Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[C:31]2[O:30][CH2:29][CH2:28][O:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>C(Cl)Cl.O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][C:1]([NH:2][NH:3][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[O:27][CH2:28][CH2:29][O:30][C:31]=3[C:22]=2[CH3:21])=[O:33])=[O:4])=[CH:8][CH:9]=1
Reactant: COc1ccc(COC(=O)NN)cc1
Reactant: Cc1c(C(=O)Cl)ccc2c1OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)NNC(=O)c2ccc3c(c2C)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
17.85 g (90.98 mmol) of 4-methoxybenzyl carbazate was dissolved in 50 mL of CH2Cl2 in a 250 mL flask and then cooled in ice water. 21.42 g (155 mmol) of potassium carbonate dissolved in 80 mL of water was added. While the reaction mixture was being stirred in the ice bath, 17.0 g (79.95 mmol) of 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl chloride in 60 mL of CH2Cl2 were slowly added. The reaction mixture was stirred at room temperature overnight and then transferred to a separatory funnel with 200 mL of CH2Cl2 and 200 mL of H2O. After shaking, a floating white precipitate was filtered off, washed with water, dried in a vacuum oven to give 29.1 g of N′-(5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)hydrazinecarboxylic acid 4-methoxy-benzyl ester. The CH2Cl2 solution was dried and concentrated to give 5.19 g of a residue consisting of the original acid chloride, 4-methoxybenzyl carbazate, and some product. TLC Rf=0.38 (streak 1:1 ethyl acetate:hexane). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.4-6.7 (m, 6H), 5.139 (s, 2H), 4.279 (s, 4H), 3.81 (s, 3H), 2.303 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].CI.[CH3:14]N(C)C=O.[OH-].[Na+]>[Ag]=O.C(O)C>[CH3:14][O:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CN(C)C=O
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=[Ag]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CCO
Product: COc1c(C)cccc1C(=O)O

Procedure:
A mixture of 7.1 g. (0.05 mole) of 3-methylsalicylic acid, 23.1 g. (0.1 mole) of silver oxide and 25 ml. of methyl iodide in 150 ml. of N,N-dimethylformamide was stirred at 25° C. for 16 hours, then filtered. The filtrate was evaporated to provide a residue which was hydrolyzed by heating at 50° C. in an equivolume mixture of ethanol and 6N sodium hydroxide solution. The resulting mixture was acidified and filtered. The filtrate was evaporated, and the residue dissolved in base and treated with decolorizing charcoal. Acidification provided white solid 2-methoxy-3-methylbenzoic acid, m.p. 70°-75° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](O)([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][Si](C)(C)C>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([Cl:25])([C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)C(O)(c1ccc(OCc2ccccc2)cc1)C(C)(C)C
Solvent: CS(C)=O
Product: CC(C)(C)C(Cl)(c1ccc(OCc2ccccc2)cc1)C(C)(C)C

