Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33]>>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1)[CH3:33]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-ethyl phenyl boronic acid. MS: 572.3 [M−H]−.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C@H:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[F:21])[CH2:5]1)#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.N12CCCN=C1CCCCC2>C(#N)C>[F:21][C@H:9]1[C@@H:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:7]2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2CC(=CC#N)C2)[C@H](F)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a solution of tert-butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-fluoropiperidine-1-carboxylate (0.24 g, 0.81 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.31 g, 0.98 mmol) in acetonitrile (8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 g, 0.98 mmol) by syringe. The resulting solution was stirred at room temperature for 6 hours and concentrated. Purification with combi-flash using 40-100% EtOAc/hexanew as eluent gave 0.30 g (61% yield) of the desired compound as a solid. LCMS found: 611.1 (M+1)+.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[O:3]1)=[O:2].[CH3:15]O>Cl>[C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[O:3]1)=[O:2]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Reactant: CO
Agent: Cl
Product: COC(=O)CC1OC(=O)c2ccccc21

Procedure:
Phthalide-3-acetic acid (XCI, 9.6 g, 50 mmol) is dissolved in methanol (50 ml) saturated with anhydrous hydrochloric acid and the mixture is cooled to 0-5° for 18 hr. The solvent is concentrated under reduced pressure, treated with sodium bicarbonate, and extracted with methylene chloride (800 ml). The organic phase is washed with saturated aqueous sodium bicarbonate, saline, dried over magnesium sulfate, filtered and concentrated to give the title compound, mp 62-63°; NMR (CDCl3, TMS) 7.94-7.50, 5.90, 3.77 and 2.92 δ.
Reaction SMILES: ClC(OC(Cl)C)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.CO>ClCCCl.C(OCC)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CN1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCCl
Product: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Reaction time: 20 h
Yield: 76.1 %

Procedure:
1-Chloroethyl chloroformate (0.50 ml) was added to a solution of 5-(4-Chlorophenyl)-2-(1-methylpiperidin-4-yl)pyrimidine (0.170 g) in anhydrous 1,2-dichloroethane (10 ml) and the mixture heated to reflux, under a calcium chloride guard tube, for 20 h. The reaction was then cooled, treated with methanol (1.0 ml), and returned to reflux for a further hour. After cooling, the reaction was diluted with diethyl ether (20 ml) and extracted with water (20 ml), 0.2 M hydrochloric acid (10 ml) then 1% citric acid (50 ml). The combined aqueous extracts were back-extracted with diethyl ether (10 ml), basified to pH 13 with 46% aqueous sodium hydroxide and extracted with ethyl acetate (20 ml, then 2×10 ml). The combined ethyl acetate extracts were washed with water (10 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a white solid (0.123 g, 76%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=O.[Cl-:12].[Cl-].[Ca+2]>P(Cl)(Cl)(Cl)=O>[Cl:12][C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1
Reactant: Cn1c(=O)[nH]c2cccnc21
Reactant: [Cl-]
Agent: [Ca+2]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2cccnc21

Procedure:
The mixture of 3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.0 g) in phosphorus oxychloride (10 g) was stirred at 100° C. under a dry atmosphere (CaCl2 tube) for 5 h. The mixture was neutralized with sat.NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 2-chloro-3-methyl-3H-imidazo[4,5-b]pyridine (230 mg) as a white solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47](O)[CH:48]([CH3:50])[CH3:49]>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH2:47][CH:48]([CH3:50])[CH3:49])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: CC(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCC(C)C)cccc2[nH]1
Reaction time: 3 h

Procedure:
DEAD (10.2 ml, 65.28 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (9.57 g, 46.63 mmol), triphenylphosphine (17.12 g, 65.28 mmol) and isobutanol (5.9 ml, 63.42 mmol) in 100 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 3 hours and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using first cyclohexane as eluent, then increasing amounts of EtOAc (from 5% to 50%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]2[NH:16][C:17]([NH2:20])=[N:18][N:19]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.C[Sn](C)(C)[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=1.[Cl-].[Li+].O1CCOCC1>[Cu]I.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>[NH2:20][C:17]1[NH:16][C:15]([C:4]2[S:3][C:2]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:24]=3)=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])=[N:19][N:18]=1
Reactant: COC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: Nc1nnc(-c2sc(Br)nc2-c2ccc(Cl)cc2Cl)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nnc(N)[nH]3)s2)ccn1
Temperature: 120 °C
Yield: 23.7 %

