Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O-:7])=[O:6].[K+].[CH:13]([CH:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:14].CS(C)=O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH:15]([CH:13]=[CH2:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: O=C([O-])c1cc(O)cc(O)c1
Reactant: C=CC(Cl)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CC(OC(=O)c1cc(O)cc(O)c1)c1ccccc1
Yield: 83.6 %

Procedure:
129.4 g of potassium 3,5-dihydroxybenzoate and 102.7 g of vinylbenzyl chloride were added to 700 ml of dimethylsulfoxide and stirred and reacted at 40° C. for 4 days. Then, 1,500 ml of water was added thereto, and the resulting mixture was extracted with 500 ml of ethyl acetate. After distilling off ethyl acetate, recrystallization of the residue from an ethyl acetate-toluene mixture solvent yielded 152 g of vinylbenzyl 3,5-dihydroxybenzoate (m.p. 117°-119° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Br:10])[C:3]=1[CH3:11].CS(C)=O.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1Cl>C1(C)C=CC=CC=1>[Br:10][C:4]1[C:3]([CH3:11])=[C:2]([CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][C:28]1[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=1[Cl:22])[NH2:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)c(C)c(Br)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Into a dry 250 milliliter round bottom flask equipped with a magnetic stirrer and nitrogen inlet was added 4-amino-2-bromo-3,6-dimethylphenol (11.94 grams, 55.3 mmol) prepared in Part B and dry dimethylsulfoxide (118 milliliters). Potassium t-butoxide (7.26 grams, 64.65 mmol) was added portionwise under nitrogen and the mixture was stirred at room temperature for 0.5 hours. Solid 3,4-dichloronitrobenzene (13.33 grams, 70.52 mmol) was then added and the reaction mixture was heated at 50° C. for 48 hours. After cooling the mixture was diluted with toluene and washed successively with saturated NH4Cl solution (3x) and with 5% NaOH solution until the aqueous washes remained colorless. This was followed by washes with water and brine, drying over Na2SO4 and solvent removal under reduced pressure to afford the crude product (9.4 grams) as a dark red-brown oil. Flash column chromatography on 650 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 3-bromo-4-(2 -chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.6 mmol, 23%) as a yellow-brown solid. H'-NMR (CDCl3) 8.42 (d, J=2 Hz, 1H), 8.01 (d,d; J=2, 9 Hz; 1H), 6.55 (d, J=9 Hz, 1H), 6.58 (S, 1H), 3.73 (brS, 2H), 2.28 (S, 3H), 2.06 (S, 3H).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOCC>[C:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:8][CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[CH:12][CH:13]=1)#[N:19]
Reactant: N#CCc1ccc(Br)cc1
Reactant: C=C(C(=O)OC)C(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O

Procedure:
A stirred mixture of methyl 3-hydroxy-2-methylenebutanoate (19.5 g), 2-(4-bromophenyl)acetonitrile (40 g), PdOAc2 (2 g), tetrabutylammonium bromide (40 g) and NaHCO3 (31.5 g) in THF (300 ml) was heated under N2 at reflux for 24 h. The mixture was cooled, diluted with ether (500 ml) and filtered through celite. The filtrate was washed with water, dried and evaporated under reduced pressure to give an oil, used crude in next step.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:41][CH:42]=1
Reactant: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 110.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.55 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 95:5).
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23](O)[C:24]([CH3:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:16]([O:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:23]2[C:24]([CH3:31])=[C:25]([CH:30]=[C:21]([Cl:20])[CH:22]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:7][CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (5.36 mL, 22.93 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (4.0 g, 19.94 mmol), and cesium carbonate (9.74 g, 29.9 mmol) was added N,N-dimethylformamide (DMF) (100 mL). The suspension was stirred at RT for 15 min, then heated at 65° C. under nitrogen septum for 3 days. The reaction was allowed to cool to RT and was poured into ice/saturated NH4Cl (500 mL). The mixture was neutralized with 1 M HCl and extracted with 1:1 EtOAc/ether (2×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated. The resultant liquid was dried under high vacuum for 2 h. Purification of the residue by flash chromatography (200 gram Isco silica column, 4-50% ether/heptane) gave methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)oxy)-5-chloro-2-methylbenzoate (1.87 g, 4.70 mmol, 23.57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.48 (m, 13 H) 1.80 (d, J=10.61Hz, 2 H) 1.98-2.07 (m, 2 H) 2.25 (s, 3 H) 3.23-3.33 (m, 1 H) 3.82 (s, 3 H) 4.30-4.45 (m, 1 H) 6.86 (d, J=7.58 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.35 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 420.1 (Na adduct).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[C:10]1([Mg]Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]
