Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]=[C:9]([C@@H:11]2[O:16][CH2:15][N:14](S(C(C)(C)C)=O)[CH:13]([CH:23]([CH3:25])[CH3:24])[CH2:12]2)[S:8][CH:7]=1)=[O:5].Cl>CC#N.CCO>[CH2:2]([O:3][C:4]([C:6]1[N:10]=[C:9]([C@H:11]([OH:16])[CH2:12][C@@H:13]([NH:14][CH3:15])[CH:23]([CH3:25])[CH3:24])[S:8][CH:7]=1)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1csc([C@H]2CC(C(C)C)N(S(=O)C(C)(C)C)CO2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1csc([C@H](O)C[C@@H](NC)C(C)C)n1
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a 0.18 M solution of tetrahydrooxazine 33 (0.200 g, 0.514 mmol) in 9:1 MeCN/EtOH (2.9 mL) with MP-BH3CN (2.52 mmol/g, 0.204 g, 0.514 mmol) was added dropwise HCl (4.0 M in 1,4-dioxane, 0.515 mL, 2.06 mmol) with stirring. Stirring was continued for 3 h at rt, and then the solution was concentrated and purified by HPFC (95:5:1 to 90:10:1 CH2Cl2:EtOH:NH4OH). The product fractions were concentrated, diluted with EtOAc, and washed once with sat. NaHCO3 (aq) to remove excess ammonia salts. The aqueous fraction was back-extracted once with EtOAc. The combined organic fractions were dried with Na2SO4 and concentrated to afford 0.143 g of N-methyl tubuvaline ethyl ester 35 (97%) as a foamy solid. [α]25D=+70.5 (c=0.8, CHCl3). IR (film): 1087, 1232, 1315, 1492, 1713, 2947, 3119 cm−1. 1H NMR (500 MHz, d4-MeOD): δ 0.89 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.8 Hz), 1.39 (t, 3H, J=7.0 Hz), 1.88-2.04 (m, 3H), 2.38 (s, 3H), 2.43-2.48 (m, 1H), 4.38 (q, 2H, J=7.0 Hz), 5.14-5.18 (m, 1H), 8.32 (s, 1H). 13C NMR (125 MHz, d3-MeCN): δ 14.6, 17.3, 20.1, 28.8, 33.1, 33.9, 61.9, 63.5, 72.1, 128.6, 148.2, 162.4, 180.8. HRMS (FAB) calcd. for C13H23N2O3S (M+H): 287.1429. Found 287.1427.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:24][C:23]([Si:20]([CH3:22])([CH3:21])[O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[NH:4]1)([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1N[C@H](CO)CN2CCC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.2 %

Procedure:
To a solution of (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) in dimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol) and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooled in an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol) was added. The mixture was warmed to room temperature and stirred for 14 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a pale brown solid which was triturated with ethyl acetate to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as an off-white solid (1.74 g, 5.84 mmol, 66% yield). 1H NMR (400 Ah, CDCl3): 6.09-5.90 (m, 1H), 3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10 (ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H), 2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); MS (EI) for C14H28N2O2Si: 285 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=1.[H-].[Na+].O>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([CH3:27])[CH:16]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)CNC2=O
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc2c(c(Cl)n1)CN(Cc1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1) to give 65 mg (34% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cccc2ccccc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Temperature: 0 °C
Yield: 93 %

