Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[C:23]([Cl:25])[C:20]([C:21]#[N:22])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[N:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:25][C:23]1[C:20]([C:21]#[N:22])=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=2)[N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:15]=2)[CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(Cl)cc(-c2ccc(NC(=O)c3ccccc3)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
Benzoyl chloride (10 μL, 0.086 mmol was added to a mixture of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (13 mg, 0.033 mmol, from Step 3 of Example 199) and Hunig's base (30 μL, 0.172 mmol) in dichloromethane (0.6 mL). After 16 h at room temperature, the reaction was complete as judged by LCMS analysis. Silica gel chromatography, eluting with 0-50% ethyl acetate in hexanes, gave N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)benzamide as yellow solid (17.6 mg, 100% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (2H, δ, J=8.53 Hz), 8.02-8.06 (2H, m), 7.97 (1H, s), 7.91 (2H, δ, J=7.28 Hz), 7.80-7.87 (3H, m), 7.57-7.63 (1H, m), 7.53 (2H, t, J=7.40 Hz), 7.38-7.44 (2H, m), 7.19 (1H, t, J=7.40 Hz), 7.09-7.17 (4H, m); MS (ES+) m/z: 502 (M+H); LC retention time: 4.923 min (analytical HPLC Method A).
Reaction SMILES: S(Cl)([Cl:3])=O.C(OC([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][C:19]([OH:21])=[O:20])=O)(C)(C)C.[CH3:22]O>>[ClH:3].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: COC(=O)CC1CCCCN1
Product: Cl
Yield: 90 %

Procedure:
Thionyl chloride (5.5 ml, 75 mmol) was added to a solution of 2-carboxymethylpiperidine-1-carboxylic acid tert-butyl ester (6 g, 25 mmol) in methanol (60 ml) while stirring and the mixture was then refluxed for 16 h. The solvent was removed under vacuum and the crude product used in the next stage without purification. Yield: 90%
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1)=[O:4].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[C:30](=[O:32])[CH3:31])=[O:4]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 3.5 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 35 ml CH2Cl2 was added 8.4 ml triethylamine, followed by dropwise addition of 4.2 ml acetic anhydride. The resulting solution was stirred at room temperature for two hours and then quenched with water. The organic layer was washed successively with 5% aq. HCl, water, saturated NaHCO3 and brine, and dried (MgSO4). Concentration, trituration with hexane and recrystallization from toluene/hexane gave 3.1 g solid, m.p. 184°-186° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[C:31]([NH:34][NH2:35])(=[O:33])[CH3:32]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([NH:35][NH:34][C:31](=[O:33])[CH3:32])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(=O)NNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Under N2 atmosphere, to a dichloromethane 10 mL solution of N-tert-butyloxycarbonyl-glycine (500 mg, 2.85 mmol) was added EEDQ (706 mg, 2.85 mmol). After stirring for 15 min, to it was added acethydrazide (260 mg, 3.51 mmol) and stirring continued at rt overnight. The precipitate was collected by suction filtration to give the title compound as white fluffy solid (496 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (210 mg, 0.49 mmol) in dioxane (10 mL) and water (10 mL) was added NaOH (150 mg, 3.75 mmol), The mixture was heated to 40° C. with stirring for 2 h. The solution was concentrated in vacuo, washed with dichloromethane (10 mL×3), then additional water (10 mL) was added and this solution was adjusted to pH=4 by addition of concentrated HCl. The solid formed was filtered to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.160 g, 78%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 13.25 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.50 (s, 1H), 8.26-8.08 (m, 3H), 7.72-7.67 (m, 2H), 7.53-7.44 (m, 1H), 6.75 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.62-3.57 (m, 1H), 2.13-1.98 (m, 3H), 1.70-1.68 (m, 2H), 1.12 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 415, tR=1.68 min, HPLC: 98.2% at 214 nm, 98.37% at 254 nm, tR=6.21 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]CC=C)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.N1CCOCC1.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(N2CCC(C(=O)OCC)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of 4.74 g of 1-{4-[(allyloxy)carbonyl]phenyl}piperidine-4-carboxylic acid ethyl ester in 75 ml of THF, 2.10 ml of morpholine and 390 mg of tetrakis(triphenylphosphine)palladium were added, and the mixture was stirred at 60° C. for 1.5 hours. After the solvent was evaporated under reduced pressure, EtOAc was added to the residue, and the reaction solution was washed with NaHCO3 aq. three times. To the collected saturated NaHCO3 aq., conc. HCl was added, and the produced precipitate was collected by filtration and dried under reduced pressure to obtain 2.73 g of 4-[4-(Ethoxycarbonyl)piperidin-1-yl]benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]=[C:16]1[NH:20][CH2:19][C:18](=[O:21])[N:17]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[C:18](=[O:21])[CH2:19][NH:20][C:16]3=[O:15])=[CH:30][CH:29]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc(CN2C(=O)CNC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4C(=O)CNC4=O)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.19 g, 0.98 mmol) in N,N-dimethylacetamide (4 mL) were added 4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde (0.19 g, 0.89 mmol), sodium hydrogen sulfite (58.5 wt %, 0.24 g, 1.30 mmol) and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reaction mixture was stirred at 115° C. for 17 hours under nitrogen, then cooled to room temperature. The precipitate was filtered, washed with methanol, water, then methanol, and dried in air. The solid was suspended in hot DMSO (approximately 3 mL); saturated aqueous NaHCO3 (approximately 3 mL) and water were added. The solid was filtered, washed with water, then methanol, and air dried to give the title compound as a light yellow solid. Yield: 0.16 g (46%). MP 317-318° C. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.74 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 4.02 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES+) m/z: 395.09 (M+1).
Reaction SMILES: [H-].[Na+].C1COCC1.C(OCC)(=O)CC(OCC)=O.[CH3:19][C:20]1([CH3:49])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([O:36][C:37]3[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=3)[C:40]([O:42]CC=C)=[O:41])=[O:35])[CH:23]=[CH:22][C:21]1=2>O>[CH3:19][C:20]1([CH3:49])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([O:36][C:37]3[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=3)[C:40]([OH:42])=[O:41])=[O:35])[CH:23]=[CH:22][C:21]1=2
Reactant: C=CCOC(=O)c1cccc(OC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3cccc(C(=O)O)c3)ccc21

