Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][O:17]C3CCCCO3)[N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]=[C:12]([CH2:14][CH2:15][CH2:16][OH:17])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(CCCOC3CCCCO3)ncn2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: OCCCc1cc(-c2ccc(Cl)cc2)ncn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
3.22 g (9.67 mmol) of 4-(4-chlorophenyl)-6-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]pyrimidine, prepared in stage 5.3., are dissolved in 32 ml of methanol, and 16 ml of a 4N solution of hydrochloric acid in dioxane are added. The mixture is stirred at ambient temperature for 1.5 hours and then 150 ml of a half-saturated aqueous sodium hydrogencarbonate solution are added portionwise. Extraction is carried out with 350 ml of ethyl acetate. The organic phase is washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to produce 2.33 g (9.36 mmol) of product in the form of a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Solvent: ClCCl
Product: Clc1ccc2ccc(COc3ccc4c(c3)C(Cl)c3ccccc3CO4)nc2c1

Procedure:
While stirring under ice cooling, 0.34 ml of thionyl chloride was added to 1.88 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine dissolved in 21 ml of methylene chloride and the mixture was stirred at the same temperature for 30 minutes to produce 11-chloro-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine. After the solvent was removed from the reaction mixture, the residue was dissolved in 20 ml of methylene chloride, 1.25 ml of triethylamine and 1.69 ml of methyl thioglycolate were added to the solution while stirring under ice cooling and the mixture was stirred at room temperature for 7 hours. After the solvent was removed from the reaction mixture, 60 ml of ethanol and 45 ml of a 1N-sodium hydroxide aqueous solution were added to the residue and the mixture was stirred at room temperature for 1 hour. After the solvent was removed, 150 ml of ice water was added to the residue, the mixture was adjusted to about pH 2 with 1N-hydrochloric acid and then the aqueous layer was extracted with 150 ml of methylene chloride. After the organic layer was washed with water, the residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 0.54 g of the title compound as white powder.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[N:14]([CH:37]=[CH:38][N:39]=3)[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=4)[CH:19]=3)[N:17]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[CH:19]=[C:18]([C:16]3[N:17]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[CH:6][CH:7]=4)[C:13]4[N:14]([CH:37]=[CH:38][N:39]=4)[CH:15]=3)[CH:23]=[CH:22][CH:21]=2)=[O:36])=[CH:31][CH:30]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3)cn3ccnc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(C(=O)O)cc4)n3)c2)cc1

Procedure:
A mixture of 4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoic acid ethyl ester (20) (30 mmol), 1N aqueous sodium hydroxide (50 mL), and ethanol (80 mL) is heated at reflux for 1.5 hrs. The mixture is cooled and the ethanol removed in vacuo. The residue is diluted with 1N sodium hydroxide (30 mL) and washed with ethyl acetate (2×100 mL). The aqueous layer is brought to pH 6 with 3 N HCl, and the mixture is filtered to give 4-{6-[3-(4-tert-butyl-benzoylamino)phenyl]imidazo[1,2-a]pyrazin-8-ylamino}benzoic acid (21) as a cream solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12]>ClCCl>[CH:1]([NH:16][C:15]1[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=1[CH:11]([CH3:13])[CH3:12])=[O:3]
Reactant: O=CO
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,6-diisopropylaniline (17.729 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was recrystallized from diethyl ether (500 mL) to afford N-formyl-2,6-diisopropylaniline 8e3 as a white solid (13.96 g, 68%). 1H NMR (CDCl3, 300 MHz): δ=8.47-8.01 (m, 1H, CHO), 7.36-7.18 (m, 3H), 6.79 (broad s, 1H, NH), 3.06-3.26 (m, 2H), 1.21 (d, J=7 Hz, 12H). 2 (a) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liebigs Ann./Recueil 1997, 365-374. (b) J. Liebscher, Methoden der Organischen Chemie (Houben-Weyl) 4th ed. (Ed.: E. Schaumann), Georg Thieme Verlag, New York, 1994 Band E 8b, Heratrene III/Part 2, p. 48. (c) Hromatka, O. U.S. Pat. No. 2,160,867, 1939.3 Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem. Soc. 1988, 110, 6818-6825.
