Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([O:12][C:13](=O)[O:14]C(C)(C)C)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 25 g (247 mmol) 4-piperidinol in 350 mL dry tetrahydrofuran (THF) at 0° C. was added dropwise 60.2 g (276 mmol) di-t-butylcarbonate in 350 mL dry THF. The reaction was allowed to warm to room temperature (rt) and stirred overnight. The solvent was removed under reduced pressure, the resulting residue dissolved in 700 mL CH2Cl2 and the solution extracted with H2O (1×400 mL), dried over MgSO4, filtered and rotary evaporated to yield 45 g (91%) of N-(t-butoxycarbonyl)-4-piperidinol as an oil which slowly solidified to white crystals. 1H NMR (CDCl3) δ 3.75-3.96 (m, 3H); 2.92-3.13 (m, 2H); 1.80-1.93 (m, 4H); and 1.48 (s, 9H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:16])=[CH:10][CH2:11][S:12][C:13](=[NH:15])[NH2:14])[CH:6]=[CH:7][CH:8]=1.Cl.[OH-].[Na+]>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:16])[CH2:10][CH2:11][S:12][C:13]([NH2:14])=[N:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=CCSC(=N)N)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(c2cccc(Br)c2)CCSC(N)=N1
Temperature: 100 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A suspension of 2-[3-(3-bromo-phenyl)-but-2-enyl]-isothiourea hydrochloride (17 g, 52 mmoles) in 12 M HCl (53 mL, 640 mmoles, 12 equiv) is heated to 100° C. After 24 h, the solution is cooled to ambient temperature. The pH of the solution is adjusted to pH 10 with aqueous 2N NaOH and extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (70% yield): MS (m/z): 285.0, 287.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:7])[CH2:5][CH3:6].CCN(CC)CC.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:4]([CH2:5][CH3:6])[CH2:3][O:2][CH3:1])(=[O:18])=[O:17]
Reactant: CCC(O)COC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(COC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 1-methoxy-2-butanol (52.08 g, 57.23 mL, 0.5 mol) and Et3N (108.2 mL, 0.75 mol, 1.5 equiv) in CH2Cl2 (500 mL) was treated dropwise with methanesulfonyl chloride (68.73 g, 46.44 mL, 0.6 mol, 1.2 equiv) at 0° C. under N2. The reaction mixture was warmed to 25° C. and stirred at 25° C. for an additional 4 h before being quenched with H2O (300 mL). The two layers were separated, and the aqueuos was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were washed with H2O (2×200 mL) and saturated aqueuos NaCl (200 mL), dried (MgSO4), and concentrated in vacuo. The residue was dried enough in vacuo to afforded the desired mesylate 1 (85-90.0 g, 91 g theoretical, 93-98%) as a pale-yellow oil, which was pure enough and directly used in the next reaction without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([C@H:18]([NH:20]C(OCC4C=CC=CC=4)=O)[CH3:19])=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[CH:2]1.[ClH:32].CO.[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[ClH:32].[ClH:32].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1

Procedure:
10% Palladium hydroxide carbon (80 mg) was added to a mixture of (R)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-benzyloxycarbonylaminoethyl)benzamide (200 mg), 15% hydrochloric acid-methanol (1 ml) and methanol (6 ml), and the mixture was stirred in a stream of hydrogen at 40° C. for 1 hour. After the reaction, the catalyst was removed by filtration, and the mixture was concentrated under reduced pressure. The obtained crystals were recrystallized from methanol-ether to give 120 mg of (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide dihydrochloride 3/2 hydrate having a melting point of 286° C. (dec.).
Reaction SMILES: C([O:3][CH:4]([CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=O.[OH-].[K+]>CCO>[CH2:5]([CH:4]([CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[OH:3])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)OC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(O)CCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC
Yield: 107.4 %

