hz, 1H), 7.50-7.66 (m, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.03-7.16 (m, 2H), 4.53-4.67 (m, 4H), 4.46 (s, 1H), 3.02-3.25 (m, 2H), 2.98 (t, J=6.5 Hz, 3H), 1.64 (br. s., 5H), 1.29 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CCOCC>[Br-:9].[C:15]([O:14][C:13]([NH:12][CH2:11][CH2:10][N+:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: C1CN2CCN1CC2
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCC[N+]12CCN(CC1)CC2
Product: [Br-]
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1,4-diazabicyclo[2.2.2]octane (0.40 g, 3.57 mmol) in ether (5 mL) was added tert-butyl 2-bromoethylcarbamate (0.80 g, 3.57 mmol). The reaction was stirred overnight and the solvent was removed in vacuo. EtOAc (10 mL) was added and the reaction was stirred vigorously overnight. The precipitates were collected by filtration to give 1-(2-(tert-butoxycarbonylamino)ethyl)-4-aza-1-azonia-bicyclo[2.2.2]octane bromide (0.84 g) as a white solid. The solids were dissolved in MeOH (3 mL) and 4 M HCl in dioxane (3.5 mL, 14 mmol). The reaction was stirred at room temperature until it was determined to be complete by LCMS. The mixture was filtered to afford 1-(2-aminoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane chloride hydrochloride (0.74 g) as a white solid. 1H-NMR (D2O, 400 MHz) δ 3.98-3.72 (m, 8H), 3.79-3.69 (m, 6H), 3.66-3.61 (m, 2H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C=O)c(C)o2)cc1
Yield: 87.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 4-methoxyphenylboronic acid (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.9 g, 91%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]([OH:46])([CH3:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][C:37]([OH:46])([CH3:36])[CH3:45])[CH2:44][CH2:43]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(C)(C)O)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-methyl-1-piperazin-1-yl-propan-2-ol (example 18a) in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)+]
Reaction SMILES: Cl.[C:2]1([C:8]2([CH2:14][CH2:15]N)[CH:13]=[CH:12][CH2:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([BH3-])#[N:18].[Na+].Cl.N.[CH3:23]O>>[CH3:23][N:18]([CH3:17])[CH2:15][CH2:14][C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH2:11][CH:10]=[CH:9]1
Reactant: [BH3-]C#N
Reactant: CO
Reactant: NCCC1(c2ccccc2)C=CCC=C1
Agent: Cl
Agent: N
Agent: [Na+]
Product: CN(C)CCC1(c2ccccc2)C=CCC=C1
Reaction time: 0.17 h

Procedure:
4 g. of 1-phenyl-2,5-cyclohexadien-1-ethylamine hydrochloride are placed in 100 ml. of absolute methanol. After the addition of 3.3 g. (6.5 equivalents) of p-formaldehyde, 1 g. (about 1 equivalent) of sodium cyanoborohydride and 5 g. of molecular sieve 3A, the mixture is stirred at room temperature overnight and subsequently worked-up as follows: The mixture is poured into aqueous 3 N hydrochloric acid, stirred for 10 minutes, made basic with concentrated aqueous ammonia, extracted with ethyl acetate, washed with water, dried with sodium sulfate and filtered. There is obtained an oily product which is chromatographed on 80 g. of silica gel with methylene chloride/methanol (10:1). The yellow oil obtained (N,N-dimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine) is converted in the customary manner into the (1:1)-maleate which has a melting point of 129°-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[NH3:13]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:13])=[O:11])=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)Cc1ccc(O)cc1
Product: NC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-Hydroxyphenylacetate (4) (0.83 g) was dissolved in saturated methanolic ammonia (30 ml) and placed in a thick walled tube with Teflon screw cap. The solution was stirred in this sealed tube at room temperature for 72 hours. Reaction mixture was concentrated and redissolved in methanol-chloroform (2:8 volume by volume, 75 ml). No crystallization occurred so the solution was concentrated to half its volume and hexane was added with heating. Cooling to 0° C. gave crystals of 4-Hydroxyphenylacetamide (13) (0.524 g). This was confirmed by spectroscopy--1H NMR (d6DMSO+CF3CO2D) δ 3.23 (s, 2 H), 6.63 (d, 2 H), 7.00 (d, 2 H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:8][C:9]=1[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH3:4].[Cl:23][C:24]1[CH:31]=[C:30](O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)[S:8][C:9]=1[CH2:10][CH2:11][O:12][C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:23])[CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To an iced cooled solution of 1.1 g 2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol dissolved in 50 ml dichloromethane were added 0.56 g commercially available 2-Chloro-4-hydroxybenzonitrile and 0.95 g triphenylphosphine. To this solution was added dropwise 0.57 ml Diethylazodicarboxylate. The cooling bath was removed and reaction mixture stirred at room temperature for six hours. The solvent was removed in vacuo and the residue purified by RP-HPLC to provide 400 mg 4-{2-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-2-chloro-benzonitrile as lyophilisate.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[O:17][N:16]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])[N:14]=1.[CH3:23][NH2:24]>>[CH3:12][C:13]1[O:17][N:16]=[C:15]([CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]2[C:3]([NH:24][CH3:23])=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)[N:14]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Cc1nc(CSCCN)no1
Reactant: CN
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1noc(C)n1

