Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC1.C([O:9][C:10]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[C:19]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC=C)=[O:43])=[CH:37][CH:36]=3)=[C:31]([Cl:48])[CH:30]=2)[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C=C>O1CCOCC1.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:15]([O:14][C:12]([C:11]1[C:10]([OH:9])=[C:22]([C:23]([F:26])([F:24])[F:25])[CH:21]=[CH:20][C:19]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=2)=[C:31]([Cl:48])[CH:30]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)(C)C)cc2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)c(Cl)c2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
Pyrrolidine (0.525 ml, 6.29 mmol) and tetrakis(triphenylphosphine)palladium (0) (41 mg, 0.035 mmol) were added to a solution of tert-butyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-2-chloro-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (960 mg, 1.56 mmol) obtained in Example (13-4) in a mixture of 1,4-dioxane (9.5 ml) and water (0.5 ml), and the mixture was stirred at room temperature for 3 hours. After water was poured into the reaction mixture and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=75/25-40/60) to give the title compound as a white powder (446 mg, yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[CH2:21]([O:24][NH2:25])[CH:22]=[CH2:23].CC([O-])=O.[Na+]>CCO>[CH2:21]([O:24][N:25]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18])[CH:22]=[CH2:23]
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCON=C(CC)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 31.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluorcmethanesulfonamide 22 (316 mg, 1.0 mmol), O-allylhydroxylamine hydrochloride (119 mg, 1.05 mmol) and anhydrous NaOAc (86 mg, 1.05 mmol) in EtOH (5 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with EtOAc/PE, 1:9). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:99 to 1:19) to afford N-[2-(1-allyloxyiminopropyl)-4-chlorophenyl]trifluoromethanesulfonamide 156 (116 mg, 31%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.57, br s, 1H, 7.67, d, J=8.8 Hz, 1H, 7.48, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H, 6.00, m, 1H, 5.42, d, 3J=17.2 Hz, 1H, 5.36, d, 3J=10.4 Hz, 1H, 4.68, d, J=6.0 Hz, 2H, 2.83, q, J=7.6 Hz, 2H, 1.19, t, J=7.6 Hz, 3H. HRMS (M+) 370.0350.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][CH2:16]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:20]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 55.9 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}ethanone (30 mg, 0.072 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (19.4 mg, 56%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.07-7.96 (m, 2H), 7.56-7.48 (m, 1H), 7.44 (dd, J=11.6, 2.2 Hz, 1H), 3.48 (d, J=12.6 Hz, 2H), 3.38-3.33 (m, 4H), 3.23-3.13 (m, 4H), 2.71 (s, 3H), 2.16-2.06 (m, 5H), 2.00 (d, J=11.1 Hz, 2H), 1.78-1.65 (m, 2H); ESI MS m/z 482 [C27H29ClN3O2+H]+; HPLC 98.9% (AUC), tR=10.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[C:12]([Cl:15])(Cl)=O.Cl[C:17]([O:19][C:20](Cl)(Cl)Cl)=[O:18]>C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:17](=[O:18])[O:19][C:20]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:12]=1[Cl:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(Cl)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Oc1ccc(F)cc1Cl)Oc1ccc(F)cc1Cl
Yield: 100 %

