Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[S:34]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:36]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCN(C(=O)OC(C)(C)C)C3C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methoxy-5-methylbenzenesulfonyl chloride (25 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-methoxy-5-methylphenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (7 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 387 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:15][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 60 °C
Reaction time: 8.5 h
Yield: 87.4 %

Procedure:
To a solution of 5-nitrosalicylaldehyde (1.00 g, 6.0 mmol) in DMF (20 ml) was added NaH (246 mg) and methyl iodide (2.56 g, 18 mmol) at 0° C. The mixture was stirred for 8.5 hr at 60° C. After the reaction mixture was extracted with ether, the extract was washed with aqueous NaHCO3, brine and 5%-HCl/aq.NaCl, dried over MgSO4 and concentrated in vacuo to afford 2-methoxy-5-nitrobenzaldehyde (0.95 g, 87.8%) as a yellow needle.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][O:5][C:4](=[O:8])[CH2:3]1.[CH2:9](O)[CH3:10].[BrH:12]>O>[CH2:9]([O:5][C:4](=[O:8])[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6][Br:12])[CH3:10]
Reactant: CCO
Reactant: Br
Reactant: CC1CCOC(=O)C1
Solvent: O
Product: CCOC(=O)CC(C)CCBr
Reaction time: 8 h

Procedure:
A solution of 16.0 g. (0.14 mol) 4-methyl-3,4,5,6-tetrahydro-2-pyranone in 50 ml. anhydrous ethanol is saturated with hydrogen bromide gas at 0°-5° C., left to stand overnight, poured into water and extracted with diethyl ether. The combined ether extracts are dried over anhydrous sodium sulphate and evaporated and the residue is distilled in a vacuum to give 21.9 g. (70% of theory) of the desired product in the form of a colourless liquid; b.p. 85°-87° C./0.1 mm.; nD20 =1.4590.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:20]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:19])[CH2:13][CH:14](OC)[O:15]C)[CH2:3]1>C(O)(=O)C.O>[CH:14]([CH2:13][C:12](=[O:19])[C@@H:11]1[C@:20]2([CH3:29])[C@H:8]([C@H:7]3[C@H:23]([C:22](=[O:28])[CH2:21]2)[C@:24]2([CH3:27])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)=[O:15]
Reactant: COC(CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C)OC
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CC=O)[C@@]3(C)CC(=O)[C@@H]12
Yield: 49.5 %

