Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:10][CH:9]=[N:8][N:7]2[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1.O[C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:6]3[N:7]([C:18]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)=[C:4]([CH2:3][CH2:2][O:1][C:39]4[CH:40]=[N:41][C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:5]=3)[N:8]=[CH:9][CH:10]=2)[CH2:13][CH2:14]1
Reactant: Oc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCOc4cnc5ccccc5c4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 28f (97.3 mg, 0.191 mmol), 3-hydroxyquinoline (38.8 mg, 0.267 mmol), and PPh3 (70.1 mg, 0.267 mmol) were placed in an 8 mL vial equipped with a stir bar. DCM (2 mL) was added and the mixture was stirred at rt for 5 min. 40% Diethyl azodicarboxylate in toluene (0.104 mL, 0.229 mmol) was added dropwise and then the resulting solution was stirred at rt for 30 min. The crude reaction was chromatographed on a 12 g SiO2 pre-packed column and eluted with 0-80% ACN/DCM to afford compound 28g. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.59 (d, J=2.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.95-8.05 (m, 2H), 7.84 (dd, J=8.8, 2.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.45-7.59 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.51 (t, J=6.7 Hz, 2H), 3.87-4.00 (m, 8H), 3.52-3.65 (m, 8H), 3.38 (t, J=6.7 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H40N8O4: 637.3 (M+H). Found: 637.3.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[CH:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][CH:12]1[OH:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC/C=C\CC1(C(=O)OC(C)(C)C)C(O)CCC1CC(=O)OC

Procedure:
A 740 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (2-b)) and 120 mg of sodium borohydride are dissolved in 100 ml of methanol, and the solution is refluxed for one hour. On completion of the reaction, 2 ml of acetic acid is added to the reaction mixture. The resulting mixture is concentrated in a vacuum. The residue is distilled in a vacuum, giving 2-tert-butoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =t-Bu, R2 =CH3) in a yield of 98.5%, b.p. 75°-79° C./0.005 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[I:15].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[I:15]
Reactant: Cc1cc(C(F)(F)F)cc([N+](=O)[O-])c1I
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(CBr)c1I

Procedure:
A mixture of the title compound from Step C (0.38 g, 1.15 mmol), NBS (0.24 g, 1.38 mmol) and catalytic amount of AIBN in carbon tetrachloride (5 ml) was heated to reflux for 3 days. During the period more AIBN was added daily. The mixture was cooled and concentrated. The title compound was obtained after flash column using hexane as the eluant. 1H NMR (CDCl3, 500 MHz): δ 7.91 (s, 1H), 7.80 (s, 1H), 4.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:23][CH3:24])[C:20](O)=[O:21])=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1.C(Cl)Cl.[CH3:39][NH:40]C.CO>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20](=[O:21])[NH:40][CH3:39])[CH2:23][CH3:24])=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1
Reactant: CNC
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the compound 54 (70 mg) in a methylene chloride (3 ml) solution, dimethylamine in a methanol solution (2M, 0.14 ml), triethylamine (0.291 ml), and propyl phosphonate anhydride (T3P) (50% ethyl acetate solution, 0.21 ml) were successively added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was diluted with ethyl acetate. Then the resultant mixture was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogencarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, chloroform/ethyl acetate=9/1 to 1/1) to obtain the title compound (42.5 mg).
Reaction SMILES: C([O:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH:10]([Cl:12])[CH2:9][NH:8]1)(C)(C)C.ClC1CN[C@H:17]([C:20]([OH:22])=O)C1.N1CCC[C@H]1C(O)=O.C(OC(=O)[C@@H]1CCCN1)(C)(C)C.C(CC(Cl)=[S:48])(=O)C.C(SCC(C)C(Cl)=O)(=O)C>>[Cl:12][CH:10]1[CH2:9][N:8]([C:20](=[O:22])[CH2:17][SH:48])[C:7]([C:6]([OH:5])=[O:13])=[CH:11]1
Reactant: O=C(O)[C@@H]1CC(Cl)CN1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(Cl)CN1
Reactant: CC(=O)CC(=S)Cl
Agent: CC(=O)SCC(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(O)C1=CC(Cl)CN1C(=O)CS

