Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:13]=[CH:12][C:11]=1[C:21]1[C:22]([S:27]([N:30]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[C:38]=2[CH3:43])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>CN(C=O)C.O>[CH3:42][C:39]1[C:38]([CH3:43])=[C:37]([N:30]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:27]([C:22]2[C:21]([C:11]3[CH:12]=[CH:13][C:14]([C:16]4[O:17][CH:18]=[CH:19][N:20]=4)=[CH:15][C:10]=3[CH2:9][S:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:28])[O:41][N:40]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CBr
Reactant: CC(C)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CSCC(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 5 equiv. of 2-methyl-1-propanethiol (125 mg, 1.39 mmol) in 1 ml of dry DMF was added 2.5 equiv. of 60% sodium hydride under an argon atmosphere at room temperature. The reaction mixture was stirred for 0.5 hrs. and then a solution of the title compound of Step (B) (160 mg, 0.278 mmol) in 1 ml of DMF was added. The reaction was stirred for 1 hr, diluted with 15 ml of water and extracted with ethyl acetate (3×20 ml). The ethyl acetate extract was washed with 5% lithium chloride (2×30 ml), brine and dried over sodium sulfate. The crude material was purified on a Merck silica column eluting with 40% ethyl acetate/hexane yielding 118 mg (68%) of the title compound of this step as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:7](=[CH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH:14]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:13][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: C=C1CCCc2cc(OC)ncc21
Solvent: CO
Solvent: O
Product: COc1cc2c(cn1)CC(=O)CCC2
Yield: 66.5 %

Procedure:
3-Methoxy-8-methylene-5,6,7,8-tetrahydroisoquinoline (125) (1.27 g, 7.25 mmol) in a mixture of water (5 mL) and MeOH (45 mL) was treated with [hydroxy(tosyloxy)iodo]benzene (2.84 g, 7.25 mmol) in MeOH (7 mL). After about 30 min water (15 mL) was added then the mixture was concentrated under reduced pressure to remove most of the MeOH. The mixture was basified to about pH 10 with sat. aq. NaHCO3 then EtOAc (˜30 mL) was added. Insoluble material was removed by filtration. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were washed with brine (˜25 mL) then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using a gradient from 0-100% EtOAc in heptane. Pure product fractions were combined and concentrated under reduced pressure to yield 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (0.922 g, 67%); LC/MS, method 3, Rt=1.66 min, MS m/z 192 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.57 (s, 1H), 3.92 (s, 3H), 3.63 (s, 2H), 2.93-2.85 (m, 2H), 2.61-2.54 (m, 2H), 2.04-1.94 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOCC>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (73.3 mg, 0.308 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et2O (100 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]([CH3:21])[C:15](=[O:22])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[F:20][C:19]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:22])[N:16]2[CH3:21])=[CH:11][C:10]=1[C:6]1[C:5]([CH3:23])=[C:4]([CH2:3][NH:2][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])[CH:9]=[N:8][CH:7]=1
Reactant: Cc1c(CN)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2
Reactant: Cc1noc(C)c1C(=O)O
Agent: Cl
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1C

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 226) has been coupled with 3,5-dimethyl-isoxazole-4-carboxylic acid to give the title compound as a colorless solid. MS: 423.6 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCCC2)c2ccccc12
Temperature: 70 °C

Procedure:
To a solution of 1,4-dibromonaphthalene (500 mg, 0.002 mol), Pyrrolidine (0.18 mL, 0.0021 mol), (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.022 g, 0.000035 mol), Sodium tert-butoxide (0.24 g, 0.0024 mol) in Toluene (5.00 mL, 0.0469 mol) was added Tris(dibenzylideneacetone)dipalladium(0) (0.008 g, 0.000009 mol), and the mixture was heated at 70° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 25% hexanes/DCM) to obtain 400 mg (80%). Reference: Jean, L.; Rouden, J.; Maddaluno, J.; Lasne, M-C. J. Org. Chem. 2004, 69, 8893-8902.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Br[CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCCC(Br)CCC
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (32 mg, 0.13 mmol) in DMF (0.5 mL) is added NaH (95%, 6 mg). The reaction mixture is stirred at room temperature for 30 minutes, and 4-bromo-heptane (137 mg, 0.77 mmol) is added. The mixture is heated at 60° C. for three hours and cooled. To the mixture, water (2 mL) and EtOAc (2 mL) are added. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 8.82 (s, 1H), 7.43 (s, 1H), 7.32 (d, 1H), 7.31 (t, 1H), 7.16 (d, 2H), 6.87 (s, 1H), 6.53 (d, 1H), 4.42 (m, 1H), 2.32-2.40 (m, 4H), 1.86-1.95 (m, 4H), 1.15-1.32 (m, 4H), 1.03 (t, 6H), 0.84 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(C(=O)N(Cc2ccccc2)c2ccc(Cl)cc2)cc1)OCC