Procedure:
When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is treated successively with 2-[(5-methyl-1,2,4-oxadiazol-3-yl)methylthio]ethylamine [prepared in Step A] and methylamine, by the general procedure of Example 2, the title compound is thereby produced.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[CH3:15][Si:16]([CH3:27])([O:23][CH2:24][C:25]#[CH:26])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:14])[NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:6]=1[C:26]#[C:25][CH2:24][O:23][Si:16]([CH3:27])([CH3:15])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19]
Reactant: C#CCO[Si](C)(C)C(C)(C)C(C)C
Reactant: COC(=O)Nc1cc(C)c(Br)cc1I
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(C)c(Br)cc1C#CCO[Si](C)(C)C(C)(C)C(C)C

Procedure:
To a solution of 3.70 g (4-bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester and 0.070 g bis-triphenylphosphine palladium dichloride and 0.038 g cuprous iodide in 25 mL triethylamine was added 2.38 g dimethyl (2-propynyloxy)(1,1,2-trimethylpropyl)-silane and the mixture was heated 2 h at reflux. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was washed with 1N hydrochloric acid, sodium bicarbonate and brine, dried with magnesium sulfate and purified by chromatography on silica gel with 4:1 hexane:ethyl acetateto yield 1.92 g of the title compound as a light brown oil. MS: M+NH4+=457.0 M+Na+=462.2.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13].[OH-].[Li+].O.Cl>C1COCC1.CCOCC>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)CCCCCCOCCC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCOCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 7-(3,3,3-trifluoropropoxy)heptanoate (50 mmol) is dissolved in 500 ml of THF in a round-bottomed flask, and solid lithium hydroxide (65 mmol, 1.3 eq) is added in portions at RT. The mixture is stirred at RT for 1 hr, and 100 ml of water and 200 ml of MTB ether are subsequently added. The mixture is acidified to pH 1 using aqueous HCl, the phases are separated, and the aqueous phase is extracted a number of times with MTB. The combined organic phases are dried over sodium sulfate and evaporated in a rotary evaporator. The carboxylic acid formed in this way is employed directly in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[CH2:11]([SH:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([S:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCS
Reactant: O=Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.0 g of 4-chloro-2-fluorobenzaldehyde, 2.05 ml of ethanethiol, 3.82 g of potassium carbonate and 6 ml of DMF was stirred at room temperature for 6 hours, and was allowed to stand overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.57 g of 4-chloro-2-ethylsulfanylbenzaldehyde. 4-Chloro-2-ethylsulfanylbenzaldehyde
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:6](=[CH:12][CH:13]([CH3:15])[CH3:14])C(OCC)=O)#[N:5]>O.C(O)C>[CH:13]([CH:12]([CH2:6][C:4]#[N:5])[C:1]#[N:2])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C(C#N)=CC(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)C(C#N)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of potassium cyanide (5.81 g, 89.52 mmol) in water (12 mL) was added to a solution of ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 38.92 mmol) in ethanol (20 mL) at room temperature and the reaction mixture was stirred overnight. The resulting mixture was refluxed for 2 h and then cooled to room temperature. The ethanol was evaporated and the residue dissolved in dichloromethane. The dichloromethane layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-isopropylbutanedinitrile (3.5 g, 74%) as a liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:20][CH2:19][CH2:18][N:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[CH2:21][CH2:22][OH:23]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(F)cc2)cc1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccc(N(CCO)CCO)cc2)cc1
Temperature: 95 °C

