Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CC(C)([O-])C.[K+].[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1>CN(C=O)C.CC#N>[N:27]1([C:31](=[O:40])[CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:6]4[N:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=4)[CH2:10][CH2:11]3)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cc1ccc(Cl)nc1)N1CCC1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cn3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-((1S,2R)-2-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (40 mg, 0.145 mmol) was dissolved in DMF (2 ml) at RT under N2 and potassium tert-butoxide (0.218 ml, 0.218 mmol) was added. The mixture was stirred at RT for 5 min and 1-(azetidin-1-yl)-2-(6-chloropyridin-3-yl)ethanone (36.7 mg, 0.174 mmol) was added. The mixture was microwaved at 100° C. for 30 min. and 150° C. for 30 min. The mixture was diluted with CH3CN, filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD Sum 19×100 mm column; 25-95% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 8.01 (s, 1H), 7.61 (d, 1H), 6.75 (d, 1H), 4.70 (m, 2H), 4.39 (t, 2H), 4.21 (t, 2H), 4.03 (t, 2H), 3.38 (s, 2H), 2.85 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 2.18 (m, 1H), 1.84 (m, 2H), 1.58 (m, 1H), 1.40 (m, 2H), 1.10-1.20 (m, 5H), 0.95 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 450 (M+H)+, GPR119 Human EC50: 7.4 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.[C:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:18][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=2[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[O:29])=[CH:31][CH:32]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(NC(=O)c2c(N)cccc2F)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COc1ccc(NC(=O)c2c(F)cccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 66.3 %

Procedure:
Using the procedure described in Example 93, Part A, N-(4-methoxyphenyl)-2-amino-6-fluorobenzamide (1.9 mmol) and 4-tert-butylbenzoyl chloride (2.1 mmol) yielded 530 mg (65%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@H:13]3[C:14]([F:19])([F:18])[CH2:15][CH2:16][CH2:17][C@H:12]3[O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[NH2:20][C:10]1[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C:14]([F:18])([F:19])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:27]3[S:28][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCCC(F)(F)[C@@H]21
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)s3)ccc2F)N=C(N)O[C@@H]2CCCC(F)(F)[C@@H]21
Yield: 72 %

Procedure:
The coupling of (4S,4aR,8aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,3]oxazin-2-ylamine (intermediate XIIIa-2) and 5-chloro-thiophene-2-carboxylic acid (CAS 24065-33-6) following procedure Q yielded the title compound as a white solid (72% yield). MS: m/z=458.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1
Yield: 60.5 %

