Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1.O>C(Cl)Cl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Yield: 55.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (30.0 g) obtained from Referential Example 7 was dissolved in methylene chloride (300 ml), pivaloyl chloride (15.0 g) and pyridine (9.8 g) were added thereto, the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool, Water was added, and extracted with chloroform. The organic layer was successively washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain the 21.5 g of titled compound as white crystals.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH2:14]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C)CCC(=O)CCC)C1C=CC=CC=1>>[CH2:1]([N:8]([CH3:17])[CH2:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)CCN(C)Cc1ccccc1
Agent: CCCC(=O)CCN(C)Cc1ccccc1
Product: CCCC(O)CCN(C)Cc1ccccc1

Procedure:
Using a method similar to that for 1-(Benzyl-methyl-amino)-heptan-3-ol, 1-(benzyl-methyl-amino)-hexan-3-one affords the title compound: mass spectrum (ion spray) m/z=222 (M+1); 1H NMR (CDCl3) δ 7.34-7.24 (m, 5H), 3.79-3.73 (m, 1H), 3.55 (dd, 2H), 2.81-2.74 (m, 1H), 2.59-2.55 (m, 1H), 2.22 (s, 3H), 1.72-1.62 (m, 1H), 1.56-1.31 (m, 5H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:10]=[N:11][N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1)=[O:7].[OH-:30].[K+].OO.O>C(O)C.O>[C:28]([C:26]1[CH:25]=[CH:24][C:3]([CH2:4][NH:5][C:6]([C:8]2[C:9]3[CH:10]=[N:11][N:12]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[C:13]=3[CH:14]=[CH:15][CH:16]=2)=[O:7])=[C:2]([Cl:1])[CH:27]=1)(=[O:30])[NH2:29]
Reactant: N#Cc1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)c(Cl)c1

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 2-chloro-4-cyano-benzylamide in a 1:1 mixture of EtOH—H2O (2.0 mL) was added KOH (0.018 g, 0.32 mmol) and a 30% solution of H2O2 in H2O (0.13 mL, 1.1 mmol). The suspension was sealed and heated briefly to dissolve the mixture. The resultant solution was stirred at room temperature for 16 hours, during which time a solid precipitated. The mixture was diluted with H2O (10 mL) and the solid was collected by filtration and dried to afford the title compound as a white powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[C:1]([C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1cccc(C(=O)c2ccccc2)c1
Product: O=C(Cl)CCc1cccc(C(=O)c2ccccc2)c1

Procedure:
A mixture of 18.15 g of 3-(m-benzoyl-phenyl)-propionic acid and 25 ml of thionyl chloride was refluxed for 11/2 hours and excess thionyl chloride was removed under reduced pressure to obtain 3-(m-benzoyl-phenyl)-propionyl chloride which was used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:2]=2[N:1]=1
Reactant: Nc1c(Br)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c(Br)cccc2c(=O)o1
Temperature: 110 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Part A: A mixture of 19.2 g (89 mmol) of 2-amino-3-bromo benzoic acid (Beistein vol 14,369,vol IV,pg 1080) and 75 ml (0.79 mol) of acetic acid anhydride was heated to 110° C. under nitrogen with stirring for 3 hours. After cooling the mixture was concentrated in vacuo and co-evaporated twice with toluene. The product was purified over silicagel using CH2Cl2 as the eluent. A total of 17.0 g of 2-methyl-8-bromo-3,1-benzoxazin-4-one was obtained (80% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:8]2)=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:10]([N:11]([CH3:27])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of ethyl 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.00 g), methyl iodide (0.17 ml), potassium carbonate (0.36 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to basic silica gel column chromatography to give the title compound (0.80 g, yield 77%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 156-157° C.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:13][CH2:14][F:15])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:35][CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.O.CO>[F:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][C:7](=[O:16])[N:6]([CH3:17])[C:5]2[C:11]1=[N:12][C:2]([NH:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:24])=[CH:21][C:20]=1[O:35][CH3:36])=[N:3][CH:4]=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)CCN(CCF)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCF)CCC(=O)N2C
Yield: 37.4 %

Procedure:
10-chloro-2-(2-fluoroethyl)-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 157; 86 mg, 0.33 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 104 mg, 0.40 mmol) and p-toluenesulphonic acid monohydrate (126 mg, 0.66 mmol) were heated together in 4-methyl-2-pentanol (4 mL) at 100° C. for 24 hours. The reaction mixture was diluted with water and methanol and the solution loaded onto an SCX-2 (5 g) column pre-wet with methanol. The column was washed with methanol (×2) and the product eluted with 2M NH3/MeOH. Product containing fractions were combined and evaporated. The resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (60 mg, 37%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6]C1C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH3:6][O:30][C:29]([C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)=[O:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1

