Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=O)[CH3:2].S(Cl)(Cl)=O.[CH3:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[C:16]=1[NH2:28].C(=O)(O)[O-].[Na+].[Cl-].[Na+].O.O>C(#N)C>[CH3:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[C:16]=1[NH:28][C:5](=[O:7])[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:8][CH3:9]
Reactant: CCC(CC)CC(=O)O
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCC(CC)CC(=O)Nc1c(C)cc(N2CCOCC2)cc1C
Temperature: 110 °C
Yield: 30.6 %

Procedure:
3-Ethylpentanoic acid (0.79 g) and thionyl chloride (0.44 mL) were mixed in acetonitrile (10 mL) and heated to 110° C. for 5 minutes in a sealed microwave process vial. 2,6-Dimethyl-4-morpholin-4-yl-phenylamine (1.25 g) dissolved in acetonitrile (10 mL) was added to the reaction mixture and heated to 150° C. for 15 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate/brine/water (1:1:1, 50 mL) was added to the crude mixture and it was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was recrystallized from hot toluene, and the product was collected by filtration, washed with cold toluene and dried in vacuo to furnish 0.59 g (30% yield) of the title compound as an off-white solid. LC-MS (m/z) 319 (MH+); tR=2.04, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.87 (t, 6H), 1.35 (qui, 4H), 1.76 (m, 1H), 2.07 (s, 6H), 2.20 (d, 2H), 3.05 (t, 4H), 3.71 (t, 4H), 6.62 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:1][CH:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]2=[O:4])[N:13]=1
Reactant: CC1(C)COC(=O)C1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC2C(=O)OCC2(C)C)n1
Temperature: 25 °C
Yield: 97 %

Procedure:
13.0 g of 2-hydroxy-3,3-dimethyl-γ-butyrolactone and 24.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine were mixed in 80 ml of N,N-dimethylformamide in the presence of 27.6 g of potassium carbonate at a temperature of from 90° to 100° C. for 3 hours. The reaction solution was cooled to room temperature, then, poured into ice water and extracted with ethyl ether. The extract was washed twice with water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration and then the filtrate was concentrated to obtain 26.0 g of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[NH:23]1[C:31]2[C:26](=CC=C[CH:30]=2)[C:25]2(COC3C=C4C(=[CH:42][C:32]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:23]1[CH:42]=[CH:32][CH:25]=[CH:26][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 144-146° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (dd, J=5.1, 0.6 Hz, 1H), 7.73 (ddd, J=7.8, 7.5, 1.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.22 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.17 (dd, J=7.4, 0.9 Hz, 1H), 7.03 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.29 (s, 1H), 5.26 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.15-4.11 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.4, 155.3, 148.6, 144.8, 142.0, 138.4, 138.2, 132.2, 129.0, 124.0, 123.7, 123.3, 122.3, 121.1, 111.8, 109.7, 99.5, 80.3, 64.6, 64.0, 58.2, 45.5; MS (ES+) m/z 387.0 (M+1).
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8](OCC)=[O:9].O>O1CCCC1>[SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[CH:8]=[O:9]
Reactant: CCOC(=O)c1sc(C)nc1CS
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CS)c(C=O)s1
Reaction time: 4 h