Procedure:
The mixture of 5-[2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazol-3-amine (0.0300 g, 0.0767 mmol), methyl [4-(trimethylstannyl)pyridin-2-yl]carbamate (0.0362 g, 0.115 mmol), Lithium chloride (9.76 mg, 0.230 mmol), Copper(I) iodide (7.0 mg, 0.037 mmol) and Tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0060 mmol) in dry 1,4-Dioxane (4.0 mL, 51 mmol) was purged with N2 for 5 min, heated to reflux (120° C.) under N2 atmosphere for 3 hours, cooled to r.t. . . . . The mixture was diluted with 10% MeOH-DCM (10 mL), filtered through a short column of Celite/Na2SO4. The filtrate was rotavaped and the residue was chromatographed in a 8 g AnaLogix column using MeOH/DCM (0/100 to 5/95) to give a solid product (0.0084 g, 24% yield). LCMS: (FA) ES+ 462, 464, ES− 460, 462. 1H NMR (400 MHz, d-chloroform & d4-Methanol) 8.21 (s, 1H), 8.05 (s, 1H), 7.30-7.32 (m, 1H), 7.19-7.24 (m, 2H), 7.06-7.09 (m, 1H), 3.54 (s, 3H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:37])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O.OO>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:37])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(O)CCC/C=C/B(O)O
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-hydroxy-1-heptenyldihydroxyborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 5.9 g (yield 82%) of 5-decyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine.
Reaction SMILES: [Na].[CH2:2](O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1.C(#N)C(C)=C>ClCCl.CCCCCC>[NH2:5][C:6]1[CH:10]([CH3:2])[CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1
Reactant: NC1=NN(c2ccc(Cl)cn2)CC1
Reactant: CCO
Agent: C=C(C)C#N
Agent: [Na]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1CN(c2ccc(Cl)cn2)N=C1N

Procedure:
As for Example 4 a 0.2 g. amount of sodium metal is dissolved in 50 ml. of absolute ethanol, then 5.0 g. of 5-chloro-2-hydrazinopyridine (Example 3) is added, followed by 4.8 g. of methacrylonitrile. The reaction mixture is refluxed for 18 hours. The solvent is removed in vacuo and water is added to give a gum which solidifies. The solid is collected by filtration, and washed with water. The solid is dissolved in dichloromethane, dried over magnesium sulfate and filtered through anhydrous magnesium silicate. The filtrate is evaporated and the residue is triturated with hexane to give a brown solid. The solid is dissolved in dichloromethane and hexane is added while concentrating to separate a solid. The mixture is cooled and filtered to give 3.4 g. of a gray solid. The desired product is recrystallized from dichloromethane-hexane to give a white solid, m.p. 159°-160° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:19]=[CH:20][C:21]=2[OH:22])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37].[Cl-].[NH4+]>CN(C)C=O>[C:36]([O:39][CH2:40][CH2:41][O:22][C:21]1[CH:20]=[CH:19][C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=2)=[CH:17][C:16]=1[C:7]1[CH:8]=[CH:9][C:10]([N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
850 mg (1.9 mmol) of ethyl 3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate (obtained in Example 1d) are dissolved in dimethylformamide under nitrogen. 92 mg (2.3 mmol) of 60% sodium hydride are added. After 20 minutes at room temperature, 0.25 mL (2.3 mmol) of 2-bromoethan-1-ol acetate are added and the mixture is stirred for 24 hours at room temperature and then poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and then dried and evaporated. The residue obtained is purified by chromatography on silica gel (eluent: 70/30 heptane/ethyl acetate). 1 g of ethyl 4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate is obtained (yield=99%) in the form of a colorless oil.
Reaction SMILES: [OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.C([N:25]=C=NCCCN(C)C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH2:25])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: 25 °C
Yield: 11.8 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-7-yl)-2-naphthoic acid (449 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide•hydrochloride (321 mg) and 1-hydroxy-1H-benzotriazole•monohydrate (301 mg) were dissolved in DMF (7.6 ml), and diisopropylethylamine (216 mg) was added with stirring under ice cooling. The mixture was allowed to warm to room temperature and stirred for 18 hr. Silica gel (3 g) was added to the reaction mixture and the mixture was concentrated under reduced pressure to dryness. The obtained residue was purified by silica gel column chromatography (developing solution: chloroform/7% aqueous ammonia-containing methanol:19/1). The eluate was concentrated to dryness, and the residue was recrystallized from ethanol to give the title compound (53 mg).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Br:5])/[Br:3].Cl.[F:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(N(CC)CC)C>C(O)C>[Br:3][C:2]1[C:1](=[O:9])[N:19]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=2)[N:20]=[CH:6][C:4]=1[Br:5]
Reactant: NNc1cc(F)cc(F)c1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c(Br)c(Br)cnn1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Mucobromic acid (2.8 g, 0.011 moles) was dissolved in ethanol (75 ml) and 3,5-difluorophenyl hydrazine hydrochloride (1.8 g, 0.01 moles) was added. After 30 minutes, triethylamine (1.4 ml, 0.01 moles) was added. The reaction mixture was stirred at room temperature for 3 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (80 ml). Refluxed with stirring overnight to give a brown solution. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (3.4 g, 93%)
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:28]([OH:29])=[CH:27][C:21]4[N:22]([CH3:26])[C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)(O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1(C2C(O)=CC3ON=C(C)C=3C=2)C2C(=CC=CC=2)N(CC2C=CC(OC)=CC=2)C1=O>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:28]([OH:29])=[CH:27][C:21]4[N:22]([CH3:26])[C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cn1c(=O)oc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Agent: COc1ccc(CN2C(=O)C(O)(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Product: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21

