Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1.CON(C)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([Li])(C)(C)C>C1COCC1>[C:24]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([OH:20])=[O:19])[N:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(=O)c3ccccc3)nc(C(=O)O)c2C1
Temperature: -78 °C
Yield: 45.1 %

Procedure:
Under a nitrogen atmosphere Compound 1I (0.15 g, 0.43 mmol) was dissolved in THF (2 mL) and N-methoxy-N-methylbenzamide (0.14 g, 0.86 mmol) was added. The resulting solution was cooled to −78° C. and tert-Butyl lithium (1.7M in THF, 1.02 mL, 1.73 mmol) was added dropwise. The resulting mixture was stirred and cooled for 1 h and quenched with NH4Cl saturated solution. The solid was removed by filtration and the filtrate was concentrated, acidified to pH 6 with 5% TFA and extracted with 20% i-PrOH/DCM. The organic layer was concentrated, diluted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give product 25A (0.072 g, 45%). LCMS (+ESI) m/z 372.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20](=[O:25])[C:19]=1[CH2:26][NH:27][C:28](=[O:54])[C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[C:30]=1[CH3:53].C([O-])([O-])=O.[Na+].[Na+]>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:7]([C:6]1[CH:9]=[C:2]([C:33]2[CH:32]=[C:31]([N:44]([CH2:51][CH3:52])[CH:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[C:30]([CH3:53])=[C:29]([C:28]([NH:27][CH2:26][C:19]3[C:20](=[O:25])[NH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])=[O:54])[CH:34]=2)[CH:3]=[CH:4][C:5]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:8]
Reactant: N#Cc1cc(Br)ccc1CN1CCOCC1
Reactant: CCN(c1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)c(C#N)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 5.9 %

Procedure:
To a stirred solution of 5-bromo-2-(morpholinomethyl)benzonitrile (190 mg, 0.68 mmol) and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (200 mg, 0.45 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (0.81 mL, 1.63 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (52 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (16 mg, 6%). LCMS: 598.20 (M+1)+; HPLC: 89/15% (@254 nm) (Rt; 4.039; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase; A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.20 (t, 1H), 8.15 (s, 1H), 7.94 (d, 1H, J=6.8 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.31 (s, 1H), 5.86 (s, 1H), 4.29 (m, 2H), 3.84-3.82 (m, 2H), 3.66-3.58 (m, 6H), 3.32 (m, 5H), 3.11-3.03 (m, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.65-1.51 (m, 4H), 0.82 (t, 3H, J=6 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH3:17][NH:18][OH:19]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:18]([CH3:17])[OH:19])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNO
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)O)n1

Procedure:
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII) was prepared from 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and N-methyl-hydroxylamine hydrochloride as described in Example 13 (90% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 8.93 (1H, s), 6.92-6.43 (2H, m), 3.23-3.07 (7H, m), 1.55-1.38 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z) 241 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C>C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
tert-Butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (691 mg, 2.00 mmol) was dissolved in ethyl acetate (50 ml), and a solution of 4 N hydrogen chloride in ethyl acetate (11 ml) was added thereto, followed by stirring at room temperature for 1 hour and half. Diethyl ether (20 ml) was poured to the reaction mixture, and a solid was separated by filtration, which was dissolved in an aqueous 1 N sodium hydroxide solution (7 ml). Water was poured to the reaction mixture, and the resulting solution was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 396 mg (80.8%) of the desired product as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10]O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.P(Br)(Br)[Br:13].O>O1CCCC1>[Br:13][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2c(c1)CCO2
Solvent: O
Solvent: C1CCOC1
Product: BrCc1ccc2c(c1)CCO2
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
To a solution of (2,3-dihydrobenzofuran-5-yl)methanol (29.0 g, 0.193 mol) in tetrahydrofuran (150 mL) was added phosphorous tribromide (34.8 g, 0.129 mol) under ice/salt-cooling. The mixture was stirred for 20 minutes and then poured into water. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound (yield 27.6 g, 91%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH2:7]OS(C)(=O)=O)[CH2:4][CH2:3]1.[CH2:13]([NH:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:7][C@@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)[CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OC[C@H]1CCC(=O)N1
Reactant: OCCNCc1ccccc1
Product: O=C1CC[C@H](CN(CCO)Cc2ccccc2)N1
Temperature: 130 °C
Yield: 98.3 %