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][N:23]=3)[N:20]=2)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[H-].[Na+].Cl.Br[CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:44][CH2:45][N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[N:23]=3)[N:20]=2)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Reactant: BrCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (70 mg, 0.13 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 14 mg, 0.385 mmol) was added and the reaction was stirred at 0° C. for 10 min. 1-(2-Bromoethyl)pyrrolidine hydrochloride (41 mg, 0.19 mmol) was added and teh reaction was stirred at 0° C. for 30 min then warmed to room temperature. The reaction mixture was stirred for 2 h then quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 75 mg (91%) of 2-[6-fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=643.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13](N)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I:26]CI.N(OCCC(C)C)=O.Cl>[Cu]I.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([I:26])[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: ICI
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NCc2cnc(I)nc2-c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluorophenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:23]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>>[CH2:23]([N:30]([S:31]([C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:33])=[O:32])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 1640 166° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>>[F:18][C:19]1[CH:34]=[C:33]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:32]=[CH:31][C:20]=1[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(F)c1
Yield: 66.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.5 g, 4.8 mmol) was reacted with tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (2.6 g, 7.3 mmol) to afford the desired product (1.5 g, 65%) as a brown solid: ESI MS m/z 469 [C25H25FN2O4S+H]+.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(N[C:39]1[CH:44]=[CH:43][C:42]([C:45](=[O:50])NCCC)=[CH:41][CH:40]=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[C:42]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc2c(c1)CN(C(=O)c1ccccc1)C2)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (d, J=8.8 Hz, 1H), 7.59-7.67 (m, 3H), 7.11-7.52 (m, 9H), 4.68-4.84 (m, 8H); MS (ESI(+)) m/e 384 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:31][CH2:30][CH2:29][O:28]2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[F:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:28][CH2:29][CH2:30][O:31]2)=[CH:23][C:20]=1[CH:21]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)[OH:22]
Reactant: CC1(c2ccc(F)c(C=O)c2)OCCO1
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C(O)c1cc(C2(C)OCCO2)ccc1F
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (1.56 g, 9.83 mmol) in THF (50 mL) cooled to −78° C. was added 1.6 M n-butyl lithium (6.76 ml, 10.8 mmol) drop-wise and stirred for 30 min. Next a solution of Intermediate 416.2 (2.46 g, 11.8 mmol) in THF (15 mL) was added drop-wise and stirred for 5 min before allowing the mixture to warm to 23° C. The reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3×50 mL). The organic layer was washed with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 3.6 g of Intermediate 416.3. 1H NMR (400 MHz, CDCl3) δ ppm 1.59 (s, 3H) 3.62 (s, 3H) 3.66-3.78 (m, 2H) 3.91-4.04 (m, 2H) 6.22 (s, 1H) 6.94-7.07 (m, 1H) 7.32-7.49 (m, 5H) 7.70 (dd, J=7.25, 2.42 Hz, 1H) 7.97-8.05 (m, 2H).
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:9]=2)C(C)=CC=1.Cl.NO.[OH-].[K+].[OH-].[Na+]>C(O)C.O.O>[NH2:3][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:9]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(N)nc(CCCCCCCCCCOCc2ccccc2)c1OCc1ccccc1

Procedure:
To stirred solution containing 343 mg (0.63 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-benzyloxy-4-methyl-6-(10-benzyloxydecyl)-pyrimidine (7) in 10 mL of ethanol-water 9:1 were added 500 mg (7.19 mmol) of hydroxylamine hydrochloride followed by 400 mg (7.14 mmol) of potassium hydroxide. The reaction mixture was then stirred at reflux under argon atmosphere overnight. A second portion of 500 mg (7.19 mmol) of hydroxylamine hydrochloride was added and the reaction mixture was stirred overnight at reflux under argon atmosphere. The reaction mixture was then poured into 70 mL of water and then basified to a pH 9-10 with a 1N NaOH solution. The mixture was extracted with two portions of 70 mL of dichloromethane. The combined organic solution was washed with a portion of 70 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with acetone-hexanes 2:1 gave the expected product as a colorless oil: yield 153 mg (52%). 1H-NMR (CDCl3) δ 7.48-7.37 (m, 10H), 5.17 (br., 2H), 4.69 (s, 2H), 4.45 (s, 2H), 3.41 (t, 2H, J=6.8), 2.55 (t, 2H, J=7.6), 2.26 (s, 3H), 1.63-1.53 (m, 4H), 1.27 (m, 12H); 13C-NMR (CDCl3) δ 164.85, 161.14, 158.88, 142.81, 138.71, 136.77, 129.16, 128.59, 128.26, 75.91, 72.83, 70.50, 31.90, 29.77, 29.22, 29.55, 29.45, 29.41, 28.44, 28.19, 19.