Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[OH:10]O>C(O)(=O)C.CC(CC)=O>[CH3:1][S:2]([C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[O:10]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: OO
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: CSC(=C[N+](=O)[O-])S(C)=O
Reaction time: 17 h

Procedure:
To a stirred solution in acetic acid (4,500 ml) of 1,1-bismethylthio-2-nitroethylene (165 g) at 60° was added over 15 minutes 30% (100 volume) hydrogen peroxide (113 ml) and the reaction mixture maintained, with stirring, at 60° for 17 hours. Evaporation of the solvent under reduced pressure gave a residue which was taken up in methylethylketone, reevaporated and finally crystallised from methylethylketone to yield the title product as a yellow solid m.p. 137°-143°. Further purification yielded the pure "Z" and "E" isomers. One of these had m.p. 145°-148° and from the mother liquors the other isomer was obtained after further working up and recrystallisation from methylal, m.p. 90°-93°.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].CC(C)([O-])C.[K+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:17][CH2:16][N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]1=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1NC(=O)NC1=O
Reactant: ClCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)N(COCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Methylimidazolidine-2,4-dione (1.00 g) was dissolved in N,N-dimethylformamide (20 mL), potassium tert-butoxide (1.08 g) and benzyl chloromethyl ether (1.32 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (0.98 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)([CH3:8])[CH3:7]>>[Cl:1][CH2:2][C:3]([C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([CH:6]([CH3:7])[CH3:8])[CH:10]=1)[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cccc2ccc(=O)[nH]c12
Product: CC(C)c1cc(C(=O)CCl)cc2ccc(=O)[nH]c12

Procedure:
By using chloroacetyl chloride and 8-isopropylcarbostyril, there was obtained 6-chloroacetyl-8-isopropylcarbostyril as a light yellow powder having a melting point of 250° C. or less (decomposed).
Reaction SMILES: Cl[C:2](=[O:14])[CH2:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:2](=[O:14])[CH2:3][C:4]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1(CC(=O)Cl)CCOCC1
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of methyl 4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.06 g, 4.8 mmol) and bromobenzene (1.13 g, 7.21 mmol) in dichloromethane (20 mL) at 0° C. was added aluminum chloride (1.92 g, 14.4 mmol). The ice-water bath was removed and the reaction mixture was stirred at rt for 16 h. The mixture was then cooled at 0° C. and quenched by the addition of 1 N HCl solution and water. The mixture was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate. The crude material was then purified by flash chromatography (Biotage Flash 40 M, 2:1 hexane/ethyl acetate, to afford methyl 4-[2-(4-bromo-phenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (900 mg, 55%). LC-MS ret. time 2.76 min; m/z 342.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.58–1.69 (m, 2H), 2.12–2.18 (m, 2H), 3.28 (s, 2H), 3.64 (s, 3H), 3.69–3.77 (m, 4H), 7.59 (d, 2H), 7.77 (d, 2H).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:37][C:9]=3[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-fluoro-1-[(phthalimidooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Br:17][C:18]1[N:19]=[CH:20][N:21]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([CH3:16])[N:3]=2)[CH:22]=1
Reactant: Brc1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example A.41) (0.4 g, 1.46 mmol) and commercially available 4-bromo-imidazole (0.32 g, 2.18 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.33 g, 59%). MS (ISP) 385.0 [(M+H)+]; mp 219.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N:19][CH:20]=2)[N:15]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:13][C:14]1[C:23]2[CH:24]=[CH:25][NH:26][C:27](=[O:28])[C:22]=2[C:21]2[C:16](=[CH:17][CH:18]=[N+:19]([O-:37])[CH:20]=2)[N:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)c1cc(Cl)c(Nc2nc3cc[n+]([O-])cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 6-{[2,6-dichloro-4-(1-hydroxy-1-methylethyl)phenyl]amino}pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (Example 146, Step 1) (30 mg, 0.07 mmol) in CH2Cl2 (3 mL) at 0° C. was added m-CPBA (40.5 mg, 0.18 mmol, 77% max) and stirred for 2 hr. 10% Sodium sulfite and saturated NaHCO3 were added and stirred for 30 min. The solution was extracted with 3:1 CHCl3/iPrOH, dried with MgSO4, filtered, and concentrated under reduced pressure. Column chromatography (100% CH2Cl2 to 30% MeOH, 70% CH2Cl2) provided the desired product.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11]C(=O)OC(C)(C)C)[C:6]1=[O:19].ClCCl.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[C:6]1=[O:19]
Reactant: COc1cccc(F)c1CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(F)c1CN1CCCC(N)C1=O
Reaction time: 1 h

Procedure:
The synthetic intermediate from Step 1 (329 mg, 0.934 mmol), dichloromethane (1 ml), and trifluoroacetic acid (1 ml) were combined in an open vial, and the mixture was allowed to stir for 1 hour. The mixture was then diluted with toluene (3 ml) and subsequently concentrated to dryness. Crude (3-amino-1-(2-fluoro-6-methoxybenzyl)piperidin-2-one so obtained was used in the next synthetic transformation without additional purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-])=O)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:20][C:10]1=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.9 %

