Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][CH3:24])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][N:23]([CH3:24])[S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[(R)-6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methyl-amine hydrochloride (0.4 g, 1.13 mmol) was dissolved in 10 mL methylene chloride and 2.0 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.2 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with 1% aqueous HCl, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was eluted through silica gel at medium pressure with 1:1: EtOAc/hexanes to give 310 mg of N—[(R)-6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-N-methyl-methanesulfonamide, M+H=412.
Reaction SMILES: [CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]([C:25]1[CH:30]=[CH:29][C:28]([B:31]2[O:32][C:33]([CH3:39])([CH3:38])[C:34]([CH3:36])([CH3:37])[O:35]2)=[C:27]([CH3:40])[CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:24])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
10% palladium carbon (40 mg) was added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 0.26 g, 0.48 mmol) in ethyl acetate (2.5 mL), and the mixture was stirred under hydrogen charging for three hours. The reaction mixture was filtered and concentrated to give the title compound (0.26 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]3=[O:20])=[C:4]2[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]3=[O:20])=[C:4]2[N:3]=1
Reactant: C[O-]
Reactant: CCCC1CC(=O)N(Cc2cnn3ccc(Cl)nc23)C1
Agent: [Na+]
Solvent: CO
Product: CCCC1CC(=O)N(Cc2cnn3ccc(OC)nc23)C1
Temperature: 80 °C
Yield: 53.7 %

Procedure:
To a solution of 1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 205 (0.575 mmol, 1 eq, 0.22 g) in MeOH (10 ml) is added sodium methoxide (5.75 mmol, 10 eq, 0.4 g). The mixture is heated at 80° C. for 2 hours. The solvent is removed under reduce pressure, water is added and the resulting mixture is extracted with CH2Cl2. The organic phases are combined, and dried over MgSO4. Volatiles are removed under reduced pressure to afford 89 mg of 1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 208.
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a 30 ml N,N-dimethylformamide solution of 2.4 g (11.15 mmol) of tert-butyl 4-hydroxymethyl-1-piperidinecarboxylate, 557 mg (60% in oil, 13.9 mmol) of sodium hydride and 1.86 ml (15.6 mmol) of benzyl bromide were added with ice cooling. The mixture was stirred at room temperature for 23 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.5 g (quantitative) of the captioned compound.
Reaction SMILES: [I:1]I.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[I-:1].[I-:1].[C:16]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: [I-]

Procedure:
The 3α-iodo derivative of 4,4-nor-methyl glycyrrhetinic acid, methyl ester is prepared by a method similar to that used by Greenhouse and Muchowski [Greenhouse, R., Muchowski, J. M., Can. J. Chem. 59(1981) 1025-1027] (see Example 1). To a solution of 12.69 g (0.05 mole) of iodine in anhydrous benzene (35 mL) is added a solution of triphenylphosphine (13.12 g, 0.05 mole) in dry benzene (50 mL). After the solution becomes pale, an abundant yellow precipitate of triphenylphosphine diiodide is produced. To this solution is added directly 4,4-nor-methylglycyrrhetinic acid, methyl ester (9a) (4.56 g, 0.01 mole) and this suspension is heated to reflux with stirring for 22 hours. After cooling, the reaction mixture is mixed with ice-water (60 mL) and extracted. The benzene layer is further extracted with water (2×100 mL), dried over anhydrous sodium sulfate, evaporated and dried in vacuo to an off white solid. This residue is triturated with n-pentane (200 ml) and the insoluble triphenylphosphine oxide filtered. After rotary evaporation of the pentane solvent, the product is recrystallized from toluene:acetone.
Reaction SMILES: C([Li])CCC.[NH3:6].[NH2-].[Li+].[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([C:24]2[S:28][C:27]([C:29]([O:31]C)=O)=[N:26][N:25]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:12])[CH3:11]>CCCCCC.O1CCCC1>[CH3:21][C:20]([C:17]1[CH:16]=[C:15]([C:24]2[S:28][C:27]([C:29]([NH2:6])=[O:31])=[N:26][N:25]=2)[CH:14]=[C:13]([C:10]([CH3:11])([CH3:12])[CH3:9])[C:18]=1[OH:19])([CH3:22])[CH3:23]
Reactant: N
Reactant: COC(=O)c1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nnc(C(N)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.0 ml (3.20 mmol) of 1.6M n-butyllithium in hexane is added dropwise to liquid ammonia (3-5 ml) at -78° C. over 10 minutes under a nitrogen atmosphere. The resulting white slurry is treated slowly with 10 ml of tetrahydrofuran and the resulting mixture of lithium amide at -78° C. is treated dropwise with a solution of 1.08 g (3.10 mmol) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxylic acid, methyl ester in 3 ml of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature and stirred for a total of 18 hours. The reaction is quenched with 100 ml of saturated aqueous NH4Cl and extracted with t-butylmethylether (3×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. Chromatography (flash, SiO2, 70-230 mesh, 30% ethyl acetate-hexane) followed by recrystallization from toluene gives 0.68 g (1.03 g theor., 66%) of the desired product as a pale yellow solid, mp 200°-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34].Br[C:42]1[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=1[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:15]2[CH:14]=[C:13]([C:42]3[C:43]([O:49][CH3:50])=[N:44][CH:45]=[CH:46][C:47]=3[CH3:48])[CH:12]=[CH:11][C:10]=2[C:9]2[N:25]([CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:26]=[CH:27][C:8]=2[C:7]1=[O:34]
Reactant: COc1nccc(C)c1Br
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(B4OC(C)(C)C(C)(C)O4)cc32)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)ccnc4OC)cc32)c(OC)c1

