Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[N:10]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH2:1]([N:10]1[N:11]=[N:12][C:13]([C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)=[C:25]([C:35]([NH:37][CH3:38])=[O:36])[C:24]=4[CH:39]=3)[CH:17]=[CH:18][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(Cc5ccccc5)n4)c3)cc12
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Benzyl bromide (29 μL, 0.242 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.121 mmol) and Na2CO3 (26 mg, 0.242 mmol) in DMF (1.2 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 19%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48-8.56 (1H, m), 8.30-8.35 (1H, m), 8.06 (1H, d, J=7.63 Hz), 7.98-8.03 (2H, m), 7.90-7.93 (2 H, m), 7.78-7.83 (1H, m), 7.72-7.77 (1H, m), 7.69 (1H, t, J=7.78 Hz), 7.36-7.46 (7H, m), 6.04 (2H, s), 2.86 (3H, d, J=4.58 Hz). LC-MS retention time: 1.78 min; m/z (MH+): 504. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.69 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.95 min, purity=98%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8](OCC)=[O:9])[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([OH:13])[CH2:8][OH:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(C(O)CO)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-amino-4-thiazolglyoxylate (10 g, 50 mmol) in anhydrous THF (150 mL) was added dropwise to a suspension of lithium aluminum hydride (1.9 g) in anhydrous THF (200 mL), and the mixture stirred under nitrogen at RT for 1 h. Excess ethyl acetate was then added to destroy residual reductant, after which an excess of Glauber's Salt was added and the resultant suspension stirred at RT for 40 min. The slurry was then filtered, and the filtrate evaporated in vacuo, and then dissolved in methanol and adsorbed onto silica gel. This mixture was then applied to a flash silica column, and the product eluted using 10% methanol in dichloromethane. Homogenous fractions were combined and evaporated under vacuum to give (±)-2-amino-4-(1,2-dihydroxyethyl)-1,3-thiazole product as a pale orange colored solid, (2.6 g, 32.5%) with the following structure: ##STR42##
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][CH:6]1[C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[N:2]([CH2:3][CH2:4][CH2:5][CH:6]1[C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH3:1])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCC1c2ccccc2OC12CCCCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CCCC1c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture, kept under nitrogen, of 7.85 g of 3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] and 11.7 g of powdered sodium bicarbonate in 250 ml of toluene was added 5.2 ml of ethyl chloroformate. The mixture was refluxed overnight and thereafter an additional 2.6 ml of ethyl chloroformate was added. The mixture was refluxed for another 5 hours and thereafter stirred overnight at room temperature. Water (250 ml) was then added with stirring. The organic phase was separated and washed successively with 2N-hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. This material was used as such for subsequent synthesis. The IR, NMR and Mass Spectra were in accord with the designated structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][OH:37])=[CH:33][C:32]=2[CH:38]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][O:37][C:39](=[O:41])[CH3:40])=[CH:33][C:32]=2[CH:38]=1
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1

Procedure:
A solution of [5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-yl]-methanol (Example 50, 21 mg), acetic anhydride (100 μl) and pyridine (300 μl) was stirred at room temperature for one hour. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution and water. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give acetic acid 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-ylmethyl ester (22 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 2.12 (3H, s), 2.23 (3H, s), 2.78 (1H, m), 2.97 (1H, br d, J=11 Hz), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.86 (1H, dd, J1=9 Hz, J2=7 Hz), 3.94 (1H, dd, J1=9 Hz, J2=5 Hz), 5.09 (2H, s), 5.18 (2H, s), 6.55 (1H, d, J=8 Hz), 6.72 (1H, s), 7.00 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.04 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.20 (1H, dd, J1=8 Hz, J2=5 Hz), 7.38 (1H, d, J=9 Hz), 7.66 (1H, br d, J=8 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:3].[OH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20](C)[CH:19]=[CH:18]2.[NH3:24]>>[NH2:24][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[C:13]([O:12][CH:10]([CH3:9])[CH2:5][CH2:6][CH2:7][O:11][C:8]3[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=3)[CH:14]=[CH:15][CH:16]=2)[N:21]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N
Product: CC(=O)Nc1ccc(OCCCC(C)Oc2cccc3ccc(N)nc23)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 86 substituting acetaminophen for 8-hydroxyquinaldine. 1H NMR (500 MHz, CDCl3) δ ppm 7.90 (d, 1H), 7.29 (t, 1H), 7.20 (m, 3H), 7.11 (m, 1H), 6.95 (d, 1H), 6.61 (m, 2H), 4.70 (m, 1H), 4.05 (m, 1H), 3.91 (m, 1H), 2.14 (s, 3H), 2.08 (m, 1H), 1.95 (m, 3H), 1.48 (d, 3H); MS (DCI/NH3) m/z 380 [M+H]+.
Reaction SMILES: N[C:2]1[NH:3][N:4]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[C:5](=[O:7])[CH:6]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].Cl.[OH-].[K+].[N:25]1C=CC=CC=1>O1CCCC1.CO.C(O)(=O)C>[O:7]=[C:5]1[N:4]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:3]=[C:2]([CH:18]([CH3:19])[C:17]([NH2:25])=[O:20])[CH2:6]1
Reactant: c1ccncc1
Reactant: CCC(=O)Cl
Reactant: Nc1cc(=O)n(-c2c(Cl)cc(Cl)cc2Cl)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C(N)=O)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Amino-1-(2,4,6-trichlorophenyl)-5-pyrazolone (35.0 g, 125 mmole) was dissolved in dry tetrahydrofuran (350 ml) and pyridine (35 ml) and the solution was cooled in an ice-bath to 10° C. A solution of propionyl chloride (35.15 g, 0.18 mmole) in tetrahydrofuran (60 ml) was added dropwise keeping the temperature below 10° C. The mixture was stirred at room temperature for 48 hrs then it was poured into dilute hydrochloric acid (2.51). The resulting gum was extracted with ethyl acetate (700 ml) and the solution was washed with water and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a light brown oil which was dissolved in methanol (120 ml). A solution of potassium hydroxide (70.0 g, 125 mmol) in methanol was added dropwise with stirring and the mixture was stirred for 0.5 hrs. Glacial acetic acid was added to the suspension and stirred for 2 hr. The buff colored solid was filtered off, washed with water and dried in a vacuum oven. The yield of product was 35.54 g, 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[ClH:8].[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9](=[O:21])[CH2:10][CH2:11][CH:12]2[C:17](=[O:18])[CH:16]3[CH2:19][CH2:20][N:13]2[CH2:14][CH2:15]3)=[CH:3][C:2]=1[NH:1][C:24]([NH:23][CH3:22])=[O:25]
Reactant: Nc1cc(C(=O)CCC2C(=O)C3CCN2CC3)ccc1Cl
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Nc1cc(C(=O)CCC2C(=O)C3CCN2CC3)ccc1Cl
Product: Cl
Temperature: 25 °C

