Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:13]
Reactant: CCN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Product: CCN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with cinnamoyl chloride according to the procedure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]cinnamanilide, m.p. 119.5°-121.5°C. (corr.), from ethyl acetate and then acetonitrile.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:21][CH:20]=1)#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a suspension of sodium hydride (60% in oil, 19.1 g) in tetrahydrofuran (500 ml) was added a solution of ethyl 3-oxohexanoate (116 g) in tetrahydrofuran (500 ml) dropwise at room temperature. After being stirred at room temperature for 30 min, 4′-(bromomethyl)-biphenyl-2-carbonitrile (100 g) was added to the mixture and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the mixture. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (129 g, 100%).
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:40]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:47](=[O:48])[CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 16.46 g of diphenylmethyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 160 ml of methylene chloride are added 9.6 ml of triethylamine and 9 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred at room temperature for 2 hours. The reaction mixture is then washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 200 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 17 to 19 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)α-isopropylideneacetate in 80 to 90% yield.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:15][C:14]=1[CH2:13][C@H:12]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH3:36])(=O)C.[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C@@H:12]1[CH2:13][C:14]2[CH:15]=[C:16]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:17]=[CH:18][C:19]=2[C@@H:20]2[C@@H:11]1[C@H:8]1[C@@:6]([CH2:22][CH2:21]2)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]1
Reactant: CNCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Yield: 101.4 %

Procedure:
A solution of 307 mg of 17β-acetoxy-7α-{5-methylaminopentyl}-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene (Example 1h) in 6 ml of methanol is stirred with 1.5 ml of sodium hydroxide solution for 4 hours at room temperature. Then, it is diluted with ethyl acetate, washed with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 285 mg of 7α-{5-methylaminopentyl}-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17β-ol is obtained.
Reaction SMILES: [Cl:1]Cl.CS[CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:7]=1[NH2:8].[ClH:17].O>C(Cl)CCl>[ClH:1].[Cl:17][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:7]=1[NH3+:8]
Reactant: CSCc1cccc(C(F)(F)F)c1N
Reactant: ClCl
Agent: Cl
Solvent: O
Solvent: ClCCCl
Product: [NH3+]c1c(CCl)cccc1C(F)(F)F
Temperature: 60 °C
Yield: 92.7 %

Procedure:
Chlorine (7.60 grams, 1.07 mol) was bubbled into a mechanically stirred solution of 221.0 grams (1.00 mol) of 2-methylthiomethyl-6-trifluoromethyl aniline in 2 liters of ethylene dichloride over 60 minutes while maintaining the reaction temperature below 20° C. A white suspension formed initially, became very thick halfway through the addition, and dissolved to give way to a cloudy solution at the end of the addition. The mixture was then heated to 60° C. while maintaining a steady stream of HCl bubbling through. Water (25 ml, 1.4 mol) was added and the HCl treatment was maintained at 60° C. for 15 minutes at which point a clear solution was obtained. Excess water was removed by azeotropic distillation (780 ml of solvent were removed) and the resulting solution was cooled to 0° C. with a steady stream of HCl bubbling through. Filtration, washing of the solids with 150 ml of cold ethylene dichloride and air-drying gave 228.0 grams (92.7%) of off-white 2-chloromethyl-6-trifluromethyl anilinium hydrochloride. This compound properties and analysis are described above.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH2:36][C:37](O)=[O:38])[CH:30]=2)=[CH:25][CH:24]=1.P(Cl)(Cl)(Cl)=O>O1CCCC1>[F:9][C:6]1([F:10])[CH2:7][CH2:8][C:3]([NH:2][C:37](=[O:38])[CH2:36][C:31]2[CH:30]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH:34]=[CH:33][C:32]=2[CH3:35])([C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]1
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1CC(=O)O
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(F)cc3)ccc2C)CCC(F)(F)CC1
Reaction time: 0.08 h