Procedure:
5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (100 mg) obtained in Preparation Example 1(5) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-methoxy-4-methylpyridine obtained in Preparation Example 37 (2) (55.6 mg), Pd(PPh3)4 (10.6 mg), cesium carbonate (179 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-methoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (78 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (30 mg).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8](N(OC)C)=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C[Li].[CH3:16]COCC.C(O)(=O)C>C1COCC1>[C:8]([C:4]12[CH2:7][N:1]([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)(=[O:9])[CH3:16]
Reactant: CON(C)C(=O)C12CCN(CC1)C2
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)C12CCN(CC1)C2
Temperature: -40 °C
Yield: 68.5 %

Procedure:
1-Azabicyclo[2.2.1]hept-4-yl-N-methoxy-N-methyl carboxamide (D21) (10 g, 0.054 mole) was dissolved in dry THF (250 ml) under nitrogen cooled to -40° C. and treated with methyl lithium in ether (55 ml, 1 molar, 0.055 moles). The solution was allowed to warm to room temperature over a period of 1 h. Acetic acid (3.3 ml, leq) was added and the solution concentrated in vacuo to a gum. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum which was distilled in vacuo to afford 4-acetyl-1-azabicyclo[2.2.1]heptane (D22) (5.15 g, 0.037 mole, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][CH:61]([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][CH:61]([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperdine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.165 mL, 2.61 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 16 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (72.8 mg, 0.155 mmol, 58%) as colorless crystals.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]([N+:15]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[C:8]2[C:7]=1[CH:1]=[CH:2][NH:15]2
Reactant: C=C[Mg]Br
Reactant: CC(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)c2cc[nH]c12
Reaction time: 1 h

Procedure:
Vinyl magnesium bromide (1 M in THF) (98 mL, 98 mmol) was added to 4-bromo-1-isopropyl-2-nitrobenzene (4 g, 16.39 mmol) in THF (60 mL) at −40° C. The reaction mixture was stirred for 1 h, then poured into saturated aqueous NH4Cl and extracted with ether. The combined ethereal extracts were dried (MgSO4) and concentrated. Chromatography over silica eluting with 1-20% EtOAc/hexanes afforded the title compound. LC-MS: calculated for C11H12BrN 237,02, observed m/e 238.2 (M+H)+ Rt (1.96/4 min.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-chloro-5-hydroxynicotinate (3.71 g) in DMF (30 mL) were added potassium carbonate (5.47 g) and benzyl bromide (2.59 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at 0° C., and the resulting precipitate was collected by filtration. The obtained crude crystals were washed with water and hexane, and dried at 50° C. for 15 min under reduced pressure to give a crude product of the title compound (4.57 g) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[CH2:6][C:7]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccc(F)cc2N1
Product: CC(=O)N1C(=O)Cc2ccc(F)cc21
Temperature: 25 °C