Procedure:
To 6.14 g (0.02 mole) of 2-[3-(3-amino-4-chlorophenyl)-3-oxopropyl]-1-azabicyclo[2.2.2]octan-3-one in 150 ml of methylene chloride add 1.20 g (0.021 mole) of methyl isocyanate. Stir the reaction mixture at room temperature and follow the progress of the reaction by thin-layer chromatography. At the completion of the reaction remove the solvent in vacuo. Dissolve the residue in 100 ml of ethanol and add 2.5 ml of concentrated hydrochloric acid. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a mixture of 2-tert-butyl-5-nitrophenol (C-1-a) (100 mg, 0.52 mmol) and K2CO3 (86 mg, 0.62 mmol) in DMF (2 mL) was added CH3I (40 uL, 0.62 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was evaporated to dryness to give 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 76%) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J=4.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2oc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c2cc(O)ccc2oc2c([N+](=O)[O-])ccc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10 g of 1-chloro-7-methoxy-4-nitro-9H-xanthen-9-one and 84 ml of a 1M solution of boron tribromide in dichloromethane in 280 ml of dichloromethane was stirred at room temperature under an argon atmosphere for 16 hours, and then it was treated with 100 ml of methanol, and stirred for three hours. The mixture was filtered to give a light green solid. Recrystallization from chloroformmethanol afforded the title compound, mp 290°-292° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: COc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CN
Product: CNc1ncc2c(=O)[nH]c(-c3ccccc3OC)nc2n1

Procedure:
In a similar manner to Example 8 reaction of 7-methylthio-2-(2-methoxyphenyl)-4-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine (0.75 g) and 33% methylamine in industrial methylated spirit (25 ml) for 18 hours yielded the title compound, 0.38 g, m.p. 265°-267° C. (recrystallised twice from methanol).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:49](=[O:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (1.0 g) and pyridine (1.5 ml.) in ethyl acetate (30 ml.) was added benzoyl chloride (1.5 ml.) and the mixture allowed to stand for one hour at room temperature. The solution was then washed with 2 N-hydrochloric acid (50 ml.) and saturated brine, dried (sodium sulphate) and concentrated to ca. 5 ml. The concentrate was added dropwise to petroleum (b.p. 40°-60°; 350 ml.) and the precipitated solid filtered, washed with petroleum and dried, yielding the title ester as a yellow solid (1.0 g; 85%), [α]D +6.4° (c 0.94, DMSO), λmax. (EtOH) 259 nm (ε 26,700), νmax. (CHBr3) 1780 (β-lactam), 1640 and 1522 cm.-1 (CONH), τ (DMSO-d6) values include -0.27 (doublet J 8 Hz; NH), 1.8-2.8 (multiplet; aromatic protens), 8.01 (singlet; OCOCH3) .
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CN2C(=NCCC2)C1.[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH:31](Br)C)[N:30]=1>CC#N>[Br:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:30]=1
Reactant: CC(Br)c1csc(Br)n1
Reactant: Cn1nnnc1C(=NO)c1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: Cn1nnnc1C(=NOCc1csc(Br)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 568.6 %

