Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 157.5 %

Procedure:
To a mixture of 2-chloro-4-fluoro-5-nitrophenol (9.6 g) and potassium carbonate (3.8 g) in acetonitrile (50 ml), there was added methyl iodide (14 g), and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the resulting mixture was extracted with ether. The ether extract was washed with water, dried and concentrated. The residue was recrystallized from ethanol to give 8.9 g of 4-chloro-2-fluoro-5-methoxynitrobenzene. M.P., 67.5°-69.8° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.BrCC1(CBr)C=CC(C2C=CC=CC=2C#N)=CC1.[C:35]([O:39][C:40]([NH:42][C:43]1[C:52]([N+:53]([O-:55])=[O:54])=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]([C:43]1[C:52]([N+:53]([O-:55])=[O:54])=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: N#Cc1ccccc1C1=CCC(CBr)(CBr)C=C1
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C

Procedure:
A method according to claim 1, wherein said reaction is carried out between (1) a mixture containing 2-(4-bromomethylphenyl)benzonitrile and 2-(4,4-dibromomethylphenyl)benzonitrile and (2) methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate to give methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyano-biphenyl-4-yl)methyl]amino]-3-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10]1([N:16]=[C:17]=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: S=C=NC1CCCCC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: S=C(Nc1ccc(Cl)c(Cl)c1)NC1CCCCC1

Procedure:
A mixture of 16.2 gm. (0.1 mole) of 3,4-dichloroaniline and 14.1 gm. (0.1 mole) of cyclohexyl isothiocyanate is heated together on the steam bath for four hours. The solid is crystallized from ethanol-water; 18 gm. (59%), m.p. 159°-162°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](C)[C:3]=1N1CCCC2C(=O)N(C)NC1=2.[CH3:21][N:22]([CH3:41])[C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][C:31]3[C:35](=[O:39])[N:36]([CH3:38])[NH:37][C:30]2=3)=[C:25]([CH3:40])[CH:24]=1>>[CH3:21][N:22]([CH3:41])[C:23]1[CH:24]=[C:25]([CH3:40])[C:26]([N:29]2[CH2:34][CH2:33][CH2:32][C:31]3=[C:35]([O:39][CH:2]([CH2:7][CH2:6][CH3:8])[CH2:3][CH2:4][CH3:5])[N:36]([CH3:38])[N:37]=[C:30]23)=[CH:27][N:28]=1
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Reactant: Cc1cc(N(C)C)ncc1N1CCCc2c1[nH]n(C)c2=O
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1cnc(N(C)C)cc1C)CCC2

Procedure:
Example 12c was prepared according to the procedure described in Example 12a, except that 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one was replaced by 7-(6-dimethylamino-4-methylpyridin-3-yl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:49][C:48]1[CH:47]=[C:39]([CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:38]=[C:37]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(CCNS(C)(=O)=O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCNS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(4-bromo-3,5-dimethylphenethyl)methanesulfonamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.58 min; Mass spectrum (ESI+): m/z=568 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Si:23]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=[C:2]([Cl:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Cl)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (142 mg, 0.671 mmol) in methylene chloride (1.0 mL) at 0° C. was added 1H-imidazole (55 mg, 0.80 mmol) followed by tert-butylchlorodiphenylsilane (190 μL, 0.74 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The reaction was stirred with warming to room temperature for 64 hours. The reaction mixture was diluted with diethyl ether and was washed with water followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-4% EtOAc in hexanes afforded product as a white solid (0.20 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 4H), 7.55-7.34 (m, 8H), 4.77 (s, 2H), 1.12 (s, 9H); 19F NMR (282 MHz, CDCl3) δ −68.49 (s); LCMS (M+H)+: 450.1.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:10][CH2:11][CH2:12][OH:13].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([O:13][CH2:12][CH2:11][CH2:10][C:9]([F:18])([F:8])[C:14]([F:15])([F:16])[F:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Trietylamine (46 ml, 0.330 mol) was added to a solution of 4,4,5,5,5-pentafluoropentan-1-ol (25 g, 0.132 mol) in dichloromethane (50 ml). To this solution, methanesulfonyl chloride (20.4 ml, 0.264 mol) was added at 0° C., followed by stirring for 3 hours at room temperature under argon atmosphere. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with 1N aqueous hydrochloric acid, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=1/1) to give 1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (34 g, quantitative).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: O=Cc1ccccc1O
Reactant: NCCCCCCCCCCCCN
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCCCCCCCCCCCCNCc1ccccc1O