Procedure:
2-Chloro-4-fluorophenol (733 g, 5.0 mol) and methylene chloride (2.5 liters) were put in a 5-liter three-neck flask as equipped with a stirrer, and 4N sodium hydroxide aqueous solution (1350 ml) was added thereto and stirred with cooling. To the resulting solution was introduced phosgene as generated by decomposing trichloromethyl chloroformate (148 ml, 243 g, 1.23 mol) on an active charcoal (3.8 g) at a temperature of 40° to 50° C. After introduction of phosgene, the reaction solution was further stirred overnight at room temperature. After the reaction, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (500 ml×2). The organic layers were combined, washed with 1N sodium hydroxide aqueous solution (1000 ml) and water, and thereafter dried with anhydrous magnesium sulfate. The drying agent was removed, and the solvent was removed by distillation under reduced pressure to obtain a white solid of bis (2-chloro-4-fluorophenyl)carbonate (801 g, 5.0 mol ). Yield: 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].[CH3:22][O:23][CH:24]([O:40][CH3:41])[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1>CN(C)C=O>[CH3:22][O:23][CH:24]([O:40][CH3:41])[CH2:25][N:26]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)[C:10]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Reactant: COc1ccc(N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N(CC(OC)OC)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-methoxyaniline (1.9 g) in dimethylformamide (3 ml) was added dropwise to a solution of carbonyidiimidazole (2.51 g) in dimethylformamide (15 ml) at 0° C. After a reaction time at 0° C. of 15 minutes, the reaction was allowed to continue at room temperature for 45 minutes. Then (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (4.1 g) in dimethylformamide (2 ml) was added, and the mixture was heated at 80° C. for 2 hours. After cooling, volatiles were removed and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated brine. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 422.49 (C24H26N2O5); MS (ESI): 423 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:9]=2[CH3:10])=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nnc(-c2ccc(F)cc2)c1C
Product: Cc1c(-c2ccc(F)cc2)nnn1CCC#Cc1ccccn1
Yield: 57.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole (87 mg, 0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 68 mg (0.22 mmol, 58%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a white powder (M.P.=130-131° C.).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: ClCC(CCl)OCc1ccccc1
Solvent: O
Product: CC(C)(C)N1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 80 %

Procedure:
21.9 Parts of 2-benzyloxy-1,3-dichloro-propane, 71.3 parts of tert.-butylamine and 50 parts of water were added to an autoclave and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result, 17.5 parts of 3-benzyloxy-1-(tert.-butyl)azetidine boiling at 94°-96° C. under 2 mm Hg were obtained. The yield was 80%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis are as follows:
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[C:4](=[O:12])[NH:3][C:2]1=[O:13].C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:13])[NH:3][C:4]2=[O:12])[CH2:6][CH2:7]1
Reactant: [BH3-]C#N
Reactant: O=C1CCC2(CC1)NC(=O)NC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCC2(CC1)NC(=O)NC2=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of 1,3-diazaspiro[4.5]decane-2,4,8-trione (5.00 g, 27.4 mmol) in MeOH (91 mL) was added ammonium acetate (6.35 g, 82 mmol), and the mixture was stirred at RT for 25 minutes. To the suspension was added sodium cyanoborohydride (5.17 g, 82 mmol), and the mixture was stirred at RT. After 90 minutes, the flask was cooled, and the contents were quenched by careful addition of aqueous concentrated HCl, adjusting the pH to 7 with solid NaHCO3. The mixture was filtered through a pad of Celite® brand filter aid and concentrated in vacuo. The material was used directly in the next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:10]([O-:12])=[O:11])[NH:7][C:8]=1[CH3:9].[CH3:19]I.O1CC[CH2:23][CH2:22]1>>[Br:3][C:4]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:10]([O:12][CH2:22][CH3:23])=[O:11])[N:7]([CH3:19])[C:8]=1[CH3:9]
Reactant: CI
Reactant: Cc1[nH]c(C(=O)[O-])c(-c2ccccc2)c1Br
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(-c2ccccc2)c(Br)c(C)n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
60% Sodium hydride (320 mg, 8.03 mmol) in mineral oil was added to a solution of 4-bromo-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (1.65 g, 5.36 mmol) in tetrahydrofuran (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then the methyl iodide (0.66 mL, 10.72 mmol) was added at 0° C. and then the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with ice and the solvent was evaporated. The organics were extracted with ethyl acetate and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure to afford ethyl 4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate (1.68 g, 98%) as a liquid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Na+]>C(O)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:9]2[C:10]([CH2:17][CH3:18])=[N:11][C:12]3[C:7]([C:8]=2[O:27][CH:28]([F:30])[F:29])=[C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:25][CH:24]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.11 g), methanol (10 mL), and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 30 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid. The solvent was removed under reduced pressured and the residue purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 95% of organic modifier) to afford title compound as a white solid, 0.040 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:35])[CH2:14][C:15]2[O:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH2:24][CH2:23]3)=[O:21])=[N:18][N:19]=2)(=[O:12])=[O:11])=[C:5]([CH3:36])[CH:4]=1.[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1>CN(C=O)C>[OH:39][C:38]([CH3:41])([CH3:40])[CH2:37][N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][N:25]2[CH2:26][CH2:27][N:22]([C:20]([C:17]3[O:16][C:15]([CH2:14][N:13]([CH3:35])[S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:36])(=[O:11])=[O:12])=[N:19][N:18]=3)=[O:21])[CH2:23][CH2:24]2)[CH2:30][CH2:31]1
Reactant: CC1(C)CO1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCNCC4)CC3)o2)c(C)c1
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(CC(C)(C)O)CC4)CC3)o2)c(C)c1
Temperature: 70 °C

