Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>Cl>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCC3)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CC3)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.63 g), dimethyl carbonate (33 ml) and 7—(4-methylphenyl)-1-tetralone (4.93 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 3N hydrochloric acid(80 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (30 ml), and to the mixture was added sodium boron hydride (494 mg) at 0° C. and then was dropwise added methanol (3 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), and to the mixture was added 1N sodium hydroxide (20 ml). The mixture was refluxed for 4 hours, cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (20 ml), and to the mixture was added concentrated hydrochloric acid (4 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxylic acid (1.96 g) as pale brown crystals.
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.N1CCNCC1.C(N(CC)CC)C.[F:32][C:33]([F:37])=[C:34](F)F.C[O:39]CCOCCOC>>[F:32][CH:33]([F:37])[C:34]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:39]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Reactant: COCCOCCOC
Agent: C1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 70 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride salt (1.47 g, 5.0 mmol), piperazine (0.64 g, 7.5 mmol) and triethylamine (1.52 g, 15.0 mmol) in diglyme (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.7 liter/hr), with vigorous stirring at 70° C. for 24 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The diethyl ether layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.01 g, 3.0 mmol, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](CC#N)[CH:7]=1.[OH-:13].[K+].[CH2:15]([OH:17])[CH3:16]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH2:16][C:15]([OH:13])=[O:17])[CH:7]=1
Reactant: [OH-]
Reactant: COc1ccc(Cl)cc1CC#N
Reactant: CCO
Agent: [K+]
Solvent: O
Product: COc1ccc(Cl)cc1CC(=O)O

Procedure:
To a solution of (5-chloro-2-methoxy-phenyl)-acetonitrile (17.2 g, 96.3 mmol) in ethanol (200 mL) and water (20 mL) was added potassium hydroxide (27 g, 481 mmol). The reaction was heated to reflux for 12 hours, cooled and the ethanol was removed by concentrating in vacuo. The remaining solution was acidified with aqueous hydrochloric acid (3 M) and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound (15.6 g).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([OH:25])(=O)[CH2:20]C(O)=O.[N:26]1[CH:31]=CC=C[CH:27]=1.C(=O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O>C(OCC)(=O)C>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([CH2:20][C:19]([N:26]([CH3:31])[CH3:27])=[O:25])([OH:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: O=C(O)CC(=O)O
Agent: CN(C)C(=O)Cl
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A 500 mL flask is charged with N-benzyl isatin (55 g, 0.231 mol), malonic acid (28.95 g, 0.278 mol), and pyridine (73.4 g, 0.927 mol). To the formed red suspension, ethyl acetate (50 mL) is added, and the stirred mixture is heated to 80° C. After about 30 minutes a solution has formed which is kept stirring at 80° C. until no further formation of carbon dioxide is observed (about 2.5 h). Then triethyl amine (35.2 g, 0.347 mol) is added, and the mixture is stirred for another 10 minutes at 80° C. To the dark red solution, then dropwise (exothermicl) dimethyl carbamoyl chloride (32.4 g, 0.301 mol) is added during 10 minutes. When the evolution of carbon dioxide ceases, the mixture is kept stirring at 80° C. for another two hours, and then the solvent is removed from the brown suspension on the rotavapor. To the residue, HCl (4N, 0.2 L) is added, and the formed suspension is stirred for one hour at 80° C. After cooling and standing in the refrigerator over night, the crystals are filtered off, washed twice with water (about 150 mL each wash) and dried in vacuo to give light brown crystals. Yield of the title compound: 66.7 g (88.7% based on N-benzyl isatin). 1H-NMR (CDCl3, 300 MHz) δ 2.69, 3.03 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.91, 2.99 (2 s, 3 each, N(CH3)2); 4.87, 4.89 (AB, 2H, 2J=15.8 Hz, CH2Ph); 6.70 (d, 1H, J=7.7 Hz, H-7); 7.01 (dtr, J=7.7 Hz, J=1.1 Hz, H-5); 7.17 (dtr, 1H, J=7.7 Hz, J=11 Hz, H-6); 7.21-7.34 (m, 5H, Ph); 7.49 (dd, J=7.3 Hz, J=1.8 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.64, 37.66 N(CH3)2; 38.21 (CH2CONMe2); 44.02 (CH2Ph); 74.61 (C-3); 109.70 (C-7); 123.38 (C-5); 124.63 (C-4); 127.51, 127.90, 129.03 (Ph ortho-C, para-C, meta-C); 129.82 (C-6), 131.15 (C-9); 135.77 (Ph ipso-C); 142.47 (C-8); 171.18 (CONMe2); 176.51 (C-2).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=CC([C:39]([F:42])([F:41])[F:40])=CC=2N=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:7]4[S:8][C:4]5[CH:3]=[CH:2][C:28]([C:39]([F:42])([F:41])[F:40])=[CH:27][C:5]=5[N:6]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1ccc2sc(Cl)nc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(C(F)(F)F)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-5-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.12-2.30 (m, 4H), 3.04-3.17 (m, 2H), 3.36-3.45 (m, 2H), 4.48-4.58 (m, 1H), 7.84 (dd, J=8.6, 1.2 Hz, 1H), 8.07 (s, 1H), 8.40-8.44 (m, 2H), 8.46 (d, J=8.4 Hz, 1H), 8.54 (s, 1H), 8.57 (d, J=2.2 Hz, 1H). MS (ES+): m/z=445.09 [MH+]. HPLC: tR=2.39 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21].O.CO>C1(OC)C=CC=CC=1.[Pd]>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:21][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[CH3:1])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1C(=O)C1CCCCC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: COc1ccccc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1C
Temperature: 80 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a mixture of 2-(2-methylbenzoyl)cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-[(2-(2-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (52.9 g, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:27][C:28]=2[CH3:29])=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:27][C:28]=3[CH3:29])=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: Cc1oc(-c2cccs2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4cccs4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (300 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(2-thienyl)oxazole (450 mg), and N,N-dimethylformamide (5 ml), sodium hydride (60%, oily, 70.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained colorless oily substances, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (460 mg, yield: 70%) was obtained. This was recrystallized from acetone-hexane. Melting point: 156–157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C.C1(C)C=CC=CC=1>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[S:58])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]3[CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 0.08 h

