Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([C:13]1[S:17][C:16]([CH:18]=[CH2:19])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:19][CH:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: C=Cc1ccc(CCCC)s1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCCCc1ccc(C2CC2C(=O)OCC)s1
Yield: 64.8 %

Procedure:
This Example illustrates the preparation of 4-[2-(5-n-butylthiophen-2-yl)-trans-cyclopropylmethyl]-2,6-cis-dimethylmorpholine (Compound No. 8 in Table I). Phosphorus oxychloride (12.02 g, 0.078 mol) was added dropwise to N-methylformanilide (10.62 g, 0.079 mol) and a yellow solid was produced. This was cooled to 0° C. for 1/2 hour, then 2-n-butylthiophene (10 g, 0.071 mol) was added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was poured into ice/water, neutralised with sodium carbonate and extracted into diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate and the solvent removed to give a brown oil. Purification by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) gave 5-n-butyl-2-thiophenecarboxaldehyde (11.8 g, 99%). Sodium hydride (6.63 g-50% suspension in oil, 0.138 mol) was washed with petroleum ether, suspended in dry DMSO (100 ml) and heated with stirring at 60°-70° C. for 2 hours. The reaction mixture was then cooled to 15° C. and methyltriphenylphosphonium bromide (48.72 g, 0.136 mol) was added portionwise with rapid stirring over a 1/2 hour period. The reaction mixture was stirred at room temperature for a further 1 hour after the addition and 5-n-butyl-2-thiophenecarboxaldehyde (23 g, 0.137 mol) was added dropwise over a period of 1 hour. The resultant reaction mixture was stirred at room temperature for 12 hours, poured into water (300 ml) and extracted with ether (4×150 ml). The ethereal extracts were washed with water (4×100 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow oil which was purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give (5-n-butylthiophen-2-yl)-ethylene (18.5 g, 82%). Ethyl diazoacetate (13.0 g, 0.11 mol) in dry dichloromethane (150 ml) was added dropwise to a solution of (5-n-butylthiophen-2-yl)-ethylene (18.3 g, 0.11 mol) and anhydrous copper (II) sulphate (0.3 g) in dry dichloromethane (50 ml) at 90° C. by means of a syringe pump over a period of 5 hours. The dichloromethane was distilled over during the addition. After complete addition the remaining dichloromethane was removed in vacuo and the resulting brown oil purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 1:1) to give ethyl 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylate (18 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][C:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)(C(OCC=C)=O)[C:11]([O:13]CC=C)=[O:12])=[CH:7][CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)[C:11]([OH:13])=[O:12])=[CH:35][CH:36]=1)=[O:4]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of 40 g (80.9 mmol) of diallyl 2-[4-(methoxycarbonyl)benzyl]-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate, 1.49 g (5.67 mmol) of triphenylphosphine and 363 mg of palladium acetate in 500 ml of dioxane is mixed at room temperature with a solution of 37.2 ml (267 mmol) of triethylamine and 7.6 ml (202 mmol) of formic acid in 100 ml of dioxane. The reaction mixture is then stirred at 110° C. overnight. After conversion is complete, the reaction solution is cooled, and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 20.98 g (56.6 mmol, 70% of theory) of a colourless solid are obtained.
Reaction SMILES: C([Li])CCC.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[O:24].C1(C)C=CC=CC=1>O1CCCC1.O>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([CH3:21])[S:19][C:20]=3[CH:23]([OH:24])[C:22]([O:26][CH2:27][CH3:28])=[O:25])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: Cc1nc(-c2ccc3c(c2)CCCO3)cs1
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1sc(C)nc1-c1ccc2c(c1)CCCO2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
Under a nitrogen atmosphere, butyl lithium (1.6M, 840 μL, 1.34 mmol) was added at −78° C. to a solution of 4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methyl-1,3-thiazole (13a) (260 mg, 1.12 mmol) in anhydrous tetrahydrofuran (5 mL). After 30 minutes, ethyl glyoxylate 50% in toluene (500 μL, 2.5 mmol) was added at −78° C. and the mixture was stirred for 2 hours, hydrolyzed with water and concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired alcohol (13b) as a white solid (90 mg, 0.27 mmol, 24%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([N+:28]([O-])=O)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:21][C:20]4[C:22]([NH2:28])=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=4[O:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N)c2c1OCC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 55 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
To a solution of N-(4-morpholinophenyl)-8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxamide (1.2 g, 2.9 mmol) in N,N-dimethylformamide (10 mL) was added a solution of sodium dithionite (2.1 g, 12 mmol) in water (5 mL). The mixture was stirred at 55° C. for 3 h and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluent affording 273 mg of the title compound (55% yield): EIMS (70 eV) m/z (relative intensity) 383 (100, M+).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:12]([C:14]2[C:15]([Cl:25])=[N:16][N:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH3:13])=[O:11])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].N12CCCN=C1CCCCC2>CS(C)=O.[NH4+].[Cl-]>[C:1]([NH:4][C@H:5]1[CH2:9][C:8]([C:10]([N:12]([C:14]2[C:15]([Cl:25])=[N:16][N:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH3:13])=[O:11])=[CH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C=C[C@H](C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CC(=O)N[C@@H]1CC=C(C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of (1R,4S)-4-acetamido-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methyl-cyclopent-2-enecarboxamide (0.230 g, 0.639 mmol) dissolved in dimethylsulfoxide (DMSO, 10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.00 mL, 26.7 mmol). After stirring for 4 hours at a temperature of 100° C., the reaction was cooled and diluted with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with MeOH/CH2Cl2 to provide the title compound F41 as a yellow oil (0.120 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].CC#N>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[C:30](=[O:31])[C:29]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]5[C:27]4=[O:36])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Reaction time: 65 h
Yield: 56.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (4.0 g, 18 mmol), K2CO3 (2.7 g, 20 mmole), N-(2-bromoethyl)phthalimide (4.8 g, 19 mmole) and CH3CN (100 ml) was stirred at reflux under N2 for 4 hours. After standing at ambient temperature for 65 hours, the reaction was poured into H2O. The resultant solid was collected to yield 4.0 g of a yellow powder. The product was recrystallized twice from ethanol to yield 3.5 g (50%) of a beige powder m.p.=220°-223 ° C.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[NH:18])[S:14][CH:15]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[C:23]#[CH:24]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:25][CH2:22][C:23]#[CH:24])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[C:13]([NH:16][C:17]([NH2:19])=[NH:18])[S:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1

