Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH2:18][CH:19]=[CH2:20])[N:11]=1.S([O-])(O)=O.[Na+].[OH2:26]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:16][C:14]1[CH:15]=[C:10]([CH3:9])[N:11]=[C:12]([NH:17][CH2:18][CH:19]([OH:5])[CH2:20][OH:26])[N:13]=1
Reactant: C=CCNc1nc(C)cc(C)n1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(C)nc(NCC(O)CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-methylmorpholine-N-oxide (64.0 g, 0.47 mol) and osmiumtetroxide (0.7 g, 2.75 mmol) were dissolved in a mixture of 180 ml water and 100 ml acetone. 1-(4,6-dimethylpyrimid-2-ylamino)-prop-2-ene (73.5 g, 0.45 mol) in 100 ml acetone was added over a period of 15 minutes. The mixture was stirred at room temperature for 1 hour and then warmed to 50° C. for 2 hours. 10 ml aqueous saturated sodium hydrogensulphite was then added together with 40 g of diatomaceous earth. After filtration the reaction mixture was evaporated to dryness and the residue extracted with dioxane/ethanol 2:1 (700 ml). Filtration from insoluble material and concentration of the solution in vacuum caused crystallisation of the product. Addition of toluene completed product precipitation, which was isolated by filtration (83 g, m.p. 124°-127° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>CO>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][CH2:2][N:13]1[CH2:14][CH2:15][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12]1)[CH3:7]
Reactant: CCN(CC)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN(CC)CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
3-Chloro-N,N-diethylpropan-1-amine (1.6 g) is added to a mixture of tert-butyl piperazine-1-carboxylate (2.0 g) and NEt3 (1.5 ml) in methanol (30 ml). The mixture is stirred for 6 hours at 70° C. and cooled to room temperature. The solvent is removed under reduced pressure. Satd. aqueous NaHCO3 is added to the crude product and the aqueous layer is extracted with EtOAc (3×). The combined organic layers are dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give tert-butyl 4-(3-(diethylamino)propyl)piperazine-1-carboxylate (2.48 g). m/z(+) 300 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.29 mmol) in dioxane (30 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (1.28 g, 1.5 equiv) and Pd(PPh3)2Cl2 (246 mg, 0.15 equiv) and the resulting mixture was stirred at 90° C. for 18 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to provide the title compound as a yellow oil (200 mg, 31%). ES-MS: m/z 282.3 [M+H]+, rt 4.97 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1.Cl[CH2:17][CH2:18][CH2:19]Br.[I-].[Na+]>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]23[CH2:19][CH2:18][CH2:17][C:4]2=[CH:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCBr
Reactant: COc1cccc(C2=CCN(C)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: COc1cccc(C23CCCC2=CN(C)CC3)c1

Procedure:
Following the procedure set out in Example 47, 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine was reacted with 3-chloropropylbromide and sodium iodide to afford 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine. B.P. 132°-134° C. at 0.1 torr.
