Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:16][C:15]2[C:14]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:12][CH:11]=[N:10][C:9]=3[S:8][C:7]=2[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:44][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[C:14]3[C:15]4[CH2:16][C@H:4]([CH2:3][C:2]([OH:44])=[O:1])[CH2:5][CH2:6][C:7]=4[S:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added tert-butyl N-(4-[[(12R)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (129 mg, 0.29 mmol, 1.00 equiv) in 4 mL of DMF. Then PDC (639 mg, 1.70 mmol, 6.00 equiv) was added and the resulting solution was stirred overnight at room temperature. The reaction was then quenched with water and extracted with 4×40 mL of CHCl3/isopropanol (3:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to provide 2-[(12R)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetic acid (98 mg, 74%) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([C:18](OCC)=[O:19])[CH2:15][CH2:14][C:13]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].CC(C)C[Al+]CC(C)C.CO.Cl>CC1C=CC=CC=1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH:16]([CH:18]=[O:19])[CH2:15][CH2:14][C:13]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCc2cc(OCc3ccccc3)ccc2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=CC1CCc2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of 48 parts of ethyl 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxylate in 495 parts of methylbenzene were added dropwise 108 parts of a solution of [bis(2-methylpropyl)]aluminium hydride in methylbenzene at -80° C. Upon completion, stirring was continued for 30 minutes at -80° C. The reaction mixture was decomposed by the carefully addition of 24 parts of methanol. It was poured into 1000 parts of water and the whole was stirred for 15 minutes very carefully! The mixture was acidified with concentrate hydrochloric acid. After stirring for 5 minutes, the organic layer was separated, washed with water, dried, filtered and evaporated, yielding 39.8 parts (97%) of 3,4-dihydro-6-(phenylmethoxy)-2H-1-benzopyran-2-carboxaldehyde as a residue (intermediate 42).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])([CH3:16])[CH2:7][CH:8]=[C:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28]>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])([CH3:16])[CH2:7][CH:8]=[C:9]2[C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:18][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc2c(cc1Br)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure D-1, 7-bromo-4,4-dimethyl-6-hydroxy-1-tert-butyl-3,4-dihydronaphthalene (Compound A-31, U.S. Pat. No. 6,613,917, 070 g, 0.226 mmol), potassium carbonate (94 mg) and 1-iodopropane (0.220 mL, 2.26 mmol), were reacted in acetone (3 mL) to produce the title compound as a clear oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[S:25]1[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[CH:26]1.C(#N)C>O>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][N:30]([C:27]2[CH:28]=[CH:29][S:25][CH:26]=2)[CH3:31])=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: CNc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCOc1cccc(-c2noc3ccsc23)c1)c1ccsc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, thiophen-3-yl-methylamine (prepared according to Synthetic Metals, 26 (1988)153–168) and acetonitrile essentially as described above in example 18, except that water (0.40 mL) is added to the reaction mixture before heating. Purity by LC/MS (APCI)=100%, [M+H]+=357.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:35]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36]Br)=[C:28]2[C:33]=1[NH:32][C:31](=[O:34])[CH:30]=[CH:29]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:35]([O:38][Si:39]([C:42]([CH3:43])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH2:36][NH:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])=[C:28]2[C:33]=1[NH:32][C:31](=[O:34])[CH:30]=[CH:29]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: COC(=O)c1cccc(CC(C)(C)N)c1
Product: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Temperature: 95 °C
Yield: 49 %

Procedure:
Methyl 3-(2-amino-2-methylpropyl)benzoate (1 g, 4.82 mmol) was added to (R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one (1.57 g, 3.22 mmol) neat. The resulting mixture was heated to 95° C. for 3 d then cooled. Chromatography (1:3, hexanes/EtOAc) afforded the title compound (970 mg, 49%) as light yellow oil. ES/MS calcd. for C36H47N2O5Si+ 615.3. Found m/z=615.3 (M+H)+.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OC([NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])=O)(C)(C)C>>[C:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:23])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)O
Yield: 132.2 %

Procedure:
Octanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (1.13 g, 3.45 mmol) and N-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethyl}-succinamic acid (1 g, 2.874 mmol) were reacted as described above. 1.75 g crude product was isolated and used without further purification. LCMS (Method 6): Rt 3.86 min; m/z (M+1) 461; Calcd.: 461.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:11]1[C:12]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])(=[O:21])=[O:20])=[N:13][CH:14]=[C:15]([CH3:17])[N:16]=1>>[Cl:29][C:23]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:12]1[C:11]([O:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:16][C:15]([CH3:17])=[CH:14][N:13]=1)(=[O:20])=[O:21]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: Cc1cccnc1CO
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2ncccc2C)n1