Procedure:
To a cooled (0° C.) solution of 1-methoxy naphthalene (5 cm3, 34.5 mmol) in dichloromethane (20 cm3) was added, over a 10 minute period, chlorosulfonic acid (4.6 cm3, 69.0 mmol). Following this addition, phosphorus pentachloride (7.2 g, 34.5 mmol) was added and the reaction was maintained at 0° C. for a further 45 min. The reaction was then quenched by pouring onto ice/water (50 cm3), and allowed to warm to room temperature. Further dichloromethane (40 cm3) was added and the solution was transferred to a separating funnel, where the organic layer was collected and washed with saturated aqueous sodium chloride solution (70 cm3) and dried over sodium sulfate. The solvent was then evaporated under reduced pressure to afford title compound (8.23 g, 32.1 mmol; 93%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.C(Cl)[Cl:42].Cl>CCOCC>[ClH:42].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[C:25]4[CH2:26][NH:27][CH2:28][CH2:29][C:24]=4[NH:23][N:22]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)c2C1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (53, 142 mg, 0.26 mmol) in 1:1 MeOH/CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to give (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (54) as an off-white solid (127 mg, >99%): 1H NMR (500 MHz, DMSO-d6) δ 9.28 (br s, 2H), 8.02-7.98 (m, 2H), 7.96-7.92 (m, 1H), 5.30-5.09 (m, 1H), 4.78-4.55 (m, 1H), 4.28-4.14 (m, 2H), 3.43-3.28 (m, 2H, overlaps with H2O), 3.26-3.07 (m, 2H), 3.02-2.90 (m, 2H), 2.89-2.75 (m, 1H), 2.00-1.82 (m, 2H), 1.80-1.61 (m, 2H), missing N—H pyrazole; ESI MS m/z 447 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:31](S(C(F)(F)F)(=O)=O)[S:32]([C:35]([F:38])([F:37])[F:36])(=O)=[O:33]>ClCCl>[CH2:1]([N:8]([CH3:24])[C:9]1[C:10]([O:23][S:32]([C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:31])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)Cc3ccccc3)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[benzyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.62 mmol) in dichloromethane (30 mL) was added pyridine (196 mg, 2.48 mmol), followed by Tf2O (349 mg, 1.24 mmol) at room temperature. The mixture was stirred overnight at room temperature, then quenched with water (100 mL), extracted with dichloromethane (3×20 mL1), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 3-(benzyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red solid (300 mg, crude).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]1)[CH2:6][C:5]2=[O:20].[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:14]1([CH3:19])[CH2:13][CH:12]([CH:7]2[CH2:6][C:5](=[O:20])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]4[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=4)[C:21]#[N:22])[CH:3]=3)[O:8]2)[CH2:17][CH2:16][O:15]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)CC(C2CC(=O)c3cc(Br)ccc3O2)CCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(C2CC(=O)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
To a solution of crude 6-bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-one (460 mg, 1.36 mmol), 3-cyanophenylboronic acid (299 mg, 2.0 mmol) and Cs2CO3 (866 mg, 2.72 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) charged in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (50 mg), then the system was degassed by sweeping N2 and capped. Then the mixture was heated to 100° C. for 10 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica eel give (3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg). MS ESI +ve m/z 362 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20]Br)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:36]=[S:37]1(=[O:43])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C(Cl)Cl>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:20][N:40]3[CH2:41][CH2:42][S:37](=[O:43])(=[O:36])[CH2:38][CH2:39]3)=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[C:10]([Br:22])=[C:9]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CBr)cc([N+](=O)[O-])c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccccc2)c(Br)c2cc(CN3CCS(=O)(=O)CC3)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (1.0 g, 2 mmol) obtained in Step 2 was dissolved in DCM (10 mL), and thereto Et3N (560 uL, 4 mmol) and 1,1-dioxo-thio-morpholine (300 mg, 3 mmol) were added. The mixture was stirred for 12 hours at room temperature. At the end of the reaction, added saturated aqueous NH4Cl solution, extracted with DCM. After drying the extract, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give 1-BOC-3-bromo-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-7-nitro-2-phenyl-1H-indole (825 mg, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:15]=[C:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccccc2)c(OC(=O)C(C)(C)C)c1

