Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C=O)C.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:8]=1[CH2:18][C:19]([O:21]C)=[O:20]>O>[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:1]#[N:2])[CH:13]=2)[C:8]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1c(O)ccc2cc(Br)ccc12
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(CC(=O)O)c(O)ccc2c1

Procedure:
100 Milliliters of DMF was added to 177 g of methyl 2-hydroxy-6-bromo-1-naphthylacetate and 70.9 g of cuprous cyanide, and refluxed under heating for 3.5 hours in a nitrogen stream. With stirring under heating, 300 ml of water was added and supernatant liquid was decanted, and then this procedure was repeated. To the resulting residue was added 2.3 liters of a 4% aqueous sodium hydroxide solution, followed by stirring at 25° C. for 1 hour. The insoluble matter was filtered, and concentrated hydrochloric acid was added to the filtrate and the precipitate was collected by filtration. To this collected precipitate was added 200 ml of water, and thereto were added 501 g of ferrous sulfate.heptahydrate and 60 ml of concentrated hydrochloric acid, followed by stirring at 70° C. for 1 hour. After leaving for cooling, the resulting precipitate was collected by filtration and sufficiently washed with water. Thereafter, 3 liters of methanol was added thereto to dissolve the precipitate at 40° C. The insoluble matter was filtered off, and 3 liters of water was added to the filtrate to obtain a crude product. The product was repeatedly subjected to recrystallization with 10% hydrous methanol to obtain 42 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]1([CH:22]([C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH3:39])O)[CH2:21][CH2:20]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:22]([CH:19]2[CH2:20][CH2:21]2)[C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH3:39])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CC1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as a mixture of two diastereomeric racemates as yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].CN(C)C=O.Cl[CH2:13][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>O>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CC(C)CCO
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCOCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Into a mixture of 500 ml (4.59 mol) of 3-methyl-1-butanol and 140 ml of dimethylformamide, 158.1 g (0.92 mol) of 3-chloromethylnitrobenzene was dissolved, and 78 g (1.39 mol) of potassium hydroxide pellets was added to the thus formed solution while cooling with water under a vigorous stirring. The temperature of the reaction mixture rised to 43° C. and then dropped slowly to room temperature. Thereafter, the reaction mixture was stirred for 7 hours at room temperature to complete the reaction.
Reaction SMILES: [CH2:1](N(S(N1CCC(OC)CC1)(=O)=O)CC(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1CC[NH:36][CH2:35]C1)C1C=CC=CC=1>>[CH2:1]([CH2:35][NH2:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCC(OC)CC1
Product: NCCc1ccccc1

Procedure:
ethyl 2-[benzyl-(4-methoxypiperidine-1-sulfonyl)amino]acetate (via methylation of the corresponding 4-hydroxypiperidine analog);
Reaction SMILES: C1C2C(COC([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:36])([CH3:35])[O:20][CH:19]3[CH3:37])=O)C3C(=CC=CC=3)C=2C=CC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>N1CCCCC1.CN(C=O)C>[CH3:37][CH:19]1[O:20][C:21]([CH3:36])([CH3:35])[C:22]2[CH:27]=[C:26]([C:28]3[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)[CH:25]=[CH:24][C:23]=2[NH:18]1
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)[nH]3)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC1Nc2ccc(-c3ccc(C#N)[nH]3)cc2C(C)(C)O1
Yield: 56.1 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl-6-[5-cyano-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.1 g, 0.2 mmol) in 20% piperidine in DMF (5 mL) was stirred at room temperature under nitrogen for 10 minutes. The mixture was poured into a saturated ammonium sulfate solution (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.03 g, 56%): mp 201-202° C.; 1H-NMR (DMSO-d6) δ 12.27 (s, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.32 (dd, 1H, J=8.3, 1.1 Hz), 6.92 (dd, 1H, J=4.1, 2.6 Hz), 6.57 (d, 1H, J=8.3 Hz), 6.50 (dd, 1H, J=4.2, 2.6 Hz), 6.40 (s, 1H), 4.77-4.80 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.7 Hz); MS (ESI) m/z 266 [M−H]−.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5](C(OC)=O)[CH2:4]1)#[N:2].O>CS(C)=O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2cccc(F)c2)CCC1=O
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cccc(F)c2)CCC(=O)CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixture of 1-cyano-1-(3-fluorophenyl)-3-methoxycarbonylcyclohexan-4-one (57, 51 g, 185 mmol), water (54.8 mL) and DMSO (840 mL) was heated and stirred at 150° C. for 3 hours, followed by stirring at room temperature overnight. The reaction mixture was evaporated and purified by chromatography on silica gel. Elution with ethyl acetate/heptane (5%:95% to 30%:70%) gave 28 g of desired material as a solid product. Rt=3.89 min (Method 3). Detected mass: 218.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:28]([O:30]C)=[O:29])=[CH:8][CH:9]=[C:10]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)[C:5]=2[N:4]=[N:3]1.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]2[C:7]([C:28]([OH:30])=[O:29])=[CH:8][CH:9]=[C:10]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=4)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=3)[C:5]=2[N:4]=[N:3]1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nnn(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c21

