Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:29][NH:30][C:31]1[S:32][C:33]([S:37]([NH2:40])(=[O:39])=[O:38])=[C:34]([CH3:36])[N:35]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:40][S:37]([C:33]1[S:32][C:31]([N:30]([CH3:29])[C:15](=[O:17])[CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:13][CH:12]=2)=[N:35][C:34]=1[CH3:36])(=[O:38])=[O:39]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2ccccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccc3F)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.33 g (73.3 mmol) of (2′-fluoro[1,1′-biphenyl]-4-yl)acetic acid and 9.9 g (73.3 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 600 ml of dimethylformamide at room temperature. 16.84 g (81.4 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 15.58 g (81.4 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The dimethylformamide is substantially removed at 50° C. under high vacuum, and the residue is taken up in 400 ml of dichloromethane and then washed with 350 ml of each of water and 10% citric acid solution. Drying over magnesium sulfate and removal of the solvent in vacuo results in the compound of Example 57 in the form of a white solid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[NH:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](Cl)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
A solution of Boc-Arg-OH(1 eq), NH(CH2Ph)2 (1.1 eq) and PyCloP (1 eq) in dry DCM (filtered through alumina) (2 ml) and DMF (1 ml). The solution was cooled on ice and DIPEA (2 eq) was added under stirring. The solution was stirred for 1 h at room temperature. The reaction mixture was evaporated, and redissolved in ethyl acetate and washed with citric acid, sodium bicarbonate and brine. The solvent was removed under vacuum and the Boc protecting group of the resulting peptide was deprotected in the dark using 95% TFA.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]3)[CH:10]=[CH:11][C:12]=2[Cl:16])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(Cl)c(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(Cl)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-chloroaniline (D34) (108 mg, 0.45 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with 4-bromobenzenesulfonyl chloride (138 mg, 0.54 mmol). The solution was stirred at room temperature for 2 hours, quenched with methanol and concentrated in vacuo. The residue was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (FlashMaster) (dichloromethane to 5% methanol:dichloromethane) to afford some pure product. The impure fractions were purified further by MDAP, and combined with the above pure product to afford the title product (D35). MS (ES+) m/e 458/460/462 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:14]([CH2:13][CH2:12][CH2:11][Cl:10])(=[O:16])=[O:15]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=S(=O)(Cl)CCCCl
Product: C[Si](C)(C)NS(=O)(=O)CCCCl
Temperature: 120 °C
Yield: 72.5 %

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with hexamethyldisilazane (0.4235 mol, 91.2 ml) and 3-chloropropanesulfonyl chloride (0.4193 mol, 75.0 g). The contents of the reactor were heated. A refluxing liquid was first observed at a temperature of 85°-95° C., and the mixture became clear. The mixture became cloudy at a temperature of about 105 degrees. The temperature of the mixture was maintained at 120° C. for 90 minutes and at 145°-150° C. for 15 minutes. The mixture was then allowed to cool to room temperature, at which time it was filtered, the solids were washed with benzene, and the washing liquid combined with the liquid portion of the mixture. The combined liquids were then heated at 60°-65° C. under reduced pressure to remove volatile materials and then distilled. The fraction boiling from 127°-129° C. under a pressure of from 0.04-0.07 mm. Hg was collected, and was equivalent to a 72.5% yield based on initial reactants. The 1H NMR spectrum was consistent with the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1CCCC1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:28])/[CH:27]=[CH:1]/[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CN(C)/C=C/c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-2-nitro-4-(perfluoroethyl)benzene (10.0 g, 39.2 mmol) and pyrollidine (2.79 g, 39.2 mmol) in toluene (250 mL) was added dimethyl formamide dimethyl acetal (4.96 g, 39.2 mmol). The mixture was heated to reflux for 16 hours. After cooling to room temperature the mixture was concentrated under vacuum and the resulting oil was immediately used in the next reaction.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]1[C:13]2[CH2:12][CH2:11][CH2:10][N+:9]=2[CH2:8][CH2:7]1.[C:14]([Mg]Br)#[CH:15]>C1COCC1>[C:14]([C:13]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)#[CH:15]
Reactant: C#C[Mg]Br
Reactant: C1CC2=[N+](C1)CCC2
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C#CC12CCCN1CCC2
Reaction time: 0.75 h
Yield: 71 %