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31 mg) was dissolved in ethanol (1 ml) under a nitrogen atmosphere, and then (S)-(+)-10-camphorsulfonic acid (47 mg) was added thereto, followed by stirring for 5 min. A 0.25 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.448 ml) was added thereto, followed by stirring for 15 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; heptane:ethyl acetate=1:8, ethyl acetate, then ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated under reduced pressure to give a residue, which was then purified by LC-MS. Fractions containing the target compound were concentrated to give a residue, which was then partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (0.9 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18]3)=[CH:7][CH:8]=1
Reactant: Brc1ccc2c(c1)CCN2
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cn1
Temperature: 100 °C

Procedure:
1.6 g 2-(Trifluormethyl)pyridin-5-ylboronic acid, 1.66 g commercially available 5-Bromo-2,3-dihydro-1H-indole and 8.19 g cesium carbonate were dissolved in a mixture of 7 ml water and 21 ml dimethylformamide. The reaction mixture was degassed with argon and then 484 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 100° C. for two hours. The cooled reaction mixture was diluted with 200 ml ethyl acetate and washed with 100 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 885 mg 5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[Cl:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[O:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[C:4]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 29.1 %

Procedure:
A mixture of 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (1 g, 3.4 mmol), p-fluorophenylsulfonyl chloride (1.33 g, 6.8 mmol) and Eaton's reagent (20 mL) was stirred at 110° C. for 4.5 h and the solution turned brown. The brown solution was poured into ice water and extracted with EtOAc (3×30 mL). The combined extracts were washed with sat'd sodium bicarbonate (3×50 mL), brine (50 mL), dried and concentrated. The residue was purified by chromatography (20% EtOAc in Hexanes) to give the title compound of Step A (468 mg). MS (APCl−) Calc.: 471.0, Found: 470.0 (M−1).
Reaction SMILES: C([O:8][C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH3:23])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO.[Pd]>[CH3:23][O:22][C:20]([C:15]12[CH2:18][CH2:19][C:12]([CH2:11][CH2:10][C:9]([OH:24])=[O:8])([CH2:17][CH2:16]1)[CH2:13][CH2:14]2)=[O:21]
Reactant: COC(=O)C12CCC(/C=C/C(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C12CCC(CCC(=O)O)(CC1)CC2
Reaction time: 2 h

