Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([OH:26])[C@@H:21]1[OH:27])=[N+:17]=[N-:18]>C(O)C>[N:16]([CH2:19][C@H:20]1[O:25][CH:24]=[CH:23][C@@H:22]([O:26][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:21]1[O:27][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+:17]=[N-:18]
Reactant: ClCc1ccccc1
Reactant: [N-]=[N+]=NC[C@H]1OC=C[C@@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: [N-]=[N+]=NC[C@H]1OC=C[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Suspend 5.16 gm. of sodium hydride in 50 ml. of ahydrous dimethylformamide. Maintain the temperature at 0°C. and add 12.4 ml. of benzyl chloride, then 4.65 gm. of 6-azido-6-deoxy-D-glucal in 17 ml. of dimethylformamide. Stir for 4 hours and then add 15 ml. of ethanol, after a further 10 minutes, pour the reaction mixture on ice and then extract wth chloroform. Wash the extracts with water, then dry over MgSO4 and then reduce in vacuo. Chromatograph the residue on silica gel using 25% ethyl acetate in benzene as the eluant to obtain 6-azido-6-deoxy-3,4-di-O-benzyl-D-glucal, [α]26 D + 34.3° (EtOH); pmr (CDCl3)δ 3.52 (2H, m, -CH2N3), 4.6 (4H, m, Ar-CH2 -), 6.38 (1H, dd, J=1.5, 6-Hz, H-1); ν max (CHCl3) 2100, 1640 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: N#Cc1ccc(C(=O)NCCCCn2cnc3c(N)nc4ccccc4c32)cc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 4-cyanobenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-cyanobenzamide as a white powder, m.p. 222.8-225.3 ° C. 1H NMR (300 MHz, DMSO-d6) δ8.73 (t, J=5.7 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.93 (s, 4H), 7.61 (dd, J=8.4, 1.2 Hz, 1H), 7.43 (dt, J=7.6, 1.5 Hz, 1H), 7.21 (dt, J=7.6, 1.2 Hz, 1H), 6.61 (s, 2H), 4.64 (t, J=7.2 Hz, 2H), 3.33 (m, 2H), 1.96 (quintet, J=7.2 Hz, 2H), 1.58 (quintet, J=7.2 Hz, 2H); IR (KBr) 3441, 3337, 3136, 2945, 2228, 1641, 1545, 1531, 1481, 1396, 1309, 1257, 857, 755 cm−1; MS (El) m/e 384.1699 (384.1699 calcd for C22H20N6O).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:9]=1)(=O)=O.[SH:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][S:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)COc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Tert-butyl (4-{2-[(methylsulfonyl)oxy]ethyl}phenoxy)acetate (5.454 g, 17.347 mmol) was dissolved in acetonitrile (100 ml), methyl 2-mercaptobenzoate (3.502 g, 20.816 mmol) and dipotassium carbonate (4.795 g, 34.694 mmol) was added. The solution was stirred for 10 hours at 60° C. EtOAc (40 ml) was added and the organic phase was washed with two portions of brine (2×40 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 6.931 g crude of methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate. The crude was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 14.9 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-acetylphenylboronic acid (available from ASDI Incorporated; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (14 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 12.97 (br s, 1H), 8.44-8.50 (m, 2H), 8.34 (d, J=1.8 Hz, 1H), 8.20 (dd, J=7.9, 1.9 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.81-7.88 (m, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55-7.64 (m, 1H), 7.45-7.54 (m, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.19-7.28 (m, 1H), 6.52 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N+:13]([O-])=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1(C2C(C3C=CC=CC=3)=CC3C(=NC=CC=3)[N+]=2[O-])C=CC=CC=1.C[Mg]Cl>C1COCC1>[CH3:24][C:12]1[N:13]=[C:14]2[C:9]([CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15]2)=[CH:10][CH:11]=1
Reactant: [O-][n+]1cccc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: [O-][n+]1c(-c2ccccc2)c(-c2ccccc2)cc2cccnc21
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A cooled (0° C.) mixture of 6,7-diphenyl-1,8-naphthyridine 1-oxide and 2,3-diphenyl-1,8-naphthyridine 1-oxide (Intermediates C) (1 g, 3.35 mmol) in dry THF (10 ml) under an atmosphere of N2 was treated dropwise with methylmagnesium chloride (1.676 ml, 5.03 mmol). The resulting mixture was stirred at room temperature for 45 minutes and then partitioned between EtOAc and water. The aqueous portion was extracted with EtOAc (2×100 ml) and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in acetic anhydride (5 ml) and heated at 120° C. for 10 mins using microwave radiation. The resulting mixture was partitioned between DCM (150 ml) and water. The organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was loaded onto a Isolute™ SCX-2 cartridge and eluted with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford a brown oil which was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title product;
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13]C(C#N)=[CH:11][C:10]=3[O:17][CH3:18])[NH:8][C:4]=2[CH:3]=1.[OH-:22].[Na+].[CH2:24]([OH:26])[CH3:25]>>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:25]([C:24]([OH:22])=[O:26])=[CH:11][C:10]=3[O:17][CH3:18])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C#N)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 5,6-dichloro-2-(4-cyano-2-methoxyphenyl)benzimidazole, prepared as described in Preparation 5, in ethanol (50 ml) and 2N NaOH (15 ml) was refluxed for 16 h. Solvent was removed under reduced pressure and the residue was acidified with 37% HCl (10 ml), stirred for 1 h. The solid was filtered, washed with water (50 ml), dried at 50° C. under vacuum to give 0.92 g of the title compound (yield 46%), mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11]>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1F
Yield: 90 %

Procedure:
(4-Fluoro-3-methoxyphenyl)methanol (5.00 g, 0.03 mol) and manganese dioxide (33.4 g, 0.38 mol) were stirred in dichloromethane (100 ml) under an atmosphere of nitrogen, at gentle reflux for 16 hours. The cooled reaction mixture was then filtered through arbacel and concentrated in vacuo to give the title compound as a white solid (4.18 g, 0.027 mol, 85%). 1H NMR (CDCl3, 400 MHz) δ: 3.96 (s, 3H), 7.23 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H), 9.91 (s, 1H). Mpt: 61-63° C. Analysis found C, 62.18; H, 4.54%. C8H7FO2 requires C, 62.34; H, 4.58%.