Procedure:
A mixture of (−)-methanesulfonic acid (R)-5-oxo-pyrrolidin-2-ylmethyl ester (10.53 g, 54.5 mmol) and 2-(benzylamino)ethanol (32.58 g, 215.5 mmol) was heated at 130° C. in a microwave oven (Personal Chemistry Emrys™ Optimizer) for 45 minutes. The residue was partitioned between water and DCM, the organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH 95/5 respectively) to afford the title compound as yellow oil (13.3 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(NCCc2cccc(OC)c2)cc1

Procedure:
A solution of (3-methoxy-phenyl)-acetyl chloride (5.0 g) in ethyl acetate (85 mL) was added to a solution of 4methoxy-phenylamine (3.33 g) in ethyl acetate (50 mL). After 18 h the reaction was poured into water (150 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated. The resulting residue was dissolved in tetrahydrofurane (100 mL) then lithium aluminum hydride (5.2 g) was added in small portions over 30 minutes. After 18 h the reaction was slowly poured onto 200 mL of ice. The mixture was filtered through a pad of celite and the collected filtrate was extracted with ethyl acetate (300 mL). The organic extract was dried over sodium sulfate, filtered through celite and concentrated to give the title compound. MS: 258.3 (MH+); HPLC tR: 1.98 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1([CH3:21])[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9][N:8]([CH3:20])[CH2:7]1)[CH:4]=[CH2:5].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[CH2:25]>CN(C=O)C>[CH2:3]([C:6]1([CH3:21])[C:11]2[N:12]([CH2:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH2:23])[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9][N:8]([CH3:20])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Reactant: C=C(CBr)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(=C)c1ccc(F)cc1)c1ccc(C)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
To a stirred suspension of sodium hydride (0.236 g, 5.9 mmol) in dry DMF (5 mL) at 0° C. was added 4-allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 3.937 mol, in dry DMF 2 mL). After addition was complete, reaction mixture was stirred at 0° C. for an additional 10 min. 1-(1-Bromomethyl-vinyl)-4-fluoro-benzene (1.09 g, 5.118 mmol) in dry DMF (3 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (2×50 mL). The organic layer was repeatedly washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by chromatography on neutral aluminum oxide (eluting with EtOAc:Hexanes, 1:99) to obtain 700 mg of 4-allyl-5-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:30]1[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[N:32][CH:31]=1.N>ClCCl>[N:30]1[CH:35]=[C:34]([C:36]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:37])[CH:33]=[N:32][CH:31]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: O=C(Cl)c1cncnc1
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cncnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 0.044 g of 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.2 mL of triethylamine in 3 mL of dichloromethane was added 0.030 g of pyrimidine-5-carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min. The organic layer was separated, the aqueous layer extracted with two additional 20 mL portions of chloroform and the combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol in ethyl acetate gave 0.030 g of 1,3-dihydro-1-{trans-4-[4-(5-pyrimidinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.76 (s, 1H), 9.29 (s, 1H), 8.83 (s, 2H), 7.16-7.04 (m, 4H), 4.27 (m, 1H), 3.84 (s, 2H), 3.48 (s, 2H), 2.72 (s, 2H), 2.61 (s, 2H), 2.56 (m, 1H), 2.30 (q, 2H), 2.05 (m, 4H), 1.86 (br s, 1H), 1.5 (q, 2H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C22H26N6O2.2HCl.0.65 CHCl3C: 48.84, H: 5.18, N: 15.09 found C: 48.85, H: 5.36, N: 14.72.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1O)[CH3:36].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:1][CH2:2][CH:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4])[CH3:36]
Reactant: CC(CO)N1C(=O)c2ccccc2C1=O
Reactant: CCc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccccc1OCC(C)N1C(=O)c2ccccc2C1=O
Reaction time: 40 h
Yield: 39.7 %