Procedure:
A mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol), m-anisidine (16 μl, 0.140 mmol) and 2N HCl (75 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a yellow solid (20 mg, 60%). 1H NMR (CDCl3): 8.87–8.85 (m, 1H), 8.69–8.61 (m, 3H), 7.95 (s, 1H), 7.92–7.84 (m, 2H), 7.44–7.36 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.05 (t, J=2.1 Hz, 1H), 6.98 (dd, J=2.1, 8.1 Hz, 1H), 6.79–6.75 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.C(N(CC)CC)C.S(Cl)([Cl:22])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][Cl:22])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 5-chloro-2-nitrobenzyl alcohol (80 g, 0.42 mol) and triethylamine (64 ml, 0.46 mol) in dichloromethane (840 ml) was added drop wise thionyl chloride (34 ml, 0.46 mol) during a period of 30 minutes while the internal temperature was kept below 32° C. by cooling with a water bath. The reaction mixture was stirred for 3 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether (970 ml). The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (85 g, 99%) as brown oil which was used in the next step without purification. MS m/e: 205 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16].C=O.[C:43](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:43])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:15]([O:17][C:18]1[CH:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)=[CH:31][C:26]=3[N:25]=[CH:24]2)[S:20][C:19]=1[C:38]([NH2:40])=[O:39])[CH3:16]
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCNCC2)c1Cl
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1cccc(OC2CCN(C)CC2)c1Cl
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 3-({(1R)-1-[2-chloro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Example 47, 230 mg, 0.40 mmol) in DCM (4 mL) and MeOH (2 mL) was added formaldehyde (0.033 mL, 1.2 mmol) and acetic acid (0.046 mL, 0.80 mmol) followed by sodium triacetoxy borohydride (0.17 g, 0.80 mmol). The solution was stirred for 1 h. The solution was diluted with DCM (20 mL) and washed with sat'd NaHCO3 solution (10 mL). The organic layers were dried (MgSO4), filtered and the solvent removed on a rotovap. The residue was dissolved in DCM and loaded onto a 4 g ISCO chromatography column and eluted with a gradient of 100:0 to 30:70 DCM : (80:20:2 DCM:MeOH:ammonium hydroxide) over 20 min. The appropriate fractions were combined and the solvent removed to provide 0.20 g of the title compound as a white solid (85 %). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=1.1 Hz, 2H), 7.30-7.22 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.74 (bs, 1H), 6.64 (s, 1H), 5.91 (q, J=6.4 Hz, 1H), 4.45-4.38 (m, 1H), 3.97 (s, 3H), 2.71-2.61 (m, 2H), 2.47-2.27 (m, 2H), 2.29 (s, 3H), 2.05-1.87 (m, 4H), 1.77 (d, J=6.4 Hz, 3H). MS (ESI): 591 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14]C)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[OH:14])=[O:4]
Reactant: COc1ccc(NC(=O)CCl)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)c(O)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
2-Chloro-N-(2,4-dimethoxy-phenyl)-acetamide (45.8 g, 0.2 mol) was dissolved in 1000 mL methylene chloride, and the reaction mixture was stirred at 0° C. under nitrogen. Aluminum trichloride (78.9 g, 0.6 mol) was added in portions over 30 minutes, and the reaction mixture was allowed to stir for 17 hours at room temperature. The reaction mixture was concentrated to 200 mL volume under reduced pressure, and then poured onto ice. Solids were removed by filtration, and the liquid was taken up in EtOAc, washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure to yield 39.67 g of 2-Chloro-N-(2-hydroxy-4-methoxy-phenyl)-acetamide. MS (M+H)=216.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[OH-].[Na+].C(O)(=[O:19])C>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([OH:19])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: CC(=O)O
Reactant: Fc1cc2c(Cl)nc(Cl)nc2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2cc(Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 334 mg (1.33 mmol) 2,4,7-Trichloro-6-fluoro-quinazoline (WO9532205) and 6.6 mL 1N NaOH aq. in 2 mL THF was stirred for 2 h at room temperature. The pH of the mixture was adjusted to pH=4-5 with acetic acid. The precipitate was filtered of to yield the title compound which was used in the consecutive step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:12])[N:7]([CH2:40][CH2:41]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CCOC(C)=O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:12])[N:7]([CH2:40][CH2:41][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCOS(C)(=O)=O)n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCN2CCOCC2)n1
Yield: 62 %

Procedure:
In a round bottomed flask, dissolve methanesulfonic acid 2-[3-tert-butyl-5-(3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-ureido)-pyrazol-1-yl]-ethyl ester (75 mg, 0.11 mmol) in DMF (2 mL). Add morpholine (0.1 mL, 10 eq) and heat the reaction to 70° C. overnight under N2. Dilute the reaction with EtOAc then wash with water, 1 N NaOH, and saturated aqueous saturated sodium chloride. Dry the organics over magnesium sulfate, filter, and concentrate. Purify the compound on a silica gel column (EtOAc to 5% MeOH: DCM to 10% 2 M NH3 in MeOH: DCM) to give a pale yellow solid (46 mg, 62%). MS (ES), m/z 656 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[CH3:16])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:30]>ClCCl>[CH:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1[C:9]([CH3:16])=[CH:10][C:11]([NH:12][C:29](=[O:30])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:13][C:14]=1[CH3:15])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(Cc2c(C)cc(N)cc2C)cc1C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(C(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
246 mg (0.86 mmol) of 4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylaniline (Example VII) are dissolved with 97 mg (0.96 mmol) of triethylamine in 10 ml of dichloromethane, and 160 mg (1.17 mmol) of ethoxalyl chloride are added dropwise. The mixture is stirred at room temperature for 4 hours, washed with sodium bicarbonate solution and water and dried over sodium sulphate, and the solvent is removed in vacuo. Purification by chromatography affords 128 mg (38%) of ethyl 2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethylanilino]-2-oxoacetate.
Reaction SMILES: [CH2:1]([Li])CCC.[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]([CH2:27][CH3:28])[CH2:24][CH2:23][C:22]2=O.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]([CH2:27][CH3:28])[CH2:24][CH2:23][C:22]2=[CH2:1]
Reactant: [Li]CCCC
Reactant: CCN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCN(CC)c2c(CSc3nc4ccccc4[nH]3)cccc21
Temperature: -40 °C