Procedure:
4-methoxy-N,2,6-trimethyl-N-[(5-{[4-(piperidin-4-ylmethyl)piperazin-1-yl]carbonyl}-1,3,4-oxadiazol-2-yl)methyl]benzenesulfonamide (34 mg, 0.066 mmol) and 2,2-dimethyloxirane (1 mL, 13.8 mmol) were dissolved in DMF (1 mL) and the reaction heated to 70° C. in a sealed tube for 6 h. The reaction was cooled and concentrated in vacuo and the crude product purified using prep method B to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(O[O-])=[O:31])C=1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:11][CH2:12][O:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[O:31])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1
Reactant: O=C(O[O-])c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCCS(=O)c1ccc([N+](=O)[O-])cn1)c1cccc(Cl)c1

Procedure:
A solution of 2-(5-nitro-2-pyridinylthio)ethyl-3-chlorobenzoate, (5) [20 mg, 0.059 mmol; prepared according to the method outlined in Scheme 2; 1H NMR (CDCl3): δ 9.22 (d, J=1.8 Hz, 1H), 8.24 (dd, J=2.4 and 9.0 Hz, 1H), 7.95-7.91 (m, 1H), 7.90 (t, J=0.9 Hz, 1H), 7.56-7.51 (m, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.61 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.6 Hz, 2H)] and m-chloroperbenzoate (m-CPBA) 50%, 21 mg, 0.060 mmol) was stirred at room temperature for 1.25 h. The reaction mixture was then diluted with dichloromethane and washed with saturated aqueous solution of NaHCO3 and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)sulfinyl]ethyl-3-chlorobenzoate (6). LCMS: purity: 99%; MS (m/e): 355 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cncc(Br)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
5-Bromonicotinic acid (15.0 g, 74.3 mmol) was dissolved in DMF (200 mL), and the mixture was stirred at room temperature for 3 hours after adding potassium carbonate (15.4 g, 0.111 mol) and methyl iodide (9.25 mL, 0.149 mol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 5-bromonicotinate (10.0 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O.CN([CH:27]=[O:28])C>>[Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH:27]=[O:28])=[C:6]([Cl:8])[CH:5]=1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,5-dichlorophenol (10.0 g, 61.3 mmol) in DMF (120 mL) at 0° C. was added 9.19 g (135 mmol) of imidazole and the dark yellow solution was allowed to stir at 0° C. for 10 min. To this was added TBDMS-Cl (10.18 g, 67.5 mmol) and the solution went from pale yellow to clear in 1 min. The solution was allowed to stir from 0° C. to ambient temperature over 18 h. The mixture was cooled to 0° C. then water (120 mL) was added and stirred for 10 min. The mixture was extracted with EtOAc, washed with water, brine, and dried with Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica gel using EtOAc/heptane (0 to 1:9) as eluent to give 4-(tert-butyldimethylsilanyloxy)-2,6-dichlorobenzaldehyde as a clear liquid. 1H NMR (DMSO-d6, 400 MHz): δ 6.99 (t, J=1.83 Hz, 1H), 6.70 (d, J=1.89 Hz, 2H), 0.73 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1nncc(Cl)c1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichloropyridazin-3-ol (42 g, 250 mmol), 3,4-dihydro-2H-pyran (168 g, 2.00 mol) and p-toluenesulfonic acid (8.8 g, 51 mmol) in tetrahydrofuran (2 L) was heated at reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography (Gradient: 3% to 5% ethyl acetate in petroleum ether). The product was obtained as a white solid. Yield: 42 g, 170 mmol, 68%. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.01 (br d, J=11 Hz, 1H), 4.10-4.16 (m, 1H), 3.70-3.79 (m, 1H), 1.99-2.19 (m, 2H), 1.50-1.80 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=[O:17])[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[CH:15]1[CH:16]=[C:8]([C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:17])[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: NCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C(O)CCNC(=O)c1ccccc1C(=O)O
Reaction time: 3 h
Yield: 90 %

