Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 5.8 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-cyanophenylboronic acid (73 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was purified by reverse-phase prep LCMS to give the title compound (9.3 mg, 6%) m/z, 321.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][CH:29]=1.BrC1C=CC(CN(C2(CO)CCCCC2)S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1>>[O:36]1[CH:37]=[N:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:11]([C:12]3([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:29][CH:30]=2)=[N:35]1
Reactant: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncon2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1(CO)CCCCC1
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)C1(CO)CCCCC1
Yield: 9.1 %

Procedure:
The title compound was synthesized from 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (114 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (99 mg, 0.41 mmol) according to the procedure described for N-(4-bromobenzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 39) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (16 mg, 9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.08 (2H, d, J=8.31 Hz), 7.80 (2H, d, J=8.56 Hz), 7.39-7.45 (4H, m), 4.38 (2H, d, J=5.79 Hz), 4.08-4.12 (2H, m), 1.68-1.82 (2H, m), 1.29-1.49 (8H, m). LC/MS R.T.=2.93 min; [M+Na]+=484.20.
Reaction SMILES: [C:1]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@H:2]([C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[OH:5])[OH:3].[CH:25](OCC)(OCC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:27]([O:26][CH:25]1[O:5][C@H:4]([C:6]([O:8][CH3:9])=[O:7])[C@@H:2]([C:1]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[O:3]1)[CH3:28]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)[C@@H](O)[C@H](O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC1O[C@H](C(=O)OC)[C@@H](C(=O)OC(c2ccccc2)c2ccccc2)O1

Procedure:
400 mg of diphenylmethyl methyl D-tartarate was dissolved in 7 ml of toluene, and a catalytic amount of Amberlyst 15 and 1 ml of triethyl orthoformate were added, followed by refluxing under heating for one hour. Amberlyst was filtered off. Then, the filtrate was extracted by an addition of water and ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 195 mg of the above identified compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2C[CH:14]([CH2:17][NH:18][C:19](=[O:30])[CH2:20][C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1N)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](OC(=O)C(N1C=CN=C1)=O)(C)(C)C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH:17]([NH:18][C:19](=[O:30])[CH2:20][C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:14][O:13][CH2:12][C:11]=2[S:10][C:9]=1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CNC(=O)Cc1ccc3c(c1)OCO3)OC2
Solvent: ClCCl
Product: Cc1sc2c(c1C(=O)OC(C)(C)C)C(NC(=O)Cc1ccc3c(c1)OCO3)COC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the above crude 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.17 g, 0.38 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.22 g, 1.14 mmol). The reaction mixture was stirred at room temperature for 18 hours, the volatiles evaporated in vacuo and the residue diluted with ethyl acetate. The organic layer was washed with hydrochloric acid (1% (v/v), 2×25 ml), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the residue subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:2) as eluent, which afforded 0.12 g (55%) of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[NH:13])[CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]([C:21]([N:23]=[C:24]=[S:25])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:1]([O:8][C:9](=[NH:13])[C:10]([C:11]#[N:12])=[C:24]([SH:25])[NH:23][C:21]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=N)OCc1ccccc1
Reactant: O=C(N=C=S)Oc1ccccc1
Solvent: CC#N
Product: N#CC(C(=N)OCc1ccccc1)=C(S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a stirred 0° C. solution of 2-cyano-acetimidic acid benzyl ester (327 g, 1.88 mol) in acetonitrile (1 L) was added a 0° C. solution of phenoxycarbonylisothiocyanate (353 g, 1.97 mol) in acetonitrile (1 L). The reaction was allowed to warm to ambient temperature and was stirred overnight. The mixture was then placed in the refrigerator and kept still at 5° C. for 48 hours. The solid product was filtered, compressed, and washed with 20° C. acetonitrile (3×200 mL). Air was then drawn though the relatively stable solid followed by further drying under high vacuum to yield a yellow solid (282 g, 798 mmol, 42%). 1H NMR (400 MHz, DMSO) δ 5.39 (s, 2H), 7.11-7.19 (m, 2H), 7.20-7.24 (m, 1H), 7.36-7.46 (m, 7H), 10.23 (broad s, 1H), 10.67 (s, 1H), 12.19 (broad s, 1H) ppm; MS (APCl, m/z): 354 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH3:2].[OH-].[Na+].C(O)C>O>[CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:2]
Reactant: CCc1c(CCNC(=O)CCCCC(=O)OC)ccc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1c(CCNC(=O)CCCCC(=O)O)ccc(OC)c1OC
Yield: 79.5 %

