Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][N:23]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CS(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[N:18][C:17]([NH:20][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[N:24][N:23]=4)=[N:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: COc1cnc2c(Nc3cnc(N)nc3)ccnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cnc2c(Nc3cnc(Nc4nnc(-c5ccccc5)c5ccccc45)nc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N5-(7-methoxy-1,5-naphthyridin-4-yl)pyrimidine-2,5-diamine (90 mg, 335 μmol), 1-chloro-4-phenylphthalazine (97 mg, 403 μmol), THF (1677 μl, 335 μmol), and LiHMDS (1006 μl, 1006 μmol) were added into a pressure tube. The mixture was stirred at RT for 10 min. A red solution was formed. The tube was placed in a preheated oil bath at 100° C. After 1 h, LCMS showed complete conversion of SM to product. The reaction was cooled to rt. Hexane was added to induce the product to precipitate out of the reaction mixture. The resulting red solid was filtered with an aid of hexane. LCMS confirmed that the solid was the product. The product was purified by performing a column chromatography on silica gel using 60:40 CH2Cl2:(90:10:1 CH2Cl2:MeOH:NH4OH). Yellow solid was obtained. LCMS confirmed product. HPLC showed 96% pure. 1H NMR showed rotamers. Note: this cmpd was slightly soluble in DMSO at rt. MS Calcd for C27H20N8O: [M]+=472. Found: [M+H]+=473.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[C:12]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH2:19]
Reactant: C=O
Reactant: COc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1
Yield: 61.8 %

Procedure:
2',3'-Dichloro-4'-methoxy-2-cyclopentylacetophenone (51.6 g., 0.18 mole) is dissolved in dioxane (460 ml.) and paraformaldehyde (21.6 g., 0.72 mole) and concentrated sulfuric acid (9.65 g.) are added. The mixture is heated at 80°-85° C. for 20 hours. The dioxane is evaporated at reduced pressure. Water is added to the residual gum which then is extracted into ether. The ether extract is washed with water and dried over magnesium sulfate. The ether is evaporated and upon triturating the residue with hexane (5 ml.) there is obtained a solid that is crystallized from ligroin to obtain 2',3'-dichloro-4'-methoxy-2-cyclopentylacrylophenone (33.3 g.), m.p. 59°-63° C. Crystallization from butyl chloride affords a sample (m.p. 66°-67.5° C.) for analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:18][O:19][CH2:20][CH2:21][NH2:22].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:22][CH2:21][CH2:20][O:19][N:18]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: N#CCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 6.9 mmol (1.67 g) of 3', 4'-dichloro-4-cyanobutyrophenone (melting point 53°-54° C), 6.9 mmol (1.03 g) of 2-aminooxyethylamine dihydrochloride, 6.9 mmol (0.56ml) of pyridine and 5 ml of absolute ethanol was refluxed for 3.5 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:6]([N:17]([C:16]2[CH:18]=[CH:19][C:13]([O:12][CH:11]([F:10])[F:20])=[CH:14][CH:15]=2)[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride in 70 ml of toluene is heated to boiling. A solution of 15.9 g (0.1 mole) of p-difluoromethoxyaniline in 30 ml of toluene is added dropwise to it over 20 minutes with stirring. Thereafter, the resulting solution is refluxed until water is no longer distilled. This requires about 2 hours. The mixture is cooled to room temperature to precipitate crystals. The precipitated crystals are filtered off and washed with hexane to obtain 29.2 g of 2,3-dichloro-N-(p-difluoromethoxyphenyl)maleimide melting at 217.5°-218° C. in the form of light yellow plate crystals.
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:18]([C:20]1[N:21]=[C:22]([CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:29])[NH:23][C:24]=1[CH2:25][CH3:26])[CH3:19]>>[CH2:25]([C:24]1[NH:23][C:22]2[N:21]([C:20]=1[CH2:18][CH3:19])[C:1](=[O:4])[CH:2]=[CH:3][C:27]=2[C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH3:26]
Reactant: C#CC(=O)O
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1CC
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1CC

