Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(NC(=O)c3ccccc3)CC2)cc1

Procedure:
A solution of 2,3-epoxy-1-(4-acetamidophenoxy)-propane (5.18 g. and 4 -benzamidopiperidine (6.13 g.) in isopropanol (250 ml.) was refluxed for 24 hours, cooled and a white crystalline solid was filtered off (8.90 g.). This was recrystallised from isopropanol to give 7.41 g. of the title compound as a quarter hydrate, m.p. 226°-8° C. (Found: C, 66.35; H, 7.1; N, 10.1. C23H29N3O4.1/4H2O requires C, 66.4; H, 7.15; N, 10.1%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])(=[O:13])=[O:12]>CN(C=O)C>[F:10][C:8]1[CH:9]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[N:14]([CH3:15])[CH2:16][CH2:17][O:18][C:6]=2[CH:7]=1
Reactant: CN(CCO)S(=O)(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCOc2cc(F)ccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (700 mg, 17.51 mmol) was added to a solution of 2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide (2 g, 7.96 mmol) in DMF (200 mL) and the mixture stirred at RT for 48 hours. The solvent removed in vacuo, iced water (200 mL) added and the mixture extracted into ethyl acetate. The combined organic extract was washed with brine (40 mL), dried (MgSO4), filtered and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired compound as a white solid (1.08 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl.Cl[CH2:37][C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:37][C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cn1nccc1CCl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccnn6C)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 5-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (50.1 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. Another portion of 5-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (50.1 mg) and potassium carbonate (62 mg) was added and the mixture was shaken again for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 27.8 mg; LC (method 11): tR=1.13 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=[C:13]([Cl:22])[CH:12]=1>CCO.Cl.O>[Cl:22][C:13]1[CH:12]=[C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[F:1])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 64.3 %

Procedure:
2,4-Difluoroaniline (1.20 g, 9.3 mmol) and ethyl 4,6-dichloronicotinate (2.05 g, 9.3 mmol) were dissolved in a mixture of EtOH (40 ml) and conc. HCl (5 drops) and heated to reflux for 15 h. The solution was allowed to cool and H2O (3 drops) was added to initialize precipitation. The flask was then sealed and placed in a freezer for 3 h. The solid was then isolated by filtration and washed with 10% Et2O/Hexane, affording ethyl 6-chloro-4-(2,4-difluoroanilino)nicotinate (1.87 g, 64%); m.p. (EtOH/water) 107-109° C. 1H NMR [400 MHz, CDCl3] δ 9.62 (br s, 1H), 8.79 (s, 1H), 7.35-7.29 (m, 1H), 7.02-6.95 (m, 2H), 6.58 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (FAB+) 313 (50%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=O)C.O.[NH2:22][NH2:23]>CO>[NH:22]([C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:3])[NH2:23]
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2cccc3ccccc23)no1
Yield: 74.7 %

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (10.0g.) was dissolved in methanol (150 ml.) and hydrazine hydrate (10.0g.) added dropwise with cooling. The mixture was stirred for fifteen minutes and the crystalline precipitate was filtered off, washed with methanol (10 ml.), and dried to give title compound (7.08 g), m.p. 211°-212° (decomp.) λmax. (EtOH) 302 nm (ε 10,100) νmax. (Nujol) 1680 cm.-1 (--CONH--).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:37])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][OH:29])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCCO[Si](C)(C)C(C)(C)C)cccc4c3nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(OCCO)cccc4c3nc12
Reaction time: 1.5 h
Yield: 24.6 %

Procedure:
To a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (125 mg) in tetrahydrofuran (5 mL) was added a 1.0M solution of tetrabutyl ammonium fluoride (1.2 mL). After stirring for 1.5 hours the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield crude product which was purified using flash chromatography to yield the title compound as an orange solid (24 mg).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.Cl.[NH2:18][CH2:19][C:20](OCC)=[O:21]>N1C=CC=CC=1>[Cl:16][C:15]1[C:2]2[NH:1][C:20](=[O:21])[CH2:19][N:18]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1c(Cl)cccc1C(=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2)c2cccc(Cl)c2N1
Yield: 65.3 %