Procedure:
A mixture of the product of Step A (3.0 g; 8.61 mmoles) and propargylamine (6.0 ml) in acetonitrile (21 ml) was stirred and heated at reflux temperature under a positive pressure of nitrogen for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was placed on 70 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined and evaporated, and the 480 mg of product was recrystallized from isopropanol to yield the title compound containing approximately 2/3 mole of isopropanol, mp 82°-90°. Thin layer chromatography on silica, using methylene chloride:methanol (90:10), gave Rf 0.25.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([O:14][CH3:15])=[O:13])#[N:2].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)[C:4]=1[C:12]([O:14][CH3:15])=[O:13])#[N:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1[nH]c2ccccc2c1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Activated molecular sieves (6.0 g, 27 mmol) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with methyl 3-cyano-1H-indole-2-carboxylate (0.45 g, 2.2 mmol), (3-fluorophenyl)boronic acid (0.94 g, 6.7 mmol), cupric acetate (0.61 g, 3.4 mmol), methylene chloride (43 mL) and pyridine (0.73 mL, 9.0 mmol). The reaction mixture was stirred at room temperature over the weekend. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-60% EtOAc/hexane) to give the desired product (0.39 g, 59%). LCMS calculated for C17H12FN2O2(M+H)+: m/z=295.1. Found: 295.0.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@@H:13]2[CH2:17][C@@H:16]([CH2:18][CH3:19])[C@@H:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=O)=CC=1)([O-])=O>C(O)C.C([C@@H]1C[C@@H](O)C[C@@H]1C(OCC)=O)C>[CH2:18]([CH:16]1[CH2:17][CH:13]([OH:12])[CH2:14][CH:15]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC(=O)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CC
Agent: CCOC(=O)[C@H]1C[C@H](O)C[C@H]1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CC(O)CC1CC

Procedure:
A 2 L flask was charged with freshly ground sodium hydroxide (9.55 g, 239 mmol). Ethanol (500 mL) was added and the mixture was stirred until all solid went into solution. A solution of a scalemic mixture enriched in (1R,3S,4R)-3-(ethoxycarbonyl)-4-ethylcyclopentyl 4-nitrobenzoate (16.02 g, 47.8 mmol) in ethanol (120 mL) was added through an additional funnel. The reaction mixture was stirred at ambient temperature overnight. The solid was filtered off while washing with DCM (100 mL). Saturated aqueous NaHCO3 (800 mL) was added to the filtrate and mixture was stirred for about 30 min. The solid formed was filtered off while washing with DCM (500 mL). The filtrate was washed with saturated aqueous NaHCO3 (2×200 mL) and brine (300 mL). The organic layer was dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 0-60% EtOAc in DCM to give a scalemic mixture enriched in (1S,2R,4R)-ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (5.49 g, 62%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.53 (m, 1H), 4.11 (m, 2H), 3.09 (m 1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.80 (m, 1H), 1.68 (m, 1H), 1.44 (m, 2H), 1.26 (t, 3H), 1.18 (m, 1H), 0.92 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH3:1])=[CH:13][CH:12]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC(C)C(=O)OC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(CC(C)C(=O)OC)cc3)cc3ccccc23)CC1
Yield: 88.6 %