Procedure:
2.53 g (11 mmol) of the compound from Example 4A were initially charged in 50 ml of absolute tetrahydrofuran (THF). At 20° C., 3.07 ml of triethylamine were added dropwise, the mixture was stirred for 5 min and 2.44 g (10 mmol) of (4′-fluoro-4-methylbiphenyl-3-yl)acetic acid were added. After 15 min, a further 2.3 ml of triethylamine were added, followed immediately by the dropwise addition of 0.58 ml (6.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by means of flash chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 1:1. This gave 2.84 g (60% of theory) of the title compound of melting point 187° C.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:17]([O:20][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Product: CC(=O)OC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 57.5 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.30 g, 1.28 mmol) was refluxed in 50 ml of acetic acid for 10 min. Activated carbon (100 mg) was added and the reaction mixture was filtered and evaporated in vacuo to about 3 ml, and 20 ml of water was added. The precipitate was filtered off and washed with water and dried to give 229 mg of the crude compound, which was recrystallized from acetic acid-water to yield 190 mg (57.5%) of the title compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 2.13 (s, 3H), 6.36 (s, 1H), 7.15 (t, 1H), 7.29 (d, 1H) 7.35 (t, 1H), 7.5 (d, 1H), 12.0 (s, 1H), 12.4 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:5][C:4]1[CH:3]=[C:2]([C:17]2[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A mixture of 3-bromoaniline (0.48 g), N-tert-butyloxycarbonyl-2-pyrrole-boronic acid (0.6 g), sodium carbonate (0.91 g), tetrakis-(triphenylphosphine) palladium (1.3 g) in DME (30 mL) and water (5 mL) was heated under reflux under argon for 16 h. The reaction mixture was allowed to cool to room temperature and poured into water. It was then extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) and evaporated in vacuo. Repeated suction silica gel chromatography eluting with ethyl acetate in hexane (from 10% to 50%, 10% increments) gave desired product as an amber solid (0.3 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)NCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and ethanesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:30])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][C@@H:17]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:16]2)=[N:5][CH:4]=1.Cl.O1CCOCC1.C(=O)([O-])[O-]>C(Cl)Cl>[NH2:22][CH2:21][C@@H:17]1[O:18][CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:30])[CH2:16]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CNC(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CCO[C@@H](CN)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl [((2S)-4-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-2-morpholinyl)methyl]carbamate (0.46 g, 1.10 mmol) in CH2Cl2 (10 mL) was added HCl in 1,4-dioxane (1.10 mL, 4.40 mmol) and the resulting solution stirred at ambient temperature for 16 h. After concentration under reduced pressure, the free base was formed by treating with excess MP carbonate to yield a yellow oil. (0.300 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:59])[C:10]2[C:5](=[CH:6][C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)=[CH:8][CH:9]=2)[N:4]([CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3]1.[N-:60]=[N+:61]=[N-:62].[Na+].O>CN(C)C=O>[N:60]([CH2:47][CH2:46][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[O:37][CH3:38])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]3)[CH:6]=2)[C:2]([CH3:1])([CH3:59])[CH2:3]1)=[N+:61]=[N-:62]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCOS(=O)(=O)c2ccc(C)cc2)CC3(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCN=[N+]=[N-])CC3(C)C)cc1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.455 g of tert-butyl 3-{3,3-dimethyl-1-[2-(toluene-4-sulphonyloxy)ethyl]-2,3-dihydro-1H-indol-6-ylmethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 5.0 ml of N,N-dimethylformamide is admixed with 0.286 g of sodium azide and stirred at 65° C. over 1.5 hours. The reaction mixture is cooled, admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=6.56.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(OC(=O)c4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Dissolve the product of Example 3 (220 mg, 0.43 mmol) in pyridine (5 mL) and treat sequentially with benzoyl chloride (0.067 mL, 0.58 mmol), and DMAP (catalytic amount). Stir at ambient temperature for 18 hours and evaporate pyridine. Partition between saturated aqueous NH4Cl and ethyl acetate (containing 8% MeOH). After separation of the layers extract the aqueous layer with ethyl acetate (containing 5% MeOH) and combine the two organic layers. Wash with saturated aqueous NaHCO3 and brine. Dry the organic layer (Na2SO4), filter, and evaporate to obtain 276 mg of crude free base material. Pre-adsorb on to silica gel and chromatograph on a SiO2 column eluting with methanol in dichloromethane (0 to 6%) to give 260 mg of benzoic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester. Dissolve the free base in hot ethyl acetate (20 mL) and dilute with diethyl ether (20 mL). Cool in an ice bath and treat with 2M HCl in diethyl ether (0.31 mL, 0.62 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to obtain 255 mg of the title compound (91%): mass spectrum (ion spray): m/z=622.3 (M+H—HCl).
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:27](#[N:29])[CH3:28].O>N1C=CC=CC=1>[CH2:7]([CH:20]1[CH2:21][CH2:22][N:29]([S:16]([C:14]2[CH:13]=[CH:12][C:10]3[O:11][C:7]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][C:9]=3[CH:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:28]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(Cc2ccccc2)CC1
Temperature: 60 °C

Procedure:
2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (93 mg, 0.25 mmol) was dissolved in pyridine (1 ml). The appropriate amine (0.25 mmol) was added and the reaction was heated to 60° C. overnight. Water was added and solids respectively oils separated. The aqueous phase was decanted and the residue was stirred with acetonitrile. A solution was obtained, which was subjected to preparative reversed phase chromatography (gradient of acetonitrile/water containing 0.1% formic acid as the eluant) to yield the product after evaporation of the eluant and drying.
Reaction SMILES: O.[Cl-].[NH4+].[CH2:4]([N:6]1[CH:10]=[C:9]([CH2:11][N:12]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:13]([CH:15]2[C:24]3[C:19](=[C:20]([N+:25]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[O:18][CH2:17][CH2:16]2)=[O:14])[CH:8]=[N:7]1)[CH3:5]>C(O)C.[Fe]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[O:18][CH2:17][CH2:16][CH:15]2[C:13]([N:12]([CH2:11][C:9]1[CH:8]=[N:7][N:6]([CH2:4][CH3:5])[CH:10]=1)[C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)=[O:14]
Reactant: CCn1cc(CN(C(=O)C2CCOc3c2cccc3[N+](=O)[O-])c2ccc(C(C)C)cc2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCn1cc(CN(C(=O)C2CCOc3c(N)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 78.6 %

