Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[CH3:15][N:16]([CH2:18][CH:19]1[C:25](=[O:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:17]>CCCCCC.C1COCC1>[CH3:17][N:16]([CH2:18][CH:19]1[C:25]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)([OH:26])[CH2:24][CH:23]2[CH2:27][CH:20]1[CH2:21][CH2:22]2)[CH3:15]
Reactant: CN(C)CC1C(=O)CC2CCC1C2
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C2(O)CC3CCC(C3)C2CN(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Add dropwise a solution of t-BuLi (19.2 mL, 25.0 mmol) in hexane via syringe to a solution of 1-bromo-3-methoxy-benzene (3.74 g, 20.0 mmol) in THF (60 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (1.81 g, 10.0 mmol) in THF (10 mL) to the reaction mixture and stir the resultant mixture at −78° C. for additional 1 hour. Quench the reaction with saturated aqueous NH4Cl solution (20 mL). Extract the aqueous mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (1.49 g, yield: 51%). MS (m/z): 290 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7]([S:9][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2cc(Cl)ccc21
Yield: 775.4 %

Procedure:
5.96 g (0.03M) of 5-Chloro-2-mercapto-1-methylbenzimidazole of C above, 0.5 g (0.03M) of α-bromophenylacetic acid and 6.0 g (0.06M) of triethylamine are dissolved in methylene chloride (200 ml) and the mixture heated to reflux overnight. The basic solution is washed with a diluted HCl solution and a white solid is collected. The crude material is recrystallized from 5 L of acetonitrile to give 6.0 g (60% yield) of the title compound, m.p. 203°-5° C. dec.
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-])=O)([CH3:13])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.[ClH:17]>CO.O>[ClH:17].[ClH:17].[NH2:14][C:2]([CH3:13])([CH3:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCN(CC(C)(C)[N+](=O)[O-])CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)N1CCN(CC(C)(C)N)CC1
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A solution of 1-(4-(2-methyl-2-nitropropyl)piperazin-1-yl)ethanone (7.2 g, 19.4 mmol) in a mixture of methanol and water (50:10 mL) was added to a steel pressure vessel equipped with a magnetic stir bar. The vessel was flushed with nitrogen while Raney nickel (50% aqueous suspension, 1.0 mL) was added in one portion. The vessel was sealed and pressurized with hydrogen (100 psi). The suspension was stirred for 5 min and the hydrogen released until the pressure was just above 0 psi. This was repeated once more and the vessel was finally pressurized to 500 psi. The reaction was stirred at room temperature for 17 h. The hydrogen was released and the suspension was filtered through Celite®. The solid was washed with small portions of water (5×40 mL) to give a colorless filtrate. The filtrate was brought to pH 2 with 6N HCl. The filtrate was concentrated in vacuo to a yellow oil. The oil was purified by Prep-LC utilizing a gradient of methanol and water with 0.05% acetic acid as a modifier. Fractions were pooled and concentrated to give foamy solid (6.91 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 1.33 (s, 6H), 2.12 (s, 3H), 2.58 (s, 2H), 2.63-2.72 (dt, J=4.8, 4H), 3.57-3.60 (m, 4H). LRMS (ESI+) for C10H21N3O (199.1); Found: 200 (MH+).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[C:32][CH2:33][O:34][Si](C(C)(C)C)(C)C)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([C:31]#[C:32][CH2:33][OH:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(C#CCO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(C#CCO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 59.7 %

Procedure:
To a solution of 167 mg (0.257 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-{6-[3-(tert-butyl-dimethyl-silanyloxy)-prop-1-ynyl]-4-o-tolyl-pyridin-3-yl}-N-methyl-isobutyramide in 1.5 ml tetrahydrofuran a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added at room temperature. After stirring for 0.5 h water was added, followed by extraction with four portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 82 mg (60%) of the title compound as a brown viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C@@H:16]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH3:17])[C:12]2[C:7](=[CH:8][C:9]([CH3:28])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]>C(O)C.[Pd]>[C:18]([C@H:16]([O:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([CH3:28])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=1)[CH3:17])([OH:20])=[O:19]
Reactant: COC(=O)c1cc(O[C@H](C)C(=O)OCc2ccccc2)c2ccc(C)cc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(O[C@H](C)C(=O)O)cc(C(=O)O)nc2c1
Reaction time: 18 h

Procedure:
To a solution of 1.80 g 4-((R)-1-Benzyloxycarbonyl-ethoxy)-7-methyl-quinoline-2-carboxylic acid methyl ester in 15 ml ethanol were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (5 bar) for 18 h. Then, the reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 1.30 g colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=1>>[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=2)[CH:6]=[CH:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc2c(ccn2-c2ccc(N3CCOCC3)cc2)c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(ccn3-c3ccc(N4CCOCC4)cc3)c2)cc1