Procedure:
Diester 11-2 (0.625 g, 1.90 mmol) was dissolved in a 1:1 mixture of ethyl acetate/methanol (30 mL), placed under nitrogen atmosphere, then treated with 10% Pd/C (500 mg) and 0.1 mL of acetic acid. The reaction was placed under hydrogen atmosphere and stirred vigorously for 2 hr. The resulting solution was filtered through celite and the solvent was removed under reduced pressure. The residue was partitioned between 200 mL of ethyl acetate and 200 mL of 1 N NaOH solution. The aqueous layer was separated and neutralized, then extracted three times with 50 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to afford 3-[4-(methoxycarbonyl)bicyclo[2.2.2]oct-1-yl]propanoic acid (11-3). 1H NMR (500 MHz, CDCl3): δ 3.62 (3H, s), 2.20 (2H, broad t, J=9 Hz), 1.75 (6H, m), 1.47 (2H, broad t, J=9 Hz), 1.38 (6H, m) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15](=[O:17])[CH3:16])[CH2:9]1)(C)(C)C.[ClH:19].O1CCOCC1>C(Cl)Cl>[ClH:19].[NH2:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][N:10]([C:15](=[O:17])[CH3:16])[CH2:9]1
Reactant: CC(=O)N1C[C@H](C)C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1C[C@H](C)C[C@@H](N)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
((3R,5R)-1-Acetyl-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester (0.5 g, 1.971 mmol) was dissolved in DCM (15) and HCl 4M in dioxane (2.5 mL, 10 mmol) was added. The resulting colorless solution was stirred at RT until precipitation of a solid was observed. The solvent was evaporated and the residue was dried under high vacuum to give 0.45 g of 1-((3R,5R)-3-amino-5-methyl-piperidin-1-yl)-ethanone hydrochloride as an off-white solid (>95% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCC(C)(C)c2ccc(N)cc21
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(8-Amino-5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (93%). LCMS: m/z=551.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.12 (d, 1H, J=8.6 Hz), 8.01 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.41 (d, 1H, J=1.5 Hz), 7.32 (m, 2H), 6.53 (m, 2H), 4.74 (m, 1H), 3.89 (m, 7H), 3.17 (m, 4H), 2.60 (m, 1H), 2.20 (m, 1H), 1.91 (s, 3H), 1.62 (m, 3H), 1.41 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CN(C)P(N(C)C)(N(C)C)=O>O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C#N)cc1

Procedure:
A solution of 12 g. of 4-aminobenzonitrile and 15 g. of methyl 16-bromohexadecanoate in 200 ml. of hexamethylphosphoramide is heated at 120° for 22 hours, allowed to cool, and diluted with water. The mixture is chilled and the precipitate which forms is collected, dried, and recystallized from etherhexane to yield 4-(15-carbomethoxypentadecylamino)benzonitrile as a white solid.
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7]([C:9]1(C(OC)=O)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=2)[CH2:10]1)=[O:8].O.[Cl-].[Li+]>CCOCC>[Cl:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:7]([O:6][CH3:5])=[O:8])[CH2:17]2
Reactant: COC(=O)C1(C(=O)OC)Cc2ccc(Cl)cc2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1Cc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To 300 ml of dimethyl sulfoxide, were added successively 64.0 g of 2,2-dimethoxycarbonyl-5-chloroindane, 5 ml of water and 10 g of lithium chloride. The mixture was heated with stirring for 3 hours at 120° to 130° C. The reaction mixture was cooled to room temperature poured into 500 ml of ice water, and mixed with ether. After the ether layer was separated, the aqueous layer was extracted twice with ether. The ether layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was distilled in vacuo to obtain 15.97 g of the purified intended product. Boiling point, 113°-131° C./0.3 mmHg.