Procedure:
210 mg (6.8 mmol) of sodium hydride (80% in oil) and 15 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. 1 ml (6.8 mmol) of diethyl malonate is then added dropwise and the mixture is stirred until the evolution of gas has ceased. This solution is introduced dropwise into a mixture of 2.6 g (6.2 mmol) of allyl 3-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]-benzoate, 50 ml of THF and 400 mg of tetrakis-(triphenylphosphine)palladium(0) and the mixture is stirred at room temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl ether and hexane (50/50). After evaporating the solvents, 1.5 g (64%) of 3-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]-benzoic acid, with a melting point of 134-5° C., are collected.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:26][C:27]([F:38])([F:37])[CH2:28][O:29][C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[C:16]1([S:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:36]([C:33]4[CH:34]=[N:35][C:30]([O:29][CH2:28][C:27]([F:38])([F:26])[F:37])=[CH:31][CH:32]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Product: O=C1N(c2ccc(OCC(F)(F)F)nc2)CCC12CCN(S(=O)(=O)c1ccccc1)CC2

Procedure:
Light brown crystalline solid. MS (ESI): 470.3. (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), benzenesulfonyl chloride and 6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH:10]1[CH2:14][CH2:13][CH2:12][CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][OH:6])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1=CCCC1
Reactant: OCc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1cccc(C2CCCC2)c1
Yield: 232.3 %

