Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:10]([O:9][CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH2:7][CH3:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: CCCC=C/C=C/CO
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OC/C=C/C=CCCC

Procedure:
The method of Example 1 was substantially repeated with trans, trans-2,4-octadien-1-ol (50.0 g, 0.40 mol), methyl methacrylate (170 mL, 1.6 mol), phenothiazine (1.0 g) and tetraisopropyl titanate (2.0 mL). After a 2-h reaction time the methyl methacrylate was distilled at 70 mm, and the product, at 73° C./0.25 mm, to give 60.3 g (78%) of clear, colorless liquid trans, trans-2,4-octadienyl methacrylate. IR (film): ν 2985, 1712, 1631, 1449, 1310, 1287, 1149, 985, 962, 935, 811 cm-1. UV (isooctane): λmax 230 nm, ε=33,000. 90 MHz 1H NMR: δ 6.4-5.4 (6H, m, vinyl), 4.6 (2H, d, J=7, OCH2 --), 2.05 (2H, q, J=7, allylic CH2), 1.92 (3H, m, allylic CH3), 1.4 (2H, hextet, J=7, CH3CH2CH2 --), 0.90 (3H, t, J=7, CH3CH2 --). 22.63 MHz 13C NMR: δ 166.9, 136.6, 136.2, 134.8, 129.6, 125.2, 124.3, 65.1, 34.8, 22.4, 18.3, 13.6.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:50](Cl)[CH2:51]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:49])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:50][CH3:51])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 60 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 2 ml dichloromethane were added 20 mg EDC, 13 mg DMAP and 26 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 37 mg MS (ES+): m/e=710.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH3:22][N:23]([CH3:24])[S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (400 mg, 1.22 mmol, J. Med. Chem. 1980, 23, 837), dimethylamine hydrochloride (150 mg, 1.83 mmol), and triethylamine (0.50 mL, 3.66 mmol) in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10→50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example 247, Step A as a yellow oil. 1H NMR (CDCl3, 300 MHz, 9:5 mixture of rotamers) δ 7.67-7.52 (c, 2H), 7.36 (t, 1H), 4.87 (s, 1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (c, 2H), 2.72 (s, 6H); MS (TS) 337 (MH+).
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH2:3]OC(Cl)=O.[OH:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[CH:13][S:12]1>N1C=CC=CC=1>[OH:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[C:13]([C:3]2[CH:2]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:12]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSC(O)C(=O)N1
Solvent: c1ccncc1
Product: CC1=C(c2ccncc2)SC(O)C(=O)N1

Procedure:
A mixture of pyridine, 2,2,2-trichloroethylchloroformate and 2-hydroxy-5-methyl-2H-1,4-thiazin-3(4H)-one was treated in the same manner as described in Example 6. The residue was recrystallized from ethanol to give the titled compound as pale yellow crystals.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[O:7]1[CH2:12][CH2:11][CH:10]([NH:13][NH2:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH3:6][C:2]1[CH:3]=[C:4]([NH2:5])[N:13]([CH:10]2[CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[N:14]=1
Reactant: C/C(N)=C/C#N
Reactant: NNC1CCOCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C2CCOCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
(2Z)-3-Amino-2-butenenitrile (0.538 g, 6.55 mmol), tetrahydro-2H-pyran-4-ylhydrazine (1 g, 6.55 mmol) and triethylamine (0.913 mL, 6.55 mmol) were added to ethanol (300 mL), and the reaction mixture was stirred at 75° C. for 16 hours. The solvent was removed in vacuo, and the crude material suspended in EtOAc. The organic phase was washed with water and then brine. The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. Half of the crude material was purified by reverse HPLC (mobile phase: 0-30% ACN/H2O, 0.1% TFA) to afford 380 mg of the desired product. The other half of the crude material was purified via silica gel chromatography (eluent: 0% to 100% EtOAc:Hex then 0% to 20% MeOH:DCM). An additional 300 mg of the desired product was obtained (overall yield: 57%). LCMS E-S (M+H)=182.