Procedure:
To a suspension of methyl triphenylphosphonium bromide (2.65 g)in tetrahydrofuran (50 ml) was added dropwise n-butyllithium (2.2 ml) in a nitrogen flow with stirring at -40° C. After raising the temperature to -20° C., a solution of 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (500 mg) in tetrahydrofuran (5 ml) was added dropwise. The temperature was raised gradually to room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (3:1)] and recrystallized from diethyl ether-dichloromethane to give 8-(2-benzimidazolyl)thiomethyl-1-ethyl-4-methylene-1,2,3,4-tetrahydroquinoline (390 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([CH3:17])=[CH:11][C:12]([O:14]CC)=O)[CH:5]=[CH:6][C:7]=1[F:8]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[C:12]([OH:14])=[CH:11][C:10]([CH3:17])=[CH:9]2
Reactant: CCOC(=O)C=C(C)Cc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c2cc(F)c(Cl)cc2c1
Yield: 19.7 %

Procedure:
A solution of ethyl 4-(3-chloro-4-fluorophenyl)-3-methylbut-2-enoate (9.7 g, 37.8 mmol) in concentrated sulfuric acid (40 mL) was stirred at 50° C. overnight. The reaction mixture was poured onto ice and diluted with water and extracted with ethyl acetate. The organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a pale yellow solid (1.57 g). 1H-NMR: 400 MHz, (CDCl3) δ: 7.83 (d, J=10.4 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.11 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=2)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3])=[CH:22][CH:23]=1)=[O:26]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a mixture of 1.04 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 10 mL of pyridine was added 512 mg of methyl 4-aminobenzoate, followed by stirring at room temperature for 1 hour. To the reaction mixture was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.25 g of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8]([O:10]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:10])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[N:4][C:3]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN
Reactant: CCOC(=O)c1c(-n2cncn2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(-n2cncn2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 15 ml of ethanol was dissolved 0.215 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(1,2,4-triazol-1-yl)pyridine, whereto 1 ml of hydrazine monohydrate was added. The mixture was heated under reflux for 7 hours. After cooling, the resulting yellow crystals were collected by filtration and washed with ethanol. The crystals were suspended in 20 ml of water and the suspension was acidified by addition of 1 ml of acetic acid. Thereafter, the crystals were collected by filtration, washed with water and dried to give 0.11 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([C:19]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([CH3:45])[CH:39]=1)([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:37])[CH:23]=1)[CH2:20][CH3:21])[CH3:18].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([CH2:20][CH3:21])([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([CH3:45])[CH:39]=3)[CH2:17][CH3:18])=[CH:23][C:24]=2[CH3:37])=[CH:8][CH:9]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
5-Bromo-furan-2-carboxylic acid methyl ester (J. Org. Chem., 1988, 53(9), 2099.; 156 mg, 0.761 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.013 mmol) and a 2 M sodium carbonate aqueous solution (0.3 mL, 0.6 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 100 mg, 0.254 mmol) in toluene (0.5 mL) at room temperature, and the mixture was stirred at 85° C. for 17 hours. Ethyl acetate was added to the reaction solution. The organic layer was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (73.6 mg, 73.9%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[OH:19][CH2:20][CH:21]1[NH:26][CH:25]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:24][N:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:22]1>C(Cl)Cl.O.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:36]([N:23]1[CH2:24][CH:25]([C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)[N:26]([C:2]([O:4][CH2:5][CH:6]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:3])[CH:21]([CH2:20][OH:19])[CH2:22]1)=[O:37]
Reactant: COC(=O)N1CC(CO)NC(c2cc(F)c(F)c(F)c2)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC(CO)N(C(=O)OCC2c3ccccc3-c3ccccc32)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.1 %

Procedure:
9-Fluorenylmethyl chloroformate (958 mg) was added to a mixed solution of methyl 3-hydroxymethyl-5-(3,4,5-trifluorophenyl)piperazine-1-carboxylate (867 mg) in methylene chloride (20 mL) and saturated sodium bicarbonate water (20 mL), and the reaction solution was stirred at room temperature for 14 hours. The organic layer was separated from the reaction solution. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->ethyl acetate) to obtain 916 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[F:65])#[N:51]
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(C#N)c(F)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 81% yield: LCMS (ESI) m/z 415 (MH+).