Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:20][CH3:21])=[O:11])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1CCc1ccc(Br)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccccc1CCc1ccc(Br)cc1

Procedure:
A solution of 40 g. (0.131 mole) of 2-(4-bromophenethyl)-benzoic acid in 250 ml. of absolute ethanol is stirred and heated to refluxing while hydrogen chloride is introduced into the solution for 2 hours. After standing at room temperature for 2 1/2 days, the mixture again is stirred at reflux for 12 hours and, during this period, hydrogen chloride is passed into the solution for 1 hour. The two-phase mixture is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. The combined benzene layers are extracted with 5% aqueous sodium hydroxide and then washed thoroughly with water and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation of the residue in vacuo gives the product as the oily distillate, b.p. 142°/0.2 mm.
Reaction SMILES: C[N:2]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C@H:3]([C:7]([OH:9])=[O:8])[CH:4]([CH3:6])[CH3:5].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23].[OH-].[Na+]>CO>[C:10]([NH:2][C@H:3]([C:7]([OH:9])=[O:8])[CH:4]([CH3:5])[CH3:6])(=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: NCCCCCC(=O)[O-]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)C(C)(C)C)C(=O)O
Product: NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.9 %

Procedure:
In 500 ml of methanol was dissolved 44 g of methyl N-pivaloyl-L-valine-6-aminohexanoate followed by addition of 150 ml of 1N sodium hydroxide and the mixture was stirred at room temperature for 45 minutes. The ethanol was then evaporated off and 1N HCl and, then, ether were added to the residue. The mixture was shaken to extract the reaction product into the ether. The water layer was removed and the ether layer was dried over magnesium sulfate anhydride and concentrated to dryness under reduced pressure to give 35 g (0.112 mol) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:30]=O)=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9].Cl.[NH2:33]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:30]#[N:33])=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[O:9]
Reactant: NO
Reactant: CCOCCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOCCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A mixture of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.00 g), hydroxylamine hydrochloride (0.5547 g), sodium acetate (1.1382 g) in acetic acid (10 ml) was stirred for 30 minutes at room temperature. To this mixture was added acetic anhydride (1.4 ml) and the resultant mixture was stirred for an hour at room temperature and refluxed for an hour. The acetic acid was distilled off under reduced pressure, and to the residue was added water. The resultant mixture was neutrallized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried. The solvent was distilled off and thus obtained viscous oily substance (3.19 g) was subjected to column chromatography on silica gel with an eluent [a mixture of 5 parts of benzene and one part of ethyl acetate by volume] and a yellow oil (1.74 g) was obtained from the fraction which contained the designated product. The oil turned into crystals (1.56 g). These crystals were recrystallized from benzene to give yellow powder (1.5 g) of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.1/3benzene, m.p. 89° to 91° C. Thus obtained yellow powder was further recrystallized from a mixture of diethyl ether and n-hexane to give crystals of 2-ethoxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate, m.p. 115° to 116° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:9]([F:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH3:19])=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH2:24]([S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:24]([S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]([C:20]([F:23])([F:21])[F:22])[C:5]([CH3:19])=[C:6]([N+:16]([O-:18])=[O:17])[C:7]=2[C:8]2[C:9]([F:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:27])=[O:28])[CH3:25]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cnc(F)c(-c2c(Cl)cc(C(F)(F)F)c(C)c2[N+](=O)[O-])c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c([N+](=O)[O-])c2-c2cc(C)cnc2F)c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A mixture of 3-(6-chloro-3-methyl-2-nitro-4-(trifluoromethyl)phenyl)-2-fluoro-5-methylpyridine (6.0 g, 17.2 mmol), 3-ethylsulfonylphenylboronic acid (4.79 g, 22.4 mmol), bis(dibenzylidineacetone)Pd(0) (1.48 g, 2.6 mmol), tricyclohexylphosphine (1.45 g, 5.2 mmol), Cs2CO3 (14.0 g, 43 mmol), and dioxane (60 mL) was heated at reflux for 4.5 hr. After completion the reaction was cooled to room temperature, filtered, rinsed with dioxane, and concentrated in vacuo. The resulting oil was reconstituted in EtOAc (75 mL) washed with H2O (1×30 mL) and brine (1×30 mL), dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (4:1 hexanes/EtOAc) gave 6.5 g (78%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.04 (s, 1H), 7.90-7.93 (m, 1H), 7.80-7.82 (m, 1H), 7.60-7.70 (m, 3H), 3.1-3.2 (m, 2H), 2.49 (s, 3H), 2.25 (s, 3H), 0.85 (t, 3H). MS (ES) [m+H] calc'd for C22H18F4N2O4S, 483; found 483.3.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](OCC)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].[O-]CC.[Na+].[Na]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][CH:18]([CH3:20])[CH3:19])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CC(C)N
Reactant: CCOC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)NC1=Nc2ccc(Cl)cc2S(=O)(=O)N1C

