Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:14]=1[N+:21]([O-:23])=O)=[O:11])(=O)C1C=CC=CC=1.Cl>[OH-].[Na+]>[Cl:20][C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][C:17]=1[Cl:19])[NH:12][C:10](=[O:11])[CH:9]=[N+:21]2[O-:23]
Reactant: O=C(CC(=O)c1ccccc1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1c[n+]([O-])c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A suspension of the N-(benzoylacetyl)-4,5-dichloro-2-nitroaniline (0.351 g, 1 mmol) in 20% NaOH (5 mL) was refluxed under stirring for 1 h. The mixture was cooled to room temperature and acidified with 2N HCl to pH 2 to form a precipitate. The precipitated product was filtered, washed with 2N HCl (3×20 mL), H2O (5×20 mL), ethanol (20 mL), and ether (20 mL), and then air dried to give 0.207 g (90%) of the title compound as a light brown powder: mp 278°-280° C. (H2O from DMSO); IR (KBr) 3450, 3104, 2934, 1693, 1593, 1517, 1412, 1270, and 890 cm-1 ; 1H NMR (DMSO-d6) δ7.50 (s, 1H), 7.95 (s, 1H), 8.23 (s, 1H), 12.45 (br.s, 1H, N--H); 13C NMR (DMSO-d6) δ118.09, 121.32, 125.79, 129.75, 130.31, 133.25, 135.50, 157.30; HPLC: 98.1%. HRMS Calcd for C8H4N2O2Cl2 : 229.9650. Found: 229.9660.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[C:16]([NH:20][C:21]([NH2:23])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:17][C:16]([NH:20][C:21]1[O:22][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:23]=1)([CH3:19])[CH3:18]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)NC(N)=O
Solvent: ClCCl
Product: COC(=O)c1nc(NC(C)(C)C)oc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 37.4 %

Procedure:
By the procedure of Example 50, 12.35 g (50 mmol) of methyl 3-chloro-3-(o-chlorophenyl)pyruvate was reacted with 5.8 g (50 mmol) of tert-butyl urea at 105°-115° C. for 8 hours. The reaction mixture was cooled to ambient temperature and then diluted with methylene chloride, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to yield a yellow oil. This oil was purified by flash chromatography techniques on silic gel using 10% ethyl acetate in hexane as eluent. There was obtained 5.77 g of an orange viscous oil product identified in Table I.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17].C(=O)([O-])O.[Na+]>>[CH2:15]([NH:18][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH3:14])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:16]=[CH2:17]
Reactant: CCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC)c2scc(C)c2n1
Yield: 64.1 %

Procedure:
In a sealed tube were heated 273 mg (1.2 mmol) of 2-chloro-4-ethylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 191 mg (yield: 64.3%) of the title compound.
Reaction SMILES: Br[O:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].B([O-])([O-])O[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(OCC)(=O)C>[C:14]1([C:9]2[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]([OH:2])=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]B([O-])Oc1ccccc1
Reactant: O=C(O)c1ccccc1OBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
In 400 ml of water, 21.7 g of bromosalicylic acid, 13.41 g of phenyl borate and 15.28 g of potassium carbonate were dissolved. The solution was stirred at room temperature for 40 minutes. The completion of the reaction was confirmed by TLC, and the reaction solution was poured into a mixture of diluted hydrochloric acid and ethyl acetate. The organic phase was extracted, separated, and washed with a saturated aqueous sodium chloride solution. The organic phase was dried with magnesium sulfate, and concentrated. The concentrate was recrystallized with acetonitrile to obtain 5-phenylsalicyclic acid as colorless crystals. The amount was 18.58 g (yield: 87%). The molecular structure was confirmed with a mass spectrum. Synthesis of ethyl 5-phenylsalicylate
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3[O:44][CH:43]=[N:42][CH:41]=3)[CH:37]=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:44]1[C:40]([C:36]2[CH:35]=[C:34]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:39]=[N:38][CH:37]=2)=[CH:41][N:42]=[CH:43]1
Reactant: CC1(C)OB(c2cncc(-c3cnco3)c2)OC1(C)C
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2cccc3nc(-c4cncc(-c5cnco5)c4)nc(NCc4ccccn4)c23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.115 g, 0.330 mmol) in 1,4-dioxane (6 mL) and H2O (1.5 mL) under nitrogen was added, 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxazole (0.10 g, 0.36 mmol) and potassium carbonate (0.136 g, 0.990 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)-ferrocene)palladium (II) chloride dichloromethane complex (0.026 g, 0.033 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 100° C. for 16 h, then allowed to cool to room temperature and quenched with water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to provide 2-(5-(oxazol-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.015 g) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H); 9.03 (s, 1H); 8.27 (d, 2H, J=3.6 Hz); 8.03 (s, 1H0; 7.77 (t, 1H, J=7.6 Hz); 7.70-7.58 (m, 2H); 7.54-7.47 (m, 5H0; 7.33-7.28 (m, 1H); 7.20-7.10 (m, 5H0; 6.82 (br, 1 h); 4.80 (d, 2H, J=4.4 Hz). LCMS Method Y: retention time 1.98 min; [M+1]=457.2; HPLC Method A1: purity 98.7%, retention time=7.09 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])=[CH:19][CH:18]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Nc1c(C(=O)Nc2ccc(Cl)cc2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