Procedure:
By substituting 4-chloro-L-proline tert-butyl ester [prepared from 4-chloro-L-proline by the procedure described in J.Am. Chem. Soc., 82, 3359 (1960) for L-proline] for the L-proline tert-butyl ester and 2-acetylthioacetyl chloride for the 3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1 and then submitting the product to the procedure of Example 2, 4,5-dihydro-4-chloro-1-(2-mercaptoacetyl)-1H-pyrrole-2-carboxylic acid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[O:21]1[C:27]2[CH:28]=[CH:29][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23][CH2:22]1>>[O:21]1[C:27]2[CH:28]=[CH:29][C:30]([S:32]([N:8]3[C:9]4[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)(=[O:34])=[O:33])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCCO2
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc3c(c2)OCCCO3)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a yellow solid. MS (ESI+) for C21H24N2O5S m/z 417 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:29][C:26]2[CH:25]=[CH:24][C:23]([C@H:22]3[C:15]4=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]4[CH2:19][CH2:20][CH2:21]3)=[CH:28][CH:27]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (802 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 ml), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.00 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (132 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:17][S:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29])N[CH2:23][CH2:22]2.C(C1NC=CN=1)(C1NC=CN=1)=O>>[CH3:17][S:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[C:28]([F:29])([F:31])[F:30])[N:1]([C:2](=[O:3])[NH:4][C:15]1[CH:16]=[CH:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=1)[CH2:23][CH2:22]2
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: NC(N)=O
Reactant: CSc1cc2c(cc1C(F)(F)F)NCC2
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: CCOC(=O)c1cccc(NC(=O)N2CCc3cc(SC)c(C(F)(F)F)cc32)c1
Yield: 74 %

Procedure:
This was prepared in 74% yield by urea formation between ethyl 3-aminobenzoate and 5-methylthio-6-trifluoromethyl indoline, (D7) using carbonyl diimidazole as the coupling agent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2([CH3:29])[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:29][C:18]1([N:15]2[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]2)[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
A solution of oxalyl chloride in dichloromethane (2M, 2.05 mL, 4.1 mmol) was cooled to −78° C. under nitrogen atmosphere and was added to a solution of dimethylsulfoxide (0.58 mL, 8.1 mmol) in dichloromethane (6 mL) at −78° C. under nitrogen atmosphere via cannula. After 10 minutes, a solution of ethyl 4-(4-hydroxy-1-piperidyl)-4-methyl-piperidine-1-carboxylate (2.7 mmol) in dichloromethane (3 mL) was added at −78° C. under nitrogen atmosphere to the reaction mixture via cannula. The mixture was stirred at −78° C. for 10 minutes and then triethylamine (1.51 mL, 10.8 mmol) was added dropwise. The reaction was stirred at −78° C. under nitrogen atmosphere for another 20 minutes, and then allowed to warm up to 0° C. over 1 hour. The reaction was quenched with water (10 mL) and diluted with dichloromethane (30 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with saturated aqueous ammonium chloride, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (672 mg, 93%), which was used for the subsequent step without further purification. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.96 (s, 3H), 1.24-1.30 (m, 3H), 1.39-1.53 (m, 2H), 1.72-1.92 (m, 2H), 2.11-2.30 (m, 1H), 2.42 (t, J=5.86 Hz, 2H), 2.51 (t, J=6.05 Hz, 1H), 2.81 (t, J=5.86 Hz, 2H), 2.97 (t, J=6.05 Hz, 1H), 3.22 (t, J=12.01 Hz, 1H), 3.35-3.47 (m, 2H), 3.53-3.72 (m, 2H), 4.14 (q, J=7.10 Hz, 2H). MS (M+1): 269.24.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[K].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:10])=[CH2:9].O>CS(C)=O.C1COCC1>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2([CH3:2])[CH2:10][CH2:9]2)=[C:12]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[O:22])[CH:13]=1)(=[O:19])=[O:18]
Reactant: C=C(C)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of Trimethylsulfoxonium iodide (21.9 mg, 0.1 mmol) in dry DMSO (300 uL) was added Potassium tert-butoxyde (11.3 mg, 0.101 mmol) portionwise. A solution of (2-Isopropenyl-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone; Example 44 (20 mg, 0.0442 mmol) in dry THF (200 uL) was prepared separately and then added to the above suspension dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 20 hours.The it was cooled down to rt and a solution of Trimethylsulfoxonium iodide (21.9 mg, 0.1 mmol) and Potassium tert-butoxyde (11.3 mg, 0.101 mmol) in dry DMSO (300 uL) was slowly added. Water was added and the solution was extracted 2 times with Ethylacetate. The combined organic phases were washed with water (3 times), dried over Na2SO4 ,filtered and the solvent was removed in vacuo. The residue was chromatographed on SiO2 Eluent: Heptane/EtOAc to provide the title compound (4.2 mg, 20%, white solid; Solid; M+H=467.2)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].O1CCCC1.C(N(CC)CC)C.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>CO>[CH2:32]([NH:34][C:35]([NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17])=[O:36])[CH3:33]
Reactant: CCN=C=O
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Reaction time: 1 h