Reactant: Cn1ncc(Br)c1C=O
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-methyl-2H-pyrazole-3-carbaldehyde (1.00 g; 5.29 mmol) is dissolved in 5.0 ml of anhydrous THF and cooled down to −78° C. Phenylmagnesium chloride 2 mol/l (6.61 ml; 13.2 mmol) is added and the reaction mixture is stirred for 1 hour. It is warmed up to 0° C. and is quenched carefully with water, then extracted with DCM. The organic layers are pooled, dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[N:27][CH:28]=2)[CH2:21][NH2:22])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([N:17]1[CH2:16][CH2:15][CH:14]([O:13][CH3:12])[CH2:19][CH2:18]1)[C:23]1[CH:24]=[N:25][C:26]([CH3:29])=[N:27][CH:28]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: COC1CCN(C(CN)c2cnc(C)nc2)CC1
Product: COC1CCN(C(CNC(=O)c2cccc(Cl)c2Cl)c2cnc(C)nc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxypiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C[Al](C)C.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30](OC)=[O:31])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:30]([C:26]2[S:27][CH:28]=[CH:29][C:25]=2[NH:24][CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[CH:14][CH:15]=2)=[O:31])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: COC(=O)c1sccc1NCc1ccnc2ccccc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3 phenylenediamine (5.43 g, 50.3 mmol) in anhydrous toluene (100 mL) was added AlMe3 (2M in toluene, 7.5 mL, 15.1 mmol) and the solution was stirred at rt overnight. Methyl 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate (3 g, 10.05 mmol) was added and the mixture was stirred at 130° C. for 3 h. The reaction mixture was cooled to rt and the toluene was decanted. To the remaining residue, 50 mL of 2N NaOH and 100 mL of CH2Cl2 were added and the solution stirred for 30 min. The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The toluene and CH2Cl2 layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (50% hexanes:ethyl acetate→100% ethyl acetate) followed by trituration of the solid with CH2Cl2 yielded pure N-(3-aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as a tan powder. MS (ES): m/z 374.86 (100) [MH+]; 1H NMR (DMSO-d6, 400 MHz): δ 4.98-4.50 (m, 2H), 5.04 (d, J=5.6 Hz, 2H), 6.25 (d, J=7.2 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.79 (d, J=5.6 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.96-6.97 (m, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.78 (t, J=6.8 Hz, 1H), 8.00-8.05 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.82 (d, J=4.4 Hz, 1H), 9.08 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:21][C:22]([CH3:25])([CH3:23])[N:26]=[C:18]23)=[CH:6][CH:7]=1
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Reactant: CC(C)(N)CN
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccc(F)cc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (25 g) (Step 1 of Example 2), 2-methyl-1,2-diaminopropane (40 mL), and toluene (125 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was slurried with ethanol. The solid was collected by filtration and dried to give the title compound (26 g) as a white solid, m.p. 168-170° C. Anal. for C19H17N2O2F: Calculated: C, 70.35; H, 5.28; N, 8.64. Found: C, 70.16; H, 5.35; N, 8.55.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[CH2:1]([N:8]1[C:12]([NH:13][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(Cc2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(Cc2ccccc2)n1
Yield: 61.4 %

Procedure:
Following the procedure in Example 118A, 1-benzyl-3-tert-butyl-1H-pyrazol-5-amine (666 mg, 2.64 mmol) and phenyl chloroformate (1.0 mL, 8.0 mmol) to give phenyl 1-benzyl-3-tert-butyl-1H-pyrazol-5-ylcarbamate (565 mg, 1.62 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 7.43-7.10 (m, 10H), 6.14 (s, 1H), 5.29 (s, 1H), 1.22 (s, 9H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][NH:8][CH3:9].[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:8]([CH3:9])[CH2:7][C:6]2[S:5][C:4]3[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=3[C:2]=2[CH3:1])=[O:25])=[CH:17][CH:16]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)sc2ccccc12
Reaction time: 16 h
Yield: 72.2 %

Procedure:
To a stirred solution of 3-methyl-2-(methylaminomethyl)benzo[b]thiophene (0.30 g, 1.6 mmole) in 1:1 DMF/CH2Cl2 was added (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.33 g, 2 mmole), HOBt.H2O (0.27 g, 2 mmole), and DCC (0.41 g, 2 mmole). The reaction was stirred for 16 hr, then was concentrated under vacuum. The residue was taken up in CHCl3, washed with H2O, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (4% methanol/CHCl3) gave the title compound (0.39 g, 72%) as a pale yellow solid: LCMS (ES) m/e 338.2 (M+H)+.
