Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[N:10]=2)=[CH:4][C:3]=1[CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][CH3:41])=[O:39])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH:40][CH3:41])=[O:39])[CH:33]=4)[CH:15]=3)[N:10]=2)=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(Nc2ccc3cc(O)ccc3n2)ccc1Br
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Br)c(C)c4)ccc3c2)ccn1

Procedure:
The mixture of 2-[(4-bromo-3-methylphenyl)amino]quinolin-6-ol and potassium bis(trimethylsilyl)amide (2 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and microwaved for 6 mins at 170° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product.
Reaction SMILES: Cl.Cl[CH:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[C:15]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[CH:14]2.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>C(#N)C>[N:34]1([CH:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([NH2:21])[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:14]3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: Cc1cccc(C(Cl)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C(c2ccccc2)n2ccnc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a small, sealed Smith synthesizer vial, 6-(2-(chloro(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine hydrochloride (0.030 g, 0.062 mmol) and imidazole (0.021 g, 0.312 mmol) were treated with ACN (0.416 mL). The solution was stirred at ambient temperature for 1 h. The reaction mixture was warmed to 100° C. for 1 h and then allowed to cool to ambient temperature. The mixture was purified by HPLC (1-70% acetonitrile/H2O, TFA modifier). A single clean fraction was treated with NH4OH and concentrated to ¼ volume. The resulting precipitate was collected and dried under a stream of N2 to afford 6-(2-((1H-imidazol-1-yl)(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 476 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.4 %

Procedure:
Dissolve 5-(4-formylphenoxy)pyrazine-2-carbonitrile (1.87 g, 8.30 mmol) and K2CO3 (0.573 g, 4.15 mmol) in DMSO (21 mL). Add 30% H2O2 (2.4 mL, 20.8 mmol) and stir at room temperature for 22 hours. Add additional K2CO3 (0.573 g, 4.15 mmol) and heat at 55° C for about 2.5 hours. Cool the reaction mixture and dilute with CH2Cl2, (200 mL). Wash with water (1×100 (mL) and saturated aqueous NaHCO3 (1×100 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.478 g, 23.7%): TOF MS ES+ 244.1 (M+H)+, HRMS calcd for C12H10N33 244.0722 (M+H)+, found 244.0709, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.2 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([N+:12]#[C-:13])([CH3:11])([CH3:10])[CH3:9].N#[C-].[CH3:16][S:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>Cl(O)(=O)(=O)=O>[C:8]([NH:12][C:13]1[N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]2=[N:1][C:23]=1[C:21]1[S:22][C:18]([S:17][CH3:16])=[CH:19][CH:20]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CSc1ccc(C=O)s1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1ncccn1
Agent: [C-]#N
Agent: [O-][Cl+3]([O-])([O-])O
Product: CSc1ccc(-c2nc3ncccn3c2NC(C)(C)C)s1

Procedure:
Compound (26) was prepared in accordance with general instructions 1 from 1.0 ml 2-aminopyrimidine solution (0.1 M, MC), 0.575 ml tert-butylisonitrile isocyanide solution (0.2 M, MC), 0.500 ml 5-methylsulfanyl-thiophene-2-carbaldehyde solution (0.3 M, MC), and 10 μl perchloric acid (w=20%). Calculated mass 318.5; found mass 319.2 (ESI-MS)
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:17][CH2:18][CH2:19][C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Br[CH2:32][CH2:33][S:34][C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[O:6]=[C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:17][CH2:18][CH2:19][C:20]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:25][CH2:24][N:23]([CH2:32][CH2:33][S:34][C:35]2[S:36][CH:37]=[CH:38][CH:39]=2)[CH2:22][CH2:21]1
Reactant: BrCCSc1cccs1
Reactant: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCN(CCSc2cccs2)CC1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 95 mg of ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)piperidine-4-carboxylate, 69 mg of 2-(2-bromoethylthio)thiophene and 84 mg of potassium carbonate were added at room temperature, and stirred at 50-55° C. for 1 hour. Additional 35 mg of 2-(2-bromoethylthio)thiophene was added and stirred at 50-55° C. for 1 hour, then stirred at 60° C. for 1 hour. The mixture was cooled to the room temperature, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to give 98 mg of ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a light brown oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II)chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (II) chloride (0.024 g), copper (1) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate was combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(C(C)=O)C(C)C.[NH4+]=[S:26]>O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([N:9]([CH2:12][C:13]([Cl:15])=[CH2:14])[C:10]([NH2:11])=[S:26])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(Cl)CN(C(N)=S)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
A mixture of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)cyanamide (168.67 g), methyl isobutyl ketone (674.70 g) and ammonium sulfide solution, yellow (518.77 g) having an S content of 6% was stirred at 50° C. for 9 hours. After cooling to 20° C., water (1774.70 g) was poured into the reaction mixture, which was then shaken and fractionated with a separatory funnel. The water layer was extracted twice with methyl isobutyl ketone (53.72 g×2). The combined methyl isobutyl ketone layer was washed with water (81.05 g) to give a methyl isobutyl ketone solution (938.58 g) of N-(3-(trifluoromethyl)phenyl)-N-(2-chloro-2-propenyl)thiourea.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C(OCC)(=O)C>O>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:45]4[CH:44]=[C:43]5[C:48](=[CH:47][CH:46]=4)[N:40]([CH3:39])[N:41]=[CH:42]5)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Cc1cc2nc(-c3cncc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 115 °C