Reaction SMILES: CSC1C=CC(C=C)=CC=1.ClCl.[CH2:13]([OH:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>ClCCl.CCOCC>[CH:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCO
Agent: C=Cc1ccc(SC)cc1
Agent: ClCl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCC=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a stirred suspension of 1.0 g (3.56 equivalents of sulfide group) of poly (p-methylmercaptostyrene) in dichloromethane (20 ml) was added at -10°C a solution of 280 mg (3.94 mmoles) of chlorine (as cl2) in 10 ml of CH2Cl2, after which the mixture was cooled to -78°C, treated with 130 mg (1 mmole) of octanol in 1.6 ml of CH2Cl2, and stirred at -78°C for 0.5 hr., and then -25°C for 4.5 hours. The reaction mixture was treated at -25°C with 612 mg (6 mmoles) of triethylamine in 2 ml of CH2Cl2 and stirred for an additional 20 minutes. Ether (50 ml) was next added, and after stirring for 10 minutes, the resulting mixture was filtered and the beads washed with another 30 ml of ether. The combined filtrate was next washed with 1 N HCl solution and brine, and dried (MgSO4). After removal of the solvent by evaporation under reduced pressure, the product was evaporatively distilled (bulb to bulb) at an oven temperature of 50°C and 0.1 mm pressure to yield 122 mg (95%) of octanal. GLC analysis (4% SE-30) of the product indicated the presence of 97% octanal and 3% starting material.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])[C:7]=1[O:14][CH3:15])(=[O:31])=[O:30]
Reactant: COc1c(CO)cccc1OCc1c(C)cccc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-2-methoxyphenyl)methanol (Step B, 9.5 g, 32.7 mmol) and triethylamine (5.80 g, 57.4 mmol) in dry CH2Cl2 (100 ml) was added drop wise methanesulfonyl chloride (3.5 ml, 45 mmol) at 0° C. under argon. The reaction mixture was warmed to room temperature for 6 hours or until all the starting material is consumed, neutralized with cooled 10% Na2CO3 and extracted with CH2Cl2. The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex: methylene chloride 2:1) to give the title compound as light yellow oil
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CC[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (R)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D33)(0.9 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].Cl[Si](C)(C)[CH3:19]>CO>[C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:19])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc(C(=O)O)c2ccccc2n1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)nc2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCI) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCI (161 mg, 1.2 eq.), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1 M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%-3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]-aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1 N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2), 3.4-3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]([NH:23][CH3:24])=[O:22])=[CH:16][N:17]2[CH3:20])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[CH3:24][NH:23][C:21]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:17]([CH3:20])[C:16]=1[Cl:1])=[O:22]
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Temperature: 60 °C
Yield: 86.6 %

Procedure:
N-Chlorosuccinimide (0.150 g, 1.12 mmole) was added to a solution of 6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75a (0.243 g, 1.11 mmole) in CCl4 (10 ml) and DMF (3 ml). The reaction mixture was heated to 60° C. for 3 h and concentrated. The residue was purified by reverse phase chromatography eluting with 0-1% CH3OH in 1:1 EtOAc and CH2Cl2 to give a brown colored oil (0.243 g, 87% yield); 1H NMR (300 MHz, CDCl3) δ7.61 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 6.19 (1H, s), 3.35 (3H, s), 2.96 (3H, s), 2.52 (3H, s); ESIMS (MH+): 253.05
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:23][CH2:22][CH2:21][CH2:20][O:7]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-4-nitro-benzophenone (11f) (20.0 g, 78.4 mmol), 1,3-propandiol (7.15 g, 94.0 mmol), p-toluenesulfonic acid monohydrate (50 mg) in toluene (300 mL) was refluxed using a Dean-Stark-trap for 24 hours. The Dean-Stark-trap was then replaced by a Soxhlet-extractor filled with molecular sieve and the mixture was refluxed for an additional 48 hours to achieve complete conversion. The reaction mixture was then cooled to ambient temperature, washed with an aqueous, saturated solution of NaHCO3 and concentrated in vacuo until crystallization started. The suspension was cooled for 0.5 hours in an ice bath and after which the crystalline product was filtered, washed with a small volume of hexane and air dried to give 22.48 g (72 mmol, 91.5%) compound 17 as yellow crystals.