Procedure:
A one liter three necked flask fitted with a mechanical stirrer, condenser and thermometer is charged with 21.7 g of 4-fluoro-4'-nitrobiphenyl, 31.0 g of diethanolamine, 13.8 g of potassium carbonate, 1.0 g of Aliquot 336, and 500 ml of dimethyl sulfoxide. The reaction mixture is heated at 95° C. for a period of three days, cooled, and poured into 4 litersof ice water. The crude solid product is filtered, washed with water, and dried.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1Cl
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-dichlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.29 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.29-7.32 (1H, m), 7.42 (1H, dd, J=1.2, 5.2 Hz), 7.45 (1H, d, J=2.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=1.6 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10Cl2N4O, 345; Found, 345.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[CH2:10][CH2:11][NH:12][CH3:13].O1CCCC1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1[Cl:27]>O>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([N:12]([CH2:11][CH2:10][N:9]([CH3:14])[CH3:8])[CH3:13])(=[O:30])=[O:29])[CH:24]=[N:25][C:26]=1[Cl:27]
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CNCCN(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
With cooling with ice, triethylamine (0.57 ml, 4.06 mmol) and N,N,N′-trimethylethane-1,2-diamine (0.30 ml, 2.23 mmol) were added to a tetrahydrofuran solution (5 ml) of 5,6-dichloropyridine-3-sulfonyl chloride (500 mg, 2.03 mmol) obtained in the above reaction, and stirred for 5 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=5:1 to 3:1) to obtain 5,6-dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (460 mg, yield: 73%) as a red solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.N1CCCC1.O.C1(C)C=CC([S:20](O)(=O)=O)=CC=1.[N:25]#[C:26][NH2:27]>C1CCCCC1>[C:2]([C:3]1[S:20][C:26]([NH2:27])=[N:25][CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)CC=O
Reactant: N#CN
Solvent: C1CCNC1
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)(C)c1cnc(N)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-dimethylbutyraldehyde (10 g, 99.8 mmol) in 200 mL of cyclohexane was added pyrrolidine (8.7 mL, 0.11 mol) followed by p-toluenesulfonic acid monohydrate (0.95 g, 5.0 mmol). This reaction flask was equipped with a Dean-Stark trap and the mixture was warmed to reflux and was allowed to stir for 3 hours. The mixture was cooled to ambient temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in 75 mL of CH3OH, sulfur was added (3.2 g, 99.8 mmol), and the mixture was cooled to 0° C. Cyanamide (4.2 g, 99.8 mmol) was added portion-wise over 10 minutes and the mixture was allowed to warm to ambient temperature and stir for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, ethyl acetate then 10% methanol in ethyl acetate) to afford the title compound. MS (DCI/NH3) m/z 157 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23][C:22]1=[O:31].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][N:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:21][C:22](=[O:31])[CH2:23]2)[CH:7]=1
Reactant: O=C1CNc2ccccc2N1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(=O)Nc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (105 mg) and 3,4-dihydro-1H-quinoxalin-2-one (R. E. TenBrink et al., J. Med. Chem., 1994, 37, pp. 758-768) (267 mg) in dimethylformamide (0.75 mL) was heated at 140° C. for 45 hours. The resulting mixture was poured into water and extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 30% ethyl acetate-hexanes) to give the title compound as a pale yellow solid (67.8 mg), m.p. 69° C.-71° C.
Reaction SMILES: [C:1]1([S:7][C:8](=[S:14])[NH:9][CH2:10][C:11]([Cl:13])=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>BrCCl>[BrH:15].[Br:15][CH2:12][C:11]1([Cl:13])[S:14][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][CH2:10]1.[BrH:15]
Reactant: BrBr
Reactant: C=C(Cl)CNC(=S)Sc1ccccc1
Agent: ClCBr
Product: Br
Product: ClC1(CBr)CN=C(Sc2ccccc2)S1
Temperature: 0.5 °C
Reaction time: 0.33 h

Procedure:
Under a slight stream of nitrogen, 18.4 g of (2-chloro-allyl)-dithiocarbamic acid phenyl ester are placed in 100 ml of bromochloromethane and cooled to 0-1° C. Before and during the addition of bromine, the apparatus is flushed thoroughly with nitrogen. 13.8 g of bromine are added in the course of 120 minutes in such a manner that the temperature can be maintained at 0-10° C. When the addition is complete, stirring is carried out for about 20 minutes. The reaction mixture is concentrated in vacuo at 20-25° C. 50 ml of hexane are added to the residue, and the product is filtered off with suction at 20-25° C., washed with 30 ml of hexane and dried in vacuo at room temperature. The title product is obtained in the form of the hydrobromide (compound 2.2).