Procedure:
The compound is prepared as described in example 6 with 122.1 mg (1.67 mmol) of propiolic acid, 325.6 mg (2.01 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 300 mg (1.12 mmol) of 2-(4,5-Diethyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone (example XXVII).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[C:38]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1>>[NH2:30][C:4]1[S:3][C:2]([C:38]2=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(C2=CCCCCC2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCCC3)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 14 %

Procedure:
Following the procedure for Example 350 starting with (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and 1-cycloheptenylboronic acid pinacol ester gave 339 as an orange solid (7.0 mg, 14%). 1H NMR (400 MHz, d4-MeOD) δ 7.57 (s, 1H), 6.46 (t, J=6.7 Hz, 1H), 3.74 (s, 3H), 3.31-3.22 (m, 4H), 3.14-3.06 (m, 1H), 2.88-2.82 (m, 2H), 2.39-2.32 (m, 2H), 2.05-1.56 (m, 12H). LCMS (ES+) m/z 430 (M+1)
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)#[CH:14]>>[CH3:12][C:4]1[CH:3]=[C:2]2[C:7](=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=1)[NH:8][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)=[CH:14]2
Reactant: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Reactant: C#Cc1cccc(C)n1
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3cccc(C)n3)cc2c1
Yield: 35.3 %

Procedure:
6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) and 2-ethinyl-6-methylpyridine (210 mg, 1.8 mmol) were reacted according to the same procedure as Preparation 19 to give the title compound (170 mg, Yield 35%).
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]O.C1(C(C)C)C=CC=CC=1.C1([OH:27])C=CC=CC=1>CC(C)=O>[CH3:8][C:7]([OH:27])([CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1ccccc1
Reactant: Oc1ccccc1
Agent: [O-]O
Solvent: CC(C)=O
Product: CC(C)(O)c1ccccc1

Procedure:
The dominant method for producing phenol and acetone is via air oxidation of cumene to cumene hydroperoxide (CHP), followed by acid catalyzed decomposition of the CHP selectively to phenol and acetone. Dimethylbenzyl alcohol (DMBA) is formed as the principal side product in the oxidation step, and is subsequently dehydrated to alpha-methyl styrene (AMS) in the same acid catalyzed decomposition step.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Temperature: 140 °C
Yield: 24.8 %

