Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:20]=1[CH3:36].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3,3-dimethyl-6-morpholinoindoline (85 mg, 0.367 mmol) in DMF (6 mL), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 367 μmol) and sodium hydride (18 mg, 733 μmol) and heating at 130° C. overnight. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 8.73-8.76 (1H, m), 7.80-7.94 (4H, m), 7.40 (1H, ddd, J=7.6, 4.9, 1.5 Hz), 7.20-7.27 (1H, m), 7.08 (1H, d, J=8.3 Hz), 6.31 (1H, dd, J=8.1, 2.2 Hz), 5.59 (1H, d, J=2.4 Hz), 3.69-3.81 (6H, m), 2.89-3.03 (4H, m), 2.37 (3H, s), 1.51 (3H, s), 1.46 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11](=[O:20])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C[Si]([I:32])(C)C.II>C(Cl)Cl>[I:32][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]1=[O:20]
Reactant: C[Si](C)(C)I
Reactant: COc1ccc(C2CC(=O)Nc3ccccc3C2)cc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2Cc3ccccc3NC(=O)C2I)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (-20° C.) solution of 500mg (1.87mmole) of 2,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1H-1-benzazepin-2-one in 10 mL of methylene chloride was added triethylamine (1.04g, 9.35 mmol, 5eq.) followed by trimethylsilyl iodide (749mg, 3.74mmol, 2eq.). After 15 minutes, 950 mg (3,74 mmol, 2eq) of iodine was added and the brown mixture was stirred at 0° C. for one hour. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium bisulfite solution, water and brine and then dried (MgSO4). Filtration followed by evaporation of the solvent under vacuum gave the product as a mixture of cis and trans isomers (675 mg,92%). FAB-MS: calculated for C17H16NO2I 393; found 393 (100%), 394 (20%).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:24][CH:23]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:40]([O:42]CC)=[O:41].[OH-:47].[Li+].Cl.[O:50]1CCOCC1>>[C:3]([OH:50])([C:2]([F:46])([F:45])[F:1])=[O:47].[F:46][C:2]([F:1])([F:45])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)[N:9]=2)[N:6]=[CH:5][C:4]=1[C:40]([OH:42])=[O:41]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(COc4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C(O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(COc4ccc(C(F)(F)F)cc4)cc3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 7 Step B (15.0 mg, 0.023 mmol) 1,4-dioxane (0.500 mL) was added lithium hydroxide (0.5 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (30 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 614.2 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.73 (dd, J=7.5, 1.5 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 5H), 7.27 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.09 (t, J=7.5 Hz, 1H), 5.25 (s, 2H), 5.18 (s, 2H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1Cl
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccccc2Cl)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2-chlorophenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H21ClFN2O3: 403.1225. found: 403.1237. 1H NMR (500 MHz, CDCl3) δ: 2.96 (s, 3), 3.05 (t, 2, J=7), 3.75 (t, 2, J=7), 3.99 (s, 2), 4.58 (s, 2), 7.01–7.34 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 32.37, 34.52, 42.90, 49.36, 51.47, 109.38, 115.66, 115.83, 127.18, 128.37, 129.26, 129.32, 129.67, 130.92, 132.13, 132.15, 134.01, 135.79, 152.71, 161.37, 163.33, 164.91, 166.11.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]S)[CH3:34]>>[CH:1]1([N:7]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:33][N:35]([CH2:39][CH3:40])[CH2:36][CH3:37])=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)CCS
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.Cl.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:19][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: CCNCC
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CCN(CC)CCC(=O)c1c(-c2ccccc2)oc2ccccc12

Procedure:
To a solution of 47.2 grams of 2-phenyl-3-acetyl benzofuran in 150 milliliters of isopropanol, were added 8.4 grams of paraformaldehyde, 30.8 grams of diethylamine hydrochloride and 3 milliliters of a saturated solution of hydrogen chloride in ethanol and the mixture was heated at its boiling point under reflux for 8 hours. The solvent was then evaporated from the mixture under vacuum and the residue was triturated with water and the insoluble portion thereof was extracted therefrom with ethyl ether. The aqueous solution was made alkaline by the addition of a 5% aqueous sodium hydroxide solution and the oily base which separated was extracted with ethyl ether. After drying the ether extract over anhydrous sodium sulfate a solution of hydrogen chloride in ethanol was added thereto and the crystalline hydrochloride of the compound named in the heading of this example precipitated. The crystals thus obtained were recrystallized in a mixture of ethanol and ethyl ether. In this manner, 34.2 grams of the recrystallized hydrochloride, which had a melting point of 113°-115°C, was obtained.