Procedure:
(S)-2-(2-(5-bromopyridin-3-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate was telescoped into the subsequent reaction. 1-Methyl-1H-indazol-5-ylboronic acid (0.024 g, 0.14 mmol) was added to the one-half of the previous reaction mixture and reaction heated in microwave at 115° C. for 30 minutes. Reaction mixture was portioned between ethyl acetate and H2O, the organic layer removed and concentrated to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate. LCMS-ESI+: calc'd for C38H40ClN4O3S: 667.2 (M+H+); found: 667.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (160 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with water and ethyl acetate. The organic layer was further washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded crude 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide as a yellow solid. Recrystallization from 2/1 hexanes/ethyl acetate afforded pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide (114 mg, 44%) as a white solid: mp 195-196° C.; EI-HRMS m/e calcd for C18H22N2OS2 (M+) 346.1174, found 346.1171.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N+:13]([C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][CH2:22][NH:23][C:18]=2[CH:17]=1)([O-:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:23]1[CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCN1CCOc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To an oven dried, argon purged flask fitted with a magnetic stirbar was added tert-butyl methyl(2-oxoethyl)carbamate (0.135 g, 0.777 mmol), and DCE (10 mL). At this time, stirring began, and 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.10 g, 0.555 mmol) was added, followed by acetic acid (0.064 mL, 1.110 mmol) and sodium triacetoxyborohydride (0.294 g, 1.388 mmol). The resulting mixture stirred overnight at room temperature. After 18 hours, the reaction was quenched by the addition of saturated NaHCO3 (10 mL) and extracted with CH2Cl2. The aqueous layer was extracted further, and the combined organics were washed with brine, dried (Na2SO4), and concentrated. The crude product was combined with the product of a second reaction (prepared in accordance with the above procedure, with the omission of acetic acid). The combined products were purified on silica gel eluting with 50-70% EtOAc/hexanes to yield the title compound as a yellow residue (130 mg, 34.7%). 1H NMR (DMSO-d6) δ 7.58-7.37 (m, 2H), 6.92-6.80 (m, 1H), 4.25 (t, 2H, J=4.2 Hz), 3.58-3.36 (m, 6H), 2.87-2.74 (m, 3H), 1.27, 1.18 (2×s, 9H); ESI-MS (m/z, %): 360 (MNa+, 100).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13]C(C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.16 (d, J=7.4, 1H), 7.57 (d, J=8.6, 2H), 6.62 (d, J=8.7, 2H), 4.36 (dd, J=13.0, 6.9, 1H), 3.53 (dd, J=10.2, 3.4, 1H), 3.39-3.33 (m, 1H), 3.29 (q, J=6.9, 1H), 3.22 (dd, J=9.7, 8.1, 1H), 3.01 (dd, J=9.9, 4.0, 1H), 2.77-2.63 (m, 2H), 2.42 (s, 3H), 2.20-2.13 (bs, 1H), 2.12-2.03 (m, 1H), 1.99-1.86 (m, 1H), 1.64 (dq, J=12.7, 7.9, 1H), 1.41 (d, J=6.8, 3H), 1.39-1.32 (m, 1H); MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[S:12]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[N:18]=2)=[CH:15][C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2>O1CCOCC1>[ClH:23].[ClH:23].[ClH:23].[S:12]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)[N:18]=2)=[CH:15][C:14]2[CH:24]=[CH:25][CH:26]=[CH:27][C:13]1=2
Reactant: CN1CCN(CCCN)CC1
Reactant: Clc1nccc(-c2cc3ccccc3s2)n1
Solvent: C1COCCO1
Product: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Product: Cl
Yield: 213.5 %

