Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[C:9]1[C:15](OC)=O.C(O)(=O)C.Cl.Cl.[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]>O.[Fe]>[CH3:29][C:30]([CH3:42])([CH2:35][N:36]1[CH2:41][CH2:40][N:39]([C:15]2[C:9]3=[CH:10][C:11]([S:13][CH3:14])=[CH:12][N:8]3[CH2:7][C:6]3[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[N:20]=2)[CH2:38][CH2:37]1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)(C)CN1CCNCC1
Reactant: COC(=O)c1cc(SC)cn1Cc1cc(C)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(C)cc3Cn3cc(SC)cc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
Treat methyl 1-(5-methyl-2-nitrobenzyl)-4-(methylsulfanyl)-1H-pyrrole-2-carboxylate (3.49 mmoles; 1.12 g) with acetic acid (15 mL) then treat with iron, powder (10.5 mmoles; 585 mg) then slowly heat in an oil bath at 80° C. After a few hours increase the oil bath temperature to 90° C. Then leave the reaction at 60° C. for 2 days. Then concentrate to dryness to remove acetic acid then treat with EtOAc and wash through a pad of silica with more EtOAc until the orange colour stops coming off. Concentrate the red eluant to dryness then treat with methanol then re-concentrate and dissolve in DCM (20 mL) and treat with phosphoryl chloride (1.0 mL). Heat the reaction in an oil bath at 50° C. overnight. Then cool the reaction to RT and treat with ice then wash with water twice and then NaHCO3 (aq). Dry the organic layer over MgSO4, filter and concentrate to a tar. Meanwhile dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.60 g, 5.86 mmoles) in water then load on to a SCX-2 cartridge (2×10 g) and wash with methanol and then elute with ammonia in methanol. Concentrate the basic solution to dryness to an oil. Then dissolve this oil in acetonitrile (50 mL) and add to a mixture of the tar and potassium carbonate (1.0 g) then heat to reflux. After 2 hours, microwave the reaction to 140° C. for 2 hours. Then filter the reaction and extract with acetonitrile and acetone. Combine and concentrate the mother liquors to dryness onto silica then purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane). Take the fractions which contain clean product, combine and concentrate to yield methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoate (418 mg; 27% yield). MS (m/z): 441.18 (M+1).
Reaction SMILES: NC1CCCC(=[O:8])C=1.BrCC(=O)C(OCC)=O.[Br:18][CH2:19][C:20](=[C:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][C:27]1=[NH:33])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[Br:18][CH2:19][C:20](=[C:26]1[CH2:31][C:30](=[O:8])[CH2:29][CH2:28][C:27]1=[NH:33])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(CBr)=C1C(=N)CCCC1=O
Reactant: NC1=CC(=O)CCC1
Agent: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CBr)=C1CC(=O)CCC1=N
Temperature: 60 °C

Procedure:
111.1 g. 1-Aminocyclohex-1-en-3-one (see Arch. Pharm., 294, 763/1961) are added at 30° C., with stirring, to 760 ml. ethyl bromopyruvate. The reaction mixture is then heated to 60° C. for 8 hours. After cooling, the reaction mixture is mixed with 200 ml. ethyl acetate and 1000 ml. diethyl ether and filtered with suction. After washing the solid product with diethyl ether, there are obtained 247 g. (85% of theory) ethyl 3-bromo-2-(2-imino-6-oxocyclohexylidene)-propionate; m.p. 170°-175° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Cl)(=[O:3])[CH3:2].[CH2:25]([O:27][C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:28]([O:27][CH2:25][CH3:26])=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Reactant: CCOC(=O)CCCCCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(C)=O
Yield: 74 %

Procedure:
Condensation of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride with 5-ethoxycarbonyl-1-pentanol under the same conditions as reported in example II gave a 74% yield of 5-ethoxycarbonylpentyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranoside, mp 101°-102°, [α]D25 - 16.8° (c 1.06, chloroform). De-O-acetylation of this compound using sodium methoxide gave after crystallization a 92% yield of 4 mp 154°-155° (melts and resolidifies) remelts 167°, [α]D18 - 25.5° (c 1.1, water).