A suspension of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.46 mmol) in thionyl chloride (2.0 mL) is stirred at room temperature for about 15 min before it becomes a clear solution. After removal of the solvent, the crude acid chloride is taken in anhydrous DCM (5.0 mL), and transferred dropwise to a solution of 4-chloroaniline (376.7 mg, 2.95 mmol) and TEA (1.03 mL, 7.38 mmol) in anhydrous DCM (5.0 mL) at 0° C. The reaction mixture is allowed to warm up to room temperature in an hour and lots of precipitate is generated. After filtration, the precipitate is washed with water, followed by small amount of DCM, and air-dried to provide crude 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (4-chloro-phenyl)-amide (506.2 mg, 66% yield) as a white solid product; HPLC-MS calculated for C16H13ClN4O (M+H+) 313.1. Found: 313.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>CO>[CH3:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To ethyl 2-methyl-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate (C37) (0.986 g, 2.35 mmol) in methanol (7.8 mL) was added sodium hydroxide (2 N, 5.9 mL, 11.8 mmol) and the solution was stirred at room temperature for 4 hours. The reaction was acidified with hydrogen chloride (2 N), and the white precipitate was vacuum-filtered to afford the title compound as a white solid (0.865 g, 93%): mp 142-144° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.39 (s, 1H), 8.14-7.95 (m, 4H), 7.71-7.55 (m, 2H), 7.42-7.27 (m, 2H), 3.04-2.89 (m, 1H), 2.75-2.62 (m, 2H), 1.07 (d, J=6.2 Hz, 3H). 19F NMR (376 MHz, acetone-D6) δ −58.03; ESIMS m/z 392 ([M+H]+).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:18]=CC=C[C:12]=1C#N>>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][C:12]=1[C:11](=[O:10])[CH3:18]
Reactant: N#Cc1ccccc1O
Reactant: N#Cc1ccccc1S
Product: CC(=O)c1sc2ccccc2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 2-mercapto-benzonitrile (3A) in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:25][CH2:24][C:17]3([O:21][CH:20]([CH3:22])[CH:19]([CH3:23])[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:25][CH2:24][C@H:17]([O:18][CH:19]([CH3:23])[CH:20]([OH:21])[CH3:22])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)C(C)O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)O)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 4′-{[7-butyl-4-(2,3-dimethyl-1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.2 g), sodium cyanoborohydride (0.71 g), boron trifluoride-diethyl ether complex (1.4 mL) and tetrahydrofuran (20 mL) was stirred at 50° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.66 g, 53%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH2:9](I)[CH2:10][CH3:11]>CN(C)C=O.[Ag]=O>[CH2:9]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11]
Reactant: CCCI
Reactant: CCOC(=O)[C@H](C)O
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCCO[C@@H](C)C(=O)OCC
Yield: 73.7 %

Procedure:
Twenty grams of ethyl (S)-lactate, 45.0 g of propyl iodide, and 30.0 g of silver oxide were stirred in 100 ml of dimethylformamide for 40 hours. Any insoluble matter was removed by filtration, and water was added to the filtrate. The filtrate was extracted three times with hexane. The hexane layer was dehydrated, and the organic solvent was removed therefrom by distillation under reduced pressure to obtain 20.0 g of ethyl (S)-2-propoxypropionate (b.p.=78° C./50 mmHg). Eighteen grams of the product was stirred in 100 ml of a 5N sodium hydroxide aqueous solution for 6 hours, and adjusted to a pH of 3 to 4 with dilute sulfuric acid under ice-cooling. The reaction mixture was extracted with diethyl ether several times, and the extract was dehydrated and distilled to remove the diethyl ether to obtain 10.2 g of (S)-2-propoxypropionic acid. To the whole quantity of the product were added 20 ml of thionyl chloride and 0.5 ml of pyridine, followed by stirring at reflux for 2 hours. The excess thionyl chloride was removed from the reaction mixture by distillation under reduced pressure. The residue was dissolved in benzene, and any insoluble matter was separated by filtration. The benzene was removed from the filtrate by distillation to obtain 10.5 g of (S)-2-propoxypropanoyl chloride as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:25])(=[O:24])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([OH:26])[CH:5]=1.C1(O)C=CC=CC=1.[N:35]1[C:44]2[C:39](=[C:40]([CH2:45][CH2:46]O)[CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:25])[NH:11][C@H:12]([C:21](=[O:23])[NH2:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([O:26][CH2:46][CH2:45][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]3[C:39]=2[CH:38]=[CH:37][CH:36]=[N:35]3)[CH:5]=1
Reactant: OCCc1cccc2ncccc12