Procedure:
10 mmol of ethyl 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carboxylate was dissolved in 100 ml of dried tetrahydrofuran, then 42 ml of 0.5M SDBBA solution was gradually added with keeping the temperature at −30 to −20° C. After the adding, the reaction was carried out for 4 hours at −20° C. Then 20 ml of water was added into the reaction system to stop the reaction and then an organic layer was separated. To the remaining water phase, sodium hydrogen carbonate was added until the pH of the water phase reached a value of 8 to 9. The product was extracted and separated into an organic layer using ethyl acetate. This organic layer and the previous organic layer were mixed together and dried under sodium sulfate. The solvent was evaporated out and then the product was purified using a column separation with solvents of ethylacetate and hexane, obtaining 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carbaldehyde.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)=[CH:3]1.[H][H]>[Pd].O>[NH2:11][C:7]1[N:6]=[C:5]2[C:4]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)=[CH:3][NH:2][C:10]2=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CN1CC=C(c2cn(O)c3ccc(N)nc23)CC1
Agent: [Pd]
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
A suspension of 1 gm (3.15 mMol) 1-hydroxy-5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine (H) dihydrochloride and 0.20 gm 10% palladium on carbon in 10 mL demineralized water was hydrogenated at ambient temperature with an initial hydrogen pressure of 45 p.s.i. After four hours the reaction mixture was filtered and the filtrate treated with 6 mL 2N aqueous sodium hydroxide. After the addition of 0.2 mL tetrahydrofuran the reaction mixture was stirred for 3 hours and the resulting precipitate collected by filtration. The solid was dried under reduced pressure at 50° C. to provide 0.59 gm (94%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[F:19][C:20]([F:38])([F:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=1[CH3:36].C(N(CC)CC)C>ClCCCl>[CH3:36][C:28]1[CH:29]=[C:30]([C:31]([N:13]2[C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:18]=[CH:17][C:8]=3[CH2:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[CH2:12]2)=[O:32])[CH:34]=[CH:35][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:19])([F:37])[F:38]
Reactant: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Reactant: Cc1cc(C(=O)Cl)ccc1-c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(-c3ccccc3C(F)(F)F)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid methyl ester of Step B (1.64 g) in 1,2-dichloroethane (25 mL) was added 4-(2-trifluoromethylphenyl)-3-methylbenzoyl chloride (2.0 g, 1.1 eq) prepared in the manner of Example 1, Step D and triethylamine (1.0 g) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with 10% ethyl acetate in petroleum ether to provide the title compound as a white crystalline solid, m.p. 180–182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:29])=[O:28])[CH:24]=2)[N:19](C(OC(C)(C)C)=O)[N:18]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36]([CH3:39])(=[O:38])=[O:37])(=[O:28])=[O:29])[CH:24]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc(Br)c3)c2c1
Temperature: 20 °C
Yield: 69.4 %

Procedure:
N-[3-(3-Bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained in the follow way: 1.6 g of (3-bromophenyl)boronic acid, 8.7 ml of a saturated aqueous sodium hydrogencarbonate solution and 0.11 g of tetrakis(triphenylphosphine)palladium[0] are added successively to a suspension, maintained under an atmosphere of argon, of 2.3 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate in 90 ml of dimethylformamide. The reaction mixture is refluxed for 5 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is hydrolyzed with 200 ml of water and extracted with 200 ml and then 100 ml of ethyl acetate. The pooled organic extracts are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The brown oil thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a yellow lac. This product is repurified by chromatography on a silica column (particle size 63-200 μm), with pure dichloromethane as eluent. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.73 g of N-[3-(3-bromophenyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are obtained in the form of a white foam melting at 104° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2)(=[O:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([C:31](=O)[C:32]([F:35])([F:34])[F:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.FC(F)(F)C1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]([C:32]([F:35])([F:33])[F:34])=[CH:2][C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9]2([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[O:8][CH2:7]3)=[O:3])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)COC21CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)cc(Cl)c3)C(F)(F)F)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
In 100 mL two neck RBF equipped with dean-stark apparatus, the stirred solution of tert-butyl 5′-acetyl-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 1, 6.65 g, 21.95 mmol) in toluene (20 mL) and trifluorotoluene (20 mL) was added 1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-ethanone (6.133 g, 25.24 mmol) and Cs2CO3 (0.71 g, 2.20 mmol) at room temperature. Resulting reaction mixture was stirred at 110° C. for 16 hours. After complete consumption of starting material, the reaction mixture was diluted with tert-butylmethyl ether (60 mL) and filtered through celite bed. Filtrate was concentrated to get as brown sticky oil (7.2 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 20% ethyl acetate in n-hexane to give light yellow solid (5.1 g, 43.97%). LC-MS (m/z): 525.9 (M−H).
Reaction SMILES: COC[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1>C1COCC1.CCO.[N+]([O-])([O-])=O.[Ag+]>[SH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: COCSc1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Temperature: 40 °C
Reaction time: 21 h