Procedure:
To a stirred solution of H2SO4 (16 mL) in MeOH (400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methyl benzenesulfonate (37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours. Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH. The pH was adjusted to 10-11 by adding more 6 N NaOH and extracted with CH2Cl2 (3×150 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a viscous oil. The product (20.2 g, 92%) was used without further purification.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]=[O:10]>O.C(O)C>[CH3:7][CH:8]([CH2:11][CH2:12][CH3:13])[CH:9]([OH:10])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: CCCC(C)C=O
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C)C(O)C[N+](=O)[O-]
Reaction time: 2 h
Yield: 82.6 %

Procedure:
After dissolving 7.0 g of sodium hydroxide in 50 ml of water and 50 ml of ethanol at 4° C., 10.7 g of nitromethane and 10.0 g of 2-methylpentanal were added thereto. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for two hours. After concentrating the ethanol under reduced pressure, the solution was neutralized with 1 mol/l of hydrochloric acid so that the pH of the solution was approximately 7. Ethyl acetate was added to the solution, and the organic layer was washed with saturated saline. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 13.3 g of 3-methyl-1-nitro-2-hexanol (yield: 94.2%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=1.CN(C)[CH:23]=[O:24]>>[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:23]=[O:24])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Phosphorus oxychloride (3.36 ml) is added dropwise over a period of 20 minutes to dimethylformamide (10.6 g) maintained at 0°-3°. After complete addition a solution of 2-(3-pyridyl)indole (6.50 g) in dimethylformamide (20 ml) is added dropwise over a period of 30 minutes at such a rate so that the reaction temperature does not exceed 10°. The cooling bath is then removed and the viscous solution heated to and maintained at 35°-40° for 1 hour. The reaction mixture is treated with crushed ice (50 g). A solution of sodium hydroxide (24.4 g) in 65 ml of water is added slowly. After the addition the resulting red-orange solution is heated rapidly to reflux and maintained at reflux for about 2 minutes. The solution is allowed to cool to room temperature, then placed in a freezer for 2 days. The resulting precipitate is collected and washed well with water to give an orange solid which is recrystallized from methanol (240 ml) to give 2-(3pyridyl)-indole-3-carboxaldehyde, m.p. 236°-238°.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[F:23][C:24]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:30]=[CH:29]2.C(=O)([O-])[O-].[Cs+].[Cs+].N#N.C([O-])(O)=O.[Na+]>COCCOC.O.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:23][C:24]1[C:25]([C:2]2[N:3]=[C:4]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[CH2:13]3)[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=23)=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[C:31]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:30]=[CH:29]2
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2F)OC1(C)C
Reactant: CN1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CC(c3nc(-c4ccc5ccc(-c6ccccc6)nc5c4F)c4c(N)nccn34)C2)CC1
Temperature: 75 °C

Procedure:
A solution of 1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (93 mg, 0.22 mmol), 8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline (87 mg, 0.25 mmol) and cesium carbonate (88 mg, 0.27 mmol) in DME (3.33 mL) and H2O (0.67 mL) was degassed with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) was added, and the reaction heated at 75° C. overnight. The reaction was allowed to cool to rt, poured into saturated NaHCO3 solution (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics were washed with brine (3×50 ml), dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (DCM stepping up to 5% MeOH in DCM) gave the title compound as an off-white solid; NMR (CDCl3, 400 MHz) δ 8.27 (1H, d, J=8.6 Hz), 8.23 (2H, d, J=7.1 Hz), 7.99 (1H, d, J=8.8 Hz), 7.73-7.67 (2H, m), 7.55-7.48 (3H, m), 7.16 (1H, d, 5.1 Hz), 7.06 (1H, d, J=5.1 Hz), 3.46 (1H, m), 2.94 (1H, m), 2.71-2.32 (15H, m); MS (ES+): m/z 508.03 [MH+]; HPLC: tR=1.71 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].C=O.[CH3:12]CCCC=C>>[CH3:12][N:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:1][CH3:2]
Reactant: C=CCCCC
Reactant: CCNC1CCCCC1
Agent: C=O
Product: CCN(C)C1CCCCC1
Yield: 391 %