Reaction SMILES: C(OC(=O)COCC[C@H](O)C)(C)(C)C.[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][OH:26])([CH3:18])([CH3:17])[CH3:16].Cl[C:30]1[C:31]2[C:38]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)=[C:37]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:15]([O:19][C:20](=[O:28])[CH2:21][O:22][C@H:23]([CH3:27])[CH2:24][CH2:25][O:26][C:30]1[C:31]2[C:38]([C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)=[C:37]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[O:36][C:32]=2[N:33]=[CH:34][N:35]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: C[C@H](CCO)OCC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: C[C@@H](O)CCOCC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC[C@@H](C)OCC(=O)OC(C)(C)C)c23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
Put 455 mg (2.23 mmol) {[(3R)-3-hydroxybutyl]oxy}acetic acid tert.-butyl ester (which contains up to approx. 10% {[(1R)-3-hydroxy-1-methylpropyl]oxy}acetic acid tert.-butyl ester) under argon in 5 ml THF and cool to 0° C. Add 1.15 ml (2.23 mmol) of a 2 M solution of phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 500 mg (1.49 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and stir overnight at RT. Then dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 450 mg (60.1% of theor.) of the target compound is obtained. 75 mg (9.0% of theor.) of (−)-{[(1R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpropyl]oxy}acetic acid tert.-butyl ester is isolated as by-product (see Example 77).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CO>[CH2:23]([S:12][C:10]1[CH2:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:19]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC(SCc1ccccc1)=N2
Reaction time: 0.5 h

Procedure:
To a solution of 1.43 parts of 7-chloro-5phenyl-3-H-1,4-benzodiazepine-2-thione in 12.5 parts by volume of 0.4 N sodium methoxide in methanol is added dropwise with stirring 0.6 part by volume of benzyl bromide and the stirring is continued for an additional 30 minutes. Water is added to the reaction mixture and the resulting oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate. Evaporation of the solvent yields 2-benzylmercapto-7-chloro-5-phenyl-3H-1,4-benzodiazepine as an oil.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22]>ClCCCl>[C:1](=[N:14][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NC1CCCNC1=O
Solvent: ClCCCl
Product: O=C1NCCCC1N=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 78.7 %

Procedure:
Benzophenone imine (3 mL, 17.87 mmol) was added to a solution of 3-aminopiperidin-2-one [CAS 1892-22-4] (2 g, 17.52 mmol) and molecular sieves in DCE (50 mL) under nitrogen and the reaction was warmed to 80° C. for 18 hours. The solvent was evaporated and the residue applied to a 100 g SNAP column, eluting with 50 to 100% EtOAc/ihexane to afford 3-(benzhydrylideneamino)-piperidin-2-one (D21) (3.84 g, 13.796 mmol, 78.7% yield) as a colourless solid.
Reaction SMILES: C(Cl)(Cl)=O.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]1([N:19](C)[C:20](Cl)=[O:21])C=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:24]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:20]([NH:19][C:13](=[NH:24])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:21]
Reactant: c1ccncc1
Reactant: CNc1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=N)NC(=O)N(C)c1ccccc1
Reaction time: 3 h

Procedure:
To a stirred solution of 29.4 g. phosgene in 350 ml. dry chloroform at 5°C. was added a solution of 32.1 g. N-methylaniline and 23.7 g. dry pyridine in 80 ml. dry chloroform dropwise during 45 minutes and the resulting solution was allowed to stand at 5°C. for 3 hours. The solution was evaporated to dryness under reduced pressure and the resulting residue was dissolved in ether. The ethereal solution was heated with magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure and the resulting solid was slurried in n-hexane and filtered to give 31.5 g. N-phenyl- N-methylcarbamyl chloride; m.p. 90°-91°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH2:29][CH2:30][CH2:31][CH3:32])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1nnnc1-c1ccc(-c2c(C#N)c(CC)n(C)c2C(=O)OCC)cc1
Temperature: 0 °C
Yield: 33.9 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g, 0.428 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.019 g, 0.479 mmol, 60% in mineral oil). Let stir for 1 h, then add butyl iodide (0.054 mL, 0.479 mmol) and let stir for 2.5 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×15 mL). Combine the organic layers and wash with brine (2×20 mL), aqueous NH4Cl (1×20 mL), aqueous NaHCO3 (1×20 mL) and water (1×20 mL). Dry the organic layer over anhydrous Na2 SO4, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes). Concentrate under reduced pressure the purified fractions and place under vacuum to provide the title compound as a colorless oil (0.059 g); mass spectrum (m/e): 407.4 (M+H)
