Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH:34]([N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1)([CH3:36])[CH3:35]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:46]1[CH2:45][CH2:44][CH:43]([N:40]2[CH2:39][CH2:38][N:37]([CH:34]([CH3:36])[CH3:35])[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)=[O:8]
Reactant: CC(C)N1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(C)C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-isopropyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][Si](C(C)(C)C)(C)C)[CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([OH:34])[CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O[Si](C)(C)C(C)(C)C)cc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
1.50 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-6-(tert-butyldimethyl-silanyloxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester in solution in 35 ml of tetrahydrofuran with 770 mg of tetrabutylammonium fluoride hydrate are stirred at ambient temperature. After stirring for 1 h 30 min, the medium is diluted with dichloromethane and the organic phase is then washed with distilled water. After drying over magnesium sulfate and filtration, the solvent is evaporated off under vacuum in a rotary evaporator to obtain 1.05 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-6-hydroxy-1H-indol-2-yl)indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:37]1([NH:36][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=2)[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1cn(C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)Nc1ccccc1)Cc1cn(C)c2ccccc12
Reaction time: 16 h

Procedure:
A mixture consisting of 43.2 mg of 4-[N'-methyl-N'-(3,5-bis-trifluoromethyl-benzoyl)-amino]-5-(1-methyl-indol-3-yl)-pentanoic acid, 8.9 mg of aniline, 36.65 mg of propanephosphonic acid anhydride, 60 μl of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 16 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.547 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24]CC)=[O:23].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 0.33 h

Procedure:
A solution of 5.3 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in 30 ml of dimethylformamide is added dropwise to a suspension of 0.65 g of sodium hydride (50% suspension in oil) in 30 ml of dimethylformamide. After stirring for 20 min, 1.4 ml of ethyl bromoacetate is added. The reaction mixture is stirred for 1 hr, poured into water and the precipitate is collected. The precipitate is added to 30 ml of 15% sodium hydroxide solution and 30 ml methanol and heated at reflux for 3 hr. The mixture is poured into water, acidified and filtered. Recrystallization from toluene and acetonitrile gives {[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid, mp 207° C.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].CC([O-])(C)C.[K+].[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Cl>CN(C=O)C>[CH2:1]([S:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=2[CH3:19])[C:8](=[O:12])[CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CSc1cc[nH]c(=O)c1
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cn2ccc(SCC(C)C)cc2=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
A mixture of 100 mg of 4-(isobutylthio)pyridine-2(1H)-one, 2 ml of DMF, 65 mg of t-BuOK was stirred at room temperature and 105 mg of 2-methyl-3-nitrobenzyl chloride was added. After 3 hour, the resulting solution was evaporated, extracted with dichloromethane and subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain the compound (90 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].N#N>CO.C1COCC1>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][C:6](=[O:26])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
(1-Benzyl-6-bromo-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (2.00 g, 4.79 mmol), prepared as described in Example 29A, 4-fluorophenyl-boronic acid (2.01 g, 14.37 mmol) and K2CO3 (2.65 g, 19.16 mmol) in a mixed solvent of THF (50 mL) and MeOH (25 mL) were stirred at RT for 30 min while N2 was allowed to bubble through the mixture, and then PXPd (258 mg, 0.48 mmol) was added. The reaction mixture was heated at 60° C. under N2 for 3 h. After cooling to RT, the solvent was stripped and the residue was diluted with H2O (60 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted with CH2Cl2 (100 mL×3), and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried (Na2SO4), filtered and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (1.11 g, 54%) as a white foam.
Reaction SMILES: [BrH:1].Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:5]=1[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1)=[O:18]>Br>[BrH:3].[BrH:1].[CH2:41]([N:38]([CH2:39][CH3:40])[CH2:37][CH2:36][N:19]([CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1)[C:17](=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:5]1[CH:4]=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=1)[CH3:42]
Reactant: CCN(CC)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1cc(OC)ccc1Br
Agent: Br
Product: CCN(CC)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1cccc(O)c1
Temperature: 100 °C