Procedure:
Prepared by the method of Example 20 using 3-methylpyridine-2-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.021 g.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[Br:31]>CO.C(Cl)(Cl)Cl>[Br:31][C:26]1[C:27]([CH3:30])=[N:28][O:29][C:25]=1[NH:24][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1
Reactant: Cc1noc(N)c1Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)s2)c1Br
Yield: 34.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene (250 mg, 0.63 mmol) with 5-amino-4-bromo-3-methylisoxazole (118 mg, 0.67 mmol) yielded, after column chromatography using 5% MeOH/CHCl3, 115.2 mg N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5 bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide as a white powder (34% yield). A portion of this sample was further purified by preparative HPLC, m.p. 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]2[CH2:14][C:12]([CH3:26])([CH3:11])[O:13][C:9]=2[CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (115 mg, 0.77 mmol), Cs2CO3(507 mg, 1.54 mmol), and methyl 6-hydroxyl-2-methyl-2,3-dihdrovenzofuran-4-carboxylate (3e) (171 mg, 0.77 mmol). Purification by column chromatography eluting with 15-40% EtOAc in hexanes gave a pale brown solid (230 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.88-7.94 (m, 2 H) 7.09 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 2 H) 6.66 (d, J=2.53 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.33 (s, 6 H); LCMS for C19H20O6S m/z 377.10 (M+H)+.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:10]([CH3:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:8]=1[CH:7]=[CH:6][CH:5]=[C:4]2[S:1]([NH:21][CH2:20][CH2:18][OH:19])(=[O:3])=[O:2]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)NCCO)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, dansyl chloride (5.05 g, 18.72 mmol) was placed in a dry 250 mL round bottom flask equipped with a stir bar. Dry methylene chloride (50 mL) was added via syringe, the flask attached to an addition funnel and the system cooled to 0° C. Ethanolamine (1.25 g, 1.24 mL, 20.59 mmol), triethylamine (2.27 g, 3.13 mL, 22.46 mmol), and 75 mL of dry methylene chloride were loaded into the addition funnel, and the solution was added dropwise with stirring over 30 min. The solution was stirred for an additional 30 min before the ice bath was removed, the solution allowed to reach ambient temperature and left to stir for an additional 14 hours.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13]([S:15]Cl)=[O:14]>C(Cl)(Cl)Cl>[C:4]1(/[CH:3]=[CH:2]/[C:1]2[O:10][C:13](=[O:14])[S:15][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)C=Cc1ccccc1
Reactant: O=C(Cl)SCl
Solvent: ClC(Cl)Cl
Product: O=c1oc(/C=C/c2ccccc2)ns1
Yield: 72.3 %

Procedure:
Cinnamamide (1.9 g, 13 mmol) was mixed with chlorocarbonylsulphenylchloride (1.0 mL, 13 mmol) in chloroform and heated to reflux for 18 h. The reaction mixture was concentrated in vacuo and the resultant material was taken up in boiling hexane (100 mL). The solvent was decanted from the remaining solid, the volume of this solution was reduced by half, and the solution was allowed to cool. The crystalline solids which formed were collected and washed with hexane to afford 5-[(E)-2-phenylethenyl]-1,3,4-oxathiazol-2-one (1.93 g, 72% yield) as pale yellow needles. M.p. 105–106° C. 1H NMR (DMSO-d6, 300 MHz) δ 7.52 (m, 3H), 7.46 (s, 0.5H), 7.41 (m, 2.5H), 6.63 (d, J=16 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:42])([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH2:27][C:28](O)=[O:29]>C(Cl)Cl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:11][C:10]1[C:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][C:26]([N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])([CH3:42])[CH3:25])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC(C)(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)COc1cccnc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1cccnc1CNC(=O)CC(C)(C)N1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 2-aminomethyl-3-(ethoxycarbonylmethoxy)pyridine dihydrochloride (610 mg, 2.155 mmol), triethylamine (732 μl, 5.258 mmol), N,N-dicyclohexylcarbodiimide (596 mg, 2.892 mmol) and 4-(N,N-diemethylamino)-pyridine (10 mg) in 6 ml of dry methylene chloride is added β,β-dimethyl-1,3-dioxo-2-isoindolinepropionic acid (650 mg, 2.629 mmol) at ambient temperature. The mixture is stirred for 24 hours. The precipitate of dicyclohexyl urea is filtered off. The filtrate is evaporated and the residue is purified via flash chromatography on silica gel using a methylene chloride/methylene chloride-ethanolic ammonia gradient (100 to 97:3) to give 591 mg of (2-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methyl-butyrylamino]-methyl}-pyridin-3-yloxy)-acetic acid ethyl ester (46%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([CH3:31])=[CH:4]4)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])(=[O:34])[CH3:33]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Reactant: CC(=O)Cl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(C)=O
Yield: 58 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 11, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline. (120 mg, 0.28 mmol) was reacted with acetyl chloride (24 μl, 0.34 mmol). The crude product was purified by column chromatography eluting with methanol/methylene chloride (2/98) to give 7-[(2S)-1-acetylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (76 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([N+:33]([O-:35])=[O:34])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1ccccc1OCCN
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 23 °C
Yield: 74.3 %

