Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (0.67 g, 3.2 mmol) and DIEA (0.46 ml, 2.65 mmol) in EtOH (20 ml) was added a 5-cyclopropyl-1H-pyrazol-3-amine (0.26 g, 2.12 mmol) solution in EtOH (5 ml) dropwise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 24 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=5:1) to give the title compound as a yellow solid (0.58 g, 98%). NMR (400 MHz) 12.36 (s, 1H), 10.20 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 1.94 (m, 1H), 0.96 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 279; Found: [M+H]+ 280.
Reaction SMILES: CC1C=CC(C[C:7]2[CH:15]=[C:14](CC3C=CC(C)=CC=3)[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=2[OH:24])=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)C1C=CC=CC=1.Cl>C(OC(C)C)(C)C>[C:10]([OH:12])(=[O:11])[C:9]1[C:8](=[CH:7][CH:15]=[CH:14][CH:13]=1)[OH:24]
Reactant: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(O)c(C(=O)O)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCc1ccccc1
Solvent: CC(C)OC(C)C
Product: O=C(O)c1ccccc1O
Reaction time: 2 h
Yield: 434.4 %

Procedure:
A glass-made reactor was charged with 6.9 g (0.02 mole) of 3,5-di(4-methylbenzyl)salicylic acid, 50 ml of isopropyl ether and as a catalyst, 2.7 g of anhydrous aluminum chloride. The resultant mixture was maintained at 50° C. under stirring. At the same temperature, 7.6 g (0.06 mole) of benzyl chloride was added dropwise over 8 hours to conduct a reaction. After completion of the dropwise addition, the reaction mixture was aged for 2 hours at the same temperature and was then poured into a dilute aqueous solution of hydrochloric acid. The resultant mixture was allowed to separate into layers. The solvent was then distilled out to obtain 12.0 g of a reddish brown resin. The weight average molecular weight of the thus-obtained resin was 1250, while its softening point was 65° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CN1C=CN=C1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].C(N(CCCC)CCCC)CCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CNC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)[C@@H](NC(C)=O)C(=O)c1ccccc1C
Temperature: -45 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl N-acetylglycinate (98%, 7.41 g, 50.0 mmol) and 1-methyl-1H-imidazole (99%, 4.81 mL, 60.0 mmol) in dichloromethane (100 mL) was cooled to −45° C. and treated with 2-methylbenzoyl chloride (99%, 6.59 mL, 50.0 mmol). The reaction was stirred at −45° C. for 10 minutes. Titanium(IV) chloride (19.2 mL, 175 mmol) was added, followed by tri-n-butylamine (98%, 48.6 mL, 200 mmol), and stirring was continued at the same temperature for 30 minutes. The reaction was quenched with water and extracted with diethyl ether; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Eluents: 1:5 ethyl acetate/heptane followed by 1:2 ethyl acetate/heptane) afforded the product. Yield: 6.00 g, 22.8 mmol, 46%. APCI m/z 264.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=7.6, 7.5, 1.4 Hz, 1H), 7.26-7.34 (m, 2H), 6.89 (br d, J=7 Hz, 1H), 6.05 (d, J=7.2 Hz, 1H), 4.04-4.19 (m, 2H), 2.45 (br s, 3H), 2.11 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[C:27]([O:31][CH2:32][CH2:33][C:34](O)=[O:35])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:27]([O:31][CH2:32][CH2:33][C:34]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]([CH3:11])=[C:5]([O:4][C:3]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:2]=3[F:1])[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1)=[O:35])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OCCC(=O)O
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)CCOC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), 3-tert-butoxy-propionic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and triethylamine (0.4 mmole, 2 eq) in 2 mL DMF was stirred at room temp for 2 hours. Mixture was purified by HPLC to give compound C161 as a white solid (88 mg, 86%). 1H NMR (CDCl3, 400 MHz) δ 1.20 (s, 9H), 1.91-1.96 (m, 2H), 2.02-2.10 (m, 2H), 2.22 (s, 3H), 2.72 (t, 2H), 3.11 (s, 3H), 3.62-3.64 (m, 2H), 3.72 (t, 2H), 3.86-3.91 (m, 2H), 5.41-5.46 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.23 (s, 1H). Exact mass calculated for C24H32FN3O6S 509.2, found 510.6 (MH+).
Reaction SMILES: ClC1C=CC(N(CC)C([C@@H]2C3C(=CC=CC=3)N([C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)=[O:22])[C@@H](C)C2)=O)=CC=1.C1C=C2C=C(C(O)=O)SC2=CC=1.C(Cl)(=O)C([Cl:50])=O.CN(C)C=O>C(Cl)Cl>[S:27]1[C:23]([C:21]([Cl:50])=[O:22])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2cc3ccccc3s2)c2ccccc21)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc2ccccc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
(±)-trans-1-(Benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude 1-(benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol/methylene chloride) followed by purification via HPLC yielded (±)-trans-2-methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.65-1.75 (m, 1H), 2.55-2.65 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 5.05-5.15 (m, 1H), 6.70 (d, 1H), 6.80-7.00 (m, 3H), 7.20-7.40 (m, 4H), 7.45 (s, 1H), 7.50 (d, 2H), 7.70 (d, 1H), 7.80 (d, 1H). MS m/z: 489/491 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O1CCCC1>[OH-].[OH-].[Pd+2].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)[C@H]1CCCC[C@@H]1Cc1cc(F)cc(F)c1
Reaction time: 96 h