Procedure:
A solution of 5.0 g (24.4 mmol) of 2-(2-hydroxy-1-methylethyl)-1H-isoindole-1,3(2H)-dione (Y. Becker, A. Eisenstadt, J. K. Stille, J. Org. Chem., 1980, 45, 2145) and triphenylphosphine (7.00 g, 27.0 mmol) in 40 mL of dry tetrahydrofuran was stirred at 20° C. for 1 h. To the solution was added 2-ethylphenol (3.90 g, 32.0 mmol) and diethyl azodicarboxylate (5.0 mL, 32.0 mmol) and the solution was stirred an additional 40 h. The reaction mixture was concentrated in vacuo and the residue was diluted in diethyl ether and washed with water and brine. The organic layer was concentrated in vacuo and the crude product was purified by flash silica chromatography using 5% ethyl acetate/hexanes solution as eluent to give 3.0 g (40%) of 2-[2-(2-ethylphenoxy)-1-methylethyl]-1H-isoindole-1,3(2H)-dione as a colorless oil: 1H NMR (CDCl3) δ0.96 (t, 3H), 1.60 (d, 3H), 2.40 (m, 2H), 4.18 (dd, 1H), 4.48 (t, 1H), 4.84 (m, 1H), 6.80 (m, 1H), 6.90 (m, 1H), 7.10 (m, 2H), 7.70 (m, 2H), 7.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[OH-:28].[Na+]>O>[CH3:1][O:2][C:3]1[C:23]2[C:22](=[O:28])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(C)c3n(c(=O)c2c1OC)CCc1cc2c(cc1-3)OCO2
Yield: 20 %

Procedure:
A mixture of 9,10-dimethoxy-13-methyl-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (0.95 g, 2.0 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 16 h. The precipitate was collected and treated with hot 3% hydrochloric acid. Purification by flash silica gel chromatography (silica gel from QingDao, 100-200 mesh, glass column from Shanghai SD company) (50% dichloromethane/ethyl acetate) afforded 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (150 mg. 20%) LC/MS m/e calcd for C21H19NO5 (M+H)+: 366.69, observed: 366.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3 H) 2.80 (t, J=5.56 Hz, 2 H) 3.78 (s, 3 H) 3.90 (s, 3 H) 3.96-4.07 (m, 2 H) 6.09 (s, 2 H) 7.00 (s, 1 H) 7.16 (s, 1 H) 7.54-7.61 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([NH:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.CSC.B.Cl>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH3:9]
Reactant: O=CNc1cccc(Br)c1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CNc1cccc(Br)c1F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
Step 2 A suspension of N-(3-bromo-2-fluorophenyl)formamide (216 mg, 0.991 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2.0 M in THF, 1.486 mL, 2.97 mmol) and the resulting mixture was heated at reflux for 2 h. 1 M hydrochloric acid was added and the mixture was again heated at reflux for 1 h. The mixture was cooled to rt and concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated to provide 3-bromo-2-fluoro-N-methylaniline as a light yellow oil (60 mg, 30%). Mass spectrum m/z 204, 206 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].C[N:8]1[CH2:13][CH2:12][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:10][CH2:9]1>C1C=CC=CC=1>[C:4]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH2:12][CH2:13]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CN1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1
Temperature: 25 °C

Procedure:
To a solution of 10.9 g (0.1 mole) of ethylchloroformate in 300 ml of anhydrous benzene is added dropwise, with stirring at room temperature, a solution of 14.5 g (0.05M) of 11-(N-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo-[5,6]-cyclohepta[1,2-b]-pyridine (hereinafter referred to as Compound IA) in 200 ml of benzene. The solution is stirred and is heated under reflux overnight (16-20 hrs.). The mixture is cooled and is poured into ice water and the organic layer is separated, washed with water, dried, and then concentrated to dryness. The residue is triturated with petroleum ether and a white solid having a melting point of 106°-107° C. is recrystallized from isopropyl ether after decolorization with decolorizing carbon.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:1]1([C@@H:4]([OH:11])[C@H:5]([O:10][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H](O)[C@H](O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)C1CC1
Reaction time: 72 h
Yield: 79 %