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
12.4 grams of 2-benzyl-2-ethoxycarbonyl-cyclopentanol obtained from Example 14 were diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, and then using 10% aqueous solution of sodium carbonate for three times. The organic layer was dried, and removing solvent gave 19.71 g of yellow liquid. MS: m/e 353(M++1), 352(M+), 351(M+−1), 279(M+—CO2CH2CH3), 261(M+—CH2C6H5), 247(M+—C6H5CO), 231(M+—C6H5CO2), 201, 184, 156, 139, 105 (base), 91, 77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][CH:13]2[CH2:12][O:11][C:10]3=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:10][OH:15])[CH2:14][CH:13]2[CH2:12][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OCC2C[C@@]12c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1C[C@]1(CO)c1ccc(Cl)c(Cl)c1
Yield: 917.2 %

Procedure:
BMS (17.16 mL, 18 mmol) was added to (1R)-1-(3,4-dichlorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (22 g, 9 mmol) in dry tetrahydrofuran (200 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction mass was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 20.4 g (92%) of desired product. 1H NMR δ(300 MHz,CDCl3): 0.9-1.25 (1H,m), 1.35-1.52 (1H,m), 1.75-1.79 (1H,m), 3.32-3.42 (2H,m) 3.97-4.12 (2H,m) 7.26-7.30 (1H,dd,J=8.4,2.1 Hz), 7.40-7.43 (1H,d,J=8.4 Hz), 7.52-7.53 (1H,d,J=2 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (14.5 mL, 198 mmol) was added to a solution of 2-amino-6-methylbenzoic acid (10.0 g, 66.1 mmol) in benzene (250 mL). The resulting suspension was heated to reflux and stirred overnight. After cooling, the reaction was concentrated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). Aniline (15 mL, 165 mmol) was added, and the mixture heated to reflux. After three hours, the reaction was allowed to cool and the resulting suspension was filtered. The filtrate was subjected to flash chromatography, and the crude product recrystallized from isopropanol to provide compound 15 as a yellow crystalline solid. MS (ES): m/z 227 (M+H), 134. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 15 are shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[N:14][S:15][CH:16]=2)=[CH:8][CH:7]=1.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(OCC)(=O)C.CC(CC(C)C)=O>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[N:14][S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: ClCCCCc1ccc(-c2csnn2)cc1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(N3CCN(CCCCc4ccc(-c5csnn5)cc4)CC3)nsc2c1

Procedure:
To a 65 ml round-bottom flask equipped with condenser and N2 inlet were added 1.43 g (5.66 mmol) 4-(4-(4-chlorobutyl)phenyl)-1,2,3-thiadiazole, 0.90 g (4.11 mmol) N-benzisothiazolylpiperazine, 1.43 ml (8.22 mmol)diisopropylethyl amine, 0.87 g (8.22 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobutyl ketone. The reaction was refluxed for 24 hours, cooled, filtered, and the filtrate evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent to give an oil, which was taken up in ethyl acetate and precipitated by addition of ethyl acetate saturated with HCl. The solid was filtered, washed with ethyl acetate, and dried to afford 1.70 g (87.6%), m.p. 246°-247° C., white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:19]1[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][CH:24]=1>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[CH:16]=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(Br)c1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Product: COc1cccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Compound 5e (162 mg, 0.698 mmol) was coupled with 3-bromoanisole (0.13 mL, 1.04 mmol) according to the procedures described in Example 20, Step A to obtain compound 77a. Mass spectrum (LCMS, ESI pos.) Calcd. For C18H18N4O3 339.1 (M+H). found 339.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-])=O)[C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([NH2:23])[C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1c(NC(=O)c2cc3c([N+](=O)[O-])cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3c(N)cccc3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
The above nitro compound (200 mg, 0.42 mmol) was suspended in about 10 mL EtOAc and 10% Pd/C (50 mg) in 2 mL EtOAc was added. Hydrogen gas was introduced into the flask from an H2-filled balloon attached to a needle inserted through a septum. The black suspension was stirred 12 h at room temperature. After stirring 12, the black suspension was filtered through diatomaceous earth and the filter cake was washed several times with EtOAc. The combined filtrates were dried (MgSO4), filtered and the solvent was removed to afford 4-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a pale yellow solid (170 mg, 90%).