Procedure:
According to example 61, 10.0 g of 3-iodobenzyl alcohol (Aldrich) was treated with 30 mL of cyclopentene using 0.96 g of Pd(OAc)2, 2.60 g of tri-ortho-tolylphosphine, and 6.6 mL of Et3N. The resulting olefin mixture was hydrogenated for 2.5 h using 0.62 g of 5% Pt(C) in MeOH to afford 5.77 g (76%) of 3-cyclopentylbenzyl alcohol as a light yellow liquid.
Reaction SMILES: Cl[C:2](=[N:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([N:15]=[C:16]=[S:17])[CH:12]=[CH:13][CH3:14].C(OCC)C.C(N(CC)CC)C>O1CCCC1>[N:15]([CH2:11][CH2:12][CH:13]1[O:10][N:9]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14]1)=[C:16]=[S:17]
Reactant: CC=CCN=C=S
Reactant: ON=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: S=C=NCCC1CC(c2ccccc2)=NO1
Reaction time: 24 h

Procedure:
A 23 g. portion of α-chlorobenzaldoxime, prepared as in Example 1 above, was combined with 17 g. of crotylisothiocyanate in 300 ml. of diethyl ether. The solution was cooled to 15° and 40 ml. of triethylamine in 100 ml. of tetrahydrofuran was added dropwise. The mixture was stirred for 24 hours at 15°, and was then filtered. The filtrate was washed with water, and evaporated to dryness. The residue was dissolved in chloroform, and chromatographed over a column (2.5 cm. diameter by 8 meters long) of polystyrene gel beads. The eluate was evaporated to dryness, and the residue was recrystallized from diisopropyl etherhexane. The product was identified as 10 g. of 5-(2-isothiocyanatoethyl)-3-phenyl-2-isoxazoline, m.p. 54°-56°. The microanalytical results were as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=2[CH2:22][CH:21]1[OH:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[CH2:22][CH:21]2[OH:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1c2ccccc2-c2ccccc2CC1O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1c2ccccc2-c2ccccc2CC1O

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol hydrochloride (Example 2-A), the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl3/MeOH.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=1.Br[CH2:26][C:27]([CH3:29])=[CH2:28].Cl>C1COCC1.C(OCC)(=O)C>[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:28][C:27]([CH3:29])=[CH2:26])[C:16]([OH:18])=[O:17])[CH:10]=1
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1cccc(-c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
A solution of LDA (2.2 mL, 2.0 M in THF) in THF (20 mL) was cooled to 0° C. and then treated with biphenyl-3-ylacetic acid (0.212 g, 1.0 mmol). The mixture was stirred for 40 minutes, cooled to −78° C. and then treated with 3-bromo-2-methylpropene (135 μL, 1.3 mmol). The mixture was stirred for 1 hour, treated with 1 M hydrochloric acid (5 mL) and then diluted with ethyl acetate (50 mL). The organic layer was separated washed with water, brine, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 33% ethyl acetate in hexane to provide 2-biphenyl-3-yl-4-methylpent-4-enoic acid (250 mg, 0.93 mmol). 1H NMR (DMSO-d6): 1.71 (s, 3H), 2.52 (m, 2H), 3.68 (dd, 1H), 4.75 (m, 2H), 7.08 (d, 1H), 7.28-7.37 (m, 8H). LCMS: 267.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CO.CS(O[C@H:14]1[CH2:19][CH2:18][C@H:17]([CH3:20])[CH2:16][CH2:15]1)(=O)=O>O>[CH3:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15][CH2:16]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](C)CC1
Reactant: C1CNCCN1
Solvent: O
Solvent: CO
Product: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Piperazine (54.9 g) and methanol (5 ml) was stirred at 120° C. to melt for 15 minutes. To the solution was dropwise added trans-4-methylcyclohexyl methanesulfonate (33.0 g) and the mixture was stirred at the same temperature for 2 hours. After cooling, to the reaction mixture was added water (150 ml) and extracted three times with a mixture of ethyl acetate (100 ml) and THF (100 ml). The extracts were collected, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane, methanol and conc. ammonium hydroxide (4:1:0.1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give cis-1-(4-methylcyclohexyl)piperazine (17.76 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Fc1ccccc1CCl
Product: Fc1ccccc1Cn1nc2ccccc2n1
Product: Fc1ccccc1Cn1nnc2ccccc21

