Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)CCCCBr)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a mixture 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (1.29 g, 5.20 mmol) and triethylamine (0.58 g, 5.72 mmol) in anhydrous dichloromethane (25.0 mL) was added dropwise 5-bromopentanoyl chloride (1.141 g, 5.72 mmol) in anhydrous dichloromethane (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil (1.91 g, 92%): 1H NMR (300 MHz, CDCl3) δ 8.81 (br s, 1H), 7.33-7.23 (m, 5H), 5.91 (s, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.51 (t, J=6.7 Hz, 2H), 2.46 (s, 3H), 2.35 (t, J=6.7 Hz, 2H), 1.82 (m, 2H), 1.53 (m, 2H); MS (ES+) m/z 410.1 (M+1), 412.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([NH:20][C:21]2[C:22]3[N:23]([N:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:25][N:26]=2)[CH:17]=[CH:16][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:10]=N[C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].C(N)C1C=CC=CC=1>>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([NH:20][C:21]2[C:22]3[N:23]([N:32]=[CH:33][N:34]=3)[C:24]([C:27]3[CH:31]=[N:30][NH:29][CH:28]=3)=[CH:25][N:26]=2)=[CH:19][C:3]=1[O:2][CH3:1])[C:9]1[CH:10]=[CH:15][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1C(=O)NCc1ccc(C)nc1
Solvent: NCc1ccccc1
Product: COc1cc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)ccc1C(=O)NCc1ccccc1

Procedure:
This compound may be prepared using the methods described for Compound 120, using benzylamine in step 1. LCMS: Rt 1.62 min (100%) m/z (ESI) 440 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Br:15][C:16]1[CH:17]=[C:18](/[C:22](/[C:30]2[C:31]([C:36]#[N:37])=[N:32][CH:33]=[CH:34][CH:35]=2)=[N:23]\S(C(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[C:30]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccnc1C#N
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ncccc32)cc1
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
Butyllithium (2.5 M in hexanes, 0.947 mL) was added dropwise to a solution of 4-bromoanisole (483 mg, 2.58 mmol) in anhydrous THF at −78° C. under an atmosphere of argon. The mixture was stirred at that temperature for 30 min and then a solution of N-[(1E)-(3-bromophenyl)(2-cyanopyridin-3 -yl)methylene]-2-methypropane-2-sulfinamide (Example 2, 840 mg, 2.15 mmol) in THF (10 mL) was added dropwise. Stirring was continued for 3 h at −78° C., and then for 1 h at −25° C. The reaction was quenched by the addition of water, the mixture was diluted with ethyl acetate and washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (20 mL) and to this was added 2 M hydrochloric acid in diethyl ether (2.5 mL). The mixture was stirred at room temperature for 22 h and then concentrated. The residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. Purification by column chromatography using a gradient of increasing concentration of ethyl acetate in dichloromethane (0-50%) and finally 5% of 2 M ammonia in methanol in ethyl acetate-dichloromethane (45:50) gave 115 mg (14% yield) of the title compound. 1H NMR (CDCl3) δ 8.62 (dd, 1H), 7.88 (dd, 1H), 7.46 (t, 1H), 7.37 (m, 2H), 7.26 (m, 1H), 7.21 (m, 2H), 7.14 (t, 1H), 6.81 (m, 2H), 3.78 (s, 3H); MS (ESI) m/z 394, 396 [M+1]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=[C:8]([CH3:18])[N:7]=1)=[O:5])C.[NH2:19][C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1>>[CH3:25][N:22]1[CH:23]=[CH:24][C:20]([NH:19][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[CH:9]=[C:8]([CH3:18])[N:7]=2)=[O:5])=[N:21]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(-c2cncnc2)cc(C)n1
Product: Cc1cc(-c2cncnc2)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-pyrimidin-5-yl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 3-Amino-1-methylpyrazole instead of 3-chloroaniline to yield the final compound as a gray crystalline, MS (ISP): m/e=295.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[NH:21][C:20](=[O:22])[NH:19][C:18]=2[C:23]([O:25]CC)=[O:24])[CH2:12][CH2:11]1.[OH-].[Li+].Cl>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[NH:21][C:20](=[O:22])[NH:19][C:18]=2[C:23]([OH:25])=[O:24])[CH2:14][CH2:15]1
Reactant: CCOC(=O)c1[nH]c(=O)[nH]c1CN1CCN(c2ccccc2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1N1CCN(Cc2[nH]c(=O)[nH]c2C(=O)O)CC1
Reaction time: 48 h

Procedure:
The ethyl 2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylate obtained in Example 6 is dissolved in a solution of 3 equivalents of lithium hydroxide in water. The solution is allowed to stand at room temperature for 48 hours before it is neutralized carefully with 2 equivalents of hydrochloric acid. The precipitate which forms is separated by filtration and recrystallized from a mixture of ethanol and ethyl acetate to give 2,3-dihydro-5-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-2-oxo-1H-imidazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[C:13]([C:15]([O:17]CC)=[CH2:16])[N:12]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:10]=2)[CH2:3]1.O.Cl>O1CCOCC1>[F:35][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[N:10]=[C:11]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)[N:12]=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=2)[CH2:3]1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