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[K+].C(=O)(O)[O-].[Na+].[Cl:20][CH2:21]OS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[Cl:20][CH2:21][O:2][P:1](=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
According to a literature procedure (Tetrahedron Letters; 2002, 43, 3793), compound I was prepared as follows: Potassium di-tert-butyl phosphate (6.35 g), tetra-n-butylammonium hydrogen sulphate (917 mg) and sodium bicarbonate (8.96 g) were dissolved in water (230 mL). Dichloromethane was added (130 mL) and the resulting mixture was cooled down to 0° C. A solution of chloromethylchlorosulphate (917 mg) in dichloromethane (100 mL) was slowly added under vigorous stirring. The reaction mixture was allowed to reach room temperature and further stirred overnight at this temperature. The organic layer was then separated, washed with brine (50 mL), dried over Na2SO4 and concentrated under vacuum. The desired product 1 was obtained as a colourless oil (2.4 g). Phosphoric acid di-tert-butyl ester chloromethyl ester 1. Colourless oil, 1H-NMR (CDCl3) δ 5.65 (d, J=15.0 Hz, 2H), 1.52 (s, 18H); 13C-NMR (CDCl3) δ 84.2 (d, J=7.6 Hz), 73.3 (d, J=6.9 Hz), 29.8 (d, J=4.3 Hz); 31P-NMR (CDCl3) δ −11.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([CH3:12])[CH:3]=1.B>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
(4-Bromo-2-methylphenyl)acetic acid (59 g, 258 mmol) was dissolved in THF (100 mL), and cooled in an ice-bath to 0° C. Borane (1 M in THF, 310 mL, 1.2 eq) was added dropwise. During the addition the temperature rose slowly to 20° C. After complete addition, the ice-bath was removed and stirring was continued for 2 hours. The reaction mixture was poured into sat. aq. K2CO3 (300 mL), and the obtained suspension was diluted with H2O (500 mL). The THF layer was separated and concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (2×250 mL, 1×100 mL). The residue from the concentrated THF layer was dissolved in the combined organic layer, which was washed with brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding the crude product (54.6 g) as a brown oil. The crude product was purified by column chromatography (SiO2, 2 L of 30% EtOAc in heptanes, Rf=0.3). Desired fractions were combined and concentrated under reduced pressure, yielding the title compound as a yellow oil (31.6 g, 144 mmol, 56%). 1H-NMR (CDCl3, 300 MHz) δ ppm 2.3 (s, 3H); 2.68 (t, 2H); 2.82 (t, 2H); 7.07 (d, 1H); 7.30 (d, 2H).
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH2:14][C:15]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[N:22][CH:23]=1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([C:18]1[CH:19]=[C:20]([B:25]([OH:30])[OH:26])[C:21]([F:24])=[N:22][CH:23]=1)([CH3:17])[CH3:16])([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
n-Butyllithium (1.66 M in hexane) (Aldrich, St. Louis, Mo.; 0.429 mL, 0.712 mmol) was added (dropwise over 1 min) to a solution of 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridine (183.5 mg, 0.647 mmol) in THF (3.3 mL) at −78° C., and the resulting yellow solution was stirred at −78° C. for 1 h. Tri-isopropyl borate (Aldrich, St. Louis, Mo.; 0.179 mL, 0.777 mmol) was then added, and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was subsequently partitioned between EtOAc (50 mL) and water (30 mL) (1N HCl (about 200 μL) was added to bring the pH of the aqueous layer to 6.5). The organic layer was separated, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-ylboronic acid (228.0 mg, 0.697 mmol, 108% yield) as a colorless oil. m/z (ESI, +ve) 328.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[N:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:33][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)Nc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 482 mg, 1.45 mmol) in methylene chloride (14.6 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.80 mL, 1.60 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of N-(5-amino-pyrazin-2-yl)-methanesulfonamide (548.8 mg, 2.91 mmol) and pyridine (0.24 mL, 2.91 mmol) in tetrahydrofuran (7.29 mL). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride (50 mL) and was washed consecutively with a 1N aqueous hydrochloric acid solution (1×100 mL) and a saturated aqueous sodium bicarbonate solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 95/5 methylene chloride/methanol) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclo-pentyl-N-(5-methanesulfonylamino-pyrazin-2-yl)-propionamide (43.0 mg, 5.9%) as an off-white solid: mp 108–110° C.; EI-HRMS m/e calcd for C20H25ClN4O5S2 (M+H)+ 501.1028, found 501.1031.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31][CH2:32]CC.N1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]2[CH2:32][CH2:31][CH2:30][CH2:20]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCNC1