Procedure:
A mixture of crude 7-chloro-3-ethoxy-2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (0.45 g) and isopropylamine (4 ml) in an ethanolic sodium ethoxide solution, prepared by dissolving 0.4 g of sodium in 10 ml of ethanol, was refluxed for 3 hours and then neutralized with 4M acetic acid. The mixture was evaporated to dryness and partitioned between 25 ml of water and 25 ml of dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column with a 7:3 mixture of n-heptane and ethyl acetate as solvent to give the title compound;
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.CN(C)CCCN=C=NCC.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[C:31]2[CH3:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:37][C:32]1[NH:33][C:34]2[C:30]([C:31]=1[CH3:38])=[CH:29][C:28]([NH:27][C:12](=[O:14])[CH2:11][C:1]13[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]1)[CH2:8]3)=[CH:36][CH:35]=2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1[nH]c2ccc(NC(=O)CC34CC5CC(CC(C5)C3)C4)cc2c1C
Reaction time: 8 h

Procedure:
To a solution of 1-adamantaneacetic acid (0.30 g) in dichloromethane (10 ml) were added 4-dimethylaminopyridine (0.19 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.30 g). The reaction mixture was stirred for 0.5 hour before addition of 5-amino-2,3-dimethylindole (0.25 g). Stirring was then continued overnight at ambient temperature. The next day the reaction mixture was washed with dilute hydrochloric acid, water and brine, dried over sodium sulphate (Na2SO4) and finally concentrated under reduced pressure to leave a residue. Purification of the residue by silica gel chromatography, eluting with 40% ethyl acetate in isohexanes, gawe the title compound as a white solid (0.14 g).
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[I-].ClC1C=CC=C[N+]=1C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[N:29]=[C:28]([C:37]([OH:39])=O)[CH:27]=2)=[CH:22][CH:21]=1.[Br:40][C:41]1[CH:49]=[CH:48][C:44](C(O)=O)=[CH:43][N:42]=1>C1COCC1>[Br:40][C:41]1[N:42]=[C:43]([NH:3][C:37]([C:28]2[CH:27]=[C:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[N:29]=2)=[O:39])[CH:44]=[CH:48][CH:49]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.2 %

Procedure:
DIPEA (5.5 ml, 29 mmol) and 2-chloro-1-methylpyridinium iodide (8 g, 26 mmol) were added to a solution of 5-bromopyridin-2-amine 1 (2.56 g, 14.8 mmol) and 6-bromonicotinic acid (3 g, 14.8 mmol) 2 in THF (150 ml). The reaction mixture was stirred at RT for 4 days. Then the precipitate was filtered off. The filtrate was concentrated and dissolved in chloroform (250 ml), washed with water and brine and dried over Na2SO4. The solvent was evaporated to give a crude product, which was recrystallized from ethyl acetate to give 6-bromo-N-(5-bromopyridin-2-yl)nicotinamide 3 (4.3 g, 81%) as a white solid. Mp. 204-205° C.
Reaction SMILES: CC1C=CC=CC=1C.[Cl:9]Cl.[CH3:11][C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:13]=1[CH3:22]>C(Cl)(Cl)(Cl)Cl.[Hg]>[CH3:22][C:13]1[C:14]([Cl:21])=[C:15]([Cl:20])[C:16]([Cl:19])=[C:17]([Cl:18])[C:12]=1[CH2:11][Cl:9]
Reactant: Cc1c(C)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCl
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Reaction time: 6 h
Yield: 78.7 %