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78 (dd, 2H), 1.94 (qd, J=12.13, 4.55 Hz, 2H), 2.19 (s, 3H), 3.30-3.46 (m, 2H), 3.99 (dd, J=11.49, 4.17 Hz, 2H), 4.49 (m, J=11.65, 11.65, 4.11, 3.92 Hz, 1H), 5.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:19]([CH3:18])(=[O:21])=[O:20])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under a nitrogen flow under ice-cooling. The mixture was stirred for 1 hr and the reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene as a pale-brown solid (4.77 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C1COCC1>O1CCOCC1>[Cl:17][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:2]([O:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1OCCc1ccc(F)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
2,6-dichloro-N-cyclohexylnicotinamide (Intermediate 1, 273 mg, 1 mmol) was stirred in 1,4-dioxane (4 ml). To this solution was added 4-fluorophenethyl alcohol (154 mg, 1.1 mmol) followed by bis-sodium hexamethyldisilylamide 1.0M in THF (1.1 ml, 1.1 mmol). The tube was sealed and subjected to microwave heating 150° C. (Biotage Initiator 300 W) for 2 hours. The solvent was evaporated and the residue was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The combined extract was washed with brine (20 ml) dried over MgSO4, filtered and evaporated. The crude product was purified on SiO2 (40 g) eluting with ethyl acetate/isohexane 0-40% and gave 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide (153 mg, 40%) as a white solid
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CCO[C:10]([CH3:12])=O>>[N:1]1[CH:12]=[CH:10][CH:5]=[CH:6][C:2]=1[C:5]1[CH:6]=[C:2]([NH2:1])[NH:3][N:4]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(C)=O
Product: Nc1cc(-c2ccccn2)n[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The product was prepared according to general procedure for aminopyrazole synthesis (route A2). The crude product was dissolved in EtOAc, washed with NaHCO3, dried and evaporated. NMR analysis showed that a major portion of the crude mixture was still in the opened form: the mixture was then dissolved in CH3COOH and heated at 80° C. overnight, to allow for ring closure of the opened form. The product was then recovered as the acylated form, which was de-acylated stirring with HCl 6N at 60° C. overnight obtaining the title product (0.816 g, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>[Pd+2]>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Agent: [Pd+2]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 48.9 %

Procedure:
This compound was prepared in the manner of Example 6, with 1.03 grams (0.0025 mole—1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 0.365 gram (0.0025 mole—1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 1.6 grams (0.0084 mole—3.36 equiv.) of tributylamine, and 0.062 gram (0.000029 mole—0.01 equiv.) of 5% palladium(II) on carbon as reagents. A yield of 0.52 gram of 98% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (49.6% yield) was obtained.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)[CH3:2].[Li+].[CH3:9][C:10]1([C:13]([O:15]C)=O)[CH2:12][CH2:11]1.CC#N>C1COCC1>[CH3:9][C:10]1([C:13](=[O:15])[CH2:2][C:1]#[N:4])[CH2:12][CH2:11]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C(=O)CC#N)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Combine lithium diisopropylamide (LDA, 2.0 M/heptanes; Aldrich; 2.2 eq, 88 mmol, 44 mL) with THF (1.5 mL/mmol; 60 mL) and cool to −78° C. Combine methyl 1-methylcyclopropane carboxylate (TCI US; 4.56 g, 40 mmol) and CH3CN (4.20 mL, 80 mmol) in THF (10 mL) and add slowly with stirring. Stir the mixture at −65 to −78° C. for 1 hour, then remove the bath and warm the mixture to room temperature. Concentrate the reaction mixture to a slurry under reduced pressure. Add hexanes (150 mL) to form a precipitate from the slurry. Collect the solid by vacuum filtration and wash with hexanes (2×50 mL). Replace the catch flask with a clean one, and dissolve the solid on the frit in 50 mL 2.5 M HCl and collect in the flask. Rinse with 20 mL 2.5 M HCl followed by 200 mL Et2O. Separate the layers in the filtrate and extract the acidic phase with Et2O (150 mL). Combine the Et2O organic phases, dry with MgSO4, filter and concentrate under reduced pressure to yield 3-(1-Methyl-cyclopropyl)-3-oxo-propionitrile as a clear amber oil (3.58 g, 29.1 mmol, 73%). Use without purification in reaction with tolylhydrazine hydrochloride (5.23 g, 33.0 mmol) and ethanol (2 mL/mmol) at reflux for 20 hr. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with ethyl acetate (250 mL) and wash with water (2×60 mL), saturated aq. NaHCO3 (60 mL) and saturated aq. sodium chloride (60 mL). Dry the organic phase with MgSO4, filter and concentrate by rotary evaporation. Subject residue to silica gel chromatography eluting with a gradient of ethyl acetate and hexane to provide 5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (4.2238 g, 18.5 mmol, 46%). LCMS (ES+): m/z=228.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3ccccc3)c2cn1
Temperature: 180 °C
Yield: 50.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (0.136 g, 0.7 mmol) and aniline (0.5 mL, 5.5 mmol) is refluxed under N2 at 180° C. for 2 h. The reaction mixture is cooled to 25° C., when it precipitates. The solid is collected by suction filtration and recrystallized from isopropanol, and dried in a vacuum oven overnight. 7-Amino-4-anilinopyrido[4,3-d]pyrimidine (84 mg, 51%) is isolated as a light yellow solid. 1H NMR (DMSO) δ 9.82 (1H, s), 9.34 (1H, s), 8.37 (1H, s), 7.80 (2H, d, J=7.5 Hz), 7.38 (2H, t, J=7.5 Hz), 7.12 (1H, t, J=7.5 Hz), 6.61 (2H, brs) 6.43 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
In a 3-neck 1 L round-bottom flask fitted with a condenser, nitrogen inlet, and 2 stoppers was added 2,6-dibromopyridine (15.3 g, 64.58 mmol), phenylboronic acid (7.87 g, 64.58 mmol), and potassium carbonate (17:85 g, 129.16 mmol) in 228 mL of dimethoxyethane and 150 mL of water. Nitrogen was bubbled directly into the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) was added (1.85 g, 1.60 mmol) and the reaction mixture was heated to reflux. The reaction was complete after 3 h of heating. It was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 2% ethyl acetate/hexanes followed by vacuum distillation using a Kugelrohr collecting product at 150° C. 5.2 g of product was obtained (34%)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:17][C@H:16]2[CH3:31])(=[O:14])=[O:13])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C=C(C([O-])=[O:41])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO>[F:33][C:2]([F:1])([F:32])[C:3]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N+:24]([O-:41])=[CH:23][C:22]=3[C:27]([F:28])([F:29])[F:30])[CH2:17][C@H:16]2[CH3:31])(=[O:13])=[O:14])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: C[C@@H]1CN(c2ccncc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CN(c2cc[n+]([O-])cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a flask containing 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol (60 mg, 0.12 mmol) and 1.5 mL of DCM/MeOH (9/1, v/v) was added MMPP (74.6 mg, 0.15 mmol). The resulting slurry was stirred at room temperature over night. Reaction was complete as determined by TLC. This was filtered, washed with DCM. The filtrate was concentrated under reduced pressure. Purification by flash column chromatography to yield 1,1,1-trifluoro-2-[4-({(2R)-2-methyl-4-[1-oxido-3-(trifluoromethyl)pyridin-4-yl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (13.5 mg, 21.9 yield). HRMS: calcd for C20H21F6N3O4S+H+, 514.12297. found (ESI-FTMS, [M+H]1+), 514.12174.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH2:13][CH:14]([OH:16])[CH3:15]>>[OH:16][CH:14]([CH3:15])[CH2:13][S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: C=CCc1cccc(C)c1O
Reactant: CC(O)CS