Procedure:
The compound from step 15a above (1.0 g, 4.8 mmol) was added to a solution of 0.5 M ethynylmagnesium bromide (29 mL, 14.3 mmol) in THF at room temperature. The reaction mixture was stirred for 45 minutes, quenched with 15% NaOH solution, and diluted with brine:water (1:1). The aqueous phase was extracted with CH2Cl2, and the organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 90:10) to afford an amber oil (463 mg, 71%): 1H NMR (CDCl3, 300 MHz) δ 1.75-2.06 (m, 6H), 2.14-2.23 (m, 2H), 2.33 (s, 1H), 2.53-2.62 (m, 2H), 322-3.28 (m, 2H); MS (CI/NH3) m/z: 136 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]N)=[CH:11][CH:10]=1.O=[C:18]([CH2:22][CH3:23])[C:19]([OH:21])=[O:20].[CH2:24](O)[CH3:25]>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[NH:15][C:18]([C:19]([O:21][CH2:24][CH3:25])=[O:20])=[C:22]2[CH3:23]
Reactant: COc1ccc(NN)cc1
Reactant: CCO
Reactant: CCC(=O)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1[nH]c2ccc(OC)cc2c1C
Yield: 59 %

Procedure:
Concentrated sulphuric acid (1 ml) was added to a solution of 4-methoxyphenyl hydrazine hydrochloride (11.2 g) and 2-oxobutyric acid (8.72 g) in ethanol (250 ml), and the solution heated at reflux for 16 hours. The reaction was cooled, concentrated in vacuo, and the residue triturated with ethanol to give the title compound as a white solid (8.8 g, 59%). NMR δ 1.36 (t, 3H), 3.76 (s, 3H), 4.30 (q, 2H), 6.88 (dd, 1H), 7.03 (d, 1H), 7.28 (d, 1H), 11.28 (bs, 1H); m/z 232 (M−H+).
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)CCC.[Cl-].[Li+]>O1CCCC1.[Cu]I>[F:10][C:3]1[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(F)c(-c2ccccn2)c1F
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (5.2 g, 25 mmol), 2-tri-n-butylstannylpyridine (11.0 g, 30 mmol), lithium chloride (10.6 g, 250 mmol) and copper(I) iodide (476 mg, 2.5 mmol) in tetrahydrofuran (100 ml) was degassed with nitrogen for 20 min before adding tetrakis(triphenylphosphine)palladium(0). The reaction was then heated at reflux for 5 days. The mixture was cooled to ambient temperature then partitioned between ethyl acetate and 10% ammonium hydroxide. The organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 0.5% triethylamine) on a gradient of ethyl acetate (20-50%) gave 2,4-difluoro-3-(pyridin-2-yl)phenylamine as a brown oil (550 mg, 11%): δH (400 MHz, CDCl3) 3.65 (2H, br), 6.74-6.84 (2H, m), 7.31 (1H, ddd, J 7, 5 and 1), 7.46-7.51 (1H, m), 7.78 (1H, ddd, J 8, 8 and 2), 8.74-8.77 (1H, m); m/z (ES+) 207 (M++H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][CH2:12][C@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31]([NH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][O:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]1)=[O:32])=[CH:25]2
Reactant: CC(C)N1CCC(COC[C@H](N)c2ccccc2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: CC(C)N1CCC(COC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)c2ccccc2)CC1
Product: Cl