Procedure:
To a solution of 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 622 μmol, prepared as described in example 31) in NMP (2.1 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (402 mg, 1.86 mmol) in 3 portions approximately every 12 h and heated to 140° C. in the periods between additions. After a total of 36 h, the mixture was cooled, diluted with ethyl acetate and brine, then the organic phase separated and washed with brine (3×). The organic phase was then concentrated in vacuo and the residue obtained was purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (77 mg, 154 μmol, 25%) as a light brown solid. MS (EI/CI) m/z: 502.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=3)[N:14]=1)[CH2:9][CH2:8]2.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:12][CH:10]1[C:11]3[C:7](=[CH:6][C:5]([CH3:24])=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9]1)[CH:22]=[CH:21]2)=[O:30])([CH3:27])[CH3:26]
Reactant: COc1cc(C)cc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CC(C)N=C=O
Product: COc1cc(C)cc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methoxy-5-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=405.6 (M+H+).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:6])=[O:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of trimethylaluminium in toluene (10 mL of 2.0 M) is added over 30 minutes to a stirred suspension of ammonium choride (107 g, 20 mmol) in toluene (20 mL) at 5° C. under an argon atmosphere. The mixture is stirred at 20° C. for 2 h, treated with a solution of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.65 g, 4.3 mmol) in toluene (40 mL) and stirred at 60° C. for 18 h. The cooled mixture is washed with hydrochloric acid (50 mL of 0.5 M) followed by saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by crystallization from ethyl acetate-t-butylethyl ether to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxamide as a colourless crystalline solid, m.p. 201-205° C.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.[C:22](=O)(O)[O-:23].[Na+].C(Cl)(Cl)=S.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:22]=[O:23])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: O=C([O-])O
Agent: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=O)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 75 g of 6-amino-2-tert-butyl-5-(4-methylpiperazin-1-yl)benzothiazole and 29 g of sodium bicarbonate in 1100 ml of chloroform at 0° is added 41 g of thiophosgene and the mixture stirred at 10° for 4 hours. After filtering off the solid, the solution is evaporated to get an yellow solid which is dissolved in water and the pH of the solution is brought to 7 by the addition of dilute sodium hydroxide. The solid separated is extracted with hexane and filtered through 150 g of neutral alumina to give 2-tert-butyl-6-isocyanato-5-[4-methyl-piperazin-1-yl]benzothiazole melting at 124°-126°.
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:15]3[O:19][C:18]([C:20]4[CH:25]=[C:24]([OH:26])[C:23]([C:27]5[O:28][C:29]([C:32]6[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]7[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=7)[CH:33]=6)=[N:30][N:31]=5)=[CH:22][C:21]=4[OH:48])=[N:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([C:15]3[O:19][C:18]([C:20]4[CH:25]=[C:24]([OH:26])[C:23]([C:27]5[O:28][C:29]([C:32]6[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]7[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=7)[CH:33]=6)=[N:30][N:31]=5)=[CH:22][C:21]=4[OH:48])=[N:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:49][CH:50]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(-c3nnc(-c4cc(O)c(-c5nnc(-c6cccc(Oc7ccc([N+](=O)[O-])cc7)c6)o5)cc4O)o3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc(-c3nnc(-c4cc(O)c(-c5nnc(-c6cccc(Oc7ccc(N)cc7)c6)o5)cc4O)o3)c2)cc1
Reaction time: 18 h
Yield: 36.6 %