Procedure:
A solution of 2-amino-3-chlorobenzophenone (0.730 g, 3.15 mmol) and ethyl glycinate hydrochloride salt (0.660 g, 4.72 mmol) in pyridine (15 mL) was refluxed using a Dean-Stark trap to remove water. After 30 h the reaction was cooled and concentrated. The residue was dissolve in methylene chloride and washed with saturated sodium bicarbonate. The crude product was purified by chromatography (silica gel, 0–30% ethyl acetate in hexane gradient elution) to give the title compound as a solid (0.557 g). 1H NMR (500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.61 (dd, J=1, 8 Hz, 1H), 7.52 (m, 2H), 7.46 (tt, J=1,8 Hz, 1H), 7.39 (t, J=8 Hz, 2H), 7.26 (m, 1H), 7.11 (t, J=8 Hz, 1H), 4.36 (br s, 2H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([N+:18]([O-])=O)=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:3]1>C(O)C.O.Cl.[Fe]>[NH2:18][C:15]1[S:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:17][N:16]=1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (500 mg, 1.15 mmol, 1.00 equiv, 90%) in ethanol/H2O (15/5 mL). This was followed by the addition of Fe (280 mg, 5.00 mmol, 4.00 equiv). Then added 2 drops of HCl. The resulting solution was stirred for 2 h at 85° C. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. This resulted in 0.8 g (90%) of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[OH:17])[C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncc(C=O)c(C)c1OCc1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c(C)c1OCc1ccccc1

Procedure:
1.0 g of methyl 3-(benzyloxy)-5-formyl-4-methylpicolinate (3.50 mmol, 1 eq) was dissolved in 20.0 mL of tetrahydrofuran and 4.2 mL of a 4-fluorophenyl magnesium bromide solution (1M in tetrahydrofuran, 4.20 mmol, 1.2 eq) was added at −78° C. over a period of 1 hr. The reaction mixture was then stirred for 20 min. −78° C. A saturated bicarbonate solution was added and reaction mixture was extracted with ethyl acetate.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:43]=[CH:42][C:25]([C:26](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>O1CCOCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:25]2[CH:42]=[CH:43][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Tetraethyleneglycol (14.0 g, 72 mmol) was coevaporated with dry pyridine (2×50 mL), dissolved in dry dioxane and 4,4′-dimethoxytrityl chloride (8.0 g, 23.6 mmol) was added portion-wise to the stirred solution. The reaction was monitored by TLC. After overnight stirring at ambient temperature, the reaction mixture was evaporated and dissolved in CH2Cl2 (200 mL), and washed with saturated aq. NaHCO3 (3×100 mL) and brine (100 mL). The organic phase was dried over Na2SO4 and concentrated. Purification on silica gel column using a stepwise gradient of MeOH (0 to 10%) in CH2Cl2 containing 0.2% pyridine yielded 8.5 g (73%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:32]1[N:37]=[C:27]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[O:9])[CH2:11]2)[O:28][N:31]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 42 mg (0.36 mmol, 1.5 eq.) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 60 mg (51% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([C:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1)#[CH:29]>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:29]#[C:28][C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)C1=CCCCC1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (81.5, 54%); 1H NMR δ (CDCl3): 7.8 (d, J=8.05 Hz, 1H), 7.4-7.19 (m, 8H), 6.37-6.3 (m, 1H), 5.6 (s, 2H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 312.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[N:8](C2CCCCO2)[N:7]=1.[N:23]([Sn](CCCC)(CCCC)CCCC)=[N+:24]=[N-:25].Cl>C1(C)C=CC=CC=1.O1CCOCC1>[N:23]1[NH:24][N:25]=[N:16][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1ccco1)nn2C1CCCCO1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1coc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1
Yield: 4.7 %