Procedure:
A solution of 3-methyl-4-methoxycarbonyl-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzotriazole (0.1 g), lithiumhydroxide (11 mg) in tetrahydrofuran (10 ml) and water (5 ml) was stirred for 30 minutes. Tetrahydrofuran was removed and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 3-methyl-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzotriazole-4-carboxylic acid. 1H-NMR (400 MHz, DMSO): 7.80 (t, 1H), 7.73 (d, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 4.74 (bd, 1H), 4.50 (s, 3H), 4.46 (bd, 1H). LC-MS: m/z=458.98 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:6][CH:5]([CH3:7])[C@H:4]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:3]([OH:43])=[O:2]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5cccnc5)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(-c3cccnc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.8 %

Procedure:
To 100 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid methyl ester was dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The pH of the solution was adjusted to 7 and the resulting suspension was filtered. The solid product was dried under vacuum to give 75 mg of (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid, obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.2 (s, 3 H) 3.6 (dd, J=9.3 Hz, 1 H) 7.3 (dd, J=7.3, 1.0 Hz, 1 H) 7.5 (m, 1 H) 7.6 (dd, J=8.3, 7.6 Hz, 1 H) 7.8 (m, 3 H) 7.9 (m, 4 H) 7.9 (m, 1 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.1 Hz, 1 H) 8.7 (m, 2 H) 10.6 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=[C:13]([NH:23][NH2:24])[N:12]=1.[N:25]([O-])=O.[Na+]>CC(O)=O>[N:23]([C:13]1[N:12]=[C:11]([O:10][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:14]=1)=[N+:24]=[N-:25]
Reactant: NNc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
As shown in Scheme I above, to a solution of 2-[2-(pyridin-2-yloxy)-ethoxy]-6-hydrazino-4-morphlinopyrimidine (4.98 g, 15.00 mmol, 1.00 equiv.) in 40 mL HOAc was added NaNO2 (1.553 g, 22.50 mmol, 1.50 equiv.) in six portions over a period of 1 hour. The reaction mixture was stirred at room temperature for 1 hour, and subjected to usual workup to yield 6-azido-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine as green viscous oil (5.0 g, 14.57 mmol, 97% yield). This oil was dissolved in 80 mL THF, and subjected to hydrogenation in the presence of 10% Pd on carbon (0.775 g of 10% Pd/C, 0.73 mmol, 0.05 equiv.) to yield 6-amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine as light yellow solid (4.25 g, 13.4 mmol, 89% total yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](O)(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:19]([O:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC(=O)O
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC(=O)OCCC(C)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A mixture consisting of 6.11 gm (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-1-butanol, 4.27 gm (0.027 mol) of pelargonic acid, 0.25 gm of p-toluene-sulfonic acid and 50 ml of absolute toluene was refluxed in a vessel equipped with a water trap until no more water separated out. Thereafter, the reaction solution was diluted with ether, the organic solution was extracted with water, dilute ammonia and again with water, dried over sodium sulfate, and the solvent was distilled off. 6.45 gm (67% of theory) of the ester of the formula ##EQU26## having a boiling point of 183°-190°C at 0.1 mm Hg were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][N:24]([CH2:35][CH2:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)[CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: CCc1cc(NC(=O)NC2CCC3CNCC32)cc(-c2nnnn2C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(NC(=O)NC2CCC3CN(CCc4ccc(F)cc4)CC32)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 75.6 %

Procedure:
A mixture of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-N′-[(3aRS,4RS,6aSR)-octahydrocyclopenta[c]-pyrrol-4-yl]urea (60 mg, 169 μmol), toluene-4-sulfonic acid 2-(4-fluorophenyl)ethyl ester (55 mg, 169 μmol), potassium carbonate (24 mg, 169 μmol) and acetonitrile (1 mL) was heated to reflux. After 15.5 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a white glass (61 mg, 76%). 1H NMR (300 MHz, CDCl3) δ7.75 (s, 1H), 7.27 (s, 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.04 (m, 2H), 6.24 (broad s, 1H), 4.23 (broad s, 1H), 4.19 (s, 3H), 3.0-2.6 (m, 10H), 2.3-2.1 (m, 2H), 2.05 (m, 1H), 1.8-1.5 (m, 4H), 1.35 (m, 1H), 1.27 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 478.3 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:4]([Cl:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[Cl:26][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Nc1cccc(CCOCc2ccc(Br)cc2Cl)c1)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1cccc(CCOCc2ccc(-c3ccc(Cl)cc3)cc2Cl)c1)C(F)(F)F