Procedure:
1-(3-Aminopropyl)-4-methylpiperazine (3.02 g, 19.2 mmol) is added to a stirred suspension of 4-(benzo[b]thiophen-2-yl)-2-chloro-pyrimidine (2.06 g, 8.34 mmol) in anhydrous 1,4-dioxane (25 mL) at ambient temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 28 hours. At ambient temperature the mixture is concentrated and subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-6%, to give the free base of the title compound as a white solid (2.83 g, 92% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([CH:24]1[CH2:28][CH2:27][N:26]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1CCNC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
4-Methoxy-benzoyl chloride (185 mL, 1.36 mol) and triethylamine (259 mL, 1.86 mol) were added to a stirred solution of pyrrolidine-3-carboxylic acid ethyl ester (177.5 g, 1.24 mol) (see Preparation 1) in THF (2500 mL) at 10° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with 10% citric acid aqueous solution (2000 mL) then ethyl acetate (2000 mL) was added. The organic layer was washed with saturated aqueous NaHCO3 (2000 mL) and water (2000 mL), dried over magnesium sulphate then concentrated under reduced pressure to afford the title compound as a brown oil (285.3 g, 83%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([NH:3][CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2]
Reactant: [H][H]
Reactant: CCNCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCNCC1CCNC1
Reaction time: 24 h
Yield: 74.6 %

Procedure:
A mixture of 151.6 g (0.69 mole) of N-ethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 5 g of 20% palladium on carbon, and 1100 ml of ethanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and at room temperature for 21.6 hours. Another 5 g of 20% palladium on carbon was added and the hydrogenation continued for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was distilled under vacuum (88-91° C., 11.5 mm Hg) to give 66.0 g N-ethyl-3-pyrrolidinemethanamine.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:22][CH:21]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:29]2[CH2:30][CH2:31][C@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[C@H:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-4-(4-chloro-phenyl)-3-phenyl-piperidine hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC[C@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)OCC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 74 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 14b as the starting material afforded the title compound (38 mg, 74% yield) as a white solid:
Reaction SMILES: C([CH:3]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6]C=1)=C.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[C:55]([Cl:59])(Cl)(Cl)Cl>>[CH:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:3]2[CH:4]=[CH:9][C:8]([CH2:55][Cl:59])=[CH:7][CH:6]=2)=[CH:17][CH:16]=1)=[CH2:20]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CC(OCc1ccc(CO)cc1)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=Cc1ccc(COc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of p-hydroxymethylbenzyl vinylbenzyl ether (39.2 g, 0.16 molar), triphenylphosphine (46.0 g, 0.18 molar), and 2,6-di-tert-butyl-p-cresol (0.5 g) in carbon tetrachloride (550 ml) was heated at reflux for 2 hours and then stirred at ambient temperature overnight. The next day the reaction was filtered and the solvent removed on a rotary evaporator. To the residue was added methanol (300 ml) to precipitate a white solid: m.p. of 110°-112° C. Yield of 83%. Analysis calculated for C16H15C10: C, 74.27, H, 5.84. Found: C, 73.15, H, 5.84. 1H NMR (CDCl3) δ 4.5)s. 2H, CH2Cl), 5.0 (s, 2H, CH2O), 5.2+5.75 (AB quartet, 2H, CH2 =), 6.75 (m, 1H, CH=), 6.9+7.3 (AB quartet, 4H, ##STR22## 7.4 (s, 4H, ##STR23##