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]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][NH: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]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccc2)c1NCCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (1.26 g) was dissolved in DMF (10 ml), NaH (0.25 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. 1-Bromo-3-methoxypropane (0.83 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-4:6) was concentrated under reduced pressure to give the object compound (1.1 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])N)=[CH:25][C:24]=2[CH3:32])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][NH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[OH-:34].[Na+]>CO>[N:19]1[NH:20][N:21]=[N:22][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:34])=[O:31])=[CH:25][C:24]=3[CH3:32])[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-c3nn[nH]n3)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-c2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To 3-{1-(4-carbamoyl-2-methyl-phenyl)-5-[4-(2H-tetrazol-5-yl)-phenyl]-1H-pyrrol-2-yl}-propionic acid ethyl ester 26B (25 mg, 0.055 mmoL) in MeOH (2 mL) was added aq. sodium hydroxide (15%, 0.5 mL). The reaction mixture was allowed to stir at rt for 16 h. The reaction mixture was poured into 20 mL ice-water solution which was extracted with diethyl ether (2×10 mL). The aqueous layer was acidified with aq HCl (2 N) to pH=1-2, and then was extracted with diethyl ether (6×10 mL). The combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to yield the desired target 4-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-(2-carboxyethyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (26D) (15 mg, 65%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:29][C:30]1[S:34][CH:33]=[N:32][CH:31]=1>>[CH3:29][C:30]1[S:34][C:33]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:32][CH:31]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12f and 5-methylthiazole
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13]([CH2:16][NH:17]S(C(C)(C)C)=O)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[ClH:41].O1CCOCC1>CO>[ClH:41].[NH2:17][CH2:16][C:13]1[S:12][C:11]([C@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]2[CH:36]=[CH:35][C:31]3[N:32]=[CH:33][S:34][C:30]=3[CH:29]=2)(=[O:27])=[O:26])[CH2:9][OH:8])=[CH:15][CH:14]=1
Reactant: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(CNS(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)CN([C@H](CO)c1ccc(CN)s1)S(=O)(=O)c1ccc2ncsc2c1
Reaction time: 5 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-{[(tert-butylsulfinyl)amino]methyl}thiophen-2-yl)ethyl]-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide (1.12 g, 1.74 mmol) in MeOH (8.7 mL) was added 4 N HCl in dioxane (5.0 mL, 20 mmol) and the reaction mixture was stirred for 5 hours. The reaction was concentrated under reduced pressure and concentrated from heptanes. The product was use as such in the next step.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:18]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A solution of tert-butyl 3-aminopyrrolidine-1-carboxylate (1.5 g; 8.05 mmol; 1.00 eq and 3,4-dichlorobenzaldehyde (1339.00 mg; 7.65 mmol; 0.95 eq.) in methanol (10.00 ml) and acetic acid (1.00 ml) was stirred for 30 minutes at ambient temperature, then sodium cyanoborohydride (9.66 ml; 9.66 mmol; 1.20 eq.) was added. The reaction mixture was stirred for an additional 12 hours at ambient temperature at which time the reaction was quenched by pouring into aqueous ammonia (30 mL). The resulting inorganic precipitate was filtered off, and washed with dichloromethane (50 mL). The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resultant oil is purified under flash chromatography using silicon column with gradient of ethyl acetate in hexanes to afford the desired intermediate, tert-Butyl 3-((3,4-dichlorobenzyl)amino)pyrrolidine-1-carboxylate (2.47 g; 7.16 mmol; 88.9%), as a clear viscous oil. LC-MS (M+H=346, obsd.=288 (M-57))
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:36][CH2:35][C:24]4([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:36][CH2:35][C:24]4([CH2:25][NH:26][CH2:27]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:38])[F:37])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC2(CNC2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
(Z)-tert-Butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (0.05 g) was dissolved in DCM (20 mL), cooled to 0° C. and CF3COOH (0.5 mL) was added. The reaction mixture was stirred at room temperature for 4 h, concentrated under reduced pressure (35° C., 20 mmHg) to give (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (0.03 g, 95% yield). 1H NMR (400 MHz, DMSO) δ=9.25 (s, 1H), 8.77 (brs, 1H), 8.59 (s, 2H), 8.30 (s, 1H), 7.39-7.37 (d, 1H, J=10.4 Hz), 6.15-6.12 (d, J=10.4 Hz, 1H), 3.86-3.65 (brs, 4H), 2.14 (s, 2H), 1.49 (s, 2H), 0.85-1.23 (m, 2H); LCMS calcd. for C19H18F6N5O [M+H]+ 446.36. found 446.12 at retention time 2.161 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH:10]=[O:11])=[CH:4][C:3]=1[CH3:18].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C)c(C=O)c(-c2ccc(F)c(C)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(CO)c(-c2ccc(F)c(C)c2)c1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
2.90 grams (12 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzaldehyde (prepared according to Stokker, Jour. Med. Chem. Vol. 29 p.170, 1986) was reduced with 0.454 grams (12 mmol) of sodium borohydride in ethanol (20 mL) at 0° C. The reaction was stirred 1 hr, quenched with aqueous ammonium chloride and the mixture extracted with ether. The organic portion was dried (MgSO4) and concentrated to give 2.90 grams of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl alcohol as an oil which solidified on standing. The crude solid was treated with 1.31 mL of thionyl chloride and heated on a steam bath for 1 hour. After cooling to room temperature, the crude mixture was taken up in water and extracted with ether. The ether was washed with water and dried(MgSO4), and concentrated to give an oily residue which was purified by silica gel chromatography (25% methylene chloride/75% hexane) to give 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride as a solid.