Procedure:
Using coupling method A, (R)-2-(1-isopropylpiperidin-4-ylmethoxy)-1-phenylethylamine (200 mg, 0.73 mmol) and 5-chloroindole-2-carboxylic acid (142 mg, 0.75 mmol) afforded, after purification (SiO2: 4:2:1 DCM:EtOAc:isopropylamine) and conversion to the HCl salt by general method A, 320 mg (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=[O:21])([O-])[O-].[K+].[K+].[C:24](#N)[CH3:25]>>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:24][CH2:25][O:21][CH3:18])[CH2:14][CH2:13]1
Reactant: CC#N
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.53 g, 1.64 mmol), acetonitrile (20 ml), potassium carbonate (0.45 g, 3.2 mmol) 1-bromo-2-methoxyethane (0.167 ml, 1.72 mmol). MS m/z (relative intensity, 70 eV) 315 (M+, 1), 271 (14), 270 (bp), 147 (10) 133 (9).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH2:12][CH3:13])(=[O:10])[C:5]([O:7]CC)=O.[CH3:14][C:15]([CH3:17])=[O:16].Cl[C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:12]([O:11][C:4](=[O:10])[C:5]([C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:25][O:16][C:15]=1[CH3:17])=[O:7])[CH3:13]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)C(Cl)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)noc1C
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a well stirred solution of sodium methoxide (10.5 g, 0.15 mol) in 100 mL of dry ethanol, diethyl oxalate (21 mL, 0.15 mol) was added dropwise and the mixture was warmed to 45° C. Then dry acetone (45 mL, 0.60 mol) was added and after 30 min the final mixture was refluxed for 3 hours and stirred at room temperature overnight. Finally solvent was removed and 100 mL of fresh dry ethanol were added. The mixture was cooled to, 0° C. and a solution of ethyl chloro(hydroximino)acetate (27.2 g, 0.18 mol) in 25 mL of dry ethanol was added dropwise. Then it was stirred at 0° C. for 30 min and at room temperature for 3 days. Finally solvent was removed and the crude thus obtained was partitioned between ethyl acetate and water. It was dried and solvent removed to yield the desired product (90%) as an orange oil.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[C:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9].CI>C1C=CC=CC=1>[C:8]([CH2:10][C:11]1([CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:18])#[N:9]
Reactant: Cc1ccccc1
Reactant: N#CCC1CCCCCC1=O
Solvent: c1ccccc1
Solvent: CI
Product: CC1(CC#N)CCCCCC1=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of sodium tert.-amylate in toluene (340 ml, 0.297 mole) is added dropwise with stirring under nitrogen to a solution of 2-cyanomethylcycloheptanone (44.6 g, 0.297 mole, obtained as described above) and methyl iodide (42.6 g, 0.3 mole) in dry benzene (200 ml), and the mixture is stirred at 65° C for 4 hrs. and allowed to stand overnight at room temperature. The reaction mixture is washed with 1% aqueous hydrochloric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated. Distillation of the residue under reduced pressure yields 2-cyanomethyl-2-methylcycloheptanone, bp. 152°-158° C/14 mm, nmr (CDCl3) δ1.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10](O)=[O:11]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=CO
Product: COc1ccc(NC=O)cc1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
The intermediate, 4-methoxy formanilide is prepared by heating 369.6 parts by weight (3.0 mole) of para anisidine to 90° C. and adding to it 147 parts by weight (3.1 mole) of 97% formic acid over a period of 80 minutes at 95°-105° C. under reflux conditions. A water trap is then installed and heating continued at 91°-111° C. for about 5 hours while collecting water. Toluene is added to aid the removal of water. The reaction mixture is cooled, crystallization induced by scratching, and heptane added. The crystalline mass is cooled to 5° C. and filtered to obtain, after air drying 447.6 parts by weight of 4-methoxy formanilide as a purple solid.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:6][CH2:7][CH:3]([N:2]([CH3:24])[CH3:1])[CH2:4]4)=[CH:13][CH:12]=3)=[O:23])=[CH:21][CH:20]=2)=[N:27][CH:28]=1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Oc4ccc(Cl)cn4)cc3)cc2)C1

Procedure:
A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4-hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of potassium carbonate in 0.8 ml of DMF was heated at 230° C. in a microwave apparatus for 30 minutes. The solution was filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 436.17 (C24H25ClN4O2); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-:29].[NH4+]>CCOCC>[ClH:29].[CH3:14][N:13]([CH:15]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH3:2])[CH:5]=1)[OH:22])[CH3:12]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: [Cl-]
Reactant: COc1cccc(CBr)c1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(CC2(O)CCCCC2C(c2ccccc2)N(C)C)c1
Product: Cl
Temperature: 25 °C
Yield: 52.8 %