Procedure:
The product from Example 21 part f) was suspended in 48% aq HBr (1 ml) and heated in a microwave at 100° C. for 30 min. The resulting solution was evaporated, azeotroped with ethanol (×2) to give a residue which solidified on standing. The solid was triturated with acetonitrile and the white solid collected by filtration which was further purified by reverse phase HPLC. The desired product fractions were evaporated in vacuo, the residue dissolved in ethanol and conc. Aq. HBr (1 ml) was added. This solution was evaporated in vacuo and the residue azeotroped with ethanol (×5). The resulting solid was triturated with ethanol and collected by filtration to give the title compound as a white solid (10 mg).
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:5][CH:4]([CH:6]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:28]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:30]=[CH:29]3)=[CH:26][CH:27]=2)[C:7]2[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O.O1CCCC1.O.[OH-].[Li+]>CO>[F:37][C:2]1([F:1])[CH2:5][CH:4]([CH:6]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:28]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:30]=[CH:29]3)=[CH:26][CH:27]=2)[C:7]2[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C([O-])CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a flask containing 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate (7.00 mg, 0.0100 mmol) was added water (0.0650 mL), tetrahydrofuran (0.0650 mL), and methanol (0.0650 mL). Lithium hydroxide monohydrate (27.3 mg, 0.650 mmol) was then added. The suspension was stirred at room temperature for 2 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+/−)-3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid (4.5 mg, 70%) of a glass-like material. 1H NMR (400 MHz, CDCl3) δ 8.36-8.34 (m, 1H), 8.16-8.12 (m, 1H), 7.86 (d, J=2.9 Hz, 1H), 7.84-7.77 (m, 2H), 7.58-7.51 (m, 2H), 7.39 (dd, J=8.8, 0.6 Hz, 1H), 7.10 (dd, J=8.8, 2.9 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 3.63 (t, J=6.9 Hz, 2H), 2.94-2.73 (m, 1H), 2.64 (t, J=6.9 Hz, 2H), 2.61-2.49 (m, 2H), 2.49-2.33 (m, 2H). MS (M+1): 524.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26](OC)=[O:27].N1CCCN2CCCN=C12>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][N:22]([CH:26]=[O:27])[CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCNCC2
Reactant: COC=O
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: O=CN1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1

Procedure:
A solution of 8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (0.1 g, 0.3 mmol), methyl formate (22 mg, 1.2 mmol), and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (2.1 mg, 0.015 mmol) in toluene (3 mL) was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated potassium bisulfate (5 mL). The solution was extracted with ethyl acetate (3×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 362 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.27-8.23 (m, 1H), 8.20-8.18 (d, J=6.24 Hz, 1H), 7.79-7.78 (m, 1H), 7.62-7.59 (m, 1H), 7.38-7.32 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.07 (m, 1H), 4.57-4.49 (m, 2H), 3.94-3.84 (m, 2H), 3.75-3.65 (m, 2H), 3.28-3.19 (m, 2H). mGluR5 PAM EC50: +++. Fold shift at 10 μM: ++.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[NH4+].[Cl-]>C1COCC1>[CH3:11][N:12]1[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][C:17]1([CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:18]
Reactant: BrC=Cc1ccccc1
Reactant: CN1C(=O)CCCC1=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(O)C=Cc1ccccc1

Procedure:
The Grignard reagent prepared in 300 ml of THF from 24 g (1.0 mole) of magnesium and 42 g (0.30 mole) of β-bromostyrene is decanted from excess metal and added dropwise under nitrogen to a solution of 27 g (0.21 moles) of N-methyl glutarimide at 3°-5°. After 1 1/2 hrs. at room temperature, the mixture is treated with 250 ml of saturated NH4Cl solution with cooling. The separated aqueous layer is reextracted and the combined THF extracts washed with salt, dried over MgSO4 and freed of solvent. Product is extracted into hot ether and crystallized on cooling to yield white crystals, mp 108°-112°C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=O)[NH:32][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=[S:10])[NH:32][C:26]=2[CH:25]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1n[nH]c2c(=S)[nH]c3cc(Cl)ccc3c(=O)c12
Yield: 82 %

Procedure:
To a suspension of Lawesson's Reagent [(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(0.32 g, 0.80 mmol) in dry toluene (15 mL) at room temperature was added 7-chloro-3-(ethoxycarbonyl)pyrazolo-[3,4-c][1]benzazepine-4,10(1H,9H )-dione (0.51 g, 1.59 mmol) in one portion. The resulting slurry was heated to reflux for 1.5 hours. The reaction mixture was filtered to remove insoluble material. The filtrate was concentrated via rotary evaporator to give a green oil which was purified by flash chromatography using chloroform:methanol (9:1) as the eluent. The yellow-green solid recovered was recrystallized from methanol to give the title compound (0.44 g, 82%, mp 248.0-252.6° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1C=O)=[CH:12][C:11]([O:19][CH3:20])=[CH:10][CH:9]=3.[CH:23]([O:30][CH2:31]C)([O:27][CH2:28]C)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:31][O:30][CH:23]([O:27][CH3:28])[C:12]1[C:13]2[O:14][C:15]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:16]=3)[C:7]([CH3:21])([CH3:22])[C:8]=2[CH:9]=[CH:10][C:11]=1[O:19][CH3:20]
Reactant: COc1ccc2c(c1)Oc1c(ccc(OC)c1C=O)C2(C)C
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)Oc1c(ccc(OC)c1C(OC)OC)C2(C)C