Procedure:
530 g of o-xylene in 5 liters of CCl4 was chlorinated in the nucleus in the presence of 10 g of FeCl3 by passing chlorine over the reaction solution while stirring the latter, at a pressure of 0.06 atmospheres excess pressure, with the exclusion of light. The first half of the amount of chlorine calculated for dimethyltetrachlorobenzene was introduced into the gas chamber of the reaction vessel at a liquid phase temperature of 20° C, and the remainder at 40° C. The reaction time was about 6 hours. Then, while irradiating the gas chamber in the reaction vessel with a 250-watt mercury vapor lamp at a liquid phase temperature of 70° C and 0.06 atmospheres excess pressure, the side-chain chlorination was performed, which required about 6 hours. Total chlorine consumption: 110% of the calculated amount, with respect to xylene. The reaction solution was stirred with 400 g of calcium hydroxide, which rendered the solution neutral and iron-free. The calcium hydroxide containing iron and chloride was removed on a suction filter and, after the CCl4 had been removed by distillation, the solution was fractionated at 12 Torr in a packed column. The main fraction distilled at 179°-189° C. 1242 g of 1-methyl-2-chloromethyl-3,4,5,6-tetrachlorobenzene was obtained in a purity of 88.3% (yield 78.7%). After recrystallization from isopropanol + 1,2-dichloroethane (1:1), the product had a purity of 96.4% and melted at 102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]([NH2:29])=[NH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:28]=[C:27]([NH:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[Cl:19])[N:29]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccccc1Cl
Product: O=C1Cc2cnc(Nc3ccccc3Cl)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(2-chlorophenyl)guanidine were converted to I-12 (26%): HRMS Calcd. for C18H12Cl2N4O: 371.0466, Found 371.0467.
Reaction SMILES: C[CH:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:15]([O-:17])=[O:16])[NH:8][CH2:7]1)[C:3]([O-:5])=[O:4].[C:18](=O)(O)[O-].[Na+].[I-].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O>[N+:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:6]([CH2:2][C:3]([O:5][CH3:18])=[O:4])[CH2:7][N:8]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([O-:17])=[O:16]
Reactant: CC(C(=O)[O-])C1CNc2cccc([N+](=O)[O-])c21
Reactant: O=C([O-])O
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CC(CC(=O)OC)c2c1cccc2[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of (±)-methyl(4-nitro-2,3-dihydro-1H-indol-3-yl)acetate from Step B (700 mg, 3.0 mmol), sodium bicarbonate (471 mg, 4.4 mmol), and potassium iodide (98 mg, 0.59 mmol) in acetone (15 mL) was added ethyl bromoacetate (9.9 mL, 88.9 mmol). The mixture was heated at reflux for 18 h, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O (15 mL) and EtOAc (2×40 mL) and the organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a volume of 50 mL. Hexane was added to the EtOAc solution and a precipitate formed. The desired crystals were collected by vacuum filtration to give the title compound. MS: m/z 323 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9](SC)[N:10]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]2)[N:10]=1
Reactant: OCCC1CCNCC1
Reactant: CSc1nc(Cc2ccccc2F)[nH]c(=O)c1C#N
Solvent: CC#N
Product: N#Cc1c(N2CCC(CCO)CC2)nc(Cc2ccccc2F)[nH]c1=O
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(2-fluorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for six days. After cooling to room temperature, the crude product is purified by preparative HPLC. 31 mg (24% of theory) of the title compound are obtained as a colourless solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]=[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCN(CC2CCC=C(c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[(3,6-dihydro-4-phenyl-1(2H) -pyridinyl)methyl]cyclohexanone (Example A) (5.9 g) in 400 mL of tetrahydrofuran is added a solution of phenylmagnesium bromide (9.13 mL, 3.0M in diethyl ether), dropwise under nitrogen, at 0° C. The mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and quenched with 250 mL of 10% aqueous hydrochloric acid solution. The solvent is evaporated in vacuo and the residue partitioned into chloroform/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate and filtered. The filtrate is treated with trifluoroacetic acid (4.2 mL) and stirred overnight at room temperature. The solvent is evaporated in vacuo, and the residue is partitioned into ethyl acetate/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography to give 3.9 g of (±)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine; mp 90°-95° C. as an off-white solid (Example 1) and 2.7 g of (±)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl) methyl]pyridine; mp 124°-126° C. as a tan solid (Example 1a).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:14].Cl.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([NH:16][C:11]([C:8]1[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=1)=[O:13])[CH2:18]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc2cccnc2c1
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccc2cccnc2c1
Yield: 71.1 %