Procedure:
To a solution of 0.50 g of 4-diethoxyphosphinylmethyl-N-(4-chlorophenyl)benzamide in 10 ml of dry THF was added in portions 0.07 g of sodium hydride (60%, in oil) under ice-cooling with stirring. After stirring for 30 minutes under ice cooling, a solution of 0.23 g of benzyl bromide in 2 ml of dry THF was added. After stirring for 5 hours at room temperature, 30 ml of water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=1:1) to give 4-diethoxyphosphinylmethyl-N-benzyl-N-(4-chlorophenyl)benzamide. It was recrystallized from benzene-n-hexane to give 0.40 g of colorless columnar crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[N:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].[CH2:19](I)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:17][C:14]1[CH:13]=[N:12][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:18][CH2:19][CH3:20])[CH:6]=2)=[N:16][CH:15]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cn2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(Oc2ncc(Cl)cn2)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
2-Nitro-5-(5-chloro-2-pyrimidyloxy)phenol (0.65 g), ethyl iodide (2 ml), potassium carbonate (0.35 g) and methyl ethyl ketone (20 ml) were heated together under reflux with stirring for 15 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and chloroform. The chloroform extracts were dried and evaporated under reduced pressure to give a pale yellow solid which was recrystallized from ethanol to give the title compound as pale yellow needles (0.54 g), m.p. 114°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26][C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C1C=C(Cl)C=C(C(OO)=[O:64])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26](=[O:64])[C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)sc2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)S(=O)c2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: -40 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
(1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.0041 mmol., 4 mg) was dissolved in 1 mL DCM and cooled to −40° C. mCPBA (0.4 mg, 0.9 eq.) was added. The reaction mixture was stirred at −40° C. for 2 hours and warmed up to 0° C. over 2 hours, then warmed up to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give a yellow powder (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5-oxo-5H-5λ4-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DD) (0.6 mg). 1H-NMR: 300 MHz, (CD3OD-d4) δ: 8.36 (m, 2H), 8.18-7.90 (m, 6H), 5.22 (m, 2H), 4.19 (m, 2H), 4.05 (m, 2H), 3.84 (m, 2H), 3.61 (d, 6H), 2.56-1.96 (m, 10H), 0.97-0.84 (m, 12H). LCMS-ESI+: calc'd for C40H48N8O6S: 768.92; Found: 769.3 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.O>[C:15]([NH:19][S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1