Procedure:
To 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (100 mg) were added tetrahydrofuran (1.20 mL), triethylamine (0.147 mL), and ethylisocyanate (0.0415 mL), followed by stirring for 1 hour. To the mixture were added silica gel and methanol, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 94:6) to obtain a colorless solid. The obtained solid was washed with hexane/ethyl acetate to obtain 3-{2-[(ethylcarbamoyl)amino]ethyl}-5-methoxy-N-methyl-1H-indole-2-carboxamide (86.0 mg) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([OH:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)#[N:2].[OH-].[Na+].[CH2:17]=O.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([S:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.[Na+].Cl>O>[C:1]([C:3]1[C:7]([CH2:17][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=2)(=[O:27])=[O:26])=[C:6]([OH:8])[N:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1cc(O)n(-c2ccccc2)n1
Reactant: C=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2c(C#N)nn(-c3ccccc3)c2O)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
3-Cyano-5-hydroxy-1-phenylpyrazole (1.8 g (10 mmol)) synthesized in Reference Example 5 and 0.6 g (15 mmol) of sodium hydroxide were dissolved in 10 mL of water. While stirring the resulting solution at room temperature, 1.7 g (20 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Subsequently, 1.8 g (10 mmol) of sodium p-toluenesulfinate was charged thereto at room temperature, and the obtained mixture was stirred for 2 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise thereto, 20 mL of water was further added, and the precipitated crystal was collected by filtration, washed twice with 20 mL of water and dried by a hot air drier to obtain 3.0 g (yield: 85.7%) of the title compound as a pale yellow crystal.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]>>[Cl:3][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Product: O=[N+]([O-])c1cnccc1Cl
Yield: 97.8 %

Procedure:
Phosphorus oxychloride (25 ml, 0.27 mol) was added to 4-hydroxy-3-nitropyridine (7.0 g, 50.0 mmol), followed by reaction at 80° to 90° C. for 1.5 hours. Phosphorus oxychloride was removed by distillation. About 100 g of ice was added to the residue, and 28% aqueous ammonia was added dropwise thereto to adjust the pH to 7. Then, 100 ml of water was added thereto, and the aqueous mixture was extracted three times with 200 ml of dichloromethane. The resulting dichloromethane layer was dried, and then dichloromethane was removed by distillation under reduced pressure to obtain 7.75 g of a yellow liquid (yield: 97.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=O.O.[NH2:14][NH2:15]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]1[CH:6]=[C:7]([NH2:8])[NH:14][N:15]=1
Reactant: N#CCC(=O)c1ccccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 20 °C