To a solution of 4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (17 mg, 0.04 mmol) in dioxane (3 mL) was added water (0.2 mL) and HCl (9 μL, 0.11 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvents were evaporate and the residue was partitioned between aqueous sodium bicarbonate and DCM. The organic phase was evaporated to give the title compound (16 mg, 100%).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:6]1)(=O)C.[OH-].[Na+].O>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C@@H:7]2[CH2:8][CH2:9][C@H:5]([OH:4])[CH2:6]2)[CH:11]=1
Reactant: CC(=O)O[C@H]1CC[C@@H](c2cccnc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O[C@H]1CC[C@@H](c2cccnc2)C1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of (1S,3R)-3-(3-pyridyl)cyclopentyl acetate (5.43 g, 26.5 mmol) in MeOH (80 ml) was added 1N NaOH aq. (26 mL) at 4° C., and stirred for 2 h at same temperature. To the reaction mixture was added H2O and then extracted with CH2Cl2 four times, and the combined layers were dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (EtOAc) to yield (1S,3R)-3-(3-pyridyl)cyclopentanol (3.99 g, 92%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=O)[NH2:12])[C:6]=1[Cl:14].CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[C:6]=1[Cl:14]
Reactant: COC(=O)Cc1cccc(C(N)=O)c1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-carbamoylphenylacetic acid methyl ester (0.35 mmol) in 5 mL DCM were added 0.15 mL Et3N followed by trifluoromethanesulfonic acid anhydride (0.70 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at RT. After 30 min, water was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[CH3:8].O.C([OH:14])C.Cl>C(OC(=O)C)(=O)C>[Br:1][C:2]1[C:3]([CH2:10][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCO
Reactant: Cc1cc[n+]([O-])c(C)c1Br
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(CO)c1Br

Procedure:
3-Bromo-2,4-dimethylpyridine-N-oxide (14.7 g) in warm acetic anhydride (150 ml) was added dropwise to acetic anhydride (500 ml) at 125° and the mixture was refluxed for 1/2 hour, allowed to cool and then poured into water/ethanol (4:1, 500 ml). The solution was acidified with dilute hydrochloric acid and evaporated to dryness. The residue was refluxed with 2 N hydrochloric acid (100 ml) for 1 hour, cooled and extracted with chloroform. The aqueous phase was adjusted to pH 12 with sodium hydroxide and was extracted with chloroform, and this chloroform extract was evaporated to a residue which was crystallised from n-hexane to give 3-bromo-2-hydroxymethyl-4-methylpyridine (5.8 g) m.p. 75°-77°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:15]=[O:16])=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][CH2:18][O:14][C:11]1[CH:10]=[C:9]([CH:15]=[O:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=Cc1cc(O)ccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(-c2ccc(Cl)cc2)c(C=O)c1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 125A (0.5 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.771 g) and cesium carbonate (1.4 g) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column purification with 0-5% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22]N=2)[NH:13][S@](C(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[ClH:26]>CO>[ClH:26].[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C:20]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:22][CH:23]=[CH:24][N:25]=2)[NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccn1
Agent: Cl
Solvent: CO
Product: N[C@@H](c1ccc(C(F)(F)F)c(F)c1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)—N—((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-2-methylpropane-2-sulfinamide (100 mg, 0.266 mmol) in MeOH (5 mL) was added hydrogen chloride (0.200 mL, 0.799 mmol) (4.0 M in 1,4-dioxane). The reaction was stirred for 2 h at rt under N2 and then concentrated in vacuo to give the amine as the hydrochloride salt which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=1.Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.CN(C)C=O>O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]2[CH:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]2)=[CH:40][CH:39]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccn1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium hydride (60%, oily, 0.22 g) was added to a mixture of ethyl 4-(2-pyridyl)pyrrole-3-carboxylate (1.10 g), 4-(4-chlorometylphenoxymethyl)-5-methyl-2-phenyloxazole (1.83 g) and N,N-dimethylformamide (25 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)pyrrole-3-carboxylate (2.43 g, yield: 97%) was obtained as an oily substance from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([F:19])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncccc1F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([O:31][CH2:32][CH2:33][S:34][CH3:35])[N:18]=[C:17]([CH2:36][CH3:37])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[OH:40]>[OH-].[Na+].O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([O:31][CH2:32][CH2:33][S:34]([CH3:35])=[O:40])[N:18]=[C:17]([CH2:36][CH3:37])[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCSC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCS(C)=O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