Procedure:
A solution of 2-(4-methoxymethylsulfanylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 77, 1.29 g, 3.28 mmol) in THF (50 mL) was added to a stirred solution of AgNO3 (0.59 g, 3.28 mmol) in EtOH (85 mL) at 40° C. The mixture was protected from light and stirred at 40° C. for 21 h. The solvents were evaporated off under reduced pressure, then the remaining solid was triturated with i-PrOH (60 mL), THF (60 mL), and Et2O (60 mL). After air-drying, the solid was stirred vigorously with CH2Cl2 (200 mL) and 6M HCl (82 mL) for 4 h under Ar. The layers were separated, then the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were filtered through Celite, washed with brine (100 mL) and dried (MgSO4). Filtration and solvent evaporation furnished 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=349.2 [M+H]+. NEt3 (0.14 mL, 1006 μmol) and a solution of 4-iodomethyltetrahydropyran (151 mg, 668 μmol) in anhydrous DMF (3 mL) were added to a stirred solution of this benzenethiol (197 mg, 565 μmol) in anhydrous DMF (7 mL) at 0° C. The mixture was warmed to 20° C., before being stirred for 16 h. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (25 mL) and 2% aqueous citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL), then the combined organic layers were washed with H2O (10 mL), saturated aqueous Na2CO3 (10 mL), H2O (10 mL), and brine (10 mL). After drying (MgSO4), filtration and solvent evaporation gave a residue that was subjected to flash chromatography (IH-EtOAc, 3:1 to 0:1) to furnish the title compound: RTA=3.61 min; m/z (ES+)=447.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: Brc1ccc(N2CCOCC2)cc1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)c1

Procedure:
The title compound was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (101.0 mg, 0.4172 mmol) in a manner analogous to Step 2d and was isolated as a pale yellow solid (0.025 g, 16%). MP=202-204° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.68 (t, J=1.6, 1H), 8.46 (dd, J=6.9, 0.9 Hz, 1H), 8.39-8.35 (m, 1H), 8.01-7.98 (m, 1H), 7.73 (dd, J=7.7, 7.7 Hz, 1H), 7.67 (dd, J=7.5, 0.8 Hz, 1H), 7.56-7.50 (m, 2H), 7.01-6.94 (m, 3H), 6.72 (s, 1H), 3.90-3.86 (m, 4H), 3.14-3.10 (m, 7H). MS=450 (MH)+.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Solvent: CCO
Product: COc1ccc(CN[C@H]2CO[C@@H](C(c3ccccc3)c3ccccc3)C[C@@H]2O)cc1
Yield: 79.3 %

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.02 g, 0.075 mmol) was reacted with p-methoxybenzylamine (0.21 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol (+)-29a 0.024 g (80%, [α]D=(+)72.8, c=1, MeOH). The 1HNMR and 13CNMR were identical with (2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(O[CH:26]([C:28]1[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:29]=1[F:36])[CH3:27])(=O)=O>>[F:34][C:33]1[CH:32]=[C:31]([F:35])[CH:30]=[C:29]([F:36])[C:28]=1[CH:26]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:20][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)[CH3:27]
Reactant: CC(C)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(OS(C)(=O)=O)c1c(F)cc(F)cc1F
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4c(F)cc(F)cc4F)CC3)ncnc2s1

Procedure:
The title compound was prepared (110 mg, 55%) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine(130 mg, 0.45 m. mol) and 1-(2,4,6-trifluorophenyl)ethyl methanesulfonate (228 mg, 0.9 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3):δ 8.40 (s, 1H), 6.75 (s, 1H), 6.65 (m, 2H), 4.95 (d, 1H), 4.15 9q, 1H), 4.05 (m, 1H), 3.00 (m, 2H), 2.70 (d, 2H), 2.20 (m, 1H), 2.10 (m, 2H), 1.90 (m, 1H), 1.55 (d, 3H), 1.25–1.65 (m, 2H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 448.55; Observed: 449.2 (M++1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].BrCCBr.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH2:26][CH:27]2[C:31](=O)[C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28]2)=[CH:24][CH:23]=1.Cl>C1COCC1.C(O)C>[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH2:26][C:27]2[O:28][C:29]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=3[C:31]=2[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc2c(c1)OC(Cc1ccc(Cl)cc1)C2=O
Agent: Cl
Agent: [Mg]
Solvent: CCO
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc2c(-c3ccc(OCCN4CCCC4)cc3)c(Cc3ccc(Cl)cc3)oc2c1
Temperature: 25 °C