Procedure:
A mixture of the product from Stage (i) (11 g), 2N sodium hydroxide solution (200 ml) and ethanol (300 ml) was heated under reflux for 1 h. The solution was cooled and poured into water (1000 ml). The mixture was washed with ether, acidified with 2N hydrochloric acid and then extracted with ether. The extracts were washed with water, dried and evaporated to give the title compound (8.4 g) as a white solid, m.p. 92°-94°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:12]2[CH2:11]1)([O-])=O>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][C@@H:13]2[O:16][C:17](=[O:26])[N:18]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@@H:12]2[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3[N+](=O)[O-])C[C@H]21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate in EtOH and EtOAc (1:1, 0.15 M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen balloon for 15 h. The solution was filtered through a pad of Celite, and the filtrate was concentrated to yield (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate as a clear oil in >95% yield. LCMS (m/z): 335.0 (MH+), Rt=1.68 min.
Reaction SMILES: [CH:1]1([PH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH2:15][C-:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21]N(C)C)C.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>C(O)(=O)C>[CH:7]1([P:6]([CH2:15][C-:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][P:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:30]
Reactant: C1CCC(PC2CCCC2)C1
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: c1cc(CP(C2CCCC2)C2CCCC2)[c-](CP(C2CCCC2)C2CCCC2)c1

Procedure:
The title compound was prepared in accordance with the procedure of Example 2 employing dicyclopentylphosphine (Strem 566 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.432 g.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To an ambient temperature solution of 4-Mercaptophenylacetic acid (5.0 g, 29.72 mmol) in MeOH (250 mL) is added sulfuric acid (1.25 mL). The reaction mixture is stirred at room temperature overnight. The reaction is concentrated and the residue is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 30% EtOAC/Hex) to yield the title compound (3.69 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H, J=7.9 Hz), 7.12 (d, 2H, J=8.4 Hz), 3.66 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Yield: 47.6 %

Procedure:
To a solution of (S)-(+)-4-(2,3-Epoxypropoxy)-carbazole (7.56 g, 0.031 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (9.48 mL, 0.063 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature and purified following the procedure similar to one described in step 11 for the synthesis of example 23, to afford the desired compound as colorless solid (6 g, 48%) with m.p: 152-154° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.88-2.92 (m, 1H), 2.98-3.00 (m, 1H), 3.74-3.87 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.45 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.40 (m, 4H), 8.08 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.96%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:23])[CH:10]=2)=[O:21])[CH2:25][CH2:26]1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: NC1CCNCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCC(N)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperidin-4-amine. MS (ESI): mass calcd. for C22H22FN5O, 391.18; m/z found, 392.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.99 (s, 1H), 7.88 (s, 1H), 7.48 (d, J=14.8, 3H), 7.35-7.20 (m, 3H), 6.69 (s, 2H), 4.31 (s, 1H), 3.08-2.50 (m, 6H), 1.75 (t, J=80.9, 2H), 1.38-0.86 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:36]([N-]C(C)C)(C)C.[Li+].CI.P([O-])([O-])([O-])=O>C1COCC1>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)N(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise a solution of lithium diisopropylamide (LDA) (2.0 N in heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over a period of 10 min. After completion of the addition, the stirring was continued for an additional 20 min at the same temperature. To the resulting mixture was added dropwise MeI (0.5 mL) at 0° C., and stirred at room temperature for 15 h. The mixture was poured into a solution of phosphate buffer (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.64 (2H, d, J=8.3 Hz), 7.53–7.25 (7H, m), 6.89 (1H, s), 3.65–3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 131 (2.8 g, 6.2 mmol), DMAP (150 mg, 1.2 mmol), triethylamine (930 g, 9.2 mol) and tert-butylchlorodimethylsilane (1.1 g, 7.5 mmol) in dichloromethane (40 mL) was stirred for 12 hours at room temperature, then quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (2×40 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by a silica gel column, eluted with 1%-3% methanol in dichloromethane to afford 132 as a white solid (2.6 g, 75%). (ES, m/z) [M+H]+ 569.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.38 (m, 5H), 6.13 (d, J=6.3 Hz, 1H), 4.49 (s, 2H), 4.34-4.36 (m, 1H), 4.06-4.08 (m, 1H), 3.83-390 (m, 1H), 3.59-3.67 (m, 2H), 3.30-3.55 (m, 5H), 1.58 (s, 9H), 0.98 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O.CC(C)=O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: OCCCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
Additional procedure. ZnCl2 (352.3 g 2.59 moles) was added to a 2 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Acetone cyanohydrin (110.0 g 1.29 moles) was slowly added to the stirred solid over 30 minutes keeping the temperature below 32° C. with external cooling. To the slurry, 2-chloroethanol (124.9 g 1.55 moles) was slowly added over 20 minutes keeping the temperature below 32° C. with external cooling. Acetone (3.75 g, 64.6 mmoles) was added and the mixture was heated to 60° C. After stirring for 4 h at 60° C., the reaction mixture was cooled to 30-35° C., diluted with water (1.10 L) and extracted with CH2Cl2 (1×440 mL and 1×220 mL). The combined CH2Cl2 extracts were washed with 0.5M sodium bicarbonate (330 mL), followed by water (3×330 mL). The dichloromethane solution was concentrated under vacuum to afford crude product (109 g). The crude product was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling at 60-80° C. was collected to afford 2-(2-chloroethoxy)-2-methylpropanenitrile as colorless oil (88.7 g).
Reaction SMILES: [C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=O.[C:20](Cl)(=O)C(Cl)=O>C1C=CC=CC=1>[C:1]([C:4]1[C:14]2[CH2:13][CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2c1CCc1ccccc1C2=O
Solvent: c1ccccc1
Product: CC(=O)c1cccc2c1CCc1ccccc1C2=O