Reaction SMILES: [CH:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:20][N:21]=1.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([N:8]2[CH2:5][CH:4]3[CH2:6][CH2:7][CH:1]2[C@@H:2]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:17]2[O:18][C:19]([C:22]4[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:30])[F:32])=[CH:26][CH:27]=4)=[CH:20][N:21]=2)[CH2:3]3)=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: FC(F)(F)Oc1ccc(-c2cnc(N[C@@H]3CCCC[C@H]3NC3CC[C@H]4CCC3N4)o2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC3CCC2[C@@H](N[C@@H]2CCCC[C@H]2Nc2ncc(-c4ccc(OC(F)(F)F)cc4)o2)C3)cc1
Temperature: 80 °C
Yield: 16.5 %

Procedure:
To a solution of (1R,2R)—N1-((5R)-8-azabicyclo[3.2.1]octan-2-yl)-N2-(5-(4-(trifluoromethoxy)phenyl)oxazol-2-yl)cyclohexane-1,2-diamine (28 mg, 0.062 mmol) and 4-fluoronitrobenzene (9.65 mg, 0.069 mmol) in DMF (0.38 ml) was added K2CO3. The reaction mixture was then heated at 80° C. for 4 hrs. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC using method A with two isomers were separating. The fractions with the desired product, which eluted later than the undesired isomer, were concentrated to give (1R,2R)—N1-((6S)-2-(4-nitrophenyl)-2-azabicyclo[2.2.2]octan-6-yl)-N2-(5-(4-(trifluoromethoxy)phenyl)oxazol-2-yl)cyclohexane-1,2-diamine (5.82 mg, 0.0102 mmol, 16.4% yield) as a yellow solid. Anal. Calcd. for C29H32F3N5O4 m/z 571.2, found: 572.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 11.04 (1 H, br. s.), 7.88 (2 H, d, J=9.3 Hz), 7.55 (2 H, d, J=8.2 Hz), 7.30 (2 H, d, J=8.2 Hz), 7.02 (1 H, s), 6.78 (2 H, d, J=9.3 Hz), 6.38 (1 H, br. s.), 4.65 (1 H, d, J=6.0 Hz), 4.36 (1 H, d, J=6.0 Hz), 4.33-4.20 (1 H, m), 3.80-3.73 (1 H, m), 3.40-3.27 (1 H, m), 2.26-1.65 (13 H, m), 1.65-1.30 (3 H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: O=C1CCN(CCCCCCO)CC1
Reactant: NO
Agent: Cl
Product: OCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Hydroxyhexyl)-4-piperidone oxime is prepared from 1-(6-hydroxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([OH:11])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-hydroxybenzoic acid (3.41 g, 15 mmol) (J. Chem. Soc. 1955, 463) in anhydrous methanol (80 mL) was added acetyl chloride (2.56 mL, 36 mmol) at 0° C. The mixture was then heated under reflux overnight. The volatiles were removed in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([O:45][CH3:46])(=[O:44])[CH:42]=[CH2:43]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:46][O:45][C:41](=[O:44])/[CH:42]=[CH:43]/[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 4-bromo-1-naphthalenecarboxylic acid (which may be prepared by the methods described in Can. J. Chem. 1981, 59, 2629-41) (100 mg, 0.4 mmol), triethylamine (0.42 ml, 3 mmol), palladium acetate (12 mg, 0.04 mmol), triphenylphosphine (13 mg, 0.04 mmol) and methyl acrylate (1.19 ml, 0.11 mmol) in anhydrous DMF (8 ml) was heated to 100° C. for 4 h under nitrogen. The mixture was allowed to cool to room temperature, evaporated to dryness under reduced pressure and purified by aminopropyl cartridge, eluting with MeOH, followed by 4M HCl in dioxane and then 2M ammonia in MeOH. The ammonia in methanol fractions were combined to afford a residue that was partitioned between DCM and water, the DCM layers combined, dried over magnesium sulfate filtered and evaporated to afford the title compound (99 mg, 97%). LCMS RT=3.25 min, ES−ve m/z 255 (M−H)−.