Procedure:
To a suspension of 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (1.0 g) in DCM (10 ml) was added tert-butylamine (0.92 ml) and the mixture was stirred at room temperature for 2d. The mixture was diluted with H2O and extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as a beige foam. Yield 1.1 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([OH:17])[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: ClCCN1CCCCC1
Reactant: On1c(-c2ccncc2)c(-c2ccc(F)cc2)c2ncccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)n(OCCN3CCCCC3)c3cccnc23)cc1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (0.20 g, 0.65 mmol) and 2-chloroethylpiperidine hydrochloride (0.24 g, 1.31 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 6.56 mmol, 60% in oil). The reaction mixture was stirred overnight and quenched with water (2 ml). The pH was adjusted to pH=11-12 by the addition of saturated sodium carbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-[2-(piperidin-1-yl)ethoxy]-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a yellow solid (182 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2>CO.[Pd]>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2
Reactant: CCOC(=O)C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2c(OC)c(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 3-(5,6,7-trimethoxynaphthalen-2-yl)propenoate (1.70 g) was dissolved in methanol (20 mL), 10% palladium on carbon (510 mg) was added to the solution, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was then concentrated to obtain the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=O)=O.[C:25]([C:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:8]2[C:7]([C:26]#[C:25][C:27]3([OH:35])[CH:32]4[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]4)[CH2:28]3)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=2)=[CH:16][CH:17]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: COc1ccc(Cc2nc(C)ccc2OS(=O)(=O)C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nc(C)ccc2C#CC2(O)CN3CCC2CC3)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyl trifluoromethane sulfonate, 116 mg of 3-ethynyl-3-quinuclidinol, 147 mg of tetrakis(triphenylphosphine)palladium(0), 24 mg of cuprous iodide, 266 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80° C. for 3 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and the mixture was extracted with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 192 mg of the target compound.
Reaction SMILES: [CH2:1](N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.CC(C)C(C1C=CC=CC=1)C(N=C=S)=O>>[F:38][C:39]1[CH:40]=[C:41]([NH:55][C:56]([NH:58][C:59](=[O:67])[CH:60]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH3:1])=[S:57])[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Agent: CC(C)C(C(=O)N=C=S)c1ccccc1
Product: CC(C(=O)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)c1ccccc1
Yield: 49 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 3-methyl-2-phenylbutanoyl isothiocyanate, title compound 192e was obtained in 49% yield. Characterization of 192e is provided in table 18.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][CH2:16][O:17][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCC1CN(Cc2ccccc2)CC1CO
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CCOCC3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
To a solution of 2-(1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl) ethanol (0.50 g) in toluene (30 mL) was added Et3N (0.8 mL), TsCl (0.75 g) and DMAP (10 mg). The mixture was stirred for 12 h at room temperature under N2, washed with water, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 10:1 (v/v) CH2Cl2/CH3OH) to give the title compound (0.18 g, 13.61%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 218.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CC(O)C.O>[CH2:11]1[O:12][C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 104 °C
Reaction time: 20 h

Procedure:
A mixture of D-sorbitol (1) (4.0 kg), water (560 mL) and H2SO4 (50 mL) was heated to a melt (104° C.) and stirred. After 20 h, 25 mL of H2SO4 was added. After a further 22 h, 25 mL of H2SO4 was added. After a further 32 h, the mixture was cooled to ambient temperature, neutralized carefully with solid Na2CO3 and stirred for 30 min. i-PrOH (12 L) was added, followed by anhydrous Na2SO4 (4 kg). The mixture was filtered and the solid was washed with i-PrOH (6 L) and EtOH (3 L). The filtrate was treated with activated charcoal (100 g), filtered through Celite, rinsing with 1.2 L each of i-PrOH and EtOH, then concentrated. Toluene (6 L) was added to the residue, and the mixture was concentrated in vacuo with heating to effect azeotropic removal of water. EtOH (10 L) was added to the solid residue with heating to effect dissolution. The solution was concentrated and cooled to ambient temperature to give a suspension (6 L). The solid was isolated by filtration, washed with cold EtOH (4 L) and dried. Recrystallization of the crude product (1.9 kg) from hot EtOH provided 2 (1693 g) as a white solid, mp112-112.5° C., [α]23D-22.9 ° (c 0.5, H2O). The 13C NMR spectrum of this compound agreed with that reported by Duclos et al., Synthesis, page 1087 (1994).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:23])=O>>[C:1]([N:5]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][C:16]([C:18]([Cl:23])=[O:20])=[CH:15][CH:14]=2)[S:6]1(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)ccc1C(=O)O
Product: CC(C)(C)N1C(=O)c2ccc(C(=O)Cl)cc2S1(=O)=O

Procedure:
15.0 g of (0.05 mol) of tert-butylsulfamoylterephthalic acid in 95 ml of thionyl chloride were heated under reflux for 8 h. The mixture was concentrated and the residue was triturated with ethyl acetate. This gave 14.6 g (97% of theory) of 2-tert-butylsaccharin-6-carbonyl chloride of m.p. 185-186° C.