Procedure:
Compound 376 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-morpholinophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C27H28N4O2: 441.22; found: 441.02.
Reaction SMILES: O[CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17](C)[N:16]=1>C1(C)C=CC=CC=1>[CH2:5]([O:4][P:3]([CH2:2][C:17]1[CH:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[N:16]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:6]
Reactant: CCOP(=O)(CO)OCC
Reactant: Cc1cc(C)nc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(C)cc(C)n1)OCC

Procedure:
A solution of diethyl hydroxymethylphosphonate (1 mmole)in toluene was treated with sodium hydride (1.1 mmole) at 0° C., and after 15 min 2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added. After 3 h the reaction mixture was subjected to extraction and chromatography to give 2-diethylphosphonomethyl-4,6-dimethylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C1(C)C=CC=CC=1>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(O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][N:22]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccc(F)nc2)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2.51 g (14.29 mmol) of 4-fluorophenylboronic acid, 0.825 g (0.71 mmol) of Pd(PPh3)4 and 50 mL of 1M sodium carbonate solution are added to a solution of 2.0 g (14.29 mmol) of 5-bromo-2-fluoropyridine in 140 mL of a 4/1 mixture of toluene and ethanol. The mixture is stirred at 90° C. for 2 hours.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2.N12CCN(CC1)CC2.CN(C)C=O.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([C:38]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:39])[C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2
Reactant: O=C(Cl)N1CCCC1
Reactant: Cn1c(=O)[nH]c2cnc(/C=C/c3ccccc3)nc21
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(/C=C/c3ccccc3)nc21
Reaction time: 1 h

Procedure:
To a mixture of 9-methyl-2-[(E)-2-phenylethenyl]-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 3> (100 mg), 1,4-diazabicyclo[2.2.2]octane (133 mg) and N,N-dimethylformamide (3 ml) was added dropwise 1-pyrrolidinecarbonyl chloride (106 mg) at room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added water (50 ml) and the mixture was extracted with ethyl acetate (80 ml×2). The organic layer was dried over anhydrous magnesium sulfate and was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜0/100) to give the title compound 56 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][CH:42]1[CH2:41][CH2:40][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:35][CH2:34]2)[CH2:44][CH2:43]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122 (see example 94) and amine 50.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:13][CH2:14]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CC2)c1Cl
Yield: 94 %

Procedure:
To a solution of 5-Chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (296 mg, 1.38 mmol) in methanol (15 mL) and water (15 mL) was added LiOH (40 mg, 1.66 mmol). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH=2 with concentrated HCl, and extracted with ethyl acetate. The organic extracts were evaporated in vacuo to give 5-chloro-1-cyclopropyl-1H-pyrazole-4-carboxylic acid (242 mg, 93%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[C:27]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.[ClH:35]
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4cccnc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and nicotinic acid chloride hydrochloride (70 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a hydrochloride.
Reaction SMILES: [CH2:1]([O:6][C:7](Cl)=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([NH2:26])=[N:23][CH:22]=[N:21][C:20]=3[N:19]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=2)=[CH:13][C:12]=1[O:33][CH3:34]>N1C=CC=CC=1.ClCCl>[NH2:26][C:24]1[C:25]2[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:7](=[O:8])[O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[C:12]([O:33][CH3:34])[CH:13]=3)=[CH:18][N:19]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1N
Reactant: CC(C)(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCC(C)(C)C
Reaction time: 0.17 h

Procedure:
Neopentylchloroformate(13 uL, 0.110 mmol) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25 mg, 0.074 mmol) in pyridine (0.7 ml) and dichloromethane (0.7 ml) under nitrogen at 0° C. After 10 minutes, the ice water bath was removed and the resulting mixture was stirred for 4 hours. The solvent was evaporated and the residue was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give neopentyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate. 1H NMR (CDCl3) δ 1.00 (s, 3H), 2.07 (m, 4H), 3.65 (m, 2H), 3.91 (s, 2H), 3.94 (s, 3H), 4.13 (m, 2H), 4.97 (m, 1H), 5.18 (s, 2H), 6.97 (s, 1H), 7.03 (s, 1H), 7.07 (d, J=8 Hz, 1H), 7.25 (s, 1H), 8.19 (br. s, J=8 Hz, 1H). 8.33 (s, 1H). LC/MS (MH+=454).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:5]=[N:4]1)[CH3:2].[CH3:22][O:23][CH:24]([O:32][CH3:33])[CH2:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:32][CH3:33])[O:23][CH3:22])[C:16](=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[CH:9]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCC1)OC
Product: CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCC3)c2)cn1