Reaction SMILES: N.C[N:3]([CH:5]=[O:6])C.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH3:32])=[C:18](C(O)=O)[CH:19]=[C:20]4[C:28]=3[C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=[CH:21]4)=[CH:15][C:10]=2[O:9][CH2:8]1>O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH3:32])=[C:18]([C:5]([NH2:3])=[O:6])[CH:19]=[C:20]4[C:28]=3[C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=[CH:21]4)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Agent: N
Solvent: O
Product: Cc1c(C(N)=O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
WSC[1-Ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride](33 mg) and ammonia (3N ethanol solution:0.14 ml) were added under ice-cooling to a DMF solution of 9-(1,3-benzodioxole-5yl)-8-methyl-naphtho[1,2-d]-1,3,-dioxole-7-carboxylic acid (50 mg) which was prepared in Reference Example 13. The mixture was stirred at room temperature for 2 hours, and the reaction was stopped with addition of water. The residue was purified with column chromatography (Silica-Gel 5 g, eluent:ethyl acetate-hexane=1:1) and recrystalized from methanol to yield the title compound (23 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]#[N:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.CC(O)=O.[C:25]([CH:27](C)[CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)#[N:26].[BH3-]C#N.[Na+]>CO>[C:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][C:25]#[N:26])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)#[N:13]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: CC(C#N)CCOc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CCCCOc1ccc(CNc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Pyridyl)-5-cyano-1-(4′-aminophenyl)pyrazole (0.5 mmol) was dissolved in MeOH (4 mL) and treated with HOAc (4 mL). The reaction was treated with a solution of 4-(3-cyanobutoxy)benzaldehyde (from Example above) (0.75 mmol) in MeOH (1 mL) and stirred at room temperature for 30 minutes. NaCNBH3 (1.25 mmol) was added in one portion. After 2 hr, volatiles were removed, the residue taken up in water, neutralized with NaHCO3 (aq) and extracted with dichloromethane. Organic extracts were combined, dried over MgSO4 and concentrated to leave a clear oil. Pure product was eluted from silica gel column using 50% dichloromethane in EtOAc giving a light yellow solid (140 mg, 64%), m.p. 128-129° C. 1H NMR (CDCl3): δ 1.98-2.04 (m, 2H), 2.63-2.66 (t, J=7.1 Hz, 2H), 4.00-4.04 (t, J=6 Hz, 2H), 4.27-4.29 (d, J=5.8 Hz, 2H), 6.72-6.79 (m, 3H), 6.92-6.94 (d, J=8.5 Hz, 2H), 7.31-7.33 (d, J=8.5 Hz, 2H), 7.42-7.44 (d, J=8.7 Hz, 2H), 7.50-7.53 (m, 1H), 7.96 (s, 1H), 8.24-8.26 (d, J=8 Hz, 1H), 8.60-8.61 (d, J=4.6 Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([OH:46])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:46])[CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccccc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (2RS)-1-amino-3-phenoxy-2-propanol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=524.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37]>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:37][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:7]4[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(Oc2ccc3c(C(=O)Cl)cccc3c2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(Cl)c4)cccc3c2)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(6-methoxypyridin-3-yloxy)-1-naphthoyl chloride hydrochloride salt (225 mg, 0.64 mmol) and DIPEA (0.22 mL, 1.285 mmol) in DCM (5 mL) at RT was added 3-chloro-4-fluoroaniline (93.5 mg, 0.64 mmol). After stirring for 16 h, the reaction mixture was directly purified by silica gel chromatography (elution hexanes/EtOAC: 85/15 to 35/65) to give the title compound as a tan solid. MS (ESI, pos. ion) m/z: 423.1 (M+1). Mass Calc'd for C23H16ClFN2O3: 422.84.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=3)[O:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])OC(C)(C)C)=[O:24])[CH2:19][CH2:18]2)([CH3:15])[C:12](=[O:14])[N:13]=1.NCCOC1C=[C:48]([CH:73]=[CH:74]C=1)[C:49](N1CCC(CC2(C)SC(N[C@H]3CC4CC3CC4)=NC2=O)CC1)=[O:50].O1C=CC(C(O)=O)=C1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=3)[O:28][CH2:29][CH2:30][NH:31][C:32]([C:73]3[CH:48]=[CH:49][O:50][CH:74]=3)=[O:38])=[O:24])[CH2:21][CH2:22]2)([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)N2CCC(CC3(C)SC(N[C@H]4CC5CCC4C5)=NC3=O)CC2)c1
Reactant: CC1(CC2CCN(C(=O)c3cccc(OCCN)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)c1ccoc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC1(CC2CCN(C(=O)c3cccc(OCCNC(=O)c4ccoc4)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of tert-butyl 2-(3-(4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carbonyl)phenoxy)ethylcarbamate by using 5-((1-(3-(2-aminoethoxy)benzoyl)piperidin-4-yl)methyl)-2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one (93 mg, 0.19 mmol), 3-furoic acid (Aldrich, 39 mg, 0.35 mmol), EDCI (Aldrich, 74 mg, 0.38 mmol), HOBt (Aldrich, 5.2 mg, 0.038 mmol) and triethylamine (Aldrich, 39 mg, 0.38 mmol, 2.0 eq). The title compound was obtained as an off-white solid (89 mg). MS (ESI, pos. ion) m/z. 579 (M+H).