Procedure:
In a procedure as in Example 2 but using 1H-benzotriazole (34.5 g, 0.289 mol) and 1-(chloromethyl)-2-fluorobenzene (41.8 g, 0.289 mol) for 1 h gave the title compound and (2-fluorophenyl)methyl-2-H-benzotriazole in a ratio of 80:20. Similar workup and recrystallization gave the pure 1H-isomer (73%): mp 93°-95° C. (cyclohexane); 1H NMR (270 MHz, CDCl3) δ 5.93 (s, 2H, CH2), 7.08-7.47 (m, 7H), 8.10 (d, J=7.2 Hz, 1H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]=[CH2:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H][H]>[Pd].C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH2:22][CH3:23])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: [H][H]
Reactant: C=Cc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 42 h
Yield: 74.5 %

Procedure:
A mixture of 4-(adamantan-1-ylmethoxy)-2-fluoro-5-vinylbenzoic acid (1.00 g, 3.03 mmol) and 10% palladium on activated carbon (0.10 g) in ethyl acetate (150 mL) was fitted with a hydrogen balloon. The reaction mixture was stirred at ambient temperature for 42 h. The mixture was filtered through a pad of diatomaceous earth, and washed with ethyl acetate (50 mL). The filtrate was concentrated in vacuo, the residue was recrystallized from ethyl acetate and hexanes to afford the title compound as an off-white solid (0.75 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.63 (d, J=8.6 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.61 (s, 2H), 5.57 (d, J=7.5 Hz, 2H), 1.99 (s, 3H), 1.75-1.63 (m, 12H), 1.14 (t, J=7.5 Hz, 3H); MS (ES+) m/z 333.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:19][OH:20]>F[B-](F)(F)F.C[N+](C)(C)C>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:20][CH3:19])=[O:7]
Reactant: CO
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1CCCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCN1C(=O)c1cccc(C(F)(F)F)c1
Yield: 88.2 %

Procedure:
In the same manner as in Example 5, there are electrolyzed 13.5 g of 1-(3'-trifluoromethylbenzoyl)-piperidine and 84.1 g of methanol in the presence of 0.11 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-(3'-trifluoromethylbenzoyl)-piperidine the current is switched off. The calculated mean cell voltage is 34.1 volts. Work-up of the electrolysis solution gives 13.3 g of 1-(3'-trifluoromethylbenzoyl)-2-methoxypiperidine (boiling point 75°-80° C./0.2 mm Hg; nD25 = 1.4905) are obtained which corresponds to a product yield of 88.8% and a current efficiency of 70.6%.
Reaction SMILES: [C:1]([C@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>O.CO.CO>[C:17]([C@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:34]=[C:35]([C@@:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (R,R)-di-p-anisoyltartaric acid (0.8 g, 19 mmol) and aqueous 12M hydrochloric acid solution (0.16 mL, 19 mmol) in water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 38.5 mmol) in methanol (10 mL). After 15 minutes, slowly cool to ambient temperature. Filter the solid that forms and rinse with water to give (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid: mp; 201°-204° C. (dec). Analysis by HPILC, as described in Example 2.3.2 indicates an enantiomeric excess of 97%, (97% ee).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.Cl[C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][C:25]([CH3:31])=[N:26]2>>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH3:31])=[CH:24][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CNC(=O)c1ccc(Sc2ccc(C)cc2N)cc1
Product: CNC(=O)c1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 85b (0.277 g, 1.05 mmol) was reacted with the product from Example 1d (0.09 g, 0.504 mmol) for 41 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid salt (0.078 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H) 2.70-2.82 (m, 6H) 6.36 (d, J=6.99 Hz, 1H) 7.20 (d, J=8.46 Hz, 2H) 7.35-7.45 (m, 2H) 7.51 (d, 1H) 7.64 (d, J=8.46 Hz, 2H) 7.75 (d, J=8.82 Hz, 1H) 8.33-8.45 (m, 2H) 8.90 (d, J=8.82 Hz, 1H) 11.03 (s, 1H); MS (ESI+) m/z 415.0 (M+H)+; (ESI−) m/z 413.1 (M−H)−.