Procedure:
Under argon atmosphere, a solution of 4.22 g of methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropionate in 140 ml of methylene chloride is cooled to -3° C. Then, 4.00 g of triethylamine and 5.17 g of p-toluenesulfonyl chloride are added to the mixture successively. The mixture is stirred for 3 days. Then, the solvent is removed in vacuo. The residue is poured into a mixture of ethyl acetate and water. The organic layer is washed with brine and dried. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:3) to give 6.54 g of methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(p-toluenesulfonyloxy)propionate
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:19]([C:38]3[C:39]4[C@H:46]([CH3:47])[CH2:45][CH2:44][C:40]=4[N:41]=[CH:42][N:43]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[CH3:47][C@H:46]1[C:39]2[C:38]([N:19]3[C:20]4[C:25](=[C:24]([C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[CH2:18]3)=[N:43][CH:42]=[N:41][C:40]=2[CH2:44][CH2:45]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c([C@H]5CCCN5C(=O)OC(C)(C)C)cccc43)c21
Yield: 62.8 %

Procedure:
A mixture of palladium on carbon (10% degussa typed, 10 mg), ammonium formate (50 mg, 0.80 mmol) and (R)-tert-butyl 2-(1′-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (15 mg, 0.026 mmol) in MeOH (5 mL) was heated to reflux for 5 hours. The reaction was filtered with a pad of celite and eluted with EtOAc (100 mL), and the filtrate was washed with water (10 mL). The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified with flash chromatography (eluted with 10% MeOH/ethyl acetate, 10% 7N NH3 in MeOH/ethyl acetate) to afford the product (R)-tert-butyl 2-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (8 mg, 63%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 7.13 (t, 1H), 6.86-6.92 (m, 1H), 7.40 (d, 1H), 5.30-5.40 (m, 1H), 4.20-4.30 (m, 1H), 3.58-4.00 (m, 1H), 3.70-3.80 (m, 1H), 3.55-3.65 (m, 1H), 3.40-3.50 (m, 1H), 3.00-3.20 (m, 2H), 2.80-3.00 (m, 2H), 2.65-2.80 (m, 1H), 2.40-2.50 (m, 2H), 2.30-2.40 (m, 1H), 2.10-2.20 (m, 1H), 2.00-2.10 (m, 1H), 1.80-1.95 (m, 2H), 1.55-1.75 (m, 3H), 1.40-1.50 (m, 1H), 1.20 (s, 9H), 0.80-0.90 (m, 3H). MS (APCI+) [M+H]+ 490.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:21]>C(=S)=S>[Cl:5][CH:6]([CH3:10])[C:7]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:11][C:12](=[O:21])[CH2:13][CH2:14]2)=[O:8]
Reactant: CC(Cl)C(=O)Cl
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Cl)C(=O)c1ccc2c(c1)CCC(=O)N2
Yield: 85.7 %

Procedure:
A suspension of 72.5 g (0.544 mol) of AlCl3 in 800 mL of CS2 was stirred under dry N2 while 14.1 mL (20.0 g, 0.177 mol) of 2-chloropropionyl chloride was added followed by 20.0 g (0.136 mol) of 3,4-dihydroquinolin-2(1H)-one. The reaction mixture was refluxed for 4 h at which time a separation of phases was noted. The reaction was quenched by pouring onto ice with vigorous stirring. The pale yellow precipitate which formed was separated by filtration, washed with water and dried overnight over P2O5 to give 27.7 g (91%) of the desired product, m.p. 236.5-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][S:11]([CH3:13])=[O:12])=[CH:4][N:3]=1.[N-:15]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:14])[CH2:10][S:11]([CH3:13])(=[NH:15])=[O:12])=[CH:4][N:3]=1
Reactant: CC(Cc1ccc(Cl)nc1)CS(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(Cl)nc1)CS(C)(=N)=O
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 2-chloro-5-[2-methyl-3-(methylsulfinyl)propyl]-pyridine (2.15 g, 9.3 mmol) and sodium azide (1.81 g, 28 mmol) in chloroform (30 mL) cooled in an ice-water bath was added concentrated H2SO4 (6 mL) and the resulting mixture stirred at this temperature for 10 min. The reaction was then heated at 55° C. in an oil-bath for 16 hrs. Upon cooling down, the mixture was diluted with ice-water (70 mL) and the organic layer removed. The aqueous phase was washed with CH2Cl2 (2×30 mL) and the organic phase was discarded. The aqueous phase was made basic by the careful addition of aqueous ammonia whereupon an oil separated, which was extracted with CH2Cl2 (2×30 mL). The combined organic phase was dried over MgSO4 and solvent evaporated to give 2.15 g of the product as a yellowish oil in 94% yield. [M+H]+=247, 249; δ 1.11 (overlapping d, 3H).