Procedure:
In a similar manner to Example 1, 190.8 g (1.5 mol) of N-ethylcyclohexylamine and 247.6 g (2.4 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.6 MPa is established at a temperature of 160° C. After the end of the reaction, 30 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently fractionally distilled. 196.9 g of N-methyl-N-ethylcyclohexylamine having a purity of 98.7% are isolated, corresponding to a yield of 91.8% of theory.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:23]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2ncccc2N2CCCCC2)Cc2ccccc2C1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ncccc1N1CCCCC1
Reaction time: 38 h

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (360, 370 mg, 0.94 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by LiOH monohydrate (100 mg, 2.38 mmol). After 38 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material has been completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 4 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.29, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:25][S:26][CH3:27])[CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:23]3[C:18](=[C:19]([CH2:25][S:26][CH3:27])[CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1C)c1c[nH]c2c(CSC)cc(F)cc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3C)c[nH]c12

Procedure:
A solution of 690 mg (1.64 mmol) of the compound from Example 98A in 10 ml of THF was added dropwise to 5.8 ml (5.75 mmol) of a 1N lithium aluminum hydride solution in THF under argon in 20 ml of THF at RT. 1N hydrochloric acid was then added, the mixture was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 0.60 g (97% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+]>[C:9]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(OC(=O)c2ccccc2)c1

Procedure:
Metacresyl benzoate was prepared by vigorously shaking a mixture of metacresol (1 equivalent, 5 grams) and benzoyl chloride (1.2 equivalents, 7.1 grams) in a 10% aqueous solution of sodium hydroxide (100 ml) in a stoppered flask for 15 minutes. The white crystalline solid thus formed was removed by filtration, washed with water and dried to yield metacresyl benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].N[C@@H:22]1[CH2:27]C[CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([C@@H:18]1[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:25]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
Ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.160 g, 5.79 mmol, CNH technologies), and potassium carbonate (2.042 g, 7.38 mmol, Aldrich) were combined in THF (10.0 mL). The reaction was heated at 60° C. for 2 hrs. After 2 h, DMF (5.0 mL) was added. The reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was around 4. The resulting precipitate was filtered, washed with water and dried overnight to yield a light yellow solid (2.10 g, 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[C:10]1([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC)=O)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:22][CH2:21]2)[OH:25])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 70 parts of 1-bromo-4-fluorobenzene and 10 parts of magnesium in 270 parts of tetrahydrofuran, was added dropwise a solution of 25 parts of ethyl 1-(phenylmethyl)-4-piperidinecarboxylate in 90 parts of tetrahydrofuran. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled and poured onto a saturate ammonium chloride solution. The organic phase was separated, dried, filtered and evaporated, yielding 40 parts of α,α-bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol as a residue (intermediate 12).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)nn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)nn1Cc1ccccc1
Yield: 49.2 %

Procedure:
A solution of ethyl 2-benzyl-5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylate (1.2 g) in methanol (125 mL) is treated with 10% aqueous potassium hydroxide solution (10 mL, w/v) and the mixture is heated to reflux for 2 hours. The reaction mixture is evaporated in vacuo, stirred with 1N hydrochloric acid (50 mL) and extracted with ethyl acetate (100 mL). The organic phase is dried over magnesium sulphate, evaporated in vacuo, and the residue crystallised from a mixture of ethyl acetate and cyclohexane to give 2-benzyl-5-(4-benzyloxyphenyl)-2H-pyrazole-3-carboxylic acid (0.55 g), m.p. 207-208° C. [Elemental analysis:- C,75.2; H,5.20; N,7.30%. Calculated:- C,75.0; H,5.20; N,7.30%].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:18]([O:22][C:23](=[O:43])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[CH:28][C:27]=1[CH2:33][NH:34][C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1CNC(=O)c1ccccc1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A solution of 4-(3-bromo-propoxy)-biphenyl (291 mg, 1.00 mmol; Preparation 12) and 3-[2-(benzoylamino-methyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (320 mg, 0.90 mmol; Preparation 21) in DMF (5 mL) was treated with K2CO3 (100 mg) and heated at 60° C. for 48 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organics were dried (Na2SO4), concentrated, and purified using silica gel chromatography (10-30% EtOAc/hexanes) to give 3-{2-(benzoylaminomethyl)-4-[3-(biphenyl-4-yloxy)propoxy]phenyl}propionic acid tert-butyl ester (450 mg). This material was treated with a mixture of CH2Cl2 (1.0 mL)/TFA (0.8 mL)/water (0.1 mL) at ambient temperature for 2 h. The reaction mixture was concentrated and dried under vacuum to afford the title product as a white solid (380 mg, 75%). MS (ES) m/e 510.1 (M+1).