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−5°−0° C.) of 6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol, example 78) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and is stirred for 15 min. Iodomethane (215 μL, 3.45 mmol) is added to the reaction mixture and stirred for 2 hrs. Quenched reaction with sat NH4Cl soln and diluted with EtOAc. Washed organic layer with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 30% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 206 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH2:8]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][C:24]=3[F:32])=[CH:20][C:19]=2[CH:33]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:8]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([N:1]4[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]4)[CH3:30])=[CH:25][C:24]=3[F:32])=[CH:20][C:19]=2[CH:33]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of azetidine-3-carboxylic acid (0.015 g, 0.15 mmol), 1-(4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)ethanone (0.050 g, 0.15 mmol), acetic acid (0.013 mL, 0.22 mmol) in methanol (3.0 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.037 g, 0.17 mmol) was added and the mixture was stirred for 1 h at room temperature. Evaporation and purification by flash chromatography (5% AcOH in CHCl3 and MeOH). The resulting solid was suspended in in an aqueous buffered solution (pH 6, phosphate buffer) and sonicated. The solids were collected by filtration, washed with water and Et2O to give title compound [hS1P1 EC50=313 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=7.9 Hz, 1H), 7.51-7.59 (m, 2H), 7.14-7.34 (m, 9H), 4.04 (s, 2H), 2.92-3.50 (m, 6H partially overlapping with HDO signal), 1.11 (d, J=6.3 Hz, 3H). MS (ESI) m/z: Calculated; 429.2 Observed: 430.2 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Li+].[CH3:14]C([N-]C(C)C)C.O.CCOCC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cccnc1
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cccnc1
Yield: 62.7 %

Procedure:
Ethyl 3-pyridylacetate (12.2 g, 73.9 mmol) in THF (30 ml) was added to LDA (81 mmol) in THF (150 ml) over 10 min at -78° C. After 1 h Mel (5.1 ml, 81 mmol) was added to the yellow suspension and the mixture brought to room temperature. H2O (300 ml) and ether (300 ml) was added, the mixture separated, and the organic layer washed with H2O and brine, dried and evaporated to give ethyl 2-(3-pyridyl)propanoate (8.3 g) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1cc(CN)ccc1CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(CNc2ccccc2[N+](=O)[O-])ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
2-Fluoronitrobenzene (0.358 mL, 3.4 mmol, 1.0 eq.), 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl amine (750 mg, 3.4 mmol) and anhydrous potassium carbonate (471 mg, 3.4 mmol, 1.0 eq.) were combined in dry THF (35 mL) then allowed to stir 48 h at ambient temperature. The reaction mixture was filtered through a bed of diatomaceous earth then the solvent was removed under reduced pressure. The crude oil was purified by flash chromatography (eluting with 20:1 CHCl3:MeOH, 0.5% TEA) to give the desired product as a right orange oil (676 mg, 58%).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[C:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)#[N:14].NO.C([BH3-])#N.[Na+].Cl>CO.CCOCC.O>[CH2:2]([O:9][NH:10][CH2:18][CH2:17][CH2:16][CH2:15][C:13]#[N:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCCCC=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: NO
Agent: [BH3-]C#N
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: N#CCCCCNOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
O-Benzylhydroxylamine hydrochloride (4.7 g, 29.7 mmol) was mixed with 5 mL of water and 11 mL of methanol at 0° C. and the apparent pH adjusted to 4.7 using 6N potassium hydroxide. The aldehyde, 4-cyanobutanal (1), [Izawa, supra] (2.6 mL, 27 mmol) was added to the hydroxylamine and the mixture allowed to warm to room temperature. The pH was maintained by the addition of further 6N potassium hydroxide. After 1 h, the reaction was cooled to 0° C., and sodium cyanoborohydride (1.26 g, 20 mmol) was added. The pH was adjusted to 3 and maintained by addition of saturated hydrogen chloride in methanol. When the pH stabilized, the reaction was warmed to room temperature and stirred for 3 h at a pH of 3. The reaction mixture was then poured into ether and made basic with 6N potassium hydroxide. The aqueous layer was extracted with ether (3× 50 mL). The extracts were combined, washed with brine, and dried over magnesium sulfate. The solvents were removed and the resulting liquid distilled at 150°-151° C. (0.6 mm) to give 4.65 g (84%) of (3): 1H NMR (CDCl3): δ 1.56-1.85 (m, 4H), 2.20-2.45 (m, 2H), 2.85-3.10 (m, 2H), 4.7 (s, 2H), 5.53 (t, 1H), 7.4 (s, 5H); IR (CHCl3): 3040, 2930, 2860, 2240, 1500, 1450, 1430, 1360, 1210; Anal. Calcd. for C12H16N2O: C, 70.54; H, 7.91. Found: C, 70.51; H, 7.91.