Procedure:
30.0 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of 1,12-diaminododecane and having a melting point of 72°-73° C. are hydrogenated for 2 hours in 300 ml of isopropanol in an autoclave in the presence of 3 g of Raney nickel at 90°-100° C. and under a pressure of 60 atmospheres
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:33])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]>CO.C1COCC1>[OH:31][CH:29]([CH3:30])[CH2:28][CH2:27][C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH:4]([OH:3])[CH3:33])=[CH:15][CH:14]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1)=[O:32]
Reactant: CC(=O)CCC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)CCC(C)=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)CCC(=O)Nc1ccc(S(=O)(=O)c2ccc(NC(=O)CCC(C)O)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of sodium borohydride in methanol was cooled to 5° C. A solution of 4-oxo-pentanoic acid {4-[4-(4-oxo-pentanoylamino)-benzenesulfonyl]-phenyl}-amide in THF was added and the resulting reaction mixture was stirred at room temperature. After workup and purification, the product was obtained as a colourless solid.
Reaction SMILES: C(O)[C@@H](O)[C@H:3]1[O:8][C:6](=[O:7])[C:5]([OH:9])=[C:4]1[OH:10].[CH:13](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:15])[CH3:14].C([Li])CCC.O=C[C@@H]([C@@H](CO)O)O>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:13]1([CH3:15])[O:9][C@@H:5]2[C@@H:4]([CH2:3][O:8][CH:6]2[OH:7])[O:10]1
Reactant: CC(C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1O[C@H]([C@H](O)CO)C(O)=C1O
Agent: O=C[C@H](O)[C@H](O)CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2COC(O)[C@@H]2O1
Temperature: -40 °C
Reaction time: 20 h

Procedure:
2,3-O-Isopropylidene-D-erythrose was prepared by literature procedures (Cohen, N. et al, J. Am. Chem. Soc. 1983, 105, 3661) from D-isoascorbic acid. To a suspension of isopropyltriphenylphosphine (121 g, 2.4 equiv, 0.314 mol) in tetrahydrofuran (1.5 L) at -40° C. under nitrogen was added n-butyllithium (1.6M solution in hexanes) (197 mL, 2.4 equiv) dropwise. The erythrose (21 g, 1 equiv, 0.131 mol) in tetrahydrofuran (231 mL) was also added dropwise maintaining the temperature at -40° C. The mixture was then allowed to warm to room temperature and stirred under nitrogen for 20 hours and then quenched by the addition of ammonium chloride (77 g). The insoluble material was removed by filtration through Celite and the filtrate concentrated at reduced pressure to afford a residue which was extracted (4×) with ether. The combined ether extracts were washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to afford a yellow oil. Chromatography on silica gel eluting with 20% ethyl acetate in hexanes afforded the title compound (13.0 g, 53%). 1H NMR (CDCl3, 300 MHz) δ 1.4 (s, 3H), 1.50 (s, 3H), 1.73 (s, 3H), 1.78 (s, 3H), 3.57 (t of d, J=1.5 Hz, J=6 Hz, 2H), 4.20 (q, J=6 Hz, 8 Hz, 1H), 4.44 (q, J=9 Hz, 9 Hz, 1H), and 5.75 (d, J=9 Hz, 1H). MS (DCI/NH3) m/e 204 (M+H+NH3)+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10].C(OC)(=O)C(C)=C.C(N)(=O)C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:1]([O:6][CH3:7])(=[O:5])[CH:2]=[CH2:3].[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=C(C)C(=O)OC
Agent: C=CC(N)=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: C=CC(=O)OC