Procedure:
The title compound was prepared from 3-(2-furyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.245 g, 0.202 mL, 0.74 mmol) in toluene (8 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 8 mL of 4.0N solution of hydrogen chloride in 1,4-dioxane. The compound was purified by preparative HPLC (10–100% acetonitrile in H2O, 20 min) (0.008 g, 0.032 mmol, 4.7% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 8.8 (s, 1H), 8.1 (d, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 7.1 (d, 1H), 6.7 (dd, 1H); ES-MS (m/z) 253 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Reaction time: 0.67 h
Yield: 101.8 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (4.40 g) in anhydrous DMF (75 ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04 g) and the mixture stirred for 40 min. A solution of 1-[(2-[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12 g) in DMF (10 ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product extracted with EtOAc (4×100 ml). The combined organic layer was washed with water (3×100 ml) and dried (Na2SO4). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50 g). LCMS RT=3.75 min, ES+ve 529 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:37])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15].FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([C:25](=[O:37])[CH2:26][NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC(C(=O)O)C(C(=O)CNS(=O)(=O)c1ccccc1)N1CCc2ccccc2C1=O
Yield: 74.8 %

Procedure:
A solution of 3-(1, 2, 3, 4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-hydroxy-pentanoic acid, tert-butyl ester (0.44 g, 0.48 mMol) and 15 mL of trifluoroacetic acid in 15 mL of dichloromethane was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. Crystallization from dichloromethane/ether/hexane gave 0.17 g of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-benzenesulfonylamino-4-oxo-pentanoic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.[OH-].[K+].C(O)C.[C:33](=S)=[S:34]>C(O)C>[SH:34][C:33]1[O:21][C:20]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:27]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:26]=[CH:25][CH:24]=2)=[N:22][N:23]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnc(S)o3)c1)C2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (50 mg, 0.13 mmol) obtained in Step 2 of Example 56 was suspended in ethanol (1.0 mL), and the mixture was stirred at 40° C. for 3 hours after adding a 0.25 mol/L potassium hydroxide/ethanol solution (0.52 mL, 0.13 mmol) and carbon disulfide (0.11 mL, 1.80 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the pH was adjusted to 4 by addition of a 6 mol/L aqueous hydrochloric acid solution. The precipitated white solid was filtered off to give (S)-5-[3-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (37 mg, 66%).
Reaction SMILES: CO[CH:3]1[C:11]2[C:6](=[C:7]([P:12]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH:22]([CH3:30])[CH:23]4OC)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:31].Cl.CO>O>[CH3:30][C:22]1[CH2:21][C:20]2[C:24]([CH:23]=1)=[CH:25][CH:26]=[CH:27][C:19]=2[P:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][C:4]([CH3:31])=[CH:3]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC1c2cccc(P(c3ccccc3)c3cccc4c3CC(C)C4OC)c2CC1C
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1=Cc2cccc(P(c3ccccc3)c3cccc4c3CC(C)=C4)c2C1
Temperature: 25 °C

Procedure:
A mixture of 21.3 g (49.5 mmol) of crude bis(1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)(phenyl)phosphine, 100 ml of 16 M HCl, and 150 ml of methanol was refluxed for 5 hours. This mixture was cooled to ambient temperature, and 100 ml of water was added. The white precipitate that formed was filtered off and dried in vacuum. Yield, 15.0 g (82%) of a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:26])[CH3:25]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:24](=[O:26])[CH3:25])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Reactant: CC(=O)Cl
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21

Procedure:
In analogy to the procedure described for the preparation of intermediate B-1, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with acetyl chloride gave the title compound as colorless amorphous solid. MS: 350.5 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([Cl:31])=[C:28]([CH3:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[Cl:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: COc1cc(Cl)c(C)cc1Br
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: [Na+]
Solvent: CCO
Product: COc1cc(Cl)c(C)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 5-bromo-2-chloro-4-methoxytoluene (0.12 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.13 g).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16]C)[CH:8]=2)[N:3]=1.B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O>>[OH:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]([C:12]([F:13])([F:14])[F:15])=[N:10]2
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3nc2C(F)(F)F)cc1

Procedure:
Followed the procedure described for Compound VI-1, starting from Intermediate 11 and 4-boronobenzoic acid. 1H NMR (MeOH-d4 500 MHz): δ 8.07 (d, J=8.5 Hz, 2H), 7.96 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.51 (dd, J=2.5, 9.5 Hz; 1H), 7.35 (d, J=2.5 Hz, 1H); MS (ESI): m/z 335 [M+1]+.