Procedure:
2,4-dihydroxybenzophenone 1 g (0.005 mole) was warmed to 50° C. with 1.25 g (0.015 mole) of pivaloyl chloride and 30 mls of dry pyridine solvent removed by rotary evaporation H2O+EtOAc+Et2O added and stirred. Layers were separated and the organic layer was washed with 5% K2CO3, then H2O, then dried over Na2SO4. Solvent was removed after filtration via rotary evaporator. The resulting oily residue was placed on top of a 15 g florisil column and eluted with toluene. Product isolated by removal of solvent. Oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:28](O)=[O:29])[C:22]=2[CH:21]=[CH:20]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:28]([C:23]3[C:22]4[CH:21]=[CH:20][NH:19][C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:29])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc4[nH]ccc34)CC2)ccc1Cl
Yield: 32 %

Procedure:
The title compound (13 mg, 32%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with indole-4-carboxylic acid. MS: 412.4 (MH+)
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]1[CH:72]=[CH:71][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[C@@H:44]([OH:45])[CH2:43]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:92](O)(=[O:99])[C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1>O1CCCC1.CO>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:32][C:33]2[N:41]=[CH:40][N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3[C@H:42]2[O:47][C@@H:46]([CH2:48][O:49][C:50]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:51]3[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=3)[C@H:44]([O:45][C:92](=[O:99])[C:93]3[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=3)[CH2:43]2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:71][CH:72]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](OC(=O)c3ccccc3)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of diethylazodicarboxylate (0.38 mL, 2.49 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a cooled solution (0° C.) of nucleoside 7 (0.66 g, 0.83 mmol), triphenylphosphine (0.66 g, 2.49 mmol) and benzoic acid (0.30 g, 2.49 mmol) in dry THF (20 mL). The mixture was stirred at room temperature for 18 h and methanol (1 mL) was added. The solvents were removed under reduced pressure and the crude material was purified by silica gel column chromatography (0-5% ethyl acetate in dichloromethane) to give compound 8 slightly contaminated by triphenylphosphine oxide.
Reaction SMILES: CC1C=CC(S(O[CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[CH3:13])(=O)=O)=CC=1.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][N:26]=[C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[C:28]1([C:27](=[N:26][CH:25]([C@H:12]([CH3:13])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:20])[CH:18]=[CH2:19])[C:24]([O:23][CH2:21][CH3:22])=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C=CC(C)CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CC(C)CCC[C@@H](C)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 73.2 %

Procedure:
To a solution of 2R)-6-methyloct-7-en-2-yl 4-methylbenzenesulfonate (15 g, 50.6 mmol) and N-(diphenylmethylene)glycinate ethyl ester (13.53 g, 50.6 mmol) in toluene (120 mL) was added LiHMDS (60.7 mL, 60.7 mmol, 1M solution in THF) at 0° C. The reaction mass was allowed to come to room temperature heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound (14.5 g). The crude compound was taken to the next step without further purification. MS: MS m/z 392.1 (M++1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]=12.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=1>>[ClH:2].[Cl:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:7]1[N:6]=[C:5]2[CH2:17][CH2:18][CH2:19][C:4]2=[C:3]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][OH:27])=[CH:23][CH:22]=2)[CH:8]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1ccc(Cl)c(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OCCc1ccc(Nc2cc(-c3cc(Cl)ccc3Cl)nc3c2CCC3)cc1
Yield: 47.3 %

Procedure:
Following General Procedure A1, 4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g, 0.40 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.068 g, 68%) as a light tan solid. MW=435.77. 1H NMR (DMSO-d6, 300 MHz) δ 14.23 (s, 1H), 9.76 (s, 1H), 7.80-7.78 (m, 1H), 7.71-7.63 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 4.66 (s, 1H), 3.63 (t, J=6.9 Hz, 2H), 3.1 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.73 (t, J=6.9 Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 399 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][CH:5](/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10])[CH2:4][O:3]1.Br[Mg][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.[Cl-].[NH4+]>C1COCC1>[Cl:21][C:18]1[CH:19]=[C:20]([CH:7]([CH:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:8][N+:9]([O-:11])=[O:10])[CH:15]=[CH:16][C:17]=1[Cl:22]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CC1(C)OCC(/C=C/[N+](=O)[O-])O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OCC(C(C[N+](=O)[O-])c2ccc(Cl)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-2,2-dimethyl-4-(2-nitrovinyl)-1,3-dioxolane (22.29 g) synthesized according to the method described in Tetrahedron Letters, 36 (25), 4447-4450 (1995) in THF (200 ml) was added 1 M THF solution (193 mL) of bromo(3,4-dichlorophenyl)magnesium in an inert atmosphere at −78° C. The reaction mixture was stirred at room temperature for 2 hr, and added to aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.16 g).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)/[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C(=C/c1ccc(N)c(C(C)C)c1)NC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)c(C(C)C)c1)NC(C)=O