Procedure:
To a solution of 2-chlorobenzoylacetonitrile (400 g, 2.23 mol) in ethanol (9 L) was added hydrazine hydrate (221 g, 4.42 mol) over 15 minutes while maintaining internal reaction temperature at 15 to 25° C. The mixture was then heated at 75° C. for 20 hr. After cooling, the reaction was concentrated, in vacuo, to give a brown oil. The residue was dissolved in ethyl acetate (4 L), washed with half saturated brine (4 L), and then dried (Na2SO4) to a give a crude, dark orange solution of 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine that was carried directly into the next reaciton: +ESI MS (M+1) 194.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2.O>C1(C)C=CC=CC=1.[Ti]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:15])([F:14])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: COc1cc(F)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: [Ti]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(F)ccc1C(C)(C)CC(O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
0.25 ml of titanium tetraethylate is added to 150 mg (0.48 mmol) of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 85 mg (0.48 mmol) of 5-amino-7-fluoro-2-methylquinazoline in 8 ml of toluene, and the mixture is heated to 100° C. over 2 hours. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite, and it is rewashed thoroughly with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. 220 mg of 4-(4-fluoro-2-methoxyphenyl)-1-(7-fluoro-2-methylquinazolin-5-ylimino)-4-methyl-2-(trifluoromethyl)-pentan-2-ol that is thus obtained in crude form is taken up in 8 ml of dichloromethane, and it is cooled to −70° C. 3 ml (3 mmol) of a 1 M titanium tetrachloride solution in dichloromethane is added in drops over 10 minutes, and it is allowed to heat for 4 hours to room temperature. The solution is poured into a saturated sodium bicarbonate solution and vigorously stirred for 5 minutes. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/methanol 10%), 25 mg of the desired product is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([CH:6]=[CH2:7])[CH3:5].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([O:8][C:4]([CH3:5])([CH:6]=[CH2:7])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(C)(C)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(C)(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred suspension of 18.6 g of 60% sodium hydride oil dispersion (0.46 mol) in 50 mL of dry tetrahydrofuran at 0° C. was added 40 g (0.46 mol) of 2-methyl-3-buten-2-ol over 30 minutes. The resulting mixture was warmed to room temperature and stirred for 3 hours, then heated at reflux for an additional 30 minutes. The mixture was cooled to 0° C., treated with 80 g (0.46 mol) of benzyl bromide, then heated at reflux for 5 hours. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was purified by distillation under reduced pressure to give 42 g (0.24 mol,52%) of product, b.p. 88°-89° C. (2 mm). 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 4.39 (s,2H), 5.20 (m,2H), 5.95 (m,1H), 7.2-7.4 (m,5H).
Reaction SMILES: [N+](=C)=[N-].[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[C:18](O)(=O)C>C(OCC)C>[CH3:4][O:5][C:6]1[C:7]([OH:17])=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([O:11][CH3:18])=[O:10]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)O)c(O)c1OC
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)c(OC)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of diazomethane in diethyl ether (30 ml, 0.25M, 0.0075 mol) was added to a solution of 3,4-dimethoxy-2-hydroxybenzoic acid (1.5 g, 0.0075 mol) in diethyl ether (50 ml) and the reaction stirred at room temperature for 10 minutes. Glacial acetic acid was then added and stirring continued for a further 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (40 ml) and aqueous sodium hydrogen carbonate solution (40 ml). The aqueous phase was further extracted with dichloromethane (100 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a white crystalline solid (1.5 g, 94%). 1H-NMR (CDCl3): Γ=3.82 (9H, m), 6.48 (1H, d), 7.58 (1H, d), 10.84 (1H, s).