Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:7][C:8](=[O:12])[O:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[O:7][C:8](=[O:12])[O:9][C:10]=1[CH2:11][Br:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1oc(=O)oc1CBr
Temperature: 80 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-Acetoxymethyl-5-methyl-2-oxo-1,3-dioxolene (159 mg, 0.92 mmol) was dissolved in carbon tetrachloride (5.0 mL). Thereto were added N-bromosuccinimide (164 mg, 0.92 mmol) and benzoyl peroxide (11 mg, 0.046 mmol). This mixture was stirred at 80° C. for 1 hours. Through the ordinary post-treatment, crude Compound S-31 (220 mg, yield 95%) was obtained.
Reaction SMILES: [O:1]([C@H:19]1[C@@H:26]2[N:22](/[C:23](=[N:27]/[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[C:29]=3[CH3:37])/[O:24][CH2:25]2)[CH2:21][CH2:20]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:1][C@H:19]1[C@@H:26]2[N:22](/[C:23](=[N:27]/[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[C:29]=3[CH3:37])/[O:24][CH2:25]2)[CH2:21][CH2:20]1
Reactant: Cc1c(/N=C2\OC[C@@H]3[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(/N=C2\OC[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 1I (29.0 mg, 0.0550 mmol) in THF (2 mL) at 0° C. was added HF/pyridine mixture (˜2.3:1, 0.120 mL) and the reaction was stirred at rt overnight. Saturated aqueous NaHCO3 was added (5 mL), and the product was extracted with EtOAc (3×5 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, then filtered and concentrated. Purification via flash chromatography (silica gel, 0-90% EtOAc in hexane) provided the title compound (10.0 mg). LCMS: niz 292 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([CH3:16])[S:13][C:12]=2Br)=[O:10])=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[C:11]3[CH:15]=[C:14]([CH3:16])[S:13][C:12]=3[O:18][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)Nc2ccc(Cl)cc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(s1)Oc1cc(Cl)ccc1NC2=O

Procedure:
Similar reaction is carried out using N-(4-chloro-2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate to give 8-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([CH3:22])[C:3]=1[NH:23][C:24](=O)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([CH3:22])[C:3]=1[NH:23][C:24](=[S:40])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Solvent: CC(Cl)Cl
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=S)CC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butyramide (200 mg, 0.48 mmol) in dichloroethane (10 mL) was added Lawesson's reagent (193 mg, 0.48 mmol) and the reaction mixture was stirred at reflux for 2 h. The mixture was then cooled to room temperature and concentrate. Purification by preparative thin layer chromatography (dichloromethane 100%) afforded the desired compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([Cl:21])[CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:21][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1)[O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:22])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Yield: 55.4 %

Procedure:
The product from Example 195a (2.50 g, 13.5 mmol) and 2N NaOH (7.77 ml, 15.5 mmol) in MeOH (25 mL) was refluxed for 1 hour, and then evaporated. The residue was dissolved in H2O and acidified to pH 2 with 10% HCl under stirring. The precipitate was collected by filtration, washed with H2O, and dried in vacuum overnight to give the title compound as pale brown crystal (2.30 g, 62%).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(O)c(Br)c1
Yield: 100.1 %

Procedure:
A solution of bromine (7.18 mL, 0.14 mol) in chloroform (25 mL) was added dropwise over 2 hours to a solution of 4-tert-butyl-phenol (20 g, 0.133 mol) in 1:1 v/v chloroform:carbon tetrachloride (64 mL) at 0° C. under nitrogen until a slight red coloration persisted (approximately 1 mL of bromine solution remained). The reaction mixture was then purged with nitrogen overnight. The resulting tan solution was diluted with dichloromethane (50 mL), washed with 1% aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)phenol (30.5 g, quantitative yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([CH2:9][CH2:10][NH:11][C:12](=O)[O:13]CC)=[CH:8][C:4]=2[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C:8]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)NCCc1cc2cc(F)ccc2s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2sc3ccc(F)cc3c21
Yield: 48.27 %