Procedure:
A stainless steel autoclave having a capacity of 20 liters and having baffles and Pfaudler stirring blades was supplied with a solution obtained by dissolving 2.5 g of a methyl methacrylate/acrylamide copolymer-based suspending agent (this was prepared according to the following method: a reactor was charged with 20 parts by weight of methyl methacrylate, 80 parts by weight of acrylamide, 0.3 part by weight of potassium persulfate and 1500 parts by weight of ion exchange water, and while the atmosphere in the reactor was replaced by nitrogen gas, the system was kept at 70° C.; the reaction was continued till the monomers were perfectly converted into a polymer, to obtain an aqueous solution of methyl acrylate/acrylamide copolymer; the obtained aqueous solution was used as the suspending agent), and the solution was stirred at 400 rpm, the atmosphere in the system being replaced by nitrogen gas. Then, 5000 g in total of the following monomer mixture was added while the reaction system was stirred, and the system was heated to 70° C. The moment when the internal temperature reached 70° C. was identified as the initiation of polymerization, and with this state kept for 180 minutes, the polymerization was terminated. Thereafter, the cooling of the reaction system and the separation, washing and drying of the polymer were performed according to ordinary methods, to obtain a copolymer (A) as beads. The polymerization percentage of the copolymer (A) was 98%, and the weight average molecular weight was 70000.
Reaction SMILES: S1C2C=CC=CC=2NC1=[O:10].[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[S:20][C:16]=2[CH:15]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.C(N(CC)CC)C>C(#N)C>[Cl:11][CH:12]([CH3:24])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[NH:18][C:19](=[O:21])[S:20][C:16]=2[CH:15]=1.[ClH:11].[F:40][C:26]([F:25])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH:12]([CH3:24])[C:13]([C:14]3[CH:23]=[CH:22][C:17]4[NH:18][C:19](=[O:21])[S:20][C:16]=4[CH:15]=3)=[O:10])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1[nH]c2ccccc2s1
Agent: CC(Cl)Cc1ccc2[nH]c(=O)sc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1ccc2[nH]c(=O)sc2c1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: Cl
Reaction time: 3 h

Procedure:
6-(2-chloropropyl)-3H-benzothiazol-2-one was prepared from 3H-benzothiazol-2-one according to the synthetic and working-up method of general procedure B. 6-(2-chloropropyl)-3H-benzothiazol-2-one (2.66 g, 0.011 mol) and 3-trifluoromethylphenyl piperazine (2.30 g, 0.01 mol) were dissolved in 100 ml of acetonitrile, and triethylamine (3.04 g, 0.03 mol) was added. A reaction under refluxing was allowed to proceed for 3 hours at an elevated temperature. Working up according to general procedure B gave 4.10 g of 6-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propanoyl)benzo[d]thiazol-2(3H)-one hydrochloride. The yield was 86.9%.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[C:8]([O:12][CH2:13][CH2:14][OH:15])(=[O:11])[CH:9]=[CH2:10].COC1C=CC(O)=CC=1>>[C:8]([O:12][CH2:13][CH2:14][O:15][C:6](=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OCCO
Reactant: CCCCN=C=O
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OCCOC(=O)NCCCC

Procedure:
145.3 grams of butyl isocyanate and 180.7 grams of 2-hydroxyethyl acrylate, stabilized with 400 ppm of hydroquinone monomethyl ether, were reacted together for 6 hours at 75° C. to give 1-butane carbamic acid 2-acryloyloxyethyl ester.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][C:16]=1[F:31]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:17][C:16]=1[F:31]
Reactant: C=C(C)C(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)c(F)c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl methacrylate (125.0 g, 1097 mmol) and potassium tert-butoxide (1 M in tetrahydrofuran, 115 mL, 115 mmol) were sequentially added to a solution of 1-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)ethanone (327.0 g, 1160 mmol, Example 4, Step B) in anhydrous tetrahydrofuran (2.61 L), at 0° C. The reaction mixture was stirred for 1 hour at 0° C. and then warmed to ambient temperature and stirred for 12 hours. On completion, the reaction was quenched with water (1.0 L) and extracted with ethyl acetate (2×2.5 L). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude material which was purified by flash column chromatography (silica gel: 60 to 120 mesh, product eluted in 4% ethyl acetate in hexane) affording the title compound (mixture of diastereomers) as light yellow liquid.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:31][CH:30]=2)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>C(O)C>[CH:1]1([NH:9][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][O:11][CH3:10])=[CH:19][CH:18]=2)[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:33][CH:34]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2C=O)cc1
Reactant: NC1CCCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2CNC2CCCCCCC2)cc1
Reaction time: 8 h
Yield: 89.4 %