Procedure:
0.30 g of 2,5-bis(5-(3-(4-nitrophenoxy)phenyl)-1,3,4-oxadiazole-2-yl)benzene-1,4-diol prepared in Synthesis Example 15 was dissolved in 150 ml of THF, and 0.05 g of a catalyst having 5 wt % of palladium impregnated in activated carbon was added thereto. Gases generated in the solution by purging an argon (Ar) gas were removed to create a vacuum, followed by stirring for 18 hours while supplying H2 gas (approximately 2-3 atm) for inducing a reaction. After the reaction was completed, the reaction product was filtered with Celite powder to remove the catalyst, and performing silica gel column chromatography (developed with a solution having ethylacetate:n-hexane mixed in a ratio of 1:2) to yield 0.1 g of a product having Formula 39. 1H NMR (300 MHz, CDCl3) analytical results of the product were as follows:
Reaction SMILES: C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC(F)=C(F)C=2)N=1)C.[CH2:22]([C:24]1[C:33]([CH3:34])=[C:32]([O:35][C:36]([CH:38]2CC2)=[O:37])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:42])[C:30]=2[F:41])[N:25]=1)[CH3:23].O>O1CCCC1.[H-].[Na+]>[CH2:22]([C:24]1[C:33]([CH3:34])=[C:32]([O:35][C:36](=[O:37])[CH3:38])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:42])[C:30]=2[F:41])[N:25]=1)[CH3:23]
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(F)c(F)c2c(OC(C)=O)c1C
Reaction time: 1 h
Yield: 232.8 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1 g) prepared as described in Example 1 was dissolved in 10 ml of methanol to prepare a solution. A solution of 0.5 g of sodium hydroxide in 10 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitate was then collected by filtration to give 700 mg of 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended in 96 mg of 60% sodium hydride. The 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (446 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr, 200 mg of acetyl chloride (starting material 2) was then added thereto, and the mixture was stirred at room temperature for 4.5 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 424 mg of 2-ethyl-3-methyl-4-acetyloxy-5,6-difluoroquinoline (compound 12). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:22](O)[C:23]#[C:24][CH3:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]#[C:24][CH3:25])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:2]
Reactant: CC#CCO
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1cccc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
The ethyl(3-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate (4.2 g, 13 mmol) was stirred with THF (100 ml) in a dried two-necked flask under inert conditions. The 2-butyn-1-ol (0.97 ml, 13 mmol) and 1,1′(azodicarbonyl)dipiperidine (3.94 g, 15.6 mmol). Tributylphosphine (3.90 ml, 15.6 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at room temperature under nitrogen for 2 hours before it was concentrated. The residue was triturated with ether and the filtrate was concentrated, Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl}(3-chlorophenyl)acetate was isolated as a yellow oil (4.08 g) after silica-gel column chromatography, using methylene chloride as the mobile phase. Yield 84%; MS(EI): 375 (M+H)+
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(F)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Fc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-fluorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 320.2 (M+1). 1H NMR (500 MHz, CD3OD): δ partial 8.84 (br s, 1H); 8.39 (d, J=5.5 Hz, 1H); 7.97 (br s, 1H); 7.71 (d, J=8.2 Hz, 1H); 7.13 (d, J=10.1 Hz, 1H); 7.06 (d, J=5.5 Hz, 1H); 6.96 (m, 1H); 4.69 (s, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[C:30]([O:32][CH3:33])=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ICC>C1COCC1>[CH2:13]([O:20][C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@:25]1([CH2:1][CH3:2])[C:30]([O:32][CH3:33])=[O:31])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@H]1CCCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@@]1(C(=O)OC)CCCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a cold (−78° C.) solution of N-isopropylpropan-2-amine (0.77 mL, 5.49 mmol) in THF (7 mL) was added, dropwise, n-butyllithium (3.43 mL of 1.6 M solution, 5.49 mmol). The mixture was stirred at −78° C. for 10 minutes. Then a solution of methyl (1S,2S)-2-benzyloxycarbonylaminocyclohexanecarboxylate, 38a, (0.40 g, 1.37 mmol) in THF (2.5 mL) was added over a period of 3 minutes. After 15 minutes, the mixture was warmed slightly (−40° C.) for 15 minutes and recooled to −78° C. for a further 10 minutes. Then, iodoethane (0.86 g, 0.44 mL, 5.49 mmol) was added, dropwise over 3-5 minutes. The reaction mixture was maintained at −78° C. for 2 hours and allowed to warm to room temperature overnight. The reaction was quenched with 5 mL aqueous saturated NH4Cl solution, extracted with EtOAc (3×), washed successively with 1N HCl and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% EA/Hex slow gradient elution) provided 275 mg (63% yield) of the desired product (38b). NMR indicated a diastereomeric ratio greater than 10 to 1 (cis vs trans).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)O)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(S(F)(F)[F:41])CC)C.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)[F:41])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(O)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of 0.9 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-hydroxybenzyl}-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of benzene at room temperature, were added 0.85 g of diethylaminosulfur trifluoride (DAST). After stirring at room temperature for 1 hour, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.8 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-fluorobenzyl}-3-(2-chloro-6-fluorophenyl)-1 methyl-1H-1,2,4-triazole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][CH:13]=2)=O.Cl.C([O:28][NH2:29])C1C=CC=CC=1>C(O)(C)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:29]([OH:28])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=C(CCCCCl)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: On1c(CCCCCl)nc2cnc3ccccc3c21
Temperature: 82 °C
Yield: 44.2 %

Procedure:
A mixture of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide (1.0 g, 3.365 mmol) and O-benzylhydroxylamine hydrochloride (0.59 g, 3.70 mmol) in 10 mL of isopropanol was heated to 82° C. under an atmosphere of N2. After 2 days the mixture was cooled, solids were filtered off and rinsed with hexane and then ether. The brown solid was dried to give 0.4105 g of 2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-1-ol.