Reaction SMILES: [F:1][C:2]([F:28])([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[H-].[Na+].Cl/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35].O>CN1C(=O)CCC1>[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11]/[CH:32]=[CH:33]/[C:34]([F:37])([F:36])[F:35])[O:3][C:2]([F:1])([F:28])[CH:13]1[CH2:14][CH2:15][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:17][CH2:18]1
Reactant: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O)c(F)c3)CC2)CC1
Reactant: FC(F)(F)/C=C/Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCC1CCC(C2CCC(C(F)(F)Oc3cc(F)c(O/C=C/C(F)(F)F)c(F)c3)CC2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
4-(Difluoro(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)methoxy)-2,6-difluorophenol (3.0 g, 7.45 mmol) prepared by known methods and sodium hydride (55%) (0.325 g, 7.45 mmol) were stirred in NMP (N-methylpyroridone) at 60° C. for 30 minutes. (E)-1-Chloro-3,3,3-trifluoro-1-propene (2.43 g, 18.6 mmol) was then added to the reaction solution, and the mixture was stirred at 130° C. for 24 hours. The reaction solution was poured into water, which was extracted with toluene. The combined organic layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off with an evaporator and the residue was purified by silica gel chromatography and then by recrystallization to give (E)-4-((3,5-difluoro-4-((3,3,3-trifluoro-1-propen-1-yl)oxy)phenoxy)difluoromethyl)-4′-propyl-1,1′-bi(cyclohexane) (56% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]3[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=3)[CH3:29])[N:7]=2)[CH:13]=1)[CH3:16]
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.35 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.20 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.37 g of the title compound. MS (electrospray): 389 (M+1) for C16H17FN8O3.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[F:20][C:21]1[N:22]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[C:24]([CH:26]=O)[N:25]=1.CO>C(COC)OC.C1COCC1>[C:10]([CH2:26][C:24]1[N:25]=[C:21]([F:20])[N:22]([C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COCCOC
Product: N#CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.75 h

Procedure:
Examples 44, 45: Toluene-p-sulphonylmethyl isocyanide, dissolved in dimethoxyethane, was added to a suspension of potassium t-butoxide in the same solvent at -30°. The mixture was cooled to -50° and treated with a solution of 2-fluoro-4-formyl-1-triphenylmethylimidazole in THF plus dimethoxyethane. After 45 minutes, MeOH was added and the mixture heated under reflux briefly. Extractive work-up gave 4-cyanomethyl-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 3.53 (s, 2H); 6.57 (s, 1H); 7.05-7.45 (m, 15H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:18]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 2-(trimethylsilyl)ethanol (7.3 mL) and triethylamine (25 mL) in dichloromethane (80 mL). Cool in an ice bath. Add dropwise chloroacetyl chloride (6.9 g). After the addition is complete warm the reaction mixture to ambient temperature After 5 hours, add chloroacetyl chloride (2.8 g), After 2 hours, filter the reaction mixture and extract with a saturated aqueous solution of sodium bicarbonate and then water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(trimethylsilyl)ethyl chloroacetate: bp 150° C. at 28 mm of Hg.