Procedure:
In 50 ml of ethanol was dissolved 0.69 g of cyclooctylamine. To the solution was added 1.96 g of 2-[bis(4-methoxymethoxyphenyl)methyl]benzaldehyde obtained by Reference Example 7, and the mixture was stirred overnight. Then, 0.85 g of sodium borohydride was added thereto, and the reaction mixture was stirred for 2 hours. Thereafter, the solvent was evaporated under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with chloroform, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the organic layer was combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to afford 2.25 g of the desired product (Compound 77) as an oily matter.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Product: CS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(N5CCOCC5)cc4)nn23)c1
Yield: 25.2 %

Procedure:
5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and 3-methanesulfonyl phenyl boronic acid (3.08 g, 15.0 mmol), in a manner analogous to Step 73c. The residue was purified on a 80 g Isco silica gel column using a gradient of 0-20% methanol in dichloromethane as an eluent. 5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.10 g, 52%) was isolated as a beige powder. MP=181-182° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.45 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.82 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.55 (t, J=16.1 Hz, 8.5 Hz, 1H), 7.43 (d, J=9.1 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.09 (s, 2H), 3.30 (s, 3H). MS=289 (MH)+. 78b) [5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (137 mg, 0.475 mmol) and 4-(4-bromo-phenyl)-morpholine (138 mg, 0.57 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine (53.8 mg, 24%) as a yellow powder following purification on a 40 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=163° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.38 (s, 1H), 8.76 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.88 (t, J=15.5 Hz, 8.5 Hz, 1H), 7.67 (m, 1H), 7.57 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 6.88 (d, J=8.50 Hz, 2H), 3.73 (m, 4H), 3.33 (s, 3H), 2.99 (m, 4H). MS=450 (MH)+.
Reaction SMILES: O[C:2]1[C:7](C)=[C:6](O)[CH:5]=[C:4]([CH3:10])[N:3]=1.O=P(Cl)(Cl)[Cl:13].C(N(CC)C1C=CC=CC=1)C.[CH:27]([Cl:30])(Cl)Cl>>[Cl:13][C:2]1[C:7]([CH3:6])=[C:27]([Cl:30])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C)c(O)n1
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(Cl)c(C)c(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 2,4-dihydroxy-3,6-dimethylpyridine (2.86 g, 20.58 mmol), POCl3 (15 ml) and N,N-diethylaniline (3.6 ml, 22.64 mmol) was heated at reflux for 3 hours. The mixture was cooled, poured into ice water and extracted with diethyl ether. The organic layer was dried and concentrated to give 3.02 g of the crude material. After silica gel column chromatography using chloroform as eluent, 1.3102 g of the title compound was obtained as a yellow oil. 1H NMR (CDCl3) δ 7.07 (s, 1H), 2.43 (s, 3H), 2.39 (s, 3H) ppm.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](OC(=O)Nc1ccccc1Br)c1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Product: C[C@@H](OC(=O)Nc1ccccc1-c1ccc(O)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: (2-bromo-phenyl)-carbamic acid (R)-1-phenyl-ethyl ester and 4-hydroxyphenylboronic acid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].[C:6](OCC)(=[O:9])[CH2:7][CH3:8].CC(C)([O-])C.[K+:18]>O1CCCC1>[CH2:4]([O:3][C:1]([C:7]([CH3:8])=[CH:6][O-:9])=[O:2])[CH3:5].[K+:18]
Reactant: CCOC(=O)CC
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C[O-]

Procedure:
Alternatively, 4-Methyl-2-(6-methyl-pyridin-2-yl)-2H-pyrazol-3-ol was also produced as follows: To a solution of ethyl formate (117.5 g) and ethyl propionate (54.0 g) in 40 ml of tetrahydrofuran (THF) was added, drop-wise, potassium t-butoxide (502 ml of a 1.0 molar solution in THF) at ambient temperature over approximately 0.5 hour. A white precipitate began to form along with some bubbling. After another 7.5 hours the reaction was filtered, the solid was washed with diethyl ether and then dried under vacuum at 40° C. for 16 hours to give potassium 2-ethoxycarbonyl-propen-1-olate as a grey powder (23.5 g).