Procedure:
The title compound may be prepared either as described in US 2004/002495 or as follows: To a solution of (S)-2-(tert-butyloxycarbonylamino)-3-(2-nitrophenyl) propanoic acid (987 mg, 3.18 mmol) in MeOH (100 mL) was added 10% palladium on carbon (300 mg), and the mixture was stirred at RT under hydrogen at 80 psi for 24 h. Filtration and solvent evaporation under vacuum provided the title compound (800 mg) as a foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:31](O)=[O:32])=[CH:24][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30][C:31]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C:7]3[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]4[CH:11]=[N:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:16]2)=[O:32])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccncc21
Yield: 85 %

Procedure:
(R)-3-(3-Methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-c]pyridine (35E) (0.279 mmol, crude oil) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.335 mmol, 0.086 g) and N-methylmorpholine (1.95 mmol, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.335 mmol, 0.127 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(3-(3-methoxypropyl)-3H-imidazo[4,5-c]pyridin-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (35F) as a clear oil (0.238 mmol, 0.146 g, 85% yield). ESI-ESI-MS: adz 614.3 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20](=[O:22])[CH3:21]>O1CCCC1>[Br:13][C:14]1[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC=O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1cccnc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Butyllithium (1.6M in hexanes, 26.7 mL, 42.7 mmol) was added over 15 minutes to a solution of diisopropylamine (6.0 mL, 42.8 mmol) in tetrahydrofuran (45 mL) at 0 to 5° C. under nitrogen, then stirred for 30 minutes. This solution was cooled to −78° C. and 2-bromopyridine (3.45 mL, 35.8 mmol) was added. The reaction was stirred at −78° C. for 1 hour. Acetaldehyde (2 mL, 35.6 mmol) was added and the reaction stirred at −78° C. for 1 hour then quenched with saturated ammonium chloride solution and allowed to warm to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 0-10% diethyl ether/dichloromethane, to give 1-(2-bromopyridin-3-yl)ethanol (2.65 g, 37%). 1H NMR (400 MHz, CDCl3) δ8.27 (1H, dd, J=2.0, 4.7 Hz), 7.92 (1H, dd, J=2.0, 7.4 Hz), 7.31 (1H, dd, J=4.7, 7.8 Hz), 5.19 (1H, q, J=6.3 Hz), 2.18 (1H, s), 1.51 (3H, d, J=6.4 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:15]=2)=[CH:10][CH:9]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>CC#N>[NH2:20][C:17]1[C:16]([C:21]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:29])=[N:15][C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])=[CH:13][CH:12]=2)=[CH:19][N:18]=1
Reactant: CS(=O)(=O)OCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Reactant: COCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCNCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A mixture of the product of step (iv) (250 mg, 0.61 mmol), K2CO3 (250 mg, 1.8 mmol), 3-methoxypropylamine (82 mg, 0.92 mmol) in MeCN (20 mL, Aldrich, HPLC grade) was stirred at 90° C. under N2 atmosphere overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue subjected to prep-HPLC for purification, the eluents were concentrated and 1N NaOH solution added into the residue to control the pH=8˜9. The mixture was extracted with DCM three times. The combined extracts was dried over anhydrous sodium sulphate, filtered, concentrated in vacuo, which afforded the title compound (yellow solid, 158 mg)
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C>CO.[Pd]>[NH2:25][CH2:24][C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C#N)cn3)cc(C)c21
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2cnc(CN)cn2)cc2c1C(CC(=O)O)OB2O
Yield: 95.4 %

Procedure:
To a mixture of [6-(5-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (1.63 g) and Pd/C (250 mg) in methanol (80 mL) was degassed 3 times and the suspension was charged with H2 balloon at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness, affording the title compound (1.45 g). 1H NMR (300 MHz, CD3OD) δ 8.49 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 5.70-5.66 (m, 1H), 4.29 (s, 2H), 4.19 (q, 2H), 3.22-3.16 (m, 1H), 2.54-2.46 (m, 1H), 2.40 (s, 3H), 1.24 (t, 3H). MS found: (M+H)+=358.2.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2[Cl:20])=[CH:17][C:16](O)=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:26])=O>>[Cl:20][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:26])[CH:17]=2)[N:12]([CH3:22])[C:11](=[O:23])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)c(C(=O)NC2CCCCC2)c(Cl)c2cc(O)ccc21
Product: Cn1c(=O)c(C#N)c(Cl)c2cc(Cl)ccc21
Yield: 48 %

