Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(OCCCCSc3ccc(F)cc3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(F)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-fluorophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:16]2[C:15](=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:20]CCO)[CH:13]=3)[C:8](=[O:24])[C:7]=2[CH:6]=1.BrCCO.Br[CH2:30][CH2:31][Cl:32].S(Cl)([Cl:35])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:32][CH2:31][CH2:30][O:20][C:12]1[CH:11]=[CH:10][C:9]2[C:8](=[O:24])[C:7]3[C:16](=[CH:17][CH:18]=[C:5]([O:4][CH2:3][CH2:2][Cl:35])[CH:6]=3)[C:15](=[O:19])[C:14]=2[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: ClCCBr
Reactant: O=C1c2ccc(OCCO)cc2C(=O)c2ccc(OCCO)cc21
Agent: OCCBr
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2ccc(OCCCl)cc2C(=O)c2ccc(OCCCl)cc21

Procedure:
2,6-Bis(2-hydroxyethoxy)anthraquinone can be prepared as in (A) above by substituting 75 g. (0.60 mole) of 2-bromoethanol for 1-bromo-2-chloroethane. Then, with stirring, 25 g. of thionyl chloride is added to a mixture of 20 g. (0.06 mole) of the 2,6-bis(2-hydroxyethoxy)anthraquinone and 0.5 ml. of pyridine in 200 ml. of chloroform. The mixture is heated to reflux on a steam bath for six hours, after which the excess thionyl chloride and chloroform are removed under reduced pressure. The residue is dissolved in chloroform and the solution washed with saturated sodium bicarbonate solution and water, then dried with anhydrous magnesium sulfate. As in (A) above, the 2,6-bis(2-chloroethoxy) anthraquinone is isolated and recrystallized, if needed.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:6][C:5]([NH:12]C(=O)C)=[C:4]([F:16])[CH:3]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[C:7]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:6][C:5]([NH2:12])=[C:4]([F:16])[CH:3]=1
Reactant: COC(C)c1cc(NC(C)=O)c(F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(C)c1cc(N)c(F)cc1Cl
Yield: 118.7 %

Procedure:
A mixture of 0.6 g (0.0024 mole) of N-[4-chloro-2-fluoro-5-(1-methoxyethyl)phenyl]acetamide, 0.14 g (0.0025 mole) of potassium hydroxide, 10 ml of water, and 10 ml of methanol was heated at reflux for 24 hours. This mixture was cooled and diluted with 50 ml of water. The resulting mixture was extracted successively with methylene chloride and diethyl ether. The combined extracts were dried, filtered, and the solvent was evaporated under reduced pressure, leaving 0.58 g of 4-chloro-2-fluoro-5-(1-methoxyethyl)aniline as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19](=[O:21])[NH2:20])[CH2:15][CH2:14]1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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(O)C.C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19](=[O:21])[NH2:20])[CH2:15][CH2:14]1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(Br)c2n1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CC=C(C(N)=O)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, 8-bromo-2-methyl-4-(4-carbamoyl-1,2,3,6-tetrahydropyridin-1-yl)quinoline (4.7 g), 2,4-dichlorophenylboric acid (2.9 g) and sodium carbonate (4.5 g) were suspended in a mixed solvent of deaerated water (14 mL), toluene (7 mL) and ethanol (7 mL), followed by adding thereto tetrakis(triphenylphosphine)palladium (0.81 g), and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature and stirred at room temperature for 3 hours. The solid precipitated was collected by filtration and washed with a water-ethanol (2:1) mixed solvent (30 mL) and then ethanol (30 mL) to obtain the title compound (4.7 g).
Reaction SMILES: [CH:1]([Mg][Cl:5])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[N:14]S(C(C)(C)C)=O)[CH:10]=[CH:11][CH:12]=1>O1CCCC1>[ClH:5].[Br:6][C:7]1[CH:8]=[C:9]([C:13]2([CH:1]([CH3:3])[CH3:2])[C:21]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]([NH2:28])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C1(c2cccc(Br)c2)N=C(N)c2ccccc21
Product: Cl
Temperature: 30 °C
Reaction time: 3 h
Yield: 3.2 %

Procedure:
Isopropylmagnesium chloride (1.56 mL, 3.08 mmol, 2 M in tetrahydrofuran) was slowly and drop wise added to N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Scheme #5, N) (1.00 g, 2.57 mmol) in dry tetrahydrofuran (15 mL) at room temperature under argon atmosphere. The reaction was heated to 30° C. and stirred for 3 h and then cooled to 0° C. The reaction was quenched with water (5 mL) and extracted twice with ethyl acetate. The organic phases were pooled and washed with saturated aqueous ammonium chloride. The product was extracted five times with 2 M hydrochloric acid and once with 6 M hydrochloric acid. The water phase was neutralized with sodium hydroxide and extracted twice with ethyl acetate. The organic phase was concentrated. Column chromatography using 20-100% chloroform saturated with ammonia in chloroform and 0-100% chloroform saturated with ammonia in chloroform did not yield the pure product. Further purification was made by preparative HPLC using 5-100% acetonitrile in 0.1 M ammonium acetate/water followed by preparative HPLC (Column: Gemini C8) using acetonitrile:water 37:63+1% trifluoroacetic acid. The residue was partitioned between ethyl acetate and sodium bicarbonate. The organic phase was washed (water), dried over magnesium sulfate and concentrated. The residue was dissolved in hydrochloric acid in diethyl ether (0.13 mL, 1 M), stirred for 1 h at ambient temperature and then concentrated to give 30.1 mg (3.2% yield) of the title compound: 1H NMR (DMSO-d6) δ 8.27 (d, J=8.03 Hz, 1 H), 7.92 (d, J=7.78 Hz, 1 H), 7.84-7.76 (m, 2 H), 7.70 (d, J=8.03 Hz, 1 H), 7.64 (t, J=7.53 Hz, 1 H), 7.57-7.52 (m, 1 H), 7.39 (t, J=7.91 Hz, 1 H), 3.17-3.07 (m, 1 H), 0.88 (d, J=7.03 Hz, 3 H), 0.51 (d, J=6.78 Hz, 3 H); MS (ES) m/z 329, 331 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH:37]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH2:38]1>ClCCl.O>[N:44]1[CH:45]=[CH:46][CH:47]=[C:42]([CH:39]2[CH2:40][CH2:41][N:37]([C:29]([N:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=4)[CH2:5][CH2:4][CH2:3]3)=[O:35])[CH2:38]2)[CH:43]=1
Reactant: COC(=O)c1ccc2c(c1)CCCN2
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCCN2C(=O)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 176.8 %

