Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][CH:3]=1.[I:14][CH2:15][CH3:16]>CC(C)=O>[I-:14].[CH2:15]([N+:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[C:2]([CH3:1])=[CH:3][S:4][C:5]=12)[CH3:16]
Reactant: CCI
Reactant: Cc1csc2nc3ccccc3n12
Solvent: CC(C)=O
Product: CC[n+]1c2ccccc2n2c(C)csc21
Product: [I-]
Reaction time: 18 h

Procedure:
153 mg of 3-methyl[1,3]thiazolo[3,2-a]benzimidazole were solubilised in acetone (5 mL). Then 328 μl, (5 eq) of iodoethane were added and the solution stirred under reflux. After 18 h, 9-ethyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide was recovered as a white powder (267 mg, 96%) by filtration. Mp 268° C.; 1H NMR (300 MHz, MeOD) δ=1.64 (3H, t, J=7.3, CH3), 2.95 (3H, d, J=CH3), 4.66 (2H, q, J=7.3, CH2), 7.37 (1H, q, J=1.3, H5), 7.66-7.81 (2H, m, Ar), 8.01-8.04 (1H, m, Ar), 8.27-8.30 (1H, m, Ar); 13C NMR (75 MHz, MeOD) δ=13.21, 14.25, 43.61, 112.19, 113.66, 114.93, 126.26, 128.32, 129.05, 135.29, 137.28, 155.62.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:49][S:50]([CH3:52])=O>>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][CH2:49][S:50][CH3:52])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CS(C)=O
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
5 g of N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (11.0 mmol) dissolved in 21 mL dry DMSO was treated with 10 mL acetic acid and 32 mL acetic anhydride, and stirred for 48 h at room temperature. The crude reaction mixture was then neutralized by adding a K2CO3 solution, and extracted with ethyl acetate (100×3 mL). The combined organic extract was then washed with saturated NaHCO3 solution, dried over Na2SO4 and concentrated under vacuum. Then reaction mixture was purified by a silica gel column chromatography resulting the product 11 as white powder (3.9 g, 69% yield; Rf=0.35, CH2Cl2:MeOH/20:1). HR-MS: Obs. m/z 512.2344 cald. for C22H38O5N5SiS 512.2363 [M+H]+. 1H-NMR (CDCl3): δH 12.0 (s, 1H), 8.95 (brs, 1H), 8.09 (s, 1H), 6.24 (t, J=6.8 Hz, 1H), 4.73 (m, 2H), 4.66 (m, 1H), 4.16 (m, 1H), 3.81 (m, 2H), 2.76 (m, 1H), 2.59 (m, 1H), 2.54 (m, 1H), 2.21 (s, 3H), 1.29 (m, 6H), 0.91 (s, 9H), and 0.10 (s, 6H) ppm.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][C:22]=1[OH:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:34]([O:38][C:39](=[O:50])[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48]O)[CH2:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CO.C(OCC)(=O)C>[C:34]([O:38][C:39](=[O:50])[NH:40][CH:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:33][C:22]2[CH:23]=[N:24][C:25]3[C:30]([C:21]=2[O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH2:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: COc1ccc2ncc(O)c(OCc3ccccc3)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)c(OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 116.4 %

Procedure:
Diethyl azodicarboxylate (5.48 g, 31.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol (4.44 g, 15.73 mmol, 1.0 eq), [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (5.76 g, 23.59 mmol, 1.5 eq) and triphenylphosphine (8.25 g, 31.46 mmol, 2.0 eq) in tetrahydrofuran (150 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: ethyl acetate:methanol, 10:0 to 9:1, v/v) to afford {1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a light brown viscous oil (9.31 g, 88% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:15]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[C:4]([CH:14]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1CNC(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
6.04 g of t-Butyl N-(2-methoxybenzyl)carbamate was dissolved in 50 ml of acetonitrile, and 4.6 g of N-bromosuccinimide was added. After stirring was continued at room temperature for 3 hours, the solvent was evaporated. The residue was dissolved in ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with a mixed solution of methyl t-butyl ether and hexane, to give 6.97 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2cccc(O)c2)CC1
Reaction time: 14 h