210 mg of 4-tert-butyl-N-[5-(2-chloro-5-methoxyphenoxy)-2-ethyl-6-(2-methylsulphanyl-ethoxy)-pyrimidin-4-yl]-benzenesulfonamide were dissolved in 5 ml of MeOH and 0.2 ml of 1N NaOH. 95 mg of NalO4 dissolved in 0.5 ml of H2O were added thereto and the mixture was stirred at room temperature for 5 hours, whereby a suspension resulted. Then, 0.2 ml of 1N HCl was added and the mixture was subsequently evaporated to dryness. The residue was partitioned between ethyl acetate and 0.1N HCl and worked-up as usual. For purification, the compound was chromatographed on silica gel using ethyl acetate-MeOH (6:1 by vol.) as the eluent. There were obtained 160 mg of (RS)-4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-ethyl-6-(2-methylsulphinyl-ethoxy)pyrimidin-4-yl]-benzenesulfonamide as a white powder. MS: 581 (M).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[N+:17](C1C=CC(OC(F)C(F)(F)F)=CC=1)([O-:19])=[O:18]>S(=O)(=O)(O)O.[N+]([O-])(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1OC(F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g (0.025 moles) of 2-nitrotetrafluoroethoxybenzene or 4-nitrotetrafluoroethoxybenzene are dissolved in 20 ml concentrated sulfuric acid (density, d=1.84 g/ml) and nitrated at 5°-10° C. with a mixture of 1.2 ml nitric acid (d=1.5 g/ml) and 5 ml sulfuric acid (d=1.84 g/ml). After the addition of the nitrating acid, the aforesaid preparation is allowed to heat at room temperature. The preparation, after being left to stand overnight, is then poured onto ice water. The precipitated oil is separated by means of decanting and the aqueous phase is extracted three times with 50 ml ether. The ether extracts and the oil are then combined, washed with sodium bicarbonate solution so as to be acid-free and dried over calcium chloride. After distilling the solvent, 6.6 g (93% of the theoretical yield) dinitro compound (from the 2-nitrotetrafluoroethoxybenzene) or 6.7 g (94% of the theoretical yield) dinitrotetrafluoroethoxybenzene (from the 4-nitrotetrafluoroethoxybenzene) is obtained. The dinitro compound was further processed directly in the following step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g), 4-(2-propoxyethoxy)phenyl borate (0.66 g), 1M potassium carbonate solution (4 ml), ethanol (4 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5 g) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][O:19]3)=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][O:19]3)=[CH:14][C:12]=2[N:13]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCCC3
Reactant: CN(C)CCN
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Yield: 84.7 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.47 mL, 4.3 mmol) was added to a stirred solution of chloride 240 (341 mg, 1.4 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 241 (343 mg, 83%) as a yellow solid: mp (MeOH/EtOAc) 150-152° C.; 1H NMR δ 7.58 (s, 1H, H-10), 7.30 (s, 1H, H-5), 5.79 (br s, 1H, NH), 4.25 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.51-3.56 (m, 2H, CH2N), 2.96 (br t, J=6.0 Hz, 2H, H-6), 2.60 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.02-2.09 (m, 2H, H-7); 13C NMR δ 158.0, 152.9, 143.6, 135.1, 130.0, 126.1, 104.3, 66.9, 57.6, 45.0 (2), 38.7, 25.9, 21.7. Anal. calcd for C14H19N5O2.½H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.1; H, 6.5; N, 23.9%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](=[O:9])[CH3:8])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:21][C:22]([S@@:25](/[N:27]=[C:28](\[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[CH:35][CH:34]=1)/[C:29]([F:32])([F:31])[F:30])=[O:26])([CH3:24])[CH3:23]>C1COCC1>[CH3:24][C:22]([S@@:25]([NH:27][C@:28]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:46])[F:47])=[CH:37][CH:38]=1)([CH2:8][C:7](=[O:9])[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[C:29]([F:30])([F:32])[F:31])=[O:26])([CH3:21])[CH3:23]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[S@](=O)/N=C(\c1ccc(OCCCCCC(F)(F)F)cc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C[C@](N[S@@](=O)C(C)(C)C)(c2ccc(OCCCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
To a solution of 1-(p-tolyl)ethanone (609 mg, 4.31 mmol) in THF (10 mL) was cooled to −78° C. and to this solution was added lithium bis(trimethylsilyl)amide (4.31 mL, 4.31 mmol). The resulting mixture was stirred at −78° C. for 20 min and then Intermediate 8C (620 mg, 1.437 mmol) in THF (3 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1.5 h and then at 0° C. for 1.5 h. The reaction was quenched with NH4Cl and concentrated. The crude product was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes) to afford Intermediate 8D (482 mg, 59%) as the slower eluting diastereomer on silica gel column. LCMS Anal. Calc'd for C27H33F6NO3S 565.21, found [M+H] 566.0.