Procedure:
0.6 g of methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate hydrochloride, 13.2 ml of dichloromethane and 2.54 ml of diisopropylethylamine are placed in a 100 ml round-bottomed flask under a nitrogen atmosphere. 0.31 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for three hours. 0.39 g of 3-(pyrrolidin-3-yl)pyridine is subsequently added and the reaction mixture is stirred for eighteen hours. Water and dichloromethane are added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, washed with water and with a saturated aqueous sodium chloride solution and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.675 g of methyl 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoline-6-carboxylate is obtained.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.[Cl:12][C:13]1[CH:27]=[CH:26][C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][NH:21][C:15]=2[CH:14]=1>CCOCC.C(N(CC)CC)C>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][N:21]([C:1]([Cl:4])=[O:2])[C:15]=2[CH:14]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
13 parts of phosgene in 45 parts of toluene was stirred for 2 hours at 5°-10° C., and then 70 parts of ether was added. This was followed by the addition of a solution of 18.9 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine and 7.2 parts of triethylamine in 140 parts of ether. After the addition was complete, the mixture was stirred for 2 hours, and then was filtered. The solvent was then evaporated from the filtrate. The resulting residue was then dissolved in 200 parts by volume of hot hexane, and this mixture was then filtered and cooled.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[N:32]1([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:40]=2[N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl>[N:49]1([C:40]2[CH:41]=[C:42]([C:45]([F:46])([F:47])[F:48])[CH:43]=[CH:44][C:39]=2[CH2:38][N:32]2[CH2:33][CH2:34][N:35]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:36][CH2:37]2)[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1ccc(CN2CCNCC2)c(N2CCOCC2)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(C(F)(F)F)cc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (168 mg, 1.00 mmol, 1.10 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (381 mg, 2.95 mmol, 3.24 equiv) was added dropwise. The mixture was stirred at room temperature for 2 h. 4-[2-(Piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl]morpholine (300 mg, 0.910 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with dichloromethane (20 mL). The resulting mixture was washed with H2O (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The crude product (337 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% over 0.1 min, and holding at 20% for 1.9 min, on a waters 2767-5 chromatograph. Column: X-bridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 171.9 mg (35% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(morpholin-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.54-7.623 (m, 1H), 7.33-7.42 (m, 2H), 5.72-5.85 (m, 1H), 3.84-3.87 (m, 4H), 3.64 (s, 2H), 3.56-3.57 (m, 4H), 2.96-3.00 (m, 4H), 2.51-2.52 (m, 4H). LCMS (ESI, m/z): 524 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:26]=[C:25]([CH3:27])[C:20]([O:21][CH2:22][CH2:23][OH:24])=[C:19]([CH2:28][CH3:29])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:30][CH3:31])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C1COCC1.CC(=O)OCC>[CH3:41][S:42]([O:24][CH2:23][CH2:22][O:21][C:20]1[C:25]([CH3:27])=[CH:26][C:17]([C:14]2[N:13]=[C:12]([C:10]3[CH:9]=[C:8]([O:30][CH3:31])[N:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=3)[O:16][N:15]=2)=[CH:18][C:19]=1[CH2:28][CH3:29])(=[O:44])=[O:43]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a solution of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethanol (638 mg, 1.51 mmol) in THF, DIPEA (389 mg, 3.01 mmol) is added. The mixture is cooled to 0° C. before methanesulfonyl chloride (207 mg, 1.81 mmol) is added. The mixture is stirred at rt for 30 min before it is diluted with EA (100 mL) and washed with sat. aq. NaHCO3 solution (50 mL) and brine (50 mL). The org. extract is dried over MgSO4, filtered and concentrated to give 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethyl methanesulfonate (733 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+H]+=502.05.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]=[O:10])=[CH:4][C:3]=1[CH3:11].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24](=[O:27])(O)[O-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:9]([O:27][CH3:24])[O:10][CH3:13])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(C=O)c(C)nc1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1cc(C)c(Br)nc1C
Yield: 92 %

Procedure:
To a solution of 6-bromo-2,5-dimethyl-3-pyridinecarboxaldehyde (378 g, 1.77 mmol) in methanol (25 mL) was added p-toluenesulfonic acid hydrate (342 mg, 1.80 mmol), and the mixture was heated at reflux for 1 h. Diluted aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 2-bromo-5-dimethoxymethyl-3,6-dimethylpyridine (423 g, 92%).
Reaction SMILES: [Br:1]Br.[F:3][CH:4]([F:11])[C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[N:6]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:9]1[C:5]([CH:4]([F:11])[F:3])=[N:6][N:7]([CH3:10])[CH:8]=1
Reactant: Cn1ccc(C(F)F)n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
At 25° C., bromine (Br2, 3 g) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (2.0 g) in methylene chloride (80 ml). The reaction mixture was stirred for a total of 22 h at 25° C., and aqueous sodium thiosulfate solution (0.1 M, 210 ml) was then added. After phase separation, the organic phase was freed from the solvent under reduced pressure (40° C./5 mbar). Part of the residue obtained (2.4 g of 2.8 g) was separated by column chromatography (SiO2, ethyl acetate/cyclohexane 1:6). 4-bromo-3-difluoromethyl-1-methylpyrazole was isolated in an amount of 1.4 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:21]1[N:26]=[C:25]([Cl:27])[NH:24][C:23]2=[CH:28][CH:29]=[CH:30][C:22]=12>CN(C)C=O>[ClH:27].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:25]1[NH:24][C:23]2=[CH:28][CH:29]=[CH:30][C:22]2=[C:21]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[N:26]=1
Reactant: CC1c2ccccc2CCN1c1nc(Cl)[nH]c2cccc1-2
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)c2cccc-2[nH]1
Product: Cl
Yield: 20.9 %