Procedure:
1-(3-Hydroxyphenyl)piperazine (200 mg) was dissolved in tetrahydrofuran (10 ml), the solution was added with saturated aqueous sodium hydrogencarbonate (10 ml) and benzyl chloroformate (176 μl) at room temperature, and the mixture was stirred for 14 hours. The reaction mixture was added with ethyl acetate for extraction, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (342 mg).
Reaction SMILES: C[N:2]([CH3:19])[C:3]([C:5]1[N:14]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:19])[N:14]([CH:15]5[CH2:16][CH2:17][CH2:18]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 54.2 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclobutyl-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.718 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (262 mg, 0.789 mmol, 1.1 eq) to give 3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (218 mg, 50% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H) 1.62 (br. s., 1H) 1.67 (br. s., 1H) 1.77-2.07 (m, 6H) 2.41-2.58 (m, 2H) 3.17 (s, 6H) 3.19-3.29 (m, 2H) 3.64 (br. s., 1H) 4.28 (br. s., 2H) 4.54 (br. s., 1H) 5.01 (dq, J=8.84, 8.67 Hz, 1H) 6.50 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H) 8.42 (d, J=2.02 Hz, 2H) 8.67 (d, J=9.09 Hz, 1H) 8.78 (s, 1H); MS m/z 574.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1cc(N2CCCCC2)c(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCCC1
Yield: 50.9 %

Procedure:
A mixture of 3,6-dichloro-4-(piperidin-1-yl)pyridazine (0.55 g, 2.4 mmol), benzoyl hydrazine (370 mg, 2.7 mmol), triethylamine (375 ml, 2.7 mmol) and p-toluenesulphonic acid monohydrate (510 mg, 2.7 mmol) in xylene (mixture of isomers, 10 ml) was stirred and heated at reflux under nitrogen for 24 hours. Upon cooling the xylene was removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 30% ethyl acetate/dichloromethane to afford the undesired regioisomer (less polar) (177 mg, 23%) and the title compound (383 mg, 50%) (more polar). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 1.62-1.86 (6H, m), 3.09-3.13 (4H, m), 7.42 (1H, s), 7.50-7.60 (3H, m), 8.40-8.44 (2H, m).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Reactant: N#Cc1ccc(Br)cc1
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccc(F)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with 4-bromobenzonitrile using the procedure described for 2a. MS (ESI, pos. ion) m/z: 354 (M+1).
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH3:22])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14][CH2:13]1>O1CCOCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]=[O:2])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:14][CH2:13]1
Reactant: O=[Se]=O
Reactant: Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Selenium dioxide (1.73 g, 15.63 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (2.95 g, 7.82 mmol) in dioxane (200 mL) and the mixture heated to reflux. After 8 h, the reaction mixture was filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→40% ethyl acetate/dichloromethane) gave the title compound (2.56 g). MS 392.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.69 (s, 1H), 7.68 (s, 1H), 7.13-7.06 (m, 2H), 6.96-6.93 (m, 1H), 6.26 (d, J=6.1 Hz, 1H), 5.56 (d, J=14.2 Hz, 1H), 4.91 (dd, J=9.8, 6.6 Hz, 1H), 4.13-4.08 (m, 1H), 3.02 (t, J=11.2 Hz, 1H), 2.43 (d, J=13.4 Hz, 1H), 2.28 (dd, J=24.5, 12.1 Hz, 1H), 2.18-1.16 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:20]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of pyridin-4-ylmethanol (21.8 g, 0.20 mol) in CH2Cl2 (200 mL) were added Et3N (30.0 g, 0.30 mmol) and TBSCl (45.0 g, 0.30 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, then quenched with water. The organic phase was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford 4-((tert-butyldimethylsilyloxy)methyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=[O:17])([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:13])[C:9]([O:12][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[C:10]([O:11][CH2:4][C:3]3[CH:7]=[CH:8][C:9]([O:17][CH3:14])=[CH:10][CH:2]=3)[C:2]=2[Cl:1])=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Cl)c(O)c(O)c1Cl
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2cc(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c2Cl)cc1
Temperature: 0 °C
Yield: 156.1 %