Procedure:
A solution of 3α-hydroxy-21-dimethoxymethyl-5α-pregnane-11,20-dione (900 mg.) in glacial acetic acid (13 ml) and water (1.3 ml) was stirred at 75° C for 6 hours, then poured into a mixture of ice and water. The product was collected, washed with water and dried in vacuo to give title compound (395 mg), [α]D + 100.5° (c, 0.4), λmax. 268 nm (ε 6,325).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[N:6]#[C:7][NH2:8].Cl.C([Cl:13])(=N)N>>[ClH:13].[CH2:1]([O:5][C:7](=[NH:6])[NH2:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: N#CN
Reactant: N=C(N)Cl
Agent: Cl
Product: CCCCOC(=N)N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 222 g (3.0 mol) of butanol, 21.0 g (0.50 mol) of cyanamide and 57.5 g (0.50 mol) of carbamimidoyl chloride hydrochloric acid salt were dissolved, followed by stirring at 60° C. for 1 hour. The reaction liquid was concentrated to obtain 2-butylisourea hydrochloric acid salt. To 500 ml of N,N-dimethylformamide, 2-butylisourea hydrochloric acid salt obtained, 186 g (1.0 mol) of ethyl 2-acetyl-3-ethoxyacrylate and 82.0 g (1.0 mol) of sodium acetate were suspended, followed by stirring at 100° C. for 4 hours. The reaction liquid was cooled and then poured in ice-water, and extracted with diisopropyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, adding “Florisil” and filtering. The solution was concentrated under reduced pressure to obtain 192 g (yield: 81%) of ethyl 2-butoxy-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:21]I.O>O1CCCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]2([CH3:21])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CC2Cc3ccccc3C2=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC1(Cc2cccc(N)c2)Cc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
2-[(3-Aminophenyl)methyl]indan-1-one (5.18 g, 22.0 mmol) in tetrahydrofuran (100 mL) was slowly added to a suspension of sodium hydride (2.20 g, 65.0 mmol), and tetrahydrofuran (100 mL) at room temperature and the mixture was stirred for 30 min. Methyl iodide (1.63 mL, 26.0 mmol) was added and the resulting mixture was stirred at room temperature for 5 h. Water (150 mL) was added, followed by methylene chloride (150 mL) and the resulting aqueous layer was washed with several portions of methylene chloride. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a solid: mp 95°-98° C., MS MH+252.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[C:25]1([C:31]2[O:35][CH:34]=[N:33][C:32]=2[C:36](Cl)=[O:37])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)[C:36]([C:32]1[N:33]=[CH:34][O:35][C:31]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:37])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ncoc1-c1ccccc1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccccc2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (65 mg, 0.23 mL) in THF (2.0 mL) was added to a suspension of NaH (12 mg, 0.28 mmol) in THF (1.0 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-phenyl-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1→2:1 hept-EA) gave the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.39. LC-MS-conditions 02: tR=1.06 min, [M+H]+=454.20.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.[CH2:35]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:36][CH2:37][CH3:38].[BH4-].[Na+]>CO.O>[CH2:12]([N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@@H:3]([NH:2][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:41][CH:42]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Reactant: CCCCOc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCOc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
2-Amino-1-(4-benzyl-piperazin-1-yl)-(S)-3-phenyl-propan-1-one hydrochloride (500 mg, 1.26 mmol) were dissolved in MeOH (5 mL), DIPEA (359 mg, 2.77 mmol) and 4-n-butoxybenzaldehyde (226 mg, 1.26 mmol) was added and the mixture was heated to reflux for 2 h, cooled again to rt followed by slow addition of sodium borohydride (48 mg, 1.26 mmol) in portions. Stirring was continued for 15 min. Water (1 mL) was added and the solvents were removed under reduced pressure. The residue was taken up in diethylether (5 mL), washed with 10% aq. citric acid (5 mL) and water (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give 411 mg (67%) of 1-(4-benzyl-piperazin-1-yl)-2-(4-butoxy-benzylamino)-(S)-3-phenyl-propan-1-one. LC-MS: tR=0.74 min; [M+H]+=486.43.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Into a reaction flask under nitrogen, 2,4-difluoro-phenylamine (1, 50.00 g, 390 mmol) is combined with 550 mL of anhydrous dichloromethane and anhydrous pyridine (61.27 g, 770 mmol). Methyl chloroformate (43.92 g, 460 mmol) is added dropwise while cooling to maintain the temperature in the range of 20-30° C. The reaction is stirred overnight, then concentrated under vacuum. The resulting material is diluted with 250 mL of water, adjusted to pH 2 with 2M hydrochloric acid, and extracted with 3×250 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is slurried from hexane and the resulting solid is collected by filtration and dried to provide the desired compound (2, 71.06 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].CC(C)([O-])C.[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CS(C)=O.CO>[CH:37]1([CH2:36][O:19][C:17]2[CH:16]=[CH:15][C:14]([C:20]([F:23])([F:21])[F:22])=[C:13]([CH2:12][N:9]3[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=4[F:28])=[N:8]3)[CH:18]=2)[CH2:39][CH2:38]1
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2cc(OCC3CC3)ccc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[5-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 42)(75 mg, 0.189 mmol) in DMSO (1 ml) was added potassium t-butoxide (23 mg, 0.205 mmol, Aldrich). The solution was stirred at ambient temperature for 5 min. To the solution was added (bromomethyl)cyclopropane (0.023 ml, 0.245 mmol, Alfa Aesar) and the mixture stirred overnight at ambient temperature under nitrogen. The solution was diluted with methanol (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (36 mg); LCMS: (System 4) MH+=452, tRET=3.18 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[OH:20][C@H:21]1[CH2:25][CH2:24][N:23](O)[CH2:22]1>CCO>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:23]2[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O[C@H]1CCN(O)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)cn1
Temperature: 85 °C
Yