Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1>C(#N)C>[ClH:1].[ClH:1].[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:8]([C:12]([NH:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:24]1
Reactant: N[C@@H]1CCNC1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CC#N
Product: Cl
Product: N[C@@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43(a)) (200 mg) and (3R)-3-pyrrolidinamine (0.20 mL) in acetonitrile (2 mL) was heated at 100° C. in a microwave for 1 hour after which it was cooled to room temperature and concentrated. The residue was purified by chromatography (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) (95:5:1), and then by HPLC (Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile). Conversion to the dihydrochloride salt by treatment with hydrochloric acid (4M in 1,4-dioxane) and subsequent recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (46 mg).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 52.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-octadecanol (36 grams, 210 mmol), pyridine (20 milliliters), and dichloromethane (500 milliliters) was heated to reflux. The alcohol dissolved and the solution was allowed to cool 5° C. 4-Nitrobenzoyl chloride (39.0 grams, 210 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with 250 milliliters of water. The aqueous layer was washed with 250 milliliters of dichloromethane. The organic layers were combined and concentrated under reduced pressure to a light tan solid. Added 500 milliliters of hexane and heated to reflux. A white precipitate formed as the solution was cooled to room temperature. Filtered off the white precipitate and concentrated the filtrate to a light tan solid. The solid was recrystallized from ethanol (500 milliliters) to obtain 46 grams of octadecyl 4-nitrobenzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:20]([OH:22])=[O:21])[CH2:7][CH2:6][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:30](=O)([O:46]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2>C(#N)C.O>[C:30]([CH:7]1[CH2:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH2:3][C:2]1([NH2:1])[C:20]([OH:22])=[O:21])([O:31][CH2:32][CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1(C(=O)O)CCC(c2ccccc2)(c2ccccc2)CC1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of crude 1-amino-4,4-diphenylcyclohexane-1-carboxylic acid (510 mg, 1.73 mmole), triethylamine (0.37 ml, 2.65 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 880 mg, 2.61 mmole) in acetonitrile (25 ml) and water (25 ml) was stirred at room temperature overnight. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (200 mg) and acetonitrile (5 ml) were added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH 3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→4→8% methanol/methylene chloride) to give Fmoc-1-amino-4,4-diphenylcyclohexane-1-carboxylic acid (350 mg, 39% yield) as a white solid. HRMS (FAB): C34H32NO4 (M+H) calc. 518.2331; observed: 518.231
Reaction SMILES: [CH:1]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].CN(C(ON1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN([CH:61]=[O:62])C>ClCCl>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:61]([C:36]3[CH:35]=[CH:34][N:39]=[CH:38][CH:37]=3)=[O:62])[CH2:21][CH2:20]2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)C1COC(=O)N1c1ccnc(N[C@@H](C)C2CCNCC2)n1
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C2CCN(C(=O)c3ccncc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
To a solution of S)-4-Isopropyl-3-[2-((S)-1-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-oxazolidin-2-one (20 mg, 0.48 mmol) in dichloromethane (1 mL) and DMF (1 mL) was added HATU (23 mg, 0.06 mmol) and DIPEA (0.03 mL, 0.18 mmol) The reaction was stirred at room temperature for 18 hours. The solvent is then removed under vacuum. The crude material was then purified using reverse phase C18 ODB column water-acetonitrile 0.1% TFA modifier to give (S)-4-Isopropyl-3-(2-{(S)-1-[1-(pyridine-4-carbonyl)-piperidin-4-yl]-ethylamino}-pyrimidin-4-yl)-oxazolidin-2-one (2 mg) in 8% yield.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.[CH2:19]([N:21]([CH2:24][CH3:25])[CH2:22]C)[CH3:20].ClC(OC1C=CC=CC=1)=[O:28].N1CCCC1>C1COCC1.[Cl-].[NH4+].ClCCl>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:22]([N:21]2[CH2:24][CH2:25][CH2:20][CH2:19]2)=[O:28])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCCC1
Yield: 88.3 %