Procedure:
methyl (2Z)-2-(acetylamino)-3-(4-amino-3-isopropylphenyl)acrylate (752 mg, 2.72 mmole) and 10% Pd/C (143 mg) stirred in ethanol (20 mL) under 1 atmosphere of hydrogen for 16 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the titled compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:3].[CH3:13][CH:14]([OH:19])[CH2:15][CH:16]([OH:18])[CH3:17]>>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH:16]([CH2:15][CH:14]([OH:19])[CH3:13])[CH3:17])=[O:3]
Reactant: COc1ccccc1OC(=O)Cl
Reactant: CC(O)CC(C)O
Product: COc1ccccc1OC(=O)OC(C)CC(C)O

Procedure:
The reaction of 2-methoxyphenol chloroformate with 2,4-pentanediol is conducted on a 0.01 mole scale employing the same conditions as described in Example III. A 1.5 g yield of the pure product is obtained as an oil.
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](OC)[CH:3]=1.C1CN2[C:14](=[N:15]CCC2)[CH2:13]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.[Cl-].[NH4+]>[C:2]1([C:1]2[O:11][CH:13]=[CH:14][N:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CN=C2CCCN2C1
Reactant: COc1cccc(C(=O)O)c1
Agent: [Cl-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ncco2)cc1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a mixture of methyl isooyanoacetate (7.1 g, 171 mmol), m-anisic acid (26 g, 171 mmol) and DBN (78 mL, 522 mmol) dissolved in DMF (1.1 L), was added DPPA (37 mL, 171 mmol) by dropwise addition. The reaction mixture was stirred about 18 hours, diluted with 50% saturated ammonium chloride solution (1 vol), extracted with diethyl ether, and the organic layers washed with water and brine before drying over MgSO4. Concentration and recrystallization (diethyl ether/hexanes) gave 24 23 g (58%), mp 75°-76° C. IR (KBr, cm-1) 3110, 3066, 1712, 1604, 1590, 1560, 1516, 1488, 1472, 1456, 1432, 1346, 1314, 1254, 1209, 1170, 1110, 1093, 1036, 892, 850, 786, 646. 1H NMR (300 MHz, CDCl3)δ 3.84 (3H, s), 3.92 (3H, s , 6.99 (1H, dd, J=8.1 Hz, J=2.I Hz) 7.36 (1 H, t, J=8.l Hz), 7.63 (1H, m), 7.72 (1H, Br.s), 7.88 (1H, s). 13C NMR (75 MHz, CDCl3) ppm 52.58, 55.60, 113.66, 116.97, 120.87, 126.66, 127.87, 129.76, 149.08, 155.61, 159.69, 165.54. m/e 234 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OCC)(O[CH2:19][CH3:20])(=O)=O>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[CH3:20]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCC(=O)O)cc1
Temperature: 100 °C

Procedure:
16.62 g (100 mmol) of 3-(4-hydroxyphenyl)-propionic acid is dissolved with stirring and covering with argon in 45 ml (225.0 mmol) of 5 N sodium hydroxide solution, and 15.73 g (100 mmol), (98%) of diethyl sulfate is instilled quickly so that the temperature does not exceed 40° C. (water cooling). After completion of the addition, it is heated for 30 more minutes to 100° C. After the cooling, it is extracted with diethyl ether, then acidified with sulfuric acid to pH 4 and the precipitated compound in ether is taken up. After drying on sodium sulfate, it is evaporated to dryness in a vacuum. The title compound is obtained as solid.