Procedure:
A reaction and post-treatment were conducted following the conditions of Example 71 using 5.40 g (13.65 mmol) of 4-benzyloxy-di-t-butylbenzyl alcohol, 80 ml of chlorotrimethylsilane, and 1.07 ml of dimethylsulfoxide, to obtain 4-benzyloxy-di-t-butylbenzyl chloride.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:24][CH:23]=1)=[O:17])[CH3:15])=[O:12])[CH3:10])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:54].[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33]([C:34]#[N:35])=[C:32]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:31]=[C:30]([S:41][CH2:42][C:43]3[N:44]=[C:45]([C:48]4[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=4)[S:46][CH:47]=3)[C:29]=2[C:55]#[N:56])=[CH:26][CH:27]=1)=[O:17])[CH3:15])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g (1.84 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-(tert-butoxycarbonyl)-L-alanyl-L-alaninate (Example 7A) were initially charged in 24 ml of dichloromethane. 18.37 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the reaction solution was then stirred at RT overnight. The solid formed was filtered off and washed with diethyl ether. This gave 1.44 g (97% of theory, purity about 94%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:12][C@H:10]1[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (20.05 g, 107 mmol, MC09PH1559, Pharmacore) and triethylamine (22.34 mL, 161 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (200 mL) was cooled to −30° C. and methanesulfonyl chloride (9.94 mL, 129 mmol, Sigma-Aldrich Chemical Company, Inc.) was added dropwise over 20 min period. The mixture was stirred at room temperature for 12 h, washed with 200 mL water, then 200 mL 10% aq. citric acid followed by brine, dried over Na2SO4 and evaporated to give the title compound (29 g, 109 mmol, 102% yield). It was used in the next step without further purification.
Reaction SMILES: CC1C=CN=C(N[C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[CH:29]=1>>[CH3:21][C:19]1([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17][B:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:34][C:30]3[CH:29]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:33]=[CH:32][N:31]=3)=[O:25])=[CH:11][CH:12]=2)[O:20]1
Reactant: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Yield: 89 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 6, starting from 4-(trifluoromethyl)pyridin-2-amine, to afford the title compound (657.2 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:18]=[N+:19]=[N-:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-chlorobenzoyl)benzyl bromide (4.36 g, 14.1 mmol) and sodium azide (1.32 g, 20.3 mmol) in ethanol (40 ml) was refluxed 5 hours, cooled to ambient temperature, and stirred 16 hours. The mixture was filtered and the solids were washed twice with ethanol and once with diethyl ether. The combined filtrate and washes were evaporated under vacuum to provide 3.63 (95%) of 4-(4-chlorobenzoyl)benzyl azide, m.p. 71°-73° C.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:50]([C:49]1[CH:53]=[CH:54][C:46]([F:45])=[CH:47][CH:48]=1)=[O:51]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])=[N:8]1>O1CCCC1>[CH3:6][C:7]1([CH3:20])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH2:19][CH2:1][C:2]2[CH:14]=[CH:13][CH:12]=[C:17]([CH3:16])[C:3]=2[CH3:4])=[N:8]1
Reactant: Cc1ccc(C2=NC(C)(C)CO2)c(C)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=NC(C)(C)CO2)c(CCc2cccc(C)c2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (6.9 ml of a 2.5M soln in hexanes) was added dropwise to the product of example 21 step (i) (3.51 g) in tetrahydrofuran (60 ml) at -78° C. After 2 hours the product from step (i) (3.45 g) was added. After 1 hour the solution was left to warm to room temperature. The solution was quenched with water and extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Yield 1.83 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=1[C@H:18]1[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:21]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:19]1.O>C1COCC1>[CH2:25]([O:24][C@@H:23]1[C@@H:22]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:21]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:19][C@H:18]1[C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][C:8]=1[CH3:7])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(C)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Lithium aluminum hydride (73 mg) was added to a solution of methyl 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzoate (1.3 g) in THF (10 ml) at 0° C. and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water and the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[5-(hydroxymethyl)-2-methylphenyl]-D-glucitol (1.0 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:17][C@H:16]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1>[Pd].O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:28]([C@@H:16]1[CH2:17][CH:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:19][CH2:20][NH:15]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NC1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F

Procedure:
3.0 g of 10% palladium catalyst on carbon are added to a solution of 19.3 g (39.4 mmol) of (2R,4RS)-N-(1,2-dibenzyl-4piperidyl)trifluoroacetamide trifluoroacetate in 160 ml of dioxane under nitrogen, and hydrogenation is carried out under atmospheric pressure at room temperature. The reaction mixture is freed of catalyst over Celite® and the residue is washed with dioxane. The filtrate is evaporated to dryness and dried under high vacuum, resulting in the title compound which is used further without further purification; TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.24 and 0.3 (two poorly separated diastereomers)
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)[O:23][CH3:29])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 277B (100 mg, 0.287 mmol) in THF (2 mL) was treated with NaH (95%, 8.7 mg, 0.344 mmol). After stirring at room temperature for 20 minutes, the mixture was treated with methyl iodide (1.2 eq, 21.4 μL) and stirred for 1 hour. The mixture was concentrated under reduced pressure and CH2Cl2 (10 mL) was added. The organic layer was washed with water (5 mL×3), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 363 (M+H)+; MS (ESI−) m/z 361 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers 67 1.25 (s, 9H), 3.32 (s, 3H), 4.27 (d, J 6.1, 2H), 5.37 (s, 1H), 7.18 (d, J 8.5, 2H), 7.32 (d, J 8.5, 2H), 7.70 (t, J 7.1, 1H), 7.83 (d, J 6.1, 1H), 8.07 (m, 2H), 8.43 (d, J 6.1, 1H), 8.80 (t, J 6.1, 1H), 9.35 (s, 1H); Anal. Calcd for C23H26N2O2+0.3 H2O: C, 75.09; H, 7.29; N, 7.61. Found: C, 75.02; H, 7.34; N, 7.43.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH3:18]I>C1COCC1.[Ag]=O>[CH:14]([C:6]1[C:5]([C:3](=[O:4])[CH:2]([O:1][CH3:18])[CH3:17])=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(O)C(=O)c1c(C(C)C)nn2ccccc12
Agent: O=[Ag]
Solvent: C1CCOC1
Product: COC(C)C(=O)c1c(C(C)C)nn2ccccc12