Procedure:
0.63 g (25.9 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 5.21 g (25.9 mmole) of 3-methoxybenzyl bromide dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 5.0 g (21.6 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 40 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 7.53 g of crude base (98.6 of theory) were obtained. 4.45 g of 2-(dimethylaminophenylmethyl)-1-(3-methoxybenzyl)cyclohexanol, hydrochloride (52.8% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes when heated above 160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([C:13](O)=[O:14])[CH2:4][C:3]1=2.CSC.B.CO>C1COCC1>[CH3:12][C:8]1([CH3:11])[CH2:9][CH2:10][C:2]([CH3:1])([CH3:21])[C:3]2[CH2:4][C:5]([CH2:13][OH:14])([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][C:7]1=2
Reactant: CCCCCC1(C(=O)O)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CCCCCC1(CO)CC2=C(C1)C(C)(C)CCC2(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
3.5 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid were dissolved in 35 ml of THF and treated dropwise at room temperature with a solution of 1.4 ml of borane methylsulfide in 10 ml of THF. The reaction mixture was stirred for 2 hours, then treated dropwise with 13 ml of methanol and evaporated. The yellow, oily residue was purified with flash chromatography (silica gel, hexane/ethyl acetate=5:1) to yield 2.9 g of (4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-methanol as colorless oil.
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[CH:19][N:18]=2)[CH3:16])=[O:13])=[CH:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: C[C@@H](NC(=O)Cc1ccc(C(C)(C)O)cc1)c1ccc(OCC(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 2-[4-(1-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (400 mg, 1.01 mmol) and p-toluenesulfonic acid monohydrate (38.4 mg, 0.202 mmol) in toluene (4.5 mL) was heated at 100° C. in a sealed tube for 6 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (40 mL) and washed with water (2×50 mL). The organic layer was dried over MgSO4, concentrated and purified by normal phase chromatography (20-100% EtOAc/Hexanes) to give 316 mg (83%) of 2-(4-isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a white solid. 1H NMR (CDCl3, 400 MHz) 8.21 (d, J=2.35 Hz, 1H), 7.45 (m, 2H), 7.20 (m, 4H), 6.64 (d, J=7.32 Hz, 1H), 5.38 (s, 1H), 5.11 (m, 1H), 5.09 (s, 1H), 4.37 (q, J=7.94 Hz, 2H), 3.58 (s, 2H), 2.15 (s, 3H), 1.39 (d, J=6.77 Hz, 3H); MS (Electrospray): m/z 379.5 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)C2CCNCC2)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To the reaction solution of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) from Example 76, Scheme G, step c, is added about 188 kg of water and 37% hydrochloric acid (39 kg, 395 mol). The solution is heated to about 60° C. for about 18 hours1. The mixture is cooled to about 25° C. and about 47 kg of toluene is added. The phases are separated and the organic phase is discarded. To the aqueous phase is added about 78 kg water, 50 wt % sodium hydroxide solution (31 kg, 391 mol), and about 99 kg of toluene. The phases are separated and the aqueous phase is discarded. The organic phase is concentrated by vacuum distillation. The concentration of 4-(2,3-dimethoxybenzoyl)piperidine (16) in solution ranges from 17 to 53 wt %1, affording 14.6 to 17.9 kg of 4-(2,3-dimethoxybenzoyl)piperidine (16) (65-76% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.S(=O)(=O)(O)O>O.C(O)(C)C>[CH2:1]([N:8]1[C:15](=[O:16])[C:14](=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12](=[O:13])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(=Cc2ccccc2)C(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 50 °C
Yield: 75 %

Procedure:
In a 300-ml glass flask equipped with a thermometer, a reflux condenser and a stirrer, 4.0 g of 1-benzyl-3-phenylbarbituric acid, 1.6 g of benzaldehyde, and 40 ml of acetic acid were put, the content was added with a drop of sulfuric acid, kept under stirring, the flask was heated so as to adjust the inner temperature to 100° C., and the content was continued to be stirred at 100° C. for 3 hours. The content was then cooled to 50° C., added with a mixed solution of 39 ml of isopropanol and 17 ml of water, stirred at 10° C. or below for one hour, filtered under suction to collect a deposited crystal, and the crystal was washed with methanol, to thereby obtain 3.9 g of 1-benzyl-5-benzylidene-3-phenylbarbituric acid as an intermediate.