Reaction SMILES: [C:1]([S:5][CH2:6][O:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].S([O-])(O[O-])(=O)=[O:10].[K+].[K+].[OH2:17]>CO>[C:1]([S:5]([CH2:6][O:7][CH3:8])(=[O:10])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: COCSC(C)(C)C
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Product: COCS(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of methoxymethyl t-butyl sulphide XIV(ii) (2.68 g, 0.020 mol) in MeOH (80 mL) was added a solution of potassium peroxymonosulfate (2 KHSO5 KHSO4 K2SO4, Oxone®) (36.8 g, 0.060 mol) in water (80 mL) at 0° C. The resulting cloudy solution was warmed to room temperature and then stirred overnight. The mixture was diluted with water (30 mL), extracted with EtOAc (3×70 mL), washed with brine, dried over MgSO4, concentrated in vacuo, and then purified by column chromatography (25% EtOAc/hexanes) to give 3.05 g (92%) of Methoxymethyl t-butyl sulfone XII(iii) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.50 (s, 2H), 3.63 (s, 3H), 1.38 (s, 9H); 13NMR (100 MHz, CDCl3) δ 83.19, 60.84, 59.61, 23.32.
Reaction SMILES: CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:28][CH:29]1[CH2:36][CH:35]2[CH2:37][C:31]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=3)([CH:32]([CH3:47])[CH2:33][N:34]2[CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:30]1.Cl.[CH3:56][N:57]([CH3:64])[CH2:58][CH2:59][CH2:60][C:61](O)=[O:62].C(N(CC)CC)C>C1COCC1.CCOCC>[CH3:56][N:57]([CH3:64])[CH2:58][CH2:59][CH2:60][C:61]([NH:28][C@H:29]1[CH2:36][C@H:35]2[CH2:37][C@:31]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([OH:54])[CH:49]=3)([C@H:32]([CH3:47])[CH2:33][N:34]2[CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30]1)=[O:62]
Reactant: CN(C)CCCC(=O)O
Reactant: CC1CN(CCCc2ccccc2)C2CC(N)CC1(c1cccc(O)c1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(CCCc2ccccc2)[C@H]2C[C@H](NC(=O)CCCN(C)C)C[C@]1(c1cccc(O)c1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
BOP reagent (27 mg, 0.060 mmol) was added to a solution of (+)-7-amino-4-methyl-5-(3 -hydroxyphenyl)-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]nonane (23, 20 mg, 0.055 mmol), 4-(dimethylamino)butyric acid hydrochloride (18 mg, 0.11 mmol) and triethylamine (0.038 mL, 0.27 mmol) in dry THF (5 mL). The reaction mixture was stirred under N2 at room temperature for 4 h. The mixture was diluted with Et2O (20 mL), washed with saturated NaHCO3, followed by water, organic layer collected, dried (Na2SO4) and solvent removed under reduced pressure yielding crude product. This was purified by flash chromatography (33% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3) to afford 4-(dimethylamino)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]butanamide (13) (23 mg, 89%) as an off-white foam. 1H-NMR (CDCl3) δ7.28-7.09 (m, 6H), 6.89 (d, 1H, J=7.0 Hz), 6.64-6.59 (m, 3H), 6.31 (m, 1H), 4.65 (br., 1H), 3.16 (br., 1H), 3.02 (d, 1H, J=7.8 Hz), 2.69-2.14 (m, 16H), 1.91 (m, 1H), 1.86-1.75 (m, 4H), 1.58 (m 1H), 1.36-0.83 (m, 3H), 0.71 (d, 3H, J=6.5 Hz); LRMS (ES) m/z 478.7 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].Cl>O1CCCC1>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:2]=1[CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(C)=O
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
A solution of 3.89 g. (0.010 mol.) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 15 ml. of tetrahydrofuran was slowly added to 0.36 g. (0.015 mol.) of 70-80 mesh magnesium metal. The resultant mixture was refluxed for 20 minutes and was then cooled to -10° C. Cuprous iodide (0.115 g., 0.006 mol.) was added and stirring continued for 10 minutes. To the resultant mixture was slowly added a solution of 0.701 g. (0.010 ml.) of metyl vinyl ketone in 5 ml. of tetrahydrofuran at such a rate that the reaction temperature could be maintained below 0° C. The reaction mixture was stirred for 30 minutes longer (t<0° C.) and then added to 100 ml. of 1 N hydrochloric acid and 100 g. of ice. The quenched reaction was extracted three times with 150 ml. portions of ether. The combined ether extract was washed twice with 100 ml. portions of water, twice with 100 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified via column chromatography on 180 g. of silica gel eluted with 20% ether-cyclohexane to yield 1.07 g. (28%) of the title compound as an oil.
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23]N[CH2:21][CH2:20]1.Cl[CH2:26]Cl>>[CH2:11]([CH:5]([CH2:6][S:7]([CH:26]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCl
Reactant: CN1CCNCC1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)C1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a 1 L round bottom flask was added the resultant compound from Example 3E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3) delta 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3) delta 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.