Procedure:
To a solution of 2,5-dichloro-3,4-dihydroxybenzoic acid (2.4 g) in dimethylformamide (20 ml) are added potassium carbonate (4.90 g: 3.6 Eq.) and p-methoxybenzyl bromide (7.14 g: 3.6 Eq.). To the stirring mixture are added at room temperature every 2 hours potassium carbonate (1.6 g: 1.2 Eq.) and p-methoxybenzyl bromide (2.3 g: 1.2 Eq.). The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography giving 2.5-dichloro-3,4-bis(p-methoxybenzyloxy)benzoic acid p-methoxybenzyl ester (4.9 g) from the fraction eluting with toluene: ethyl acetate (40:1). Yield: 78%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)(=[O:19])=[O:18])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Solvent: CC(=O)O
Product: Cc1cnc(Nc2cccc(S(=O)(=O)N3CCN(C)CC3)c2)nc1N
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ˜9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (˜0.42 g) used in the next step without purification. MS (ES+): m/z 363 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and iPr2NEt (0.19 mL, 0.95 mmol) in CH2Cl2 (10 mL) was added 3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixture was allowed to stir at room temperature for 0.5 h at which time it was diluted with CH2Cl2 (20 mL). The organic layer was washed with aq. HCl (10 mL, 1 M), 9% aq. Na2CO3 (10 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:11][OH:12])[C:9]#N)[CH:5]=[CH:6][CH:7]=1.[OH-:13].[K+].C[O:16][CH2:17][CH2:18]O.Cl>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:11]/[OH:12])/[C:9]([O:16][CH2:17][CH3:18])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(=NO)c1cccc(Br)c1
Reactant: COCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)/C(=N\O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 2-(3-bromophenyl)-2-(hydroxyimino)acetonitrile (19.0 g), 4N aqueous solution of potassium hydroxide (100 ml) and 2-methoxyethanol (100 ml) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added to make the solution acidic and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (200 ml) and concentrated sulfuric acid (catalytic amount) was added. The reaction mixture was heated under reflux for 48 hours, cooled to room temperature, poured into an aqueous saturated solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2-(3-bromophenyl)-2-(hydroxyimino)acetate (3.31 g, yield 14%) as a pale-brown oil from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[C:5]([F:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:51]=[CH:50][C:33]([C:34](Cl)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)=[CH:32][CH:31]=1>ClCCl>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]([NH:18][C:10]2[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]3[C:5]([F:20])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:19])[N:9]=2)([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC1(C)OC(N)=N[C@](C)(c2nc(Br)ccc2F)C1(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a solution of (R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (106 mg, 0.301 mmol) and triethylamine (60.9 mg, 0.602 mmol) in dichloromethane (3 ml) was added solid 4,4′-dimethoxytrityl chloride (112 mg, 0.331 mmol) under argon atmosphere. The green solution was stirred at rt for 2 hrs and was then evaporated in vacuo. The crude product was taken up with ethyl acetate and washed with aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. Filtration over silica gel (4.4 g, toluene/ethyl acetate 6:4) afforded the title compound as a blue-gray foam (202 mg, 96%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[N:50]=[CH:49][C:48](O)=[CH:47][N:46]=1>O1CCCC1.C(OCC)(=O)C>[Cl:44][C:45]1[N:50]=[CH:49][C:48]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:47][N:46]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(Oc2cnc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 100 mg (0.766 mmol) of 4-hydroxy-1-methyl piperidine in 1.5 ml of tetrahydrofuran, 155 mg (1.53 mmol) of di-tert-butyl azocarboxylic acid, 402 mg (1.53 mmol) of triphenylphosphine and 0.170 ml (1.53 mmol) of 2-chloro-5-hydroxypyrimidine were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the reaction solution was extracted with 1 N hydrochloric acid. 1 N sodium hydroxide aqueous solution was added to the aqueous layer to make its pH 10 and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to provide 152 mg of the title compound as a white solid (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:32])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl)(=[O:25])=[O:24]>C(N(C(C)C)C(C)C)C>[CH3:21][N:22]([CH3:32])[S:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:24])=[O:25]
Reactant: CN(C)S(=O)(=O)CCCCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 92.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N,N-dimethyl-5-chloropentanesulfonamide (470.2 mg, 2.20 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N,N-dimethyl-5-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]pentanesulfonamide (857.7 mg) as a yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 92.4%).