Procedure:
Using analogous conditions and workup as described for the preparation of Intermediate I-1d above, ethyl 2-(5-fluorobenzo[b]thiophen-2-yl)ethylcarbamate (I-50 f: 700 mg, 2.622 mmol) was reacted with P2O5 (749.78 mg, 5.28 mmol) and POCl3 (10 mL) to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 280 mg of the product (48.27% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.I[CH2:32][CH3:33]>CN(C=O)C>[CH2:32]([O:27][CH2:26][C:22]1[N:21]=[C:20]([NH:19][C:17]2[S:18][C:14]([C:5]3[CH:6]=[CH:7][C:8]([C:10]([OH:13])([CH3:11])[CH3:12])=[CH:9][C:4]=3[F:3])=[CH:15][C:16]=2[C:28]([NH2:30])=[O:29])[CH:25]=[CH:24][CH:23]=1)[CH3:33]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (10 mg, 0.25 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 48) (50 mg, 0.125 mmol) and the mixture was allowed to stir for 20 minutes. Iodoethane (29 mg, 0.19 mmol) was then added and the reaction was allowed to warm to room temperature and subsequently heated to 60° C. overnight. The reaction was cooled to ambient temperature, quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:62]2[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]2)(=O)=O)=CC=1>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:17]([C:15]2[CH:14]=[CH:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH:62]5[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]5)=[CH:3][CH:4]=4)[CH:9]=[N:10][C:11]=3[CH:16]=2)=[O:18])[CH:22]=1
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)C1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(Oc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)C1
Temperature: 80 °C

Procedure:
Methyl 3-hydroxycyclobutanecarboxylate (671 mg, 5.16 mmol) was dissolved in CH2Cl2 (20 mL). Pyridine (0.63 mL, 7.73 mmol) was then added followed by p-toluenesulfonic anhydride (1.85 g, 5.67 mmol) and the reaction was stirred at rt for 14 h. The reaction was concentrated in vacuo, dissolved in ether, and washed with H2O, 2M HCl, 2M NaHCO3, brine, and dried over MgSO4. The solution was then filtered, and concentrated in vacuo to give methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate as a colorless oil, which was taken on crude. 1-(4-Hydroxyphenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (0.88 g, 2.56 mmol), 18-crown-6 (1.36 g, 5.13 mmol), and K2CO3 (0.71 g, 5.13 mmol) were dissolved in DMF (26 mL) in a 50 mL round bottom flask. The reaction was heated to 80° C. under N2 atmosphere upon which methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate was added drop-wise. After heating at 80° C. for 48 h, the reaction was cooled to rt, concentrated in vacuo, and purified using silica gel chromatography (5% methanol:CH2Cl2). To remove residual p-toluenesulfonic acid and 18-crown-6, the foamy white solid was washed with ethyl acetate. The combined organic washes were then washed with water and dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate as an off-white foamy solid (3:1 trans:cis isomers). MS (ES+): m/z 457 (100) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][C:13]=2[N:14]=1.[N:22]1([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=3)[NH:31][N:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:22]1([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][C:34]([NH:38][C:19]([C:17]4[CH:16]=[CH:15][C:13]5[N:14]=[C:10]([NH:9][C:3]6[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=6[Cl:1])[NH:11][C:12]=5[CH:18]=4)=[O:21])=[CH:35][CH:36]=3)[NH:31][N:30]=2)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc2nc(Nc3ccc(Cl)cc3Cl)[nH]c2c1
Reactant: Nc1ccc2c(CN3CCOCC3)n[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc2c(CN3CCOCC3)n[nH]c2c1)c1ccc2nc(Nc3ccc(Cl)cc3Cl)[nH]c2c1

Procedure:
The ester obtained as above was hydrolyzed using general procedure C to yield 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid. The carboxylic acid (0.25 mmol) was coupled with 3-(morpholin-4-yl)methyl-1H-indazol-6-ylamine (0.25 mmol) using HBTU employing general procedure D. The product, 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-morpholin-4-ylmethyl-1H-indazol-6-yl)-amide, was obtained as a light brown solid after purification by silica gel chromatography using DCM/methanol as eluent. MS: m/z 536 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:18][C:19]1([CH3:30])[C:23]([CH3:25])([CH3:24])[O:22][B:21](OC(C)C)[O:20]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([B:21]3[O:22][C:23]([CH3:25])([CH3:24])[C:19]([CH3:30])([CH3:18])[O:20]3)=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(-c2ccco2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccc(F)cc3)o2)OC1(C)C
Temperature: -78 °C

Procedure:
To a solution of 2-(4-fluorophenyl)furan (1.50 g, 9.25 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n-BuLi (4.4 mL, 2.5M solution in hexane) dropwise with stirring at −78° C. under nitrogen. The resulting solution was warmed slowly to −40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.42 g, 18.38 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue (1.20 g crude), which was used to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: COC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC)C3)cc1

Procedure:
Compound ee was prepared according to the procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with methyl chloroformate. LC-MS: m/z=+427 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: O=C1Cc2cc(-c3cccs3)ccc2N1