Procedure:
A mixture of (1S,2R)-2-(3,5-difluorophenylcarbonyl)cyclohexanecarboxylic acid (1 g, 3.7 mmol), 10% Pd(OH)2 on carbon (1 g), tetrahydrofuran (10 mL) and acetic acid (0.5 mL) was shaken under hydrogen atmosphere at 50 psi for 96 h. The reaction mixture was filtered through Celite®, and filtrate and evaporated to give (1S,2R)-2-(3,5-difluorophenyl-methyl)cyclohexanecarboxylic acid, as a white solid (0.9 g, 95%).
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:21])[C:5](=[CH:22][O:23][CH2:24][CH3:25])[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1csc2ccc(C(=O)CC(=O)C3CC3)c(OC)c12
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1

Procedure:
A mixture of 5-(3-cyclopropyl-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.5 g) and triethyl orthoformate (0.73 g) was heated under reflux with acetic anhydride (10 ml) for 3 hours. After cooling and addition of toluene the solution was evaporated to dryness to yield 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene as a red oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]1([P:15](Cl)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.O1CCOCC1.O1CCOCC1>[NH2:2][O:3][P:15](=[O:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Into a 500-mL three neck round-bottom flask, was placed a solution of hydroxylamine hydrochloride (30.0 g, 432 mmol) in H2O/dioxane (90/45 mL). The solution was cooled to 0-5° C., then sodium bicarbonate (36.5 g, 434 mmol) was added portion-wise over 10 min and the mixture was stirred at 0-5° C. for 30 min. A solution of diphenylphosphinoyl chloride (41.0 g, 173 mmol) in dioxane (45 mL) was added drop-wise at 0-5° C. over 30 min, then the resulting mixture was stirred for an additional 2 h at ambient temperature. The resulting solids were collected by filtration and washed with water (200 mL), NaOH (0.25 M, 200 mL) and PE (200 mL). The product was dried to yield the title compound as a white solid (20 g, crude).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([N:27]([CH2:35][CH2:36][CH3:37])[C:28](=[O:34])[CH2:29][CH2:30][C:31](O)=[O:32])[CH2:25][CH3:26]>>[CH2:35]([N:27]([CH2:24][CH2:25][CH3:26])[C:28](=[O:34])[CH2:29][CH2:30][C:31]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:32])[CH2:36][CH3:37]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCN(CCC)C(=O)CCC(=O)O
Product: CCCN(CCC)C(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-(dipropylamino)-4-oxobutanoic acid to yield (3aR,4S,7aR)-methyl 4-(4-(dipropylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.771 min; LC/MS LC-MS Method III
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[CH2:3]1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4-dimethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg) and pyridine (3 mL) was added benzenesulfonyl chloride (60 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by HPLC to give N-[2-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide. LC/MS m/e obsd. (ESI−) [(M−H)−] 459.3.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>C1COCC1>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
To a solution of 10.38 g (62.5 mmol) of fluorene in 250 ml of THF at 0° C. was added dropwise a 1.6 molar solution of butyllithium in hexane (39.05 ml, 62.5 mmol) in order to produce fluorenyllithium. The solution was stirred for 3 h at room temperature and then added dropwise over a period of 2 h via a cannula to 125 ml (1.45 mol) of 1,2-dibromoethane. The solution was stirred overnight at room temperature. After hydrolysis with 125 ml aqueous NH4Cl, the organic layer was separated. The aqueous layer was extracted twice with ether. The combined organic layers were dried on MgSO4, filtered and the solvents were removed. The excess 1,2-dibromoethane was recovered by trap to trap distillation at 0.5 mm Hg with gentle heating by a warm water bath. A chilled receiving flask was used. The resulting yellow residue was dissolved in pentane, filtered, concentrated and cooled to -20° C. to give 1-(9-fluorenyl)-2-bromoethane (10.25 g, 60%) as a yellow solid; melting point: 48-49° C. 1H NMR data was consistent with that reported in literature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1>CCO.C(Cl)Cl.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2Br)CC1
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (from Step 1 of Intermediate VV; 2.435 g, 5.99 mmol) in 20 mL EtOH was treated with platinum(iv) oxide (0.136 g, 0.599 mmol) and was placed under 45 psi H2 for one hour. LC/MS showed mostly product and de-brominated product. The reaction mixture was diluted with DCM and was filtered through diatomaceous earth. The filtrate was concentrated then purified directly by column chromatography (0 to 15% EtOAc/heptane) yielding tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.970 g, 2.376 mmol, 39.6% yield). m/z (ESI) 431.0 (M+Na)+.
Reaction SMILES: [C:1]([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12.CI>C1COCC1>[CH2:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:8]=12)[CH3:1]
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: [Li]C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CCCc1nc2nccc(CC)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (0.978 mL, 1.7M/pentane) was added to a cooled (-78° C.) THF (5 mL) solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (97 mg, 0.554 mmol). After 2 hour the reaction was warmed to 0° C. for 1 minute then cooled back to -78° C. MeI (0.172 mL) was added, the mixture was stirred at -78° C. for 1 hour then warmed to 0° C. for 1 minute and then quenched (NH4OH). Extractive workup and purification (SiO2, 2% MeOH/ EtOAc) gave 85 mg of 7-ethyl-2-propylimidazo[4,5-b]pyridine which was converted to the title compound as outlined in Example 7, Part B.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1