Procedure:
To a cooled (0° C.) stirred solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.7 g, 3.44 mmol, 1.0 eq.) in 25 ml of MeCN, was added dropwise DBN (0.42 g, 3.44 mmol, 1.0 eq.). The reaction was stirred for 5 mins before addition of 2-bromo-4-(1-bromoethyl)-1,3-thiazole (0.86 g, 3.2 mmol, 0.93 eq.) portionwise. The mixture was stirred for further 5 mins before removal of the cooling bath and continued at ambient temperature. LCMS after 2 h would indicate reaction complete. MeCN was evaporated and the residue was purified by chromatography on silica gel to yield N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (6.9 g, 79% yield, 9:1 mixture of stereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:9]I)=[CH:4][C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[CH2:24]([NH:31][CH2:32][CH2:33][OH:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][OH:34])[CH2:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:4]=1)[O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCNCc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(F)c(NS(C)(=O)=O)c1
Product: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1ccc(F)c(NS(C)(=O)=O)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
(R)-N-(2-fluoro-5-(2-iodo-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (500 mg) and 2-(benzylamino)ethanol (1.6 g) were mixed, and the mixture was stirred overnight at 100° C. The reaction solution was cooled to room temperature, and then was purified by column chromatography (“COLUMN-H”; n-hexane:ethyl acetate=2:1). Thus, (R)-N-(5-(2-(benzyl-(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl) -2-fluorophenyl)methanesulfonamide (477.5 mg) was obtained. Subsequently,4-N,N-dimethylaminopyridine (12 mg), triethylamine (163 μL) and THF (15 mL) were added thereto, and a Boc2O-THF solution [10 mL; solution prepared by dissolving Boc2O (230 mg) in THF (10 mL)] was added dropwise. The mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and then the residue was purified by column chromatography (“COLUMN-H”; n-hexane:ethyl acetate=3:1). Thus, the title compound (500.3 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:21](=[O:23])=[O:22]>C(OCC)C>[CH2:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:21]([OH:23])=[O:22])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nccc2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCCCc1nccc2ccc(C(=O)O)cc12
Temperature: 25 °C

Procedure:
To a −60° C. solution of 7-bromo-1-butylisoquinoline prepared in step 1 (940 mg, 3.55 mmol) in diethyl ether (15 mL) was added sec-butyl lithium (3.0 mL, 1.3 M cyclohexanes, 3.90 mmol) to yield a dark green solution. The reaction mixture was stirred at −60° C. for an additional 15 minutes at which time carbon dioxide gas was bubbled through the solution for 20 minutes with the aid of a gas dispersion tube. The resulting solution was then allowed to warm to room temperature and concentrated under reduced pressure to yield a pink solid. The residue was partitioned between ethyl acetate and water and then acidified to pH 7 with 1 N hydrochloric acid. The aqueous phase was extracted again with ethyl acetate and the combined organic phases were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield 1-butylisoquinoline-7-carboxylic acid (299 mg). ESI MS m/z 230 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#N)[C:3]=1[C:21]#[C:22][Si](C)(C)C.[C:27](=O)([O-])[O-:28].[K+].[K+].CC[O:35]CC.O>CO>[Br:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([O:28][CH3:27])=[O:35])[C:3]=1[CH2:21][CH3:22]
Reactant: CCOCC
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1c(C(=O)OC)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-trifiluoromethylphenyl)-4-trimethylsilylethynylpyrazole (100 mg, the compound of Example C1) in methanol (1 ml) was added potassium carbonate (2.9 mg). Stirring was continued at room temperature for 2 hours and then potassium carbonate (3.0 mg) was added. Stirring was continued for a further 4 hours. The reaction mixture was then poured into ether (10 ml) and water (10 ml). The organic layer was separated, dried (MgSO4) and evaporated to provide the title compound as a white solid m.p. 198° C. (decomp.).
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH:10]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:17](=[O:18])[CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)CC1CCCCC1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a 5° C. solution of dimethylaniline (320 ml, 2.54 mol) in t-butyl alcohol (480 ml) was added dropwise a solution of cyclohexyl-acetyl chloride (250.9 g, 1.56 mol) in dichloromethane (320 ml) over 30 min. At the end of the addition, the addition funnel was rinsed with dichloromethane (80 ml). The reaction mixture was stirred 90 min at 5° C. and then allowed to warm to room temperature. After 15 hours at room temperature, the reaction solution was heated to reflux for 6 hours and then cooled to 5° C. The cold reaction mixture was acidified with 6 n hydrogen chloride (640 ml) and extracted with ethyl acetate. The organic layer was washed with 1 N hydrogen chloride (860 ml), water (2×860 ml), saturated aqueous sodium bicarbonate solution (2×860 ml), and brine (860 ml). The organic solution was dried (magnesium sulfate), filtered, and concentrated (room temperature/20 mm Hg). The remaining liquid was distilled to afford the desired product as a yellow oil (259.32 g, 84%). bp.: 70-75° C./0.6 mm Hg; MS m/z: 199 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:24])([F:26])[F:25])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: C1CCNC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 29.2 %

Procedure:
With 350 mg of the compound obtained in Example 219 and 75 mg of pyrrolidine as starting materials, 110 mg of the title compound (pale orange amorphous) was obtained by a similar method to Example 220.