Procedure:
4-[2-Pyrrolidinoethoxy]phenyl bromide (1.41 g, 5.20 mmol) in dry THF (50 ml) was added to magnesium turnings (312 mg, 13.0 mmol) in a dry 3-necked round bottom flask under an oxygen-free nitrogen atmosphere and the mixture was maintained under gentle reflux. 1,2-Dibromoethane (0.22 ml, 2.60 mmol) was added dropwise over a period of 1/2 hour. The mixture was heated gently until the magnesium was nearly consumed (ca. 1/2 hour). 2-(p-Chlorobenzyl)-6-methoxy-3(2H )-benzofuranone (740 mg, 2.60 mmol) in THF (50 ml) was added dropwise to the mixture at 0° C. The reaction mixture was allowed to warm to room temperature and refluxed for 18 hours. The cooled mixture was quenched with saturated ammonium chloride (30 ml), extracted with dichloromethane (3×40 ml), washed with water, dried (anhydrous sodium sulphate) and the solvent evaporated off to yield an oil which was dehydrated with concentrated hydrochloric acid (2 ml) in ethanol (25 ml). The mixture was refluxed for 2 hours, whereupon ethanol was removed. It was then basified with 10% sodium hydroxide (20 ml) and extracted with dichloromethane (3×40 ml). The dichloromethane extract was washed with water (3×20 ml), dried (anhydrous sodium sulphate) and the solvent was evaporated off to give a solid which was chromatographed on silica gel. Elution with (dichloromethene: hexane: triethylamine=1:2:0.3), yielded a colourless solid which was recrystallised from methanol to give 2-(p-chlorobenzyl)-3-[p-(2-pyrrolidinoethoxy)phenyl]-6-methoxybenzo[b]furan (2), m.p. 75° C. Dry hydrogen chloride gas was bubbled through an ethereal solution of the free base for 10 minutes and cooled to 0° C. The hydrochloride salt which preciptated out was filtered off at the pump, rinsed with ether, and recrystallised from isopropanol to yield white crystals of the hydrochloride salt. Yield (22%); m.p. 223°-225° C.; 1H-NMR (CDCl3)δ 1.82 (m, 4H, N(CH2CH2)2), 2.65 (br s, 4H, N(CH2CH2)2), 2.93 (t, 2H, J6.0 Hz, OCH2CH2N), 3.84 (s, 3H, OCH3), 4.16 (distorted t, 4H,J 6.0 Hz, OCH2CH2N, CH2 at C-2), 6.80-7.47 (m, 11H, ArH ); m/z (%) 463 (M+ -HCl, 28), 461 (M+ -HCl, 10), 364 (17), 98 (38), 84 (100). (Found: C, 67.37, H, 5.92, N, 2.56, Cl, 13.95. C28H28ClNO3.HCl required C, 67.47, H, 5.66, N, 2.81, Cl, 14.23).
Reaction SMILES: [OH-].[K+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S-:10])=[CH:6][CH:5]=1.[K+:2]
Reactant: Sc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: [S-]c1ccc(Cl)cc1

Procedure:
To a solution of potassium hydroxide (2.5 g.) in methanol (30 ml.) was dissolved 4-chlorobenzenethiol (6.5 g.), and methanol was distilled off to give potassium 4-chlorobenzenethiolate. To this product were added ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.) and dimethylformamide (50 ml.) and stirred for 1.5 hours at 100° C. The reaction mixture was poured into water (300 ml.) and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was recrystallized from a mixture of benzene and n-hexane to give yellow needles of the captioned compound (9.9 g.). mp 77° to 79° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[N:6]([CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[H][H]>CO.[Pd]>[NH2:17][C:4]1[C:5]2[N:6]([CH3:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:2][CH:3]=1
Reactant: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1c2ccccc2c2cccc(N)c21

Procedure:
3,6-Dibromo-9-methyl-1-nitrocarbazole (10 g) was dissolved in 300 ml of methanol. To the solution was added 50 g of Rexyn™ (OH-) form) and, under an atmosphere of carbon dioxide, 2 g of 5% Pd/C. The vessel was charged with 44.5 psi of H2. During the course of the reaction the hydrogen pressure dropped to 32.8 psi (100% H2 uptake). The crude reaction mixture was filtered and the clear solution was evaporated with a rotary evaporator using a vacuum pump and a water bath at 20° C. to give a white solid, m.p. 90°-92° C. Yield 2.77 g (54.3%). The product decomposed readily in air to a red solid.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:13]1(=[O:17])[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:15](=[O:16])[NH:14]1
Reactant: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)C2CNCC12
Reaction time: 48 h
Yield: 68.6 %

Procedure:
A degassed solution of cis-5-(benzyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3-(2H,3H)-dione (250 mg, 1.30 mmol) in methanol (50 mL) was treated with Pd/C (25 mg) and a hydrogen balloon was attached. The mixture was stirred for 48 h before filtering through celite and removal of the solvents in vacuo gave the title compound as a brown solid (125 mg, 88%). δH (DMSO-d6) 11.01 (1H, s) 3.12 (4H, d, J 10.4 Hz), 2.75 (2H, m). LCMS RT 0.19 minutes, (ES+) 141 (M+H)+.