Procedure:
A solution of 3,5-dimethylanisole (102.5 g, 753 mmol) in MC (1,000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml, 3.763 mmol) in MC (250 ml) was added dropwise to this solution. After a reaction time of 10 min, the reaction solution was introduced into an ice bath (1,000 ml), the phases were separated and extraction was carried out once more with MC (250 ml). The combined organic phases were washed with water (1,000 ml) and saturated sodium chloride solution (1,000 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography over silica gel (heptane/MC 5:1). Yield: 63.5 g, 36%
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=O)[CH2:3]2.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C2C(=CC=CC=2)C=C1.O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O>C(Cl)Cl>[NH:10]1[CH:2]2[C:3]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:18][C:4]=3[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]2
Reactant: NNc1ccccc1
Reactant: O=C1CC2CCCC(C1)N2
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: c1ccc2[nH]ccc2c1
Solvent: ClCCl
Solvent: O
Product: c1ccc2c3c([nH]c2c1)CC1CCCC3N1

Procedure:
This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and phenylhydrazine by Fischer indole synthesis as described in Example 1, Method A, to give colorless crystals, mp 198°-203° C. (from methylene chloride; it was also converted to a hydrogen oxalate hemihydrate, mp 68°-72° C. (from ethanol-ether).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH2:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][NH:26][S:31]([CH3:30])(=[O:33])=[O:32])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 69 mg (0.16 mmol) of (3S,5R,6S)-3-allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 28, Step B from the non-racemic precursor described in Example 19, Step A) in 1.6 mL of DCM was added methanesulfonyl chloride (13.7 μL, 0.175 mmol) and pyridine (38.7 μL, 0.478 mmol) successively at 0° C. After being stirred at rt for 14 h the reaction mixture was acidified with 10% aq. citric acid and extracted (2×DCM). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by reversed phase HPLC (40 to 90% MeCN/H2O in 45 min, 2 injections, tR=25.94 min) provided the title compound as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.N>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Agent: N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 9.7 g. (37 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 40 ml. methylene chloride and 6.3 g. (80 mmole) anhydrous pyridine is added dropwise at 0° C., in the course of 40 minutes, a solution of 7.0 g. (37 mmole) 4-chlorophenylacetyl chloride in 20 ml. methylene chloride, a cheesy precipitate being formed. After stirring at 20° C. for 4 hours, the reaction mixture is poured into 250 ml. ice water, rendered alkaline with ammonia and extracted several times with methylene chloride. The methylene chloride solution is washed twice with water, dried with anhydrous sodium sulphate and evaporated. After the addition of ligroin, crystallisation occurs. The product is recrystallised from diethyl ether to give 51% of theory of the desired product; m.p. 88°-89° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[OH:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1O
Yield: 71.7 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-hydroxy-4-aminobenzoate (123 mg, 0.736 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (50:1)] and recrystallized to obtain methyl 2-hydroxy-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (101 mg, 72%) as colorless prisms.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cn[nH]c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCn1cc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A solution of methyl pyrazole-4-carboxylate (10 g) in N,N-dimethylformamide (100 ml) was treated with potassium carbonate (10.95 g) and 1-bromodecane (19.31 g) and the mixture was stirred for 16 hours at room temperature. Ethyl acetate was added and the solution was washed with water (6x), dried over magnesium sulfate and the evaporated residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give methyl 1-decylpyrazole-4-carboxylate (19.4 g) as a white solid.