Procedure:
82.5 g of 6-fluoro-2-indolinone are stirred in 180 ml acetic anhydride for 3 hours at 130° C. After cooling to ambient temperature the precipitate is suction filtered, washed with 100 ml petroleum ether and dried.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C(OCC)=O)C(OCC)=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24].[OH-].[Na+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=NOC(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
A solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.9 g.) in tert-butyl alcohol (5 ml.) was added to a solution of L-isoleucine (656 mg.) in a 1N sodium hydroxide aqueous solution (5.0 ml.), and the mixture was stirred for 3 hours at room temperature. tert-Butyl alcohol was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was washed with ether, adjusted to pH 3 with a 5% citric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give N-tert-butoxycarbonyl-L-isoleucine (1.2 g.), oil.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][OH:17]>CN(C)C=O>[Si:6]([O:17][CH2:16][CH2:15][Br:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Combine imidazole (59.9 g, 880 mmol), t-butyldimethylsilyl chloride (60.3 g, 400 mmol), and dimethylformamide (300 mL). Cool to 0° C. in a salt-ice bath. Add dropwise 2-bromoethanol (50.0 g, 400 mmol) at such a rate that the temperature of the reaction mixture does not rise above 0° C. After 2 hours, warm to ambient temperature. After 18 hours, extract the reaction mixture three times with hexane. Combine the hexane layers and extract three times with a saturated aqueous solution of ammonium chloride, three times with a saturated aqueous solution of sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[CH3:3][O:2]/[N:4]=[C:12](\[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)/[CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CON
Reactant: O=C(Cn1cccn1)c1ccc(Cl)cc1
Agent: Cl
Product: CO/N=C(/Cn1cccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Methoxylamine hydrochloride (0.668 g, 8.00 mmol), was added to a stirred solution of 1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone (Intermediate 90) (1.103 g, 5 mmol), at room temperature under argon. The resulting solution was stirred at room temperature overnight. The pyridine was evaporated in vacuo and the residual solid was triturated with a saturated aqueous solution of sodium hydrogencarbonate (50-100 ml). The solid was filtered, washed with water and dried to afford (Z) and (E)-1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone O-methyl oxime (1.080 g, 87%) as a dark yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:9]([Cl:20])[S:8][C:7]=1[NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])=[O:5])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[C:9]([Cl:20])[S:8][C:7]=1[NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(N)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(2-cyano-acetylamino)-4-(4-nitrophenyl)-5-chloro-thiophene-3-carboxylic acid ethyl ester (1.00 g, 2.54 mmol), Fe (432 mg, 7.71 mmol), and NH4Cl (110 mg, 2.03 mmol) in EtOH (20 mL) and H2O (10 mL) was heated to 85 C for 2 h. The reaction was cooled to room temperature and filtered through a plug of celite, eluting with hot MeOH. The eluent was concentrated under reduced pressure to give a solid that was used in the next step without further purification. MS (ESI) m/e 362 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N+:15]([C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=1)([O-:17])=[O:16]>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:27]=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc2ccc([N+](=O)[O-])cc2s1)N1CCCc2ccccc21
Yield: 33 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 6-nitrobenzo[d]thiazole-2-thiol as the nucleophile to yield 21 as a yellow solid (33%): MS m/z: 386 (M+H)+. Anal. Calcd. For, C18H15N3O3S2: C, 56.09; H, 3.92; N, 10.90; S, 16.64. Found: C, 55.98; H, 3.75; N, 10.94; S, 16.41.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23]O>>[CH3:23][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCCCCCCCOc1cnc(-c2cccc(O)c2)nc1
Product: CCCCCCCCOc1cnc(-c2cccc(OC)c2)nc1

Procedure:
5.52 g (21.05 mmol) of triphenylphosphine and 3.67 g (21.05 mmol) of diethyl azodicarboxylate are stirred at 0° C. for 30 minutes in 100 ml of tetrahydrofuran. 3.90 g (14.03 mmol) of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine and 2.74 g (21.05 mmol) of 1-octanol are subsequently added, and the resultant solution is stirred at room temperature for 18 hours. Evaporation to dryness and purification by chromatography (silica gel/dichloromethane) give 4.25 g of 2-(3-benzyloxyphenyl)-5-octyloxypyrimidine. ##STR29## Removal of the benzyl protecting group by hydrogenation analogously to Example 1 gives 2-(3-hydroxyphenyl)-5-octyloxypyrimidine. ##STR30## 2-(3-Hydroxyphenyl)-5-octyloxypyrimidine is reacted with methanol analogously to Example 1 to give 2-(3-methoxyphenyl)-5-octyloxypyrimidine. ##STR31## The compound has the phase sequence: X43 I