Procedure:
Prepared in analogy to the method for Example 1 starting from 183 mg of quinoline-7-carboxylic acid (Seibert et al. J. Am. Chem. Soc. 1946, 68, 2721) and 200 mg of 3-aminoquinuclidine dihydrochloride. 227 mg (71% yield) of the hydro-chloride were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[C:3]1=[O:38].C=O.[BH3-][C:42]#N.[Na+]>CO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[CH3:42])[C:3]1=[O:38]
Reactant: [BH3-]C#N
Reactant: Cn1c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc2n(CC2CCCN2)c1=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCCC1Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-7-(pyrrolidin-2-ylmethyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is dissolved in CH3OH (200 μL), and then 37% formaldehyde (2.3 μL) is added at room temperature. After 5 min, NaBH3CN (1.8 mg, 0.028 mmol) in CH3OH (100 μL) is added. The reaction mixture is stirred at r.t. for 30 min. The mixture is purified by HPLC to give pure product as white solids. MS (ESI) m/z 522.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccc(F)cc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccc(F)cc4)CC3)cnc12
Yield: 45.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-fluorophenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and methanesulfonamide (0.038 g, 0.400 mmol), the title compound (0.02 g, 48%) was obtained.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:36])=[O:5])(=[O:10])=[O:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine t-butyl ester (75 mg) was dissolved in a 95% solution of TFA in methylene chloride (5 mL). The solution was stirred at room temperature for 4 h and the solvent was removed under vacuum. The crude product was triturated with hexane/ethyl acetate (95:5) three times. The product was lyophilized with benzene to give 56 mg of N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine. LCMS MH+ (m/z) 451. 1H NMR (300 MHz, DMSO-d6): δ 10.54 ppm (s, 1H), 7.95-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, J1=7.5 Hz, J2=7.5 Hz), 7.20 ppm (dd, 1H, J1=7.5 Hz, J2=7.5 Hz), 3.42 ppm (d, 2H J=6.3 Hz).
Reaction SMILES: [Br:1]Br.[F:3][C-:4]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]([F:14])([F:13])[C:5]1([F:16])[F:15].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[Br:1][C:4]1([F:3])[C:5]([F:15])([F:16])[C:6]([F:13])([F:14])[C:7]([F:11])([F:12])[C:8]1([F:10])[F:9]
Reactant: BrBr
Reactant: F[C-]1C(F)(F)C(F)(F)C(F)(F)C1(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: FC1(F)C(F)(F)C(F)(F)C(F)(Br)C1(F)F

Procedure:
Bromine was added to a solution of tris(dimethylamino)sulfonium 1,2,2,3,3,4,4,5,5-nonafluorocyclopentanide in benzonitrile, prepared as described in Example 5. Distillation of the reaction mixture gave bromononafluorocyclopentane as a colorless liquid: b.p. 64°-65°; 19F NMR (CCl3F) δ- 112.4 ppm (d, J=262 Hz, 2F), -136.2 ppm (d, J=262 Hz, 2F), -141.4 ppm (m, 1F), -125.4 ppm (d, J=255 Hz, 2F) and -127.8 ppm (d, J=255 Hz, 2F).
Reaction SMILES: B.[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([N:10]1[C:18]2[C:13](=CC(C=C)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8].O.O.C[N+]([O-])(C)C.Cl>C1COCC1.O>[C:7]([N:10]1[C:18]2[C:13](=[CH:3][C:4]([CH2:5][CH2:6][OH:2])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(c1)CCN2C(C)=O
Agent: B
Agent: C[N+](C)(C)[O-]
Agent: Cl
Solvent: O
Product: CC(=O)N1CCc2cc(CCO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in THF, 20 ml, 20 mmol) was added dropwise to an ice cooled solution of 1-acetyl-2,3-dihydro-5-ethenyl-1H-indole (5.61 g, 30 mmol) in THF (150 ml). The mixture was stirred at 0° C. for 30 minute then at room temperature for 1 hr. Trimethylamine N-oxide dihydrate (8.88 g, 80 mmol) was added and the mixture was heated under reflux for 3 hr, cooled and poured into water (400 ml) and aqueous HCl (6N, 10 ml). The mixture was extracted with dichloromethane (3×400 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the alcohol as a white solid (3.41 g, 55%).