Procedure:
A mixture comprising 2-(2-methoxyphenoxy)ethylamine (10 g, 59.9 mmol), diisopropylethylamine (13.9 mL, 81.6 mmol) and dichloromethane (80 mL) was cooled to 0° C. and then a solution of 3-methoxy-4-nitrobenzoyl chloride (11.76 g, 54.4 mmol) in dichloromethane (50 mL) was added dropwise. The mixture was allowed to warm to 23° C. over two hours, quenched with aqueous hydrochloric acid (3M, 20 mL), washed with water (3×20 mL), dried (Na2SO4) and concentrated in vacuo to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (14 g, 74% yield) an off white solid; MS (PB-PCI) C17H18N2O6 m/e calc 346.34; found 347 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])(=[O:11])=[O:10])[CH2:7][CH2:6]1)=[O:4].C1COCC1.CO.O[Li].O>O>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]1)(=[O:10])=[O:11]
Reactant: COC(=O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (500 mg, 1.49 mmol) was charged, and dissolved through addition of THF (3 ml), and methanol (3 ml). LiOH.H2O dissolved in H2O (3 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 1-(2-bromophenylsulfonamido)cyclopropanecarboxylic acid (469 mg, 1.46 mmol, 98%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O.CCOC(C)=O>[N:30]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3([NH:11][C:12]([C:14]4[C:15]5[CH:22]=[N:21][N:20]([C:23]6[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=6)[C:16]=5[CH:17]=[N:18][CH:19]=4)=[O:13])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NC1(c2ccc(N3CCOCC3)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (35 mg, 0.077 mmol) and morpholine (68 μL, 0.77 mmol) in DMSO (1 mL) is heated in a pressure tube at 160° C. After 40 hours, the mixture is cooled to room temperature, diluted with EtOAc (50 mL) and washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The resulting solid is purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give a solid, which is triturated with ether (5 mL), filtered and dried to afford the title compound.
Reaction SMILES: [C:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.C[Sn:22](Cl)(C)C.[Li]>O1CCCC1>[SnH3:22][SH:12]1[C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=[CH:13]1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCC#Cc1cccs1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CC1=CC=C[SH]1[SnH3]
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a 1 L schlenk flask with egg-shaped stirbar in a glove box, the 2-decynylthiophene 22a (57.44 mmol, 12.658 g) was added by pipette. On a schlenk line, tetrahydrofuran (300 mL) was cannula transferred to the reaction vessel through a septum. The reaction mixture was cooled to −78° C. and n-butyl lithium (35.9 mL, 1.6 M solution in hexanes,) was added dropwise via syringe and the reaction mixture stirred for 45 min. The reaction vessel was fitted with an addition funnel and trimethyltin chloride (57.4 mL, 1.0 M solution in tetrahydrofuran) was cannula transferred to the funnel under positive argon pressure through a septum. The trimethyltin chloride solution was added dropwise to the stirring lithium salt solution over a period of 15 min. at −78° C. The reaction mixture was allowed to warm to ambient temperature with stirring overnight. The solvent was removed in vacuo on the schlenk line and trapped in a 1 L schlenk flask. The resulting residue was dissolved in diethyl ether (500 mL) washed with brine (3×200 mL), dried over magnesium sulfate, filtered and the solvent removed by roto-evaporation to afford 1-stannyl-5-decynyl-thiophene 22b as a light brown oil (20.6 g, 94% yield). 1H NMR (CDC13) δ7.20 (d, 1H), 7.00 (d, 2H), 2.43 (t, 2H), 1.60 (m, 2H), 1.44(m, 2H), 1.30 (m, 8H), 0.899 (t, 3H), 0.37 (s, 9H); GC/MS (M+) 384 m/z, (M+—CH3) 369 m/z.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[C:11]1([CH3:39])[C:12]([C:17]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][CH:22]([NH2:37])[C:21]2=[O:38])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>O1CCCC1>[C:11]1([CH3:39])[C:12]([C:17]([CH2:19][N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:23][CH:22]([NH:37][C:8]([NH:7][C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)=[O:9])[C:21]2=[O:38])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(N)CN(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2CN(c3ccccc3)c3ccccc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
m-Tolyl isocyanate (34 mg) was added to a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (90 mg) obtained from Step 2 of Example 18 in tetrahydrofuran (10 ml), the mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 100 mg of the title compound (Yield: 83%).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23]OS(C2C=CC=CC=2C)(=O)=O)[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[Na+].[I-:36]>>[C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][I:36])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccccc2C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Agent: [Na+]
Product: C=CCO[C@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Yield: 88 %

Procedure:
A solution of allyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-6-O-tolylsulfonyl-α-D-mannopyranoside, prepared as described above, (3.68 g, 7.37 mmol) and NaI (2.21 g, 14.7 mmol) was gently refluxed for 10 hours, and cooled. The mixture was concentrated, and the residue was chromatographed on silica gel, with toluene-EtOAc (1:2), to give allyl 2-acetamido-3,4-di-O-acetyl-2,6-dideoxy-6-iodo-α-D-mannopyranoside (2.96 g, 88 percent);