Product: Cc1cccc(CCCSCC(C)O)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6 -methylphenol and 1-mercapto-2-propanol were reacted to obtain 2-[3-(2-hydroxypropylthio)propyl]-6-methylphenol.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]([C:17]([OH:19])=O)=[CH:10]2)=[O:5].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH2:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@@H:57]([NH:58][C:17]([C:11]1[N:12]([CH3:16])[C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[OH:1])=[CH:15][CH:14]=2)=[O:19])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1cc2cc(NC(=O)c3ccccc3O)ccc2n1C)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The product of step (b) (1.36 g, 4.38 mM), PyBrOP (2.45 g, 5.26 mM), and (S)-N-benzyl-N-methyl-2-phenylglycinamide (1.91 g, 6.57 mM) were placed in a 50 mL round bottom flask. DMF (20 mL) was added and the mixture was cooled to 0° C. and treated with diisopropyl ethylamine (3 mL, 17.52 mM). After the addition was complete the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (120 mL) and the mixture was washed with 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The ethyl acetate was dried with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% diethyl ether in CH2Cl2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[F:20])[CH:3]=1.[CH3:21][O-:22].[Na+].O>CN(C=O)C>[F:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][C:4]1[CH:3]=[C:2]([O:22][CH3:21])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cccc(F)c1Oc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Oc2c(F)cccc2OC)c1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
A mixture of 4-fluoro-2-(2-fluoro-6-methoxyphenoxy)-1-nitrobenzene (1.33 g, 5 mmol) and sodium methoxide (035 g, 6 mmol) in DMF (10 ml) was heated at 80° C. for 2 h. The mixture was poured into water and was extracted with ethyl acetate (3×20 ml). The combined organic layer was washed with water, brine and dried (Na2SO4). The solution was concentrated under reduced pressure to obtain 2-(2-fluoro-6-methoxyphenoxy)-4-methoxy-1-nitrobenzene (1.02 g, 70%). This compound was reduced to 2-(2-fluoro-6-methoxyphenoxy)-4-methoxyaniline (0.62 g, 73%) following the general procedure C. N-[2-(2-Fluoro-6-methoxyphenoxy)-4-methoxyphenyl]-N′-(thiazol-2-yl)urea (136 mg, 70%) was prepared from 2-(2-methoxy-6-fluorophenoxy)-4-methoxyaniline (132 mg, 0.5 mmol) and 2-aminothiazole (60 mg, 0.6 mmol) following the general procedure D.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:25]=4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].C[Zn+].[CH3:34]N1CCCC1>[Pd].ClCCl>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([CH:10]3[CH2:11][N:8]([C:5]4[N:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=4)[CH2:9]3)=[O:13])=[CH:16][CH:17]=2)[CH:22]=[N:23]1
Reactant: CN1CCCC1
Reactant: CC(C)(C)Cn1cc(-c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)cn1
Agent: [Pd]
Agent: C[Zn+]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(N2CC(C(=O)Nc3ccc(-c4cnn(CC(C)(C)C)c4)cc3)C2)nn1
Temperature: 60 °C

Procedure:
To 1-(6-chloropyridazin-3-yl)-N-(4-(1-neopentyl-1H-pyrazol-4-yl)phenyl)azetidine-3-carboxamide (0.076 g, 0.179 mmol) was added methylzinc(II) chloride (2.0M in THF) (0.179 ml, 0.358 mmol) and 5 mg of palladium catalyst. The reaction mixture was heated to 60° C. and a thick precipitate developed. N-methylpyrrolidine (0.2 ml) was added and the mixture was heated to 85° C. for 2 hours. The mixture was diluted with dichloromethane and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.11 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 6.99 (d, J=9.1 Hz, 1H), 4.27 (t, J=8.5 Hz, 2H), 4.19 (dd, J=8.2, 6.1 Hz, 2H), 3.90 (s, 2H), 3.75 (ddd, J=17.0, 8.5, 6.0 Hz, 1H), 2.45 (s, 3 H), 0.92 (s, 9 H); MS (ESI(+)) m/e 405 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.[CH:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[C:28](O)=[O:29])=[CH2:24].CCN=C=NCCCN(C)C.O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][C:28](=[O:29])[C:27]1[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=[C:25]([CH:23]=[CH2:24])[CH:26]=1)[CH:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:5]2
Reactant: C=Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=Cc1cc(C(=O)NCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
100 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 120-b) and 65 mg of 3-vinyl-5-nitrobenzoic acid were dissolved in 1 mL of chloroform, and 96 mg of WSC was added thereto, followed by stirring for 30 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 112 mg (yield 74%) of a title compound as a yellow solidified product.