Procedure:
25 g. of 1-carboxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 250 ml. of benzene are heated with 20 g. of oxalyl chloride for 2 hours at reflux and subsequently concentrated under reduced pressure. The resulting crystalline 1-chlorocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is dissolved in 200 ml. of benzene and then it is added dropwise to a solution of the magnesium salt of diethyl malonate (about 50 g. in 500 ml. of ether) over a period of about 5 minutes and heated at reflux for 12 hours. Subsequently, the reaction mixture is divided between ether and dilute sulfuric acid, washed with water, sodium bicarbonate solution and water, dried and evaporated. The residue is heated in 30 ml. of ethyl acetate, 20 ml. of water and 3.7 ml. of concentrated sulfuric acid at reflux for 15 hours. Then, it is poured over ice water and extracted with ether. The ethereal extract is washed with water, sodium bicarbonate solution and water, dried and evaporated, whereby 1-acetyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one having a melting point of 65°-68°C. is obtained.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][NH:19][CH2:18][C:17]3[CH:21]=[CH:22][S:23][C:16]2=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH2:1]([N:19]1[CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[S:23][CH:22]=[CH:21][C:17]=2[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: c1ccc(CN2Cc3ccsc3C(c3ccccc3)C2)cc1
Yield: 34 %

Procedure:
Benzyl chloride is condensed with 7-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 4), according to the procedure of Example 8. Fumarate: M.p. = 200° C; yield: 34%.
Reaction SMILES: [Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([C:7](Br)(Br)[CH:8]=1)[CH2:5][CH2:4]2.C(#N)C.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:3]2[CH2:11][CH:6]([CH2:5][CH2:4]2)[C:7](=[O:16])[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: BrC1=CC(Br)(Br)C2CCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: Clc1ccccc1
Product: O=C1C=C(Br)C2CCC1C2
Reaction time: 0.83 h
Yield: 6.3 %

Procedure:
To a solution of 89.9 g (7.9% w/w, 100%=7.1 g, 20.6 mmol) of 2,4,4-tribromobicyclo[3.2.1]oct-2-ene in chlorobenzene there are added 100 ml of acetonitrile and 100 ml of 10% sulfuric acid and stirring is carried out for 50 minutes at ambient temperature. The pH is then adjusted to 7 using aqueous sodium hydroxide solution and the aqueous phase is separated off. The organic phase is washed with 50 ml of water and then dried using magnesium sulfate. After filtration and removal of the acetonitrile using a rotary evaporator, 57.8 g (88% of theory) of 4-bromo-bicyclo[3.2.1]oct-3-en-2-one are obtained as a 6.3% solution in chlorobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:23](=[O:25])[CH3:24])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CC1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of (4-phenyl-cyclohexyl)-acetic acid ethyl ester (15 g, 61 mmol, 1.0 equiv) in 200 Ml DCM was added aluminum trichloride (16 g, 122 mmol, 2.0 equiv) portionwise over 15 min. Acetyl chloride (4.7 Ml, 67 mmol, 1.10 equiv) was then added dropwise via syringe. The homogeneous solution was allowed to stir at 0° C. for 2 h, then carefully quenched with 300 Ml ice water. The mixture was extracted with DCM (3×150 Ml), and the organic extracts were washed with saturated bicarbonate and brine solution. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (q, J=11.96 Hz, 2 H) 1.20 (t, J=7.20 Hz, 3 H) 1.40-1.51 (m, 2 H) 1.84 (d, J=11.12 Hz, 4 H) 1.76-1.87 (m, 1 H) 2.17 (d, J=6.82 Hz, 2 H) 2.50 (s, 3 H) 4.07 (q, J=7.07 Hz, 2 H) 7.22 (d, J=8.34 Hz, 2 H) 7.81 (d, J=8.08 Hz, 2 H); (M+H)+ 289.1.