Procedure:
To a mixed solvent of ethanol (43 mL) and water (18 mL) were added iron (0.43 g) and ammonium chloride (0.06 g), and a solution of N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (0.9 g) in ethanol (10 mL) was added dropwise with heating and stirring at 50° C.-70° C. After stirring at 50° C.-70° C. for 3 hr, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 8-amino-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.66 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:19]2[CH2:18][C@H:17]3[N:20]([CH2:22][CH2:23][C@@:9]45[C@H:16]3[CH:15]=[CH:14][C@H:12]([OH:13])[C@@H:10]4[O:11][C:7]([C:8]=25)=[C:5]([OH:6])[CH:4]=1)[CH3:21].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].[NH4+].[OH-]>O.CO>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:6][C:5]2[CH:4]=[CH:3][C:19]3[CH2:18][C@H:17]4[N:20]([CH3:21])[CH2:22][CH2:23][C@:9]56[C:8]=3[C:7]=2[O:11][C@H:10]5[C@@H:12]([OH:13])[CH:14]=[CH:15][C@@H:16]46)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.5 g (37.5 mmol) of NaH (60% dispersion in mineral oil) was rinsed with 2×25 mL of hexanes to remove the oil. To the reaction mixture was added 140 mL of anhydrous DMF followed by 10.1 g (35 mmol) of morphine. This mixture was allowed to stir at room temperature for 30 minutes under nitrogen atmosphere, and 14.5 g (53 mmol) of N-(3-bromopropyl) phthalimide was added. The reaction mixture was allowed to stir 18 h at room temperature. The reaction was monitored by thin layer chromatography (silica, 7:2:1:1, MeOH:EtAc:NH4OH:H2O, l2 visualization), which showed that the reaction was incomplete. To the reaction mixture 0.15 g (3.75 mmol) of NaH (60% in oil) was added, and the mixture was allowed to stir for an additional 1.5 h. The mixture was poured into 350 mL of ice-water and extracted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2×250 mL of ethyl acetate. The organic layers were combined and washed with 2×150 mL of water, 150 mL of 1N NaOH and 2×150 mL of water. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized with diethyl ether to give 12.9 g (27.3 mmol, 77%) of the desired product 13 as a white solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:10](O)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:13])[CH:11]=[CH2:12]
Reactant: CC(C)CCCCCO
Reactant: C=CC(=O)O
Product: C=CC(=O)OCCCCCC(C)C

Procedure:
Isooctyl alcohol was reacted with acrylic acid to yield isooctyl acrylate.
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][S:14][CH3:15])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[OH:1][CH:2]([CH2:12][CH2:13][S:14]([CH3:15])=[O:21])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: CCCCCCOC(=O)C(O)CCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of hexyl 2-hydroxy-4-(methylthio)butanoate (5.03 g, 21.46 mmol) in dichloromethane at 0° C. was added m-chloroperoxybenzoic acid (mCPBA) portionwise over 20 min. The resulting mixture was allowed to warm to room temperature with stirring overnight. The reaction was washed with saturated sodium bicarbonate (3×100 mL), 1N HCl (1×80 mL), and brine (1×80 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give ˜6 g of a crude oil. The oil was purified by silica gel chromatography with 0-6% methanol/dichloromethane to give an oil (4.10 g, 76%). 1H NMR (500 MHz, chloroform-d) δ ppm 0.89 (t, J=6.68 Hz, 3 H) 1.25-1.39 (m, 6 H) 1.67 (quin, J=6.99 Hz, 2 H) 2.05-2.17 (m, 1 H) 2.32-2.42 (m, 1 H) 2.56-2.63 (m, 3 H) 2.72-2.97 (m, 2 H) 3.34-3.44 (m, 1 H) 4.15-4.24 (m, 2 H) 4.26-4.36 (m, 1 H). m/z 251 (MH+).
Reaction SMILES: [I:1][C:2]1[C:3](O)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]2[CH:8]=[CH:9][S:10][C:4]=12
Reactant: Oc1c(I)cnc2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c(I)cnc2ccsc12
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of the crude 6-iodothieno[3,2-b]pyridin-7-ol (0.99 g, 3.6 mmol) in phosphoryl chloride (20 mL) was heated at 120° C. for 2 h. The reaction was cooled to room temperature, concentrated under reduced pressure. The residue was co-evaporated with toluene, then diluted with dichloromethane and neutralized carefully with sat. NaHCO3 solution. The black tar was filtered off and the filtrate was transferred to a separation funnel. The organic layer was concentrated and purified on silica gel (eluting with 0-35% EtOAc/hexanes) to give the desired product (44% in 2 steps). LCMS calculated for C7H4ClINS (M+H)+: m/z=295.9. Found: 295.8.