Procedure:
The subtitled compound (138 mg) was prepared from 3-(3-(1-ethyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 23 Step ii)] and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii), extending the reaction time to 1 h. MS [M+H-MeOH]+=412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 4.56 and 4.37 (2×t, J=5.1 Hz, 1H), 4.26-4.16 (m, 1H), 4.19 (q, J=7.4 Hz, 2H), 3.75-3.64 (m, 4H), 3.35 and 3.22 (2×d, J=4.9 Hz, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 2.84 (t, J=6.8 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.82-1.44 (m, 8H), 1.47 (t, J=7.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[OH:13].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13]
Reactant: Cc1ccccc1C1CCCCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccccc1C1CCCCC1=O
Yield: 54.6 %

Procedure:
To (cis/trans) 2-o-tolyl-cyclohexanol (1 g) in dichloromethane (30 ml) was added Dess-Martin periodinane (Aldrich 27,462-3) at room temperature. The reaction mixture was allowed to stir at room temperature for 16 hours before diethyl ether was added. The volume of solvent was reduced in vacuo to about one quarter of the initial amount. More diethylether (87 ml) was added and the solution was washed with a 10% solution of sodium thiosulfate (87 ml), a solution of saturated sodium bicarbonate (87 ml), brine (100 mL) and water (100 ml). The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was then purified by column chromatography to give 0.54 g of 2-o-tolyl-cyclohexanone MS (EI) 188.2 (M+).
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[F:28][C:3]1[C:2]([CH3:29])=[CH:26][CH:25]=[C:24]([F:27])[C:4]=1[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(C)c1F
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) ester (226 mg), tetrakis(triphenylphosphine)palladium (56 mg), trimethylboroxine (122 mg) and potassium carbonate (200 mg) in dioxane (5 mL) was heated to reflux with stirring for 6 h. The cooled was mixture was partitioned between water and ethylacetate. The water phase was extracted once with ethylacetate, organic phases were pooled and dried with Na2SO4 to yield after evaporation a dark oil (259 mg). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate gradient) to yield 160 mg (82%) of a yellow oil. MS (ISP): 416.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O.Cl[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:12]([C:13]([OH:15])=[O:14])[CH3:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(Cl)C(=O)O
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 40 °C

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety. N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40° C. and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p.=148-149° C.
Reaction SMILES: C(C1C=CC(COC2C=C([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])C=C(C)C=2)=CC=1)#N.Cl.C(=O)([O-])[O-].[NH4+].[NH4+]>C(Cl)Cl.C(O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([OH:21])(=[O:20])=[O:18]
Reactant: Cc1cc(OCc2ccc(C#N)cc2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 179.1 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(4-cyanophenyl)methoxy]-5-methylphenyl ester (414 mg, 1.0 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (20 mL) at 0° C. The mixture was stinred at room temperature for 2 days. The solvent was evaporated and the residue was co-evaporated with methylene chloride several times. The residue was then dissolved in ethanol (20 mL) and ammonium carbonate (385 mg, 4.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% K2CO3 (50 mL). The organic phase was washed with 50 mL of 10% K2CO3 and dried over K2CO3. The solvent was removed in vacuo. The residue was diluted with CH2Cl2, treated with HCl in methanol (30 mL), and concentrated. The residue was then purified by crystallization (methanol and ethyl acetate) to give the title compound as a white solid (345 mg, 74%). 1H-NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.16 (s, 2H), 6.53 (t, 2 H, J=9.3 Hz)), 6.86 (s, 1H), 7.55-7.62 (m, 3H), 7.82-7.89 (m, 4 H), 7.93 (d, 1H, J=4.0 Hz), 9.24 (br s,2 H) and 9.44 (br s, 2 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2ClO4S: 431.1 (M+H). Found: 431.1.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:34]=[CH:33][C:11]([O:12][CH:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][N:18]=3)[CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+].Cl>CO>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][N:18]=3)[CH2:14][CH2:15][CH3:16])=[CH:33][CH:34]=2)[CH:7]=1
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cn1
Temperature: 25 °C
Yield: 99 %

Procedure:
(+/−)-Ethyl 3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoate (45 mg, 0.089 mmol) was dissolved in methanol (2 mL). 1 M NaOH (2 mL) was added with stirring at room temperature. After stirring for 6 hours, 1M HCl (2 mL) was added. The pH was adjusted to approximately 4, using 1M HCl and 1M NaOH. The resulting cloudy solution was extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (+/−)-3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoic acid (42 mg, 100%) as a foamy solid. 1H NMR (400 MHz, CDCl3, δ): 9.23 (d, J=1.6 Hz, 1H), 8.38 (dd, J=8.2, 2.1 Hz, 1H), 7.99 (s, 1H), 7.85-7.80 (m, 2H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 6.92-6.85 (m, 2H), 5.31 (dd, J=7.7, 4.8 Hz, 1H), 3.83-3.76 (m, 2H), 2.75-2.69 (m, 2H), 2.09-1.85 (m, 2H), 1.60-1.39 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1): 477.3.