Procedure:
4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (0.150 g, 0.60 mmol) was dissolved in THF (10 ml). Then triethylamine (0.17 ml, 1.2 mmol) was added to the mixture while stirring. Then phenyl chloroformate (0.15 ml, 1.2 mmol) was added to the mixture dropwise. The mixture was stirred at ambient temperature for 1.5 hours. Then pyrrolidine (0.50 ml, 6.0 mmol) was added to the mixture and stirred an additional 30 minutes. The mixture was diluted with sat. ammonium chloride (10 ml) and dichloromethane (10 ml) and stirred 10 minutes and was collected by extracted with dichloromethane (3×10 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified by chromatography (Amino-Propyl silica gel column) in a gradient of 1-5% MeOH/dichloromethane to give the desired product N-(4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.184 g, 0.53 mmol, 88% yield) as tan oil. MS (ESI pos. ion) m/z: 347 (MH+). Calc'd exact mass for C16H15FN4O4: 346. 1HNMR (300 MHz, CDCl3): 1.96 (s, 4H), 3.44 (t, J=6.65 Hz, 4H), 6.81-6.96 (m, 2H), 8.06-8.18 (m, 4H).
Reaction SMILES: [CH:1]1([CH:4]([NH:12]C(=O)OC(C)(C)C)[CH2:5][C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])[CH2:3][CH2:2]1.[ClH:20].C(OCC)C>ClCCl.CO>[ClH:20].[NH2:12][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)NC(CC(=O)NC1CC1)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: NC(CC(=O)NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To the solution of tert-butyl 1-cyclopropyl-3-(cyclopropylamino)-3-oxopropylcarbamate (38.10 g, 150 mmol) in dichloromethane (600 mL) and methyl alcohol (40 mL) was added 2 M solution of hydrochloric acid in diethyl ether (300 mL, 600 mmol) with an addition funnel at such a rate that the temperature of the reaction remained below 30° C. The reaction was allowed to stir at room temperature overnight. After 18 h, the reaction was complete as indicated by ELSD/MS. The reaction mixture was evaporated under reduced pressure. Diethyl ether (2×200 mL) was added to the residue, and the mixture was stirred for 15 min, and then decanted. This process was repeated to remove excess of hydrochloric acid. It was further dried in a vacuum oven overnight to afford 3-amino-N,3-dicyclopropylpropanamide hydrochloride (30 g, >100% yield).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.[CH2:33]([NH2:36])[CH2:34][CH3:35]>C(O)C.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:2]([NH:36][CH2:33][CH2:34][CH3:35])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:25])[CH3:26]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: CCCN
Solvent: O
Solvent: CCO
Product: CCCNc1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) and propan-1-amine (1.44 mL, 9.2 mmol) were combined in ethanol (5 mL) and heated at reflux for 24 h. The reaction was cooled to room temperature, diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a light golden oil. The oil was purified using a 25 g silica gel column eluted with 20% ethyl acetate/hexanes to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione (0.15 g, 63% yield) as a white solid. LCMS retention time=5.013 min and 97% purity, LCMS MH+ 520.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccccn2)n1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccccn4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.15 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 51.5 mg (0.61 mmol) of sodium bicarbonate and 58.6 mg (0.23 mmol) of 4-chloromethyl-2-(2-pyridyl)-1,3-thiazole are then added. The suspension is shaken RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 67.4 mg (87.9% of theory) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][C:11](OC(C)=O)=[O:12]>CC(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:12])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloroaniline (42.0 g, 260 mmol) in AcOH (40.0 mL) is added Ac2O (80 mL). The reaction mixture is warmed up to 50° C. and stirred at this temperature for 1 hour. The reaction is cooled to room temperature and poured into ice water (500 mL). A solid precipitated and the mixture is stirred for additional 1 hour at room temperature. The solid is filtered and washed with water, hexanes and air dried to give N-(2,4-dichlorophenyl)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[CH2:19][CH2:20][CH2:21][C:14]=34)=[CH:11][N:10]([CH3:22])[N:9]=2)=[CH:4][CH:3]=1.CC[O:25]C(C)=O.CO>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N+:16]([O-:25])=[C:15]4[CH2:19][CH2:20][CH2:21][C:14]=34)=[CH:11][N:10]([CH3:22])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccnc3c2CCC3)c(-c2ccc(F)cc2)n1
Reactant: CCOC(C)=O
Solvent: CO
Product: Cn1cc(-c2cc[n+]([O-])c3c2CCC3)c(-c2ccc(F)cc2)n1

Procedure:
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine was converted to the N-oxide following the general procedure described in Example 1, step 9. Silica gel chromatography using a 9:1 to 4:1 mixture of EtOAc/MeOH afforded 54% of Ex 24-Step 1 product as a yellow solid: LCMS m/z 310.5 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=6.6, 1H), 7.45 (s, 1H), 7.35 (dd, J=8.9, 5.4, 2H), 7.00 (dd, J=8.7, 8.7, 2H), 6.89 (d, J=6.6, 1H), 3.97 (s, 3H), 3.17 (t, J=7.6, 2H), 2.67 (t, J=7.6, 2H), 2.02-2.09 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.[N:20]1([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:35][CH:34]=2)=[N:16][CH:17]=1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)c1ccc(CN2CCOCC2)cc1
Yield: 75 %

Procedure:
HOBt (53 mg, 0.39 mmol) was added to (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference in its entirety; 500 mg, 3.94 mmol), 4-morpholin-4-ylmethyl-benzoic acid (1.04 g, 4.72 mmol) and EDC (907 mg, 4.72 mmol) in DCM (5.0 mL) and the reaction stirred for 4 h. The reaction was partitioned between DCM (75 mL) and saturated aqueous NaHCO3 (75 mL) and the aqueous layer extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo then purified by FCC using [0.5-7.5% 2M NH3 in MeOH] in DCM to give the title compound (980 mg, 2.97 mmol, 75%). LCMS (Method 4): Rt 0.27, m/z 331 [MH+].
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl.CN1CCCN(C)C1=O>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Reactant: ClCCCCCI
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.6 %