Procedure:
N-{3-[2-(3-Chloro-4′-chloro-biphenyl-4-ylmethoxy)-ethyl]-phenyl}-C,C,C-trifluoro methane sulfonamide was prepared from the product of Example 21 and 4-chloro benzene boronic acid according to the procedure of Example 2 and isolated as a white solid (65%), 97-99° C. NMR (400 MHz, DMSO-d6) δ 11.80 (bs, 1H, NH), 7.75 (m, 3H, ArH), 7.61 (d, J=8 Hz, 1H, ArH), 7.54 (d, J=8 Hz, 2H, ArH), 7.42 (d, J=8 Hz, 1H, ArH), 7.31 (t, J=8 Hz, 1H, Ar5), 7.19 (d, J=8 Hz, 1H, H4) 7.11 (s, 1H, H2), 7.09 (d, J=8 Hz, 1H, H6), 4.57 (s, 2H, OCH2), 3.65 (t, J=7 Hz, 2H, OCH2), 2.85 (t, J=7 Hz, 2H, ArCH2). Anal. Calcd. for C22H18Cl2F3N1O3S1: C, 52.39; H, 3.60; N, 2.78. Found: C, 52.07; H, 3.47; N, 2.70.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:67]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:68])[CH:64]([CH3:66])[CH3:65]
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (230 mg, 0.60 mmol), DCC (148 mg, 0.72 mmol) and DMAP (7 mg, 0.059 mmol) in ethyl acetate (12 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (193 mg, 0.60 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (7 mL) and cooled to 0° C. Dimethylamine (7 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 105 mg (36%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Mg].II.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: CSc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution of 4-bromophenyl methyl sulfide (Aldrich) (3.3 g, 16.4 mmol) in 10 mL of dry diethyl ether is slowly added to a stirred suspension of magnesium turnings (0.44 g, 18.1 mmol) and three crystals of iodine in 10 mL of boiling dry diethyl ether. The reaction is heated at reflux for several hours until almost all the magnesium is consumed. The reaction is cooled to room temperature, and a solution of benzaldehyde (2.0 mL, 19.7 mmol) in 50 mL of dry diethyl ether is added dropwise. The reaction mixture is diluted with ethyl acetate and washed twice with 1N HCl, followed by saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude solid is crystallized from diethyl ether/hexane to give 2.4 g (64%) of 4-methylthiobenzhydrol: melting point 92°-93.5° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:12]=1[C:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:12]=1[C:13]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:14][N:15]2[CH3:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCc1c[nH]c2c(F)ccc(OCc3ccccc3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCc1cn(C)c2c(F)ccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
At 0° C., NaH (2 eq) was added to a solution of 1 eq of compound 1-7c in DMF. After 30 min, a solution of 0.1 M methyl iodide in DMF was added slowly over 30 min, and then the reaction mixture was allowed to warm to 25° C. and stirred at that temperature for 1 h. After standard workup, the brown oil residue was purified by column chromatography, eluting with CH2Cl2/2% NH4OH. A brown oil (1-8c) was obtained in 84% yield. 1H NMR (CDCl3-d, 300 MHz) δ (ppm) 2.13 (s, 6H), 2.50-2.56 (m, 2H), 2.95-3.01 (m, 2H), 3.89 (d, 3H, J=1.9), 5.13 (s, 2H), 6.29 (dd, 1H, J=8.5, 2.8), 6.67 (dd, 1H, J=8.5, 12.1), 6.69 (s, 1H), 7.29-7.40 (m, 3H), 7.45-7.48 (m, 2H). APCI [M+1]: 327.2.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)=[O:5].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Add 4-(3,3-dimethyl-butyryl)-benzyl bromide (1 g, 3.731 mmol) to a stirred suspension of potassium phthalimide (0.705 g, 3.805 mmol) in anhydrous DMF (20 mL). Stir the mixture overnight at room temperature. Dilute with EtOAc and wash twice with ice-cold water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 4:1) to provide the desired intermediate as oil (1.24 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[C:34]1([C@H:40]([NH:42][C:43]([NH2:45])=[O:44])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:8]([C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=[C:2]([NH:45][C:43]([NH:42][C@@H:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:41])=[O:44])[N:7]=1)=[O:9]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12

Procedure:
In a manner similar to that described previously (e.g. Scheme 3/Method A and Example 40), 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B) was reacted with converted to (R)-1-(1-phenylethyl)urea (BrettPhos PreCatalyst, cesium carbonate, dioxane, 90° C. for 4 hrs) to provide (R)-1-(4-formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS: [M+H]+ m/z 582.