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of phenol 4-((S)-2-tert-butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-hydroxy-benzoic acid methyl ester (3.0 g, 7.50 mmol) in dry THF (50 mL) at 0° C. was added 2-quinolin-5-yl-ethanol (1.30 g, 7.5.0 mmol) and triphenyl phosphine (3.90 g, 15.0 mmol) then followed by dropwise addition of diethyl azodicarboxylate (2.40 mL, 15.0 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The solvent was removed and the crude product was purified using silica gel flash chromatography (30% hexanes in EtOAc). 4-((S)-2-tert-Butoxycarbonyl-1-carbamoyl-ethylsulfamoyl)-3-(2-quinolin-5-yl-ethoxy)-benzoic acid methyl ester was obtained (1.40 g, 33%) as an off white foam. MS m/z 556.2 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH2:35]OC(C)=O>CN(C=O)C.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>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:34]=[CH2:35])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Intermediate (18a) (10.0 g, 19.3 mmol) was dissolved in DMF (100 mL). Tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.4 mmol) was added, followed by (2-ethenyl)tri-n-butyltin (8.5 mL, 29.0 mmol). The reaction vessel was fitted with a reflux condenser and was heated to 110° C. with stirring for 1 hour, under nitrogen. The mixture was cooled and 200 mL EtOAc was added. The organic layer was washed with a 20% solution of potassium fluoride (2×50 mL) followed by saturated aqueous NaCl (100 mL), then dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18b) as a colorless oil (7.2 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H29FN2O4, 465.22. found 465.6.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[H-].[Na+].I[CH2:34][CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>CN(C=O)C>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][CH2:35][CH2:34][O:1][CH2:2][C@H:3]2[CH2:14][CH2:13][C:12]3[S:11][C:10]4[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]5[CH2:17][CH2:18][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:20][CH2:21]5)[C:5]=4[C:4]2=3)=[CH:39][CH:40]=1
Reactant: COc1ccc(COCCI)cc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCCOC[C@H]2CCc3sc4ncnc(OC5CCC(N(C)C(=O)OC(C)(C)C)CC5)c4c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (940 mg, 2.17 mmol, 1.00 equiv) in freshly distilled DMF (6 mL) was added sodium hydride (60% dispersion in mineral oil, 347.3 mg) slowly at 0° C. under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 min. Then 1-[(2-iodoethoxy)methyl]-4-methoxybenzene (2.535 g, 8.68 mmol, 4.00 equiv) was added to the mixture and stirred for 14 hrs at ambient temperature. The reaction was quenched slowly with saturated aqueous NH4Cl and extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give tert-butyl N-(4-[[(3S)-3-([2-[(4-methoxyphenyl)methoxy]ethoxy]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (700 mg, 54%) as a colorless oil. MS: m/z 598 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])=[C:5]([NH2:19])[NH:4][N:3]=1.[C:20](OC)(=[O:26])[CH2:21][C:22](OC)=[O:23].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])=[C:5]2[NH:19][C:20](=[O:26])[CH2:21][C:22](=[O:23])[N:4]2[N:3]=1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nn2c(c1Cc1cccc(C(F)(F)F)c1C)NC(=O)CC2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (2.0 g, 7.43 mmol), dimethyl propanedioate (1.03 g, 7.8 mmol) and in methanol (20 mL) stirred under nitrogen at 20° C. was added a solution of sodium methoxide (3.21 g, 14.9 mmol) in methanol (20 mL) dropwise during 15 minutes. The reaction mixture was stirred at 80° C. for overnight. After the reaction mixture was cooled to room temperature, precipitate was collected by filtration, then washed with methanol (5 mL×2). Product was dried under air. The product was then suspended with 1 N HCl (10 mL), stirred for 10 minutes, and filtered off HCl solution. The product was dried and used in next step without further purification. (2.41 g, 96%); LC/MS: MS (ES+) m/e 338 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].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:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2-fluoro-4-hydroxybenzoate (1.4685 g; manufactured by Changzou Fine Chemical Co., Ltd.) and potassium carbonate (3.6-917 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (21 mL; manufactured by Kanto Chemical Co., Inc.), and benzyl bromide (1.22 mL; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred overnight at 50° C. The reaction solution was cooled to room temperature, and then was poured into water. The mixture was extracted two times with ethyl acetate. The organic layer was washed twice with water and once with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=97:3→77:23). Thus, the title compound (2.2207 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:15]OS(=O)(=O)OC.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([O:11][CH3:15])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)=O)cc(Br)cc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
A mixture of the 1-(5-bromo-2-hydroxy-3-nitrophenyl)-1-ethanone (17.4 g), dimethylsulfuric acid (12.7 g), potassium carbonate (13.8 g) and acetone (200 mL) was heated to reflux for 15 hours, and then water was added to the mixture and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (16.2 g) as a yellow oil.