Procedure:
Cool lithium hexamethyldisilazane (8.4 mL of a 1.0M solution in tetrahydrofuran, 8.4 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (2.0 g, 8.3 mmol) in tetrahydrofuran (8 mL). Stir for 45 minutes then add a solution of 1-iodo-5-chloropentane (1.94 g, 8.32 mmol) i n tetrahydrofuran (8 mL). Stir for 1 hour and add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.21 mL, 10.0 mmol). Stir at 0° C. for 4 hours and at room temperature for 6 hours. Cool to -78° C., add lithium hexamethyldisilazane (8.4 mL, 8.4 mmol) and stir at room temperature overnight. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (50 mL) and water (50 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (6:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclohexane as an colorless oil (1.45 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[C@@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2.C(N(CC)CC)C.O>C(#N)C>[C@@H:22]12[CH2:30][N:29]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:3][C:2]=3[F:1])[CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of 301 mg of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (JP-A-5-163244), 463 mg of (S,S)-2,8-diazabicyclo[4.3.0]nonane, 1 ml of triethylamine in 10 ml of acetonitrile was heated under reflux for 15 hours. To the mixture was added 50 ml of water, and the solvent was removed under reduced pressure. The mixture was extracted from three 50 ml portions of chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A residue was dissolved in 10 ml of trifluoroacetic acid, and the solution was stirred at room temperature for 2 hours. Trifluoracetic acid was removed under reduced pressure and to a residue was added 1N sodium hydroxide aqueous solution till a pH became 12. To the solution was added hydrochloric acid till the pH became 7.4. The solution was extracted with six 50 ml portions of chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was recrystallized from ethanol to yield 320 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Mg].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.CC[O:23]CC>>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: CCOCC
Reactant: Clc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: [Mg]
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
A solution of 4-chlorobenzyl bromide (Lancaster Chemical) (10.0 g, 48.6 mmol) in 40 mL ether was added under nitrogen to a suspension of magnesium turnings (Alpha Chemical Inc.) in ether (60 mL) over 10 minutes. The suspension was stirred for 2 h and the supernatant was cannulated under nitrogen into another round bottom flask fitted with a magnetic stirrer bar. Then 2,4-dichlorobenzonitrile (7.0 g, 40.5 mmol) in 65 mL ether was slowly added under nitrogen to the Grignard solution and the mixture was stirred over night at room temperature. The imine precipitated out of solution and the mixture was refluxed for 3 h. The reaction mixture was cooled and poured into a flask containing 50 mL ethyl acetate and 50 mL 2N HCl. Stirred vigorously to hydrolyze the imine, separated the organic layer and dried it over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent volume reduced under reduced pressure. The crude product was flash chromatographed on silica gel (92/8 hexanes/ethyl acetate) to give product. 1H NMR 500 MHz (CDCl3): δ 4.40 (s, 2H), 7.2-7.6 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: COc1cccc(CCN)c1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCNC2c1ccccc1
Temperature: 60 °C

Procedure:
3-Methoxyphenylethylamine (1.5 g) and benzaldehyde (1.0 mL) were reacted together in benzene (10 mL) in a modified Dean-Stark apparatus, where the side arm contained activated 3 Å molecular sieve beads. The reaction was vigorously refluxed for 1 h until a uniform solution resulted. The reaction was cooled and evaporated. The resulting residue was taken up in trifluoroacetic acid (6 mL) and heated to 60° C. for 18 h. The reaction was cooled, concentrated then partitioned between 1N sodium hydroxide (70 mL) and diethyl ether (50 mL). The organic layer was washed with 0.5 N sodium hydroxide (70 mL), dried, concentrated to 20 mL and cooled in an ice-water bath. The crystals that formed were collected and dried to give the title compound (1.90 g). MS: 240.0 (MH+); HPLC tR: 1.62 min (method D); 1H NMR (DMSO-d6+TFA-d): 7.47-7.49 (m, 3H), 7.37-7.39 (m, 2H), 6.90 (broad s, 1H), 6.79 (dd, 1H, J=2.4, 8.7 Hz), 6.66 (d, 1H, J=8.7 Hz), 5.75 (s, 1H), 3.77 (s, 3H), 3.39-3.44 (m, 2H), 3.17-3.28 (m, 1H), 3.04-3.12 (m, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])=[O:11]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: C=CCCCCCCCCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCCCCCCCOC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (79.8 mL of a 2.0 M solution, 0.160 mol) is placed into a 250 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 9-Decen-1-yl acetate (14.91 g, 0.075 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 2-naphthoyl chloride (13.80 g, 0.071 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (47 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.