Procedure:
A solution of 24.15 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde in 50 ml of absolute ethanol was treated with 50 ml of triethyl orthoformate. After the addition of 100 mg of p-toluenesulphonic acid monohydrate the mixture was boiled under reflux for 1 hour, then cooled and poured into ice-cold sodium bicarbonate solution, whereupon the mixture was extracted twice with 200 ml of ether each time. The combined extracts were washed neutral with water, dried over Na2SO4 and concentrated. The residue was purified on silica gel with hexane/ethyl acetate, whereby there were obtained 19.6 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde dimethyl acetal as a pale yellow oil which crystallized slowly; m.p. 60°-62°, IR 2972, 1606, 1572, 1490 cm-1.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][N:13]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][C:27]([CH3:29])=[N:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[N:16][N:17]=[C:12]2[CH:11]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=2)[CH2:10]1)(C(C)(C)C)(C)C.[H-].[Na+].[CH2:42]=[O:43].O>CN(C=O)C>[F:39][C:34]1[CH:33]=[C:32]([C:11]2([CH2:42][OH:43])[CH2:10][CH:9]([OH:8])[CH2:14][N:13]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:12]23)[CH:37]=[CH:36][C:35]=1[F:38]
Reactant: C=O
Reactant: COc1cc(-c2nnc3n2CC(O[Si](C)(C)C(C)(C)C)CC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CC(O)CC3(CO)c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
To a mixture of (6RS,8SR)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (209 mg) in DMF (1.9 mL) was added sodium hydride (60%, 16.6 mg) at 0° C., and the mixture was stirred for 10 min. Paraformaldehyde (18.1 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (1.9 ml) was added TBAF (1M THF solution, 0.756 ml), and the mixture was stirred at room temperature for 15 min. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (154 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[CH3:11].O.CN([CH:22]=[O:23])C>>[CH2:10]([O:12][C:13](=[O:17])[C@@H:14]([NH:15][C:22]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:23])[CH3:16])[CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)[C@H](C)N
Reactant: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)NC(=O)Nc1ccc(C#N)cc1
Reaction time: 72 h

Procedure:
A solution of 4-aminobenzonitrile (2.3 g, 0.0195 mol) and N,N′-carbonyldiimidazole (3.5 g, 0.332 mol) in DMF (20 ml) was heated at 80° C. for 7 hours (h). A solution of L-alanine ethyl ester (3 g, 0.0195 mol) in DMF (15 ml) was added and stirring was continued for 3 days (d) at 80° C. Water (300 ml) was added and the precipitate was filtered off (giving 750 mg of the dimer as side product). The solution was extracted with ethyl acetate to give 3 g of the title compound which contained the corresponding acid as side product. MS (mass spectrometry) peak was at 262.1 (M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:4]1[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.4 %

Procedure:
Methyl 1-ethyl-5-oxo-prolinate (1.91 g, 11.17 mmol) was dissolved in methanol (25 ml) and treated with 2M aqueous sodium hydroxide (7.3 ml, 14.52 mmol). The mixture was stirred for 4 hrs at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give a clear oil which crystallized on standing. Trituration with hexane and ether and drying gave pure 1-ethyl-5-oxo-proline (0.271 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]([C:34](=[O:35])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH:37]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(F)c(N)c1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(F)c(N)c1
Yield: 46 %

Procedure:
The title compound was prepared from the crude amine mixture of (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-3-amino-4-fluoro-benzenesulfonamide which is described earlier (example 53, step C) and (2S)-2-tert-butoxycarbonylamino-3,3-diphenyl-propionic acid using general procedure A. The crude residue was purified by semi-preparative HPLC in several batches of 80 mg using a gradient of 50 to 80% of acetonitrile over 30 min and a flow rate of 15 mL/min, retention time=20.2 min. All the pure fractions were combined to provide 630 mg (46% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:20]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCCCCCBr
Solvent: CS(C)=O
Product: CCCCCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Yield: 116.5 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with bromohexane (0.097 g, 0.585 mmol, 0.082 mL) as described in Example 21. Aqueous workup gave 1(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone 0.161 g (100% crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar-H), 6.82 (s, 1H, Ar-H), 4.02 (t, J=6.4 Hz, 2H, OCH2), 2.61 (s, 3H, CH3), 1.83 (m, 2H, CH2), 1.67 (app br d, 4H, 2CH2), 1.50 (m, 2H, CH2), 1.36 (m, 4H, 2CH2), 1.29 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.91 (t, J=7.0 Hz, 3H, CH3).