Procedure:
25 grams (0.28 mole) of β-alanine and 41.6 grams (0.28 mole) of phthalic anhydride were heated at 150° C. while stirring for three hours and then cooled. On recrystallizing with ethyl acetate, N-phthalyl-β-alanine was obtained in 90% yield (55 grams).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12](I)=[CH:11]2)(=O)=O)C=CC=CC=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]#[CH:37])[CH:33]=[CH:34][CH:35]=1>CO>[C:36]([C:32]1[CH:31]=[C:30]([NH:29][C:18]2[C:13]3[C:12]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[CH:11][NH:10][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:35]=[CH:34][CH:33]=1)#[CH:37]
Reactant: C#Cc1cccc(N)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ncnc21
Reactant: OB(O)c1cccs1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(-c4cccs4)c23)c1
Yield: 40 %

Procedure:
Following the procedure described in Example 26, the title compound was prepared in 40% yield from 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine and thiophene-2-boronic acid followed by coupling with m-aminophenyl acetylene (27 mg, 0.233 mmoles) in methanol: MP: 230-232° C.; TS-MS: 317 (MH+); anal. RP18-HPLC RT: 5.614 minutes.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]([OH:9])[C:5]([F:8])=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCOc1c(F)ccc(F)c1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCOc1c(F)ccc(F)c1OCCCCCC
Yield: 69.6 %

Procedure:
3,6-Difluoro-2-hexyloxyphenol (25 g, 0.11 mol) was dissolved in dry, distilled ethanol (350 ml) under a stream of nitrogen. 1-Bromohexane (45.35 g, 0.275 mol, 2.2 eq) and potassium carbonate (75.1 g, 0.54 mol, 5.5 eq) were added and the reaction mixture was stirred vigorously under reflux for 2 days. Dichloromethane (300 ml) was added to the orange reaction mixture, which was then filtered through a bed of celite to remove the potassium carbonate. The filtrate was washed with water (3×100 ml), and dried with magnesium sulphate. Removal of the solvent in vacuo yields 24.07 g of pale brown oil. This was distilled under reduced pressure to yield a colourless oil (18.82 g, 80%), bp 102° C., 0.2 mbar; (Found: C, 68.8; H, 9.05. C18H28O2F2 requires C, 68.76; H, 8.98; O, 10.18; F, 12.08%); vmax(film)/cm−1 2956 and 2860 (C—H aliph), 2361 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.33 (4H, m, 2×—CH2—), 1.46 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.08 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 6.73 (2H, dd, 3J(H,F)=14.5, 4J(H,F)=7.2 Hz, C5,6H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.41 (CH3), 23.01 (CH2), 25.87 (CH2), 30.45 (CH2), 31.98 (CH2), 74.99 (CH2), 110.15 (CH, dd, 2J(C,F)=17.7, 3J(C,F)=4.3 Hz, C5,6), 141.94 (C, dd, 2J(C,F)=11.0, 3J(C,F)=7.0 Hz, C2,3), 153.12 (C, dd, 1J(C,F)=244.2, 4J(C,F)=3.6 Hz, C1,4); m/z (FAB+); 314 (M+, 99%), 146 (M+-alkoxy chains, 100%), 85 (79), 55 (40%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH:30](=O)[CH:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: CC(C)C=O
Product: CC(C)CN1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for example 26 using (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) and iso-butyraldehyde as starting materials. Purified by prep HPLC (low pH).