Procedure:
Following the procedure as described in PREPARATION 9B, and making non-critical variations using 6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one, 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (98%) as a yellow amorphous solid: MS (ES+) m/z 463.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH2:11]([Si:13]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH3:12].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[OH:18][CH2:17][CH2:16][C:15]1[C:3]2[C:2](=[CH:9][CH:8]=[C:5]([C:6]#[N:7])[CH:4]=2)[NH:1][C:14]=1[Si:13]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:11][CH3:12]
Reactant: CC[Si](C#CCCO)(CC)CC
Reactant: N#Cc1ccc(N)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCO
Yield: 51.8 %

Procedure:
4-amino-3-iodobenzonitrile (1.65 g; 5.61 mmol), 4-(triethylsilyl)but-3-yn-1-ol (1.57 mL; 7.44 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.276 g; 0.338 mmol), lithium chloride (0.287 g; 6.76 mmol), sodium carbonate (1.43 g; 13.52 mmol) in DMF (14 mL) was stirred at 100° C. for 15 hours. The solution was filtered through celite, diluted in ethyl acetate, washed with brine and sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 20% ethyl acetate in heptane) to yield 0.873 g (43%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(CCCCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 5-phenylpentanoic acid (257 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (471 mg, 69%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].ClC1C(C(F)(F)F)=CC=CC=1C(Cl)=O.NC1C(F)=CC=CN=1>>[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:7]1[CH:2]([CH3:1])[CH2:3][C:4]2[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[N:8][C:5]=2[CH2:6]1)=[O:22]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CC1Cc2c(nnn2-c2ncccc2F)CN1
Agent: Nc1ncccc1F
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Product: CC1Cc2c(nnn2-c2ncccc2F)CN1C(=O)c1cccc(Cl)c1Cl

Procedure:
Example 161 was prepared from 6-methyl-1-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine using the conditions described in Example 63 Step 5 substituting 2,3-dichlorobenzoyl chloride for 2-chloro-3-(trifluoromethyl)benzoyl chloride. 6-Methyl-1-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine was made using the route described in Example 116 beginning from 2-amino-3-fluoropyridine instead of 2-aminopyridine in step A. Subsequent steps were carried out analogous to those described in Example 116 steps B-D. MS (ESI) mass calcd. C18H14Cl2FN5O, 405.06. m/z found, 406.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[NH2:13][C:4]1[C:3]([CH2:2][NH2:1])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(CN)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(CN)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
A mixture of methyl 3-(aminomethyl)-2-nitrobenzoate (8.0 g, 38.3 mmol) and 5% Pd/C (0.9 g, 5%) in methanol (500 mL) was stirred at room temperature for 12 hours. The mixture was filtered and the filter cake was washed with methanol. The solvent was removed in vacuo to obtain methyl 2-amino-3-(aminomethyl)benzoate (5.0 g, 72% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][C:29]([F:32])([F:31])[F:30])[CH:26]=2)[N:21]([NH2:33])[CH:20]=1)[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:17]([C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][C:29]([F:30])([F:32])[F:31])[CH:26]=2)[N:21]([NH:33][C:14]([C:10]2[C:11]([CH3:13])=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:16])[CH:20]=1)[CH3:18]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(OC(F)(F)F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(OC(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of 2-(2-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid (250 mg, 1.1 mmol) and 3-ethyl-5-trifluoromethoxy-indol-1-ylamine (244 mg, 1.0 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1.0 mmol) and stirred at 50° C. for 1 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 10 min. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethoxy-indol-1-yl)-amide (300 mg, 68%). MS: 442 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.81 (d, 1H), 8.47 (d, 1H), 8.03 (m, 1H), 7.57 (m, 3H), 7.47 (s, 1H), 7.21 (d, 1H), 2.78 (s, 3H), 2.74 (q, 2H), 1.29 (t, 3H).