Procedure:
Methyl 2-methyl-3-(4-tributylstannylphenyl)propionate (2.69 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.16 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.17 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxycarbonylpropyl)phenyl]isoquinoline (1.34 g) in pale yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[N:25]1([C:30]2([C:33](O)=[O:34])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:33]([C:30]2([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:32][CH2:31]2)=[O:34])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)C1(N2CCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCCC3)CC2)CC1
Yield: 41 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(pyrrolidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16D carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(pyrrolidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a yellow solid (41%). MS ISP (m/e): 491.2 (100) [(M+H)]+.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[C:16]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[C:17]([CH:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])[N:18]([CH3:21])[C:19](=[O:20])[C:8]2=3)=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[C:5]([O:27][CH:22]([C:17]1[N:18]([CH3:21])[C:19](=[O:20])[C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:36][CH:35]=3)[C:15]3[C:10]([C:9]=2[C:16]=1[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:23]([O:25][CH3:26])=[O:24])([CH3:35])([CH3:6])[CH3:4]
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2c3ccccc3n(Cc3ccc(F)cc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.4 %

Procedure:
A solution of methyl 2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)-2-hydroxyacetate (42 mg, 0.087 mmol) in t-Butyl acetate (1 mL) was treated with perchloric acid (6.22 μL, 0.103 mmol) and then stirred at room temperature for 1 hour. The mixture was diluted with Ethyl acetate, washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford methyl 2-(tert-butoxy)-2-(9-(4-fluorobenzyl)-2-methyl-1-oxo-4-(p-tolyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-3-yl)acetate as a white solid (30 mg, 0.055 mmol, 64% yield). 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.25-7.47 (m, 8H) 6.88-7.00 (m, 3H) 6.57-6.63 (m, 1H) 6.19-6.22 (m, 1H) 6.11-6.17 (m, 1H) 5.29 (s, 1H) 3.79 (s, 3H) 3.78 (s, 3H) 2.54 (s, 3H) 1.04 (s, 9H); LCMS (m/z) ES+=541 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[CH3:12][N:13](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Zn].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:12]([C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:13]
Reactant: CN(C)C=O
Reactant: Clc1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1ncccc1Cl
Yield: 76 %

Procedure:
A mixture of 2,3-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol,), zinc (dust, 29 mg, 0.45 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (0.18 g, 0.22 mol) in N,N-dimethylformamide (10 mL) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Removal of the solvent and silica gel chromatography afforded 1.05 g (76%) of 2-cyano-3-chloropyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:12])([CH3:11])[O:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7]([CH3:12])([CH3:11])[O:6][C:5]3([CH3:14])[CH3:13])=[CH:21][CH:20]=1)[CH3:16]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1(C)OC(C)(C)c2cc(N)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Yield: 84.3 %

Procedure:
Following general procedure E and using 5-amino-1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran (Compound 78) (1 g, 4.82 mmol), ethyl-4-iodo-benzoate (1.4 g, 5.07 mmol), cesium carbonate (2.2 g, 6.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.03 mmol), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.060 g, 0.09 mmol) in 15 mL of anhydrous toluene the title compound (1.38 g, 85%) was obtained as a yellow solid after flash column chromatography using 20% ethyl acetate in hexane as the eluent. 1H NMR (300 MHz, CDCl3): δ 7.94 (d, 2H, J=8.7 Hz), 7.10 (dd, 1H J=1.8, 7.9 Hz), 7.03 (d, 1H, J=8.0 Hz), 6.99 (d, 2H, J=8.7 Hz), 6.89 (d, 1H, J=1.7 Hz), 6.36 (s, 1H), 4.34 (q, 2H, J=7.Hz), 1.52 (s, 6H), 1.51 (s, 6H), 1.37 (t, 3H, J=7.1 Hz).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[CH2:7])CCC.[Br:21]N1C(=O)CCC1=O>C1COCC1.O>[Br:21][CH2:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([F:20])[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: C=C(OCCCC)c1ccnc2c(F)cc(OC)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c2nccc(C(=O)CBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
9.0 g (32.7 mmol) of 4-(1-Butoxy-vinyl)-8-fluoro-6-methoxy-quinoline was dissolved in 200 mL of 3:1 THF/water. 6.4 g of N-bromosuccinimide was added and the contents stirred at rt for 3 hrs. Solvent was then removed by rotary-evaporation. The crude material was purified by flash chromatography on silica gel using 20% ethyl acetate/hexanes as the eluent to give 8.5 g (88%) of the desired product. 1H NMR (CDCl3, 400 MHz) 8.92 (d, 1H), 7.71 (m, 2H), 7.18 (d, 1H), 4.55 (s, 2H), 3.94 (s, 3H).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:19]([CH2:26][CH2:27][CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[O:19]([CH2:26][CH2:27][CH2:28][NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCCOc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCCCOc3ccccc3)c21
Reaction time: 5 h

Procedure:
In 600 ml of toluene and 400 ml of 30% potassium hydroxide were combined 10.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one, 39 ml of 3-phenoxypropyl bromide and 3.2 g of tetrabutylammonium hydrogen sulfate catalyst. The biphasic mixture was refluxed (bp 90° C.) with mechanical stirring for 5 hours, during which the reaction went to completion. The organic phase was separated, washed with ice cold saturated NaCl solution, dried over anhyrous magnesium sulfate, filtered and evaporated to an oil. The oil was flash chromatographed (silica, ethyl acetate) and the product-containing fractions were combined and evaporated to an oil. Trituration with ether yielded the product as a solid which was recrystallized from dichloromethane/hexane to yield 4.45 g of product, mp 104°-106° C.