Procedure:
A solution of 2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.6 g, 1 equivalent), silver oxide (5 g, 8 equivalents), and methyl iodide (2.5 mL, 15 equivalents) in 2 mL of THF was stirred in a sealed tube at room temperature for 26 hours. The mixture was filtered to remove precipitated solids. The filtrate was worked up with ethyl acetate and saturated NaHCO3. The crude oil obtained was purified by silica gel flash column chromatography to give 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methoxypropan-1-one as an oil. Compound 1069.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2
Reactant: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)CC1CCc2cc(O)ccc2C1=O
Temperature: 0 °C

Procedure:
A solution of the 6-methoxy-1-tetralone derivative (860 mg) (from Example 13) in 47% HBr (15 ml) and glacial acetic acid (5 ml) was refluxed for 30 hours and poured into ice-water. The product was extracted into ethyl acetate (3X) and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was esterified with 10% HCl in methanol to give, after work-up, the title compound, m.p. 121°-123°.
Reaction SMILES: [OH:1][C:2](=[C:14]1[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2](=[C:14]1[C:15](=[O:23])[CH2:16][C:17]([CH3:21])([CH3:22])[CH2:18][C:19]1=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OC(C)(C)C)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1006.3 %

Procedure:
t-Butyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoate (100 mg, 0.30 mmol) was dissolved in CH2Cl2/TFA 1:1 mixture (2 ml) and stirred at room temperature for 1 h. The reaction mixture was evaporated giving 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoic acid (0.81 g, 98%)
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1>CO>[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:12][CH:13]=1
Reactant: COc1ccc(Cl)nn1
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 50 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 7.23 g(0.05 mol) of 3-methoxy-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.37 g, 9 mmol) and (bromomethyl)benzene (1.71 g, 10 mmol) in acetonitrile (100 mL) was added potassium carbonate (2.76 g, 18.8 mmol). The reaction mixture was stirred at 60° C. for 2 hours. After the reaction, the solvent was removed under reduced pressure to give the crude product which was purified by column chromatography (silica gel, dichloromethane/methanol=100:1) to give the pure product (2.18 g, 99%). LRMS (M+H+) m/z: calcd 243.09. found 243.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:9].O[C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:9][C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c(C#N)c(=O)[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Using a 100 ml round bottom with reflux condenser, PCl5 (6.7 g, 32 mmol), POCl3 (3.0 mL, 32 mmol) and 30 ml CHCl3 (dry) were stirred for 5 min (see: Heterocycles, vol. 60, No. 6, 2003, 1461-1468). Added 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4 g, 26.6 mmol) and stirred for 2 h at 80° C. Quenched reaction while hot and poured into 1 L beaker with 100 “g” ice, 24 mL NH4OH, pH by paper was 8-9. Stirred 5 min and filtered. Washed solid with water. Suspended solid in ethanol and filtered and washed with ethanol. Gave: 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.7 g, 9.58 mmol, 40% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1H) 6.53 (s, 1H) 2.28 (s, 3H) MS (ES) [M+H]+ 168.9.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH3:35])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:34]([C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH3:35])=[CH:45][CH:44]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Product: CN(Cc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1)C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-benzoic acid in 99% yield as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][CH2:53][C@@H:54]2[NH:58][CH2:57][C@H:56]([OH:59])[CH2:55]2)[CH2:51][CH2:50]1>CN(C=O)C>[CH:49]1([NH:52][CH2:53][C@H:54]2[CH2:55][C@@H:56]([OH:59])[CH2:57][N:58]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:51][CH2:50]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (250 mg, 0.48 mmol), HOBt (78 mg, 1.2 eq.), EDC (110 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (300 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.