Procedure:
The above diarachidonylmethyl formate (III, 0.43 g, 0.71 mmol) and KOH (100 mg) were stirred in 95% EtOH (20 mL) at room temperature under nitrogen overnight. Upon completion of the reaction, most of the solvent was evaporated. The resulting mixture was treated with 20 mL of 2M HCl solution. The aqueous phase was extracted with ether (2×30 mL). The combined ether extract was washed with water (2×25 mL), brine (25 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent gave 0.44 g of IV as pale oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 40 mL) eluted with 0-5% ethyl acetate gradient in hexanes. This gave 0.41 g of diarachidonyl methanol (IV) as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[C:23]2[O:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:20][C:19]=2[CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:22][C:23]=3[C:15]=2[F:14])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: OB(O)c1ccc2nc(-c3ccccc3)oc2c1F
Reactant: COC(=O)c1nc(Br)cc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc3nc(-c4ccccc4)oc3c2F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
0.024 g (0.03 mmol) of (PPh3)2PdCl2 is added to a solution of 0.3 g (1.13 mmol) of methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate in 20 ml of dioxane, and this mixture is stirred at room temperature (RT) for 30 min. In succession, 0.35 g (1.35 mmol) of (7-fluoro-2-phenyl-1,3-benzoxazol-6-yl)boronic acid, 0.47 g (3.4 mmol) of K2CO3 and 2 g (111 mmol) of H2O are then added to this mixture, which is then stirred under reflux for 6 h. The mixture is allowed to stand at RT for a further 12 h and then added to 40 ml of H2O. This mixture is extracted repeatedly with CH2Cl2, and the combined organic phase is dried over Na2SO4 and then concentrated. Purification by chromatography on silica gel using the mobile phase heptane/ethyl acetate (3/7) gives 0.16 g (36%) of product. 1H-NMR (CDCl3): δ 8.30, 8.00, 7.55 (3m, 5H, C6H5), 7.60, 7.55 (2d, 2H, benzoxazole ring), 7.30 (s, 1H, pyridine) 4.85 (bs, 2H, NH2), 4.00 (S, 3H, COOCH3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[F:14])#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[C:40]([CH2:41][NH2:42])=[CH:39][C:38]([C:43]([F:46])([F:45])[F:44])=[N:37]2)[CH:33]=[CH:34][CH:35]=1>C(#N)C.O>[Cl:29][C:30]1[CH:31]=[C:32]([N:36]2[C:40]([CH2:41][NH:42][C:10](=[O:12])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:14])[CH:5]=3)[CH3:13])=[CH:39][C:38]([C:43]([F:44])([F:45])[F:46])=[N:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(C#N)c(F)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-(4-cyano-3-fluorophenyl)propanoic acid (440 mg, 2.278 mmol) in acetonitrile was added HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (659 mg, 2.392 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-cyano-3-fluorophenyl)propanamide (870 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](S(C)(=O)=O)=[CH:20][CH:19]=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1[O:48]C1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.NC1C=CC(OC2C=CN=C3C=C(C4C=CC(O)=CC=4)SC=23)=C(F)C=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([NH:31][C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[S:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:48])=[CH:20][CH:19]=3)[S:17][C:10]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Agent: Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Yield: 3 %

Procedure:
Following the procedure described above for the synthesis of Compound 50 (Scheme 10, Example 55) but substituting amine 49 for the amine 154, title Compound 155a was obtained in 3% yield. Characterization of 155a is provided in the Table 14a.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])C.C1(=O)C2CCCCCC=2C=CC1>>[C:7]1([CH2:6][C:4]([OH:5])=[O:3])[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cccc2c1CCCCC2
Agent: O=C1CC=CC2=C1CCCCC2
Product: O=C(O)Cc1cccc2c1CCCCC2

Procedure:
(Benzocycloheptan-1-yl)-acetic acid was prepared from 1-ethoxycarbonylmethylbenzocycloheptane, which was itself prepared from benzocycloheptan-1-one.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH:23]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.[CH3:50][NH:51][CH3:52].CO>O.CN(C=O)C.C(Cl)Cl.CCO>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH2:23][N:51]([CH3:52])[CH3:50])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C=O)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CN(C)C
Temperature: 70 °C
Yield: 13 %