Procedure:
The title compound was prepared as described for Example 37 using 5-bromooxindole and tri-n-butyl(2-thienyl)tin: MS (ES) n/z 216 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:28])=[N:20]1>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:20]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Reactant: Nc1n[nH]c2ccccc12
Product: Clc1ccccc1-c1nc(Nc2n[nH]c3ccccc23)c2ccncc2n1

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (72 mg, 33% yield). HPLC-Method A, Rt 3.21 min; 1H NMR (DMSO, 500 MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.65 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00(1H, m); MS (m/z), MH+ 373.1.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.[OH-].[K+].O>C(O)C>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Reactant: COc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCc2ccc(OC)cc2)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), paramethoxybenzyl bromide (0.047 ml, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol) in Ethanol (1.738 ml) was refluxed overnight. 1 ml of water was added to the cooled reaction and the mixture was extracted with EtOAc 2×. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. 1H NMR (500 MHz, CDCl3) δ ppm 8.17, 7.39-7.24, 6.88, 5.93, 5.31-5.26, 4.68, 4.57, 3.82, 3.07, 2.61, 1.75-1.72, 1.60-1.53, 1.43-1.37; MS (EI) m/z 459 (M+1)
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:26]=2)[O:3]1.[ClH:28]>CO>[ClH:28].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:27])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:26]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: Cl
Solvent: CO
Product: CC1(C)OB(c2ccc3c(c2)CNCCO3)OC1(C)C
Temperature: 60 °C
Yield: 51.1 %

Procedure:
To a slurry of 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 9, step 1) (3.3 g, 8.8 mmol) in methanol (25 mL) was added anhydrous hydrogen chloride (6.0 mL, 4 N in dioxane, 24 mmol). The reaction mixture was heated (60° C.) for 1.5 h and was concentrated. The resulting solid was suspended in ethyl ether (50 mL), collected by filtration and washed with ethyl ether (2×30 mL) to afford 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.4 g, 50% yield) as a white solid. MS (EI) for C15H22BNO3: 276 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:28][C:26]1[CH:27]=[C:22]([S:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(SC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 582.3 [M−H]−.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[N+]([C:20]1C(N2CCC(=O)CC2)=NC=CC=1)([O-])=O>>[CH3:20][C:10]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][C:2](=[CH2:1])[CH2:3][CH2:4]2)[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Product: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Yield: 62 %

Procedure:
The title product was synthesized following the procedure reported for Compound 2a but replacing 1-(6-methyl-3-nitro-2-pyridyl)-4-oxopiperidine for 1-(3-nitro-2-pyridyl)-4-oxopiperidine. Yield: 62%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(C#N)=CC=1)=C2Cl.[F:36][C:37]([F:47])([F:46])[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][N:39]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:42][C:41]1[CH:40]=[N:39][C:38]([C:37]([F:47])([F:36])[F:46])=[CH:45][CH:44]=1)=[C:5]2[OH:13]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 44: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol), in pyridine (34 mL) were heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl[O-].[Na+].Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CCc1ccccc1
Temperature: 6 °C
Yield: 89.9 %

Procedure:
A 200 ml flask was charged with a solution dissolving 20.8 g (100 mmol) of 2-hydroxy-4-phenylbutyric acid ethyl ester in methylene chloride (50 ml) and 72.6 g (purity 12.3%, 120 mmol) of sodium hypochlorite, and cooled at 6° C. To the reaction mixture was added 43 mg (0.2 mmol) of 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-1-oxy and further added 10 ml (10 mmol) of 1N hydrochloric acid. The gradual exothermal reaction proceeded, and the starting material of 2-hydroxy-4-phenylbutyric acid ethyl ester was disappeared in 30 minutes. After the reaction was stopped by adding 10 ml of 5% sodium thiosulfate aqueous solution, the reaction mixture was subjected to the after treatment as described in Example 1 to obtain 18.55 g of 2-keto-4-phenylbutyric acid ethyl ester. The yield was 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Sc1ccc(Cl)cc1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Amino-5-bromopyridine (7.8 grams), 4-chlorothiophenol (9.2 grams), sodium methoxide (3.5 grams), and copper powder (1.0 gram) were reacted in 100 ml. of methanol, for 12 hours, in a bomb, in accordance with the procedures of J. Med. Chem. 21, 235 (1978). The reaction mixture was filtered, washed with methanol, and methanol removed by evaporation. The methanol washes were combined with ethyl acetate extracts of solids made after refluxing on a steam bath for one hour. Solvents were removed and the solids dissolved in ethyl acetate and filtered to remove insolubles. The liquid was passed over a silica column with ethyl acetate, and the fraction corresponding to the product amine (Rf ≅0.2) collected., yield 6.5 grams, m.p., 161°-163° C.