Product: C[C@H](CCCS(=O)(=O)N1CCCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 61 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl]-N-[4-[(1-pyrrolidinyl)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl)-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with pyrrolidine. Yield=61%; MS (ESI+), 539 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].[C:10]([NH:13][NH:14][C:15](N)=[O:16])(N)=[O:11]>CN1CCCC1=O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15](=[O:16])[NH:14][NH:13][C:10]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)NNC(N)=O
Reactant: CCCCOCCCN
Solvent: CN1CCCC1=O
Product: CCCCOCCCn1c(=O)[nH][nH]c1=O

Procedure:
131 g of 3-butoxy propylamine and 120 g of hydrazodicarbonamide are stirred in 300 ml of N-methyl pyrrolidone for 1 hour at 150° C., for 2 hours at 175° C. and for 6 hours at 200° C. A deposit is precipitated on cooling which is isolated by filtration under suction and recrystallised from cyclohexane, giving 152 g (75% of the theoretical yield) of 4-(3-butoxypropyl)-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 83° to 85° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:38][C:23]2=[CH:24][C:25]3[C:26](=[O:37])[N:27]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:28](=O)[C:29]=3[CH:30]=[C:22]2[N:21]=1)[CH3:11]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:21][C:22]2=[CH:30][C:29]3[CH2:28][N:27]([CH2:32][CH2:33][N:34]([CH3:35])[CH3:36])[C:26](=[O:37])[C:25]=3[CH:24]=[C:23]2[N:38]=1)[CH3:11]
Reactant: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCN(C)C)C3=O
Yield: 77.3 %

Procedure:
Compound 2-(4-(1-(2,5-difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 1.92 mmol) and zinc powder (3.12 g, 24.85 mmol) were suspended in acetic acid (50 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.75 g, 77.3% yield. MS: 505.0 [M−H]−. 1H NMR (DMSO-d6, 300 MHz): δ 13.06 (s, 1H), 11.21 (s, 1H), 11.12-11.08 (m, 1H), 7.96 (s, 0.5H), 7.84 (s, 0.5H), 7.80 (s, 0.5H), 7.68 (s, 0.5H), 7.40-7.33 (m, 2H), 7.23-7.13 (m, 1H), 7.11-7.01 (m, 1H), 6.17 (d, 1H, J=7.5 Hz), 4.54 (s, 2H), 4.18-4.10 (m, 1H), 3.64 (t, 2H, J=6.0 Hz), 3.10-2.91 (m, 2H), 2.52-2.48 (m, 2H), 2.18 (s, 6H), 1.34-1.31 (m, 3H).
Reaction SMILES: [C:1]1([CH:7]([CH:15]2[CH:20]([OH:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([CH3:43])[CH:42]=1)[CH2:38]Br>>[CH3:34][C:35]1[CH:42]=[C:41]([CH2:43][O:21][CH:20]2[CH:19]3[CH2:22][CH2:23][N:16]([CH2:17][CH2:18]3)[CH:15]2[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:40]=[C:37]([CH3:38])[CH:36]=1
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: OC1C2CCN(CC2)C1C(Cc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: Cc1cc(C)cc(COC2C3CCN(CC3)C2C(Cc2ccccc2)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a solution of alcohol (Example 1, 0.78 g, 1:1 mixture of stereoisomers) was added 0.5M-potassium hexamethyldisilazide (5.84 ml, in toluene). After 1 h, 3,5-dimethylbenzyl bromide (0.58 g) was added for 3 h. The solution was evaporated to dryness after a further 3 h, and the residue partitioned between dichloromethan and water. The organic phase was dried (MgSO4), evaporated and purified by column chromatography on silica gel eluting with petroleum ether (bp 6014 80) containing increasing amounts of ethyl acetate (50% to 100%) and then methanol/ethyl acetate (15:85) to give a single diastereomer of the title compound. This was crystallised by addition of oxalic acid (72 mg) in propan-2-ol and diethyl ether to give 3-[(3,5-dimethylphenyl)methyloxy]-2-(1,2-diphenylethyl)-1-azabicyclo[2.2.2]octane hydrogen oxalate salt isomer A mp 64°-66° C.1HNMR(DMSO,360MHz)δ 7.2-6.6 (13H,m,aryl), 4.6 (1H, d, J=16.0 Hz, OCHAHB),4.4 (1H, d, J=16.0 Hz, OCHAHB),3.5 (1H, m, OCHCH),3.3 (1H, m, NCHAHB), 2.99 (1H, dd, NCHCH)),2.8-2.60 (5H, m, NCHAHB,NCH2,PhCH2), 2.4(1H,m,PhCHCH2),2.3 (6H, s, CH3, CH3),2.25 (1H, m, bridgehead CH),1.9 (1H, m, NCH2CHAHB),1.65 (1H, m, NCH2CHAHB), 1.46-1.22 (2H, m, NCH2CH2); Found C, 71.09; H, 6.84; N, 2.51. C30H35NO.C2H2O4.0.3H2O requires C, 71.19;H,6.86;N,2.67.m/e (EI) 425(M+), (CI+)426 (M+H), (CI-=)424 (M-H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1.[F:18][C:19]1([F:32])[O:31][C:22]2=[CH:23][C:24]3[NH:28][C:27]([SH:29])=[N:26][C:25]=3[CH:30]=[C:21]2[O:20]1>C(O)(C)C>[ClH:2].[ClH:1].[F:32][C:19]1([F:18])[O:31][C:22]2=[CH:23][C:24]3[NH:28][C:27]([S:29][CH2:3][C:4]4[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]5[O:14][CH:15]=[CH:16][CH:17]=5)[CH:7]=[CH:6][N:5]=4)=[N:26][C:25]=3[CH:30]=[C:21]2[O:20]1
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2cc3c(cc2[nH]1)OC(F)(F)O3

Procedure:
Following the procedure described in Example 12, the reaction of 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride with 2,2-difluoro-6-mercapto-5H-[1,3]dioxolo-[4,5-f]benzimidazole in isopropanol gives the title compound as a colorless solid; m.p. 180-183° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11].IC.[CH2:15](N(C(C)C)C(C)C)C>CN(C=O)C>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:15])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(O)c1cc(F)c(F)cc1F
Solvent: CN(C)C=O
Solvent: CI
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 2,4,5-trifluorobenzenesulfinic acid (34 g, 173 mmol), in DMF (200 mL), was added iodomethane (21.6 mL, 347 mmol), and N-ethyl-N-isopropylpropan-2-amine (60.5 mL, 347 mmol). The reaction mixture was stirred overnight at ambient temperature. The reaction was concentrated and partitioned between water and ethyl acetate and extracted with CH2Cl2. The combined organic layers were concentrated and purified over silica gel (15-100% EtOAc in hexanes) to afford 1,2,4-trifluoro-5-(methylsulfonyl)benzene (25.8 g, 123 mmol, 71% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:14]1[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:16][C:15]=1[C:30]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:31]>>[CH2:21]([O:20][C:18]([C:17]1[CH:28]=[CH:29][C:14]([N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4]2)=[C:15]([C:30]([N:32]2[CH2:41][CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[CH:16]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Reactant: O=C(OCc1ccccc1)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCOC(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 48.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (Intermediate 1A, 509 mg, 2.70 mmol) and benzyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (1.00 g, 2.57 mmol) were converted to the title compound (690 mg, 48%). 1H NMR (CDCl3, 1.5:1 mixture of amide rotamers) δ 8.35-8.28 (m, 1H), 8.18 (t, J=1.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 0.5H), 7.70 (d, J=8.4 Hz, 0.5H), 7.50-7.45 (m, 2H), 7.43-7.31 (m, 3H), 7.23-7.07 (m, 3.5H), 6.90 (d, J=7.9 Hz, 0.5H), 5.42 (s, 2H), 4.76-4.54 (m, 1H), 4.47 (s, 1H), 4.16 (q, J=7.0 Hz, 2.5H), 3.64 (br s, 1.5H), 3.13-3.02 (m, 0.5H), 2.81 (t, J=6.1 Hz, 1H), 2.34 (s, 2H), 2.26 (s, 1H), 1.21 (t, J=7.0 Hz, 1H), 1.12 (t, J=7.2 Hz, 2H); MS(ESI+) m/z 558.4 (M+H)+.
Reaction SMILES: COC([C:5]1[NH:6][CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][O:13][C:14]=2[C:15]([F:18])([F:17])[F:16])[N:9]=1)=O.O.[OH-].[Li+]>C1COCC1.O.Cl.CO>[NH:6]1[CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:12][O:13][C:14]=2[C:15]([F:18])([F:16])[F:17])[N:9]=[CH:5]1
Reactant: COC(=O)c1nc(-c2c(-c3ccccc3)noc2C(F)(F)F)c[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-1H-imidazole-2-carboxylic acid methyl ester (100 mg, 0.3 mmol) in THF (1 mL) was added a solution of lithium hydroxide monohydrate (24.8 mg, 0.6 mmol) in water (1 mL) and the resulting mixture stirred at room temperature overnight, and then at 50° C. overnight. After cooling to room temperature the mixture was acidified to pH 1 with HCl (25%, 3 drops) and methanol (2 drops) added. The mixture was then heated at 80° C. for 34 h and left at room temperature for 2 days. The mixture was then extracted with ethyl acetate and the combined organic extracts washed with an aqueous saturated sodium hydrogen carbonate solution, brine, dried over sodium sulfate and evaporated to afford the title compound (70 mg, 85%) which was obtained as an off-white solid. MS: m/e 280.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[OH:22][CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=3)[N:6]=[CH:5]4)=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: CCOC(=O)c1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2c(ccn2CCO)c1
Product: CCOC(=O)c1ccc(-n2ncc3cc(NC(=O)c4ccc5c(ccn5CCO)c4)ccc32)cc1

Procedure:
Compound 1039 was prepared according to the procedure described in Scheme IV from ethyl 4-(5-amino-1H-indazol-1-yl)benzoate and 1-(2-hydroxyethyl)indole-5-carboxylic acid. [M+H]+ calcd for C27H24N4O4: 469.18; found 469.03.