Procedure:
After 4-fluoro-2-methylaniline(0.40 ml, 3.60 mmol) was added to a mixture solution of 4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chlorocyclopenta[d]pyrimidine (0.50 g, 1.70 mmol) and dimethylformamide(5 ml), 0.15 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: Cc1ccccc1CN
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1CNc1nc(N)nc(-n2cccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-methyl-benzylamine and DBU in DME. ES-MS m/e (%): 328 (M+Na+, 35), 306 (M+H+, 100).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=O)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:23])=[CH:24][CH:25]=3)=[N:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: CCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1

Procedure:
102.75 G. of 4-[5-(4-n-butylphenyl)-2-pyrimidyl] benzoic acid amide are refluxed for 80 minutes in a mixture of 1500 ml. of ethylene chloride and 34 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, which has been dried over sodium sulfate, there is obtained 5-(4-n-butylphenyl)-2-(4-cyanophenyl)pyrimidine which is filtered on a short silica gel column and subsequently recrystallized from methylene chloride/methanol; melting point 94.7° C.; clearing point 246°-246.7° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
4-Trifluoromethoxyphenylsulfonyl chloride (4.34 g, 16.7 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (2.99 g, 19.5 mmol) and N,N-diisopropylethylamine (9.50 ml, 57.5 mmol) in CH2Cl2 (50 ml) at 0° C. and stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (250 ml), washed with aqueous 1 N HCl solution (50 ml), H2O (50 ml), saturated aqueous NaHCO3 solution (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-one (4.37 g, 81%) as a off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]12([C:30](O)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[CH2:13]([O:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:30]([C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOCc1ccccc1
Reactant: Cc1nc(N)sc1C
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCOCc2ccccc2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, (2-Bromoethoxymethyl)-benzene and 1-adamantane carboxylic acid were processed as described in Example 47 to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.58-1.73 (m, 6H) 1.79 (d, J=2.50 Hz, 6H) 1.91-2.02 (m, 3H) 2.15 (s, 3H) 2.22 (s, 3H) 3.77 (t, J=5.46 Hz, 2H) 4.29 (t, J=5.46 Hz, 2H) 4.47 (s, 2H) 7.19 (d, J=6.55 Hz, 2H) 7.22-7.33 (m, 3H); MS (ESI) m/z 425 (M=H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: CS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[-3-[(methylsulfonyl)amino]-1-oxopropyl]hydrazide (11) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methanesulfonyl chloride, in the manner described in Example 10 above on a 2-mmol scale to yield 0.46 g (52%) of product. Analysis calculated for C18H19N4O5ClS (M.W. 438.88): C, 49.26; H, 4.36; N, 12.77. Found: C, 49.05; H, 4.40; N, 12.66.
Reaction SMILES: S(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[C-:16]#[N:17].[Na+]>O.CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]([C:16]#[N:17])[OH:11])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(O)c1ccc(F)c(Br)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of sodium bisulfite (28.3 g, 271 mmol) in water at 50° C. is treated with 3-bromo-4-fluorobenzaldehyde (45.8 g, 225 mmol), stirred at 50° C. for 2 h, cooled with an ice bath, diluted with ether, treated dropwise with an aqueous solution of sodium cyanide (12.2 g, 248 mmol) over a period of 30 min and stirred at room temperature overnight. The reaction mixture is separated, and the aqueous phase is extracted with ether. The extracts are combined with the organic phase, washed with brine, dried over magnesium sulfate and concentrated to dryness to afford the title compound as a clear oil, 47.6 g (92% yield), identified by NMR analysis. 1H NMR (300 MHz, CDCl3) δ 7.75 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 5.54 (m, 1H), 3.19 (m, 1H).