Procedure:
A suspension of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 13.9 μmol), EtOH (absolute, 500 μL), NaBH(OAc)3 (8.8 mg, 41.7 μmol), and glacial AcOH (4 μL, 70 μmol) was treated with a solution of N,N-dimethylamine in MeOH (2 M, 35 μL, 69.5 μmol). DCM (50 μL) was added to improve solubility. The reaction was sealed and heated to 70° C. Conversion was limited, so more N,N-dimethylamine in MeOH (2 M, 170 μL, 0.337 mmol), glacial AcOH (20 μL, 0.35 mmol), NaBH(OAc)3 (50 mg, 0.236 mmol), and DMF (500 μL) were added. Heating was continued. Once conversion was achieved, LiOH monohydrate (200 mg, 4.7 mmol) and H2O (1.0 mL) were added. The reaction was sealed and heated to 100° C. overnight. Afterward, the reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt) (1.0 mg, 13%). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H31ClNO3: 440.2; Found: 440.0.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:18][C:17]([N+:19]([O-])=O)=[C:16]([C:22]([NH2:24])=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N#N.Br[C:29]1[N:34]=[C:33]([CH2:35][O:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[CH:32]=[CH:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>CO.[Pt].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[S:18][C:17]([NH:19][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([CH2:35][O:36][CH2:37][C:38]([OH:40])([CH3:39])[CH3:41])[N:34]=4)=[C:16]([C:22]([NH2:24])=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1cc(-c2ccc(N3CCS(=O)(=O)CC3)cc2)sc1[N+](=O)[O-]
Reactant: CC(C)(O)COCc1cccc(Br)n1
Agent: [Pd]
Agent: [Pt]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CO
Product: CC(C)(O)COCc1cccc(Nc2sc(-c3ccc(N4CCS(=O)(=O)CC4)cc3)cc2C(N)=O)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
5-[4-(1,1-Dioxidothiomorpholin-4-yl)phenyl]-2-nitrothiophene-3-carboxamide (Intermediate 16) (525 mg, 1.376 mmol) and Pt/C, doped with V (90 mg, 0.014 mmol) were stirred at room temperature overnight in degassed MeOH (5 mL) under a balloon of H2. The vial was then evacuated and back-filled with N2 (4×) and 1-[(6-bromopyridin-2-yl)methoxy]-2-methylpropan-2-ol (Example 217 Step 1) (358 mg, 1.38 mmol), Pd2dba3 (126 mg, 0.138 mmol), X-Phos (328 mg, 0.69 mmol) and K2CO3 (209 mg, 1.51 mmol) were added. The vial was evacuated and back-filled with N2 (3×) and the resulting mixture was stirred at 100° C. for 4 hours. After cooling to room temperature, the mixture was diluted with methanol, silica gel was added, and the solvent was removed in vacuo. Purification of the residue by silica gel chromatography (0-6% MeOH—CHCl3) gave the title compound as a beige solid after triturating in DCM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.C(Cl)Cl.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:25])=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol;) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccn2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
A mixture of 2-(p-tolyl) pyridine (118.88 g, 702.5 mmol), N-bromosuccinimide (131.29 g, 737.6 mmol, 1.05 equivalents) and CCl4 (1190 mL) was treated with benzoyl peroxide (1.70 g, 7.03 mmol, 0.01 equivalents) under nitrogen, stirred at 70° C. for 1.5 hours, and then allowed to cool to ambient temperature with stirring overnight. The reaction mixture was filtered, washed with CCl4 (2×250 mL), concentrated to oil, treated with isopropyl alcohol (420 mL) and cooled to −5° C. The resulting solid was filtered, washed with isopropyl alcohol (140 mL), and dried in a vacuum oven with a N2 bleed to afford the title compound (111.91 g, 64.2% yield). 1H NMR (CDCl3): δ 8.70(m, 1H), 7.99(m, 2H), 7.75(m, 2H), 7.52(m, 2H), 7.25(m, 1H), 4.58 (s, 2H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5]/[CH:6]=[C:7](/[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([Cl:26])=[CH:20][CH:19]=1)\[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8](/[C:7](/[C:18]2[CH:19]=[CH:20][C:21]([Cl:26])=[C:22]([O:24][CH3:25])[N:23]=2)=[CH:6]\[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [C-]#N
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(/C(=C/CC#N)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
Sodium cyanide (137 mg) was added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (500 mg) in ethanol (10 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a 2 M sodium hydroxide solution and brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give the title compound as a yellow oil (230 mg, 53%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].Cl>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[O:17][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 12.9 g. (47%) of an oil residue. The oil was converted to the hydrochloride ad recrystallized from isopropyl alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH3:27][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:27])[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-b-carboline-3-carboxylic acid ethyl ester (78 mg, 0.19 mmol), tetramethyltin (37 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (6.7 mg, 0.0095 mmol) in DMF (1 mL) was stirred at 120° C. for 50 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 347 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([O:23]C)[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:39]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:13]([OH:23])[CH:12]=3)=[C:8]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)[S:7][C:6]=2[CH:39]=1
Reactant: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCS
Product: Oc1ccc2c(Cc3ccc(CN4CCCC4)c(O)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
6-Hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (65 mg, 0.12 mmol) in dichloroethane (3 mL) was treated with ethanethiol (0.2 mL) and aluminum chloride (160 mg) at 0° C. for 2 h before quenching with saturated aqueous sodium bicarbonate solution (5 mL). The stirring was continued for 1 h at ambient temperature. The mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a white foam (60 mg, 95%).