Procedure:
A solution of Compound 67 (2.2 g, 6.57 mmol) in 20 mL neat phosphorus oxychloride was heated at 90° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 0.8 g (48%) of yellow solids. M.P. 256° C. 1H NMR (DMSO-d6): δ 3.65 (s, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.94 (dd, J=2.1, 9.0 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H). EIMS m/z 254 (M+1).
Reaction SMILES: I[C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([I:7])[N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[I:7][C:5]1[N:6]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[O:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1oc(I)nc1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1oc(-c2ccc(C)cc2)nc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of ethyl 2,4-diiodo-1,3-oxazole-5-carboxylate (0.13 g, 0.32 mmol), (4-methylphenyl)boronic acid (48.0 mg, 0.35 mmol) and sodium carbonate (2.0 M; 0.40 mL, 0.80 mmol) in dioxane (2 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (13.1 mg, 16.0 μmol). The mixture was stirred at ambient temperature. After 18 h, sat. NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes 50% hexanes/ethyl acetate) gave the title compound (40 mg). MS 357.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:17](=O)[CH:16]3[NH:19][CH:12]([CH2:13][S:14][CH2:15]3)[C:11]2=O)=[CH:6][CH:5]=1.S(C)C.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1.[OH-].[Na+]>C1COCC1>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:17][CH:16]3[NH:19][CH:12]([CH2:13][S:14][CH2:15]3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C1C2CSCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(N2CC3CSCC(C2)N3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 7-(4-(trifluoromethoxy)phenyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane-6,8-dione (115 mg, 0.35 mmol) and THF (5 mL) was heated at 70° C. under N2. A solution of BH3.SMe2 (2M in THF, 0.7 mL, 1.4 mmol) was added dropwise. After 2.5 h, 6N HCl (1.0 mL) was added dropwise (Caution: H2 evolution). After an additional 30 min, the reaction was allowed to cool to rt, poured into 1N NaOH (8 mL), and extracted with dichloromethane (40 mL×2). The combined organic extracts were dried, filtered and concentrated to give 7-(4-(trifluoromethoxy)phenyl)-3-thia-7,9-diazabicyclo[3.3.1]nonane: MS (ESI): 305.5 (M+H).
Reaction SMILES: [Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[S:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([SiH](CC)CC)C>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:16]1[CH2:17][CH2:18][S:13][CH2:14][CH2:15]1
Reactant: O=C1CCSCC1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSCC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
TMSOTf (3.38 mL, 18.7 mmol) was added dropwise to a solution of tetrahydro-4H-thiopyran-4-one (2.17 g, 18.7 mmol) in DCM (100 mL) at 0° C. (bath temp) under nitrogen. A solution of ethyl 5-bromo-1H-indole-7-carboxylate (5 g, 18.7 mmol) in DCM (30 mL) was then added and the reaction was stirred for 30 min. Triethylsilane (4.47 mL, 28.1 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with saturated aqueous Na2CO3 (1×100 mL, and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was washed with MeOH, giving 4.92 g (72%) of the title compound.
Reaction SMILES: C([CH:3]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=2)[C:6](=[O:16])[C:5]2[N:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:4]1=2)C.C(OC([N:41]1[CH2:46][CH2:45][NH:44][C:43](=[O:47])[CH2:42]1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.O.[Cu]I>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:17]2[C:5]3[C:6](=[O:16])[N:7]([C:9]4[CH:10]=[CH:11][C:12]([N:44]5[CH2:45][CH2:46][NH:41][CH2:42][C:43]5=[O:47])=[CH:13][CH:14]=4)[CH2:8][CH2:3][C:4]=3[C:19]([C:20]([NH2:22])=[O:21])=[N:18]2)=[CH:28][CH:27]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CCC1CN(c2ccc(I)cc2)C(=O)c2c1c(C(N)=O)nn2-c1ccc(OC)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCNCC4=O)cc2)CC3)cc1
Temperature: 130 °C
Yield: 43.4 %

Procedure:
Part A. To ethyl-6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo (3,4-c)pyridine-3-carboxamide (0.52 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.32 g, 1.4 mmol), and K2CO3 (0.22 g, 1.6 mmol) was added DMSO (5 mL). The mixture was degassed with N2. CuI (38 mg, 0.2 mmol) was added and the reaction was heated to 130° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, and dried (MgSO4). Purification by chromatography on silica gel using 5% MeOH/CH2Cl2 afforded 0.2 g (33%) of a foam; Mass Spec (M+H)+ 624.6. Part B. The product of Part A (0.2 g, 0.32 mmol) was hydrogenated at 40 psi in the presence of 10% palladium on carbon for 24 h. The reaction was filtered and then heated with 5% NH3 in ethylene gylcol in a sealed vial for 1.5 h at 80° C. The reaction was diluted with water and extracted with EtOAc. Purification by HPLC and freeze-drying afforded 30 mg (16%) of a white solid; High Resolution Mass Spec (M+H)+ for C24H25N6O4 461.1938.
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:19]>N([O-])=O.[Na+]>[OH:19][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)N1CCc2ccc(N)cc2CC1
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)N1CCc2ccc(O)cc2CC1

Procedure:
To ethyl 7-amino-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate was added a 5% aqueous sulfuric acid solution, followed by stirring under ice-cooling. An aqueous solution (30 ml) of 10.22 g of sodium nitrite was added dropwise in portions thereto, and followed by stirring at the same temperature for 0.5 hours and then stirring at 60° C. for 3 hours. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain a crude purified product having ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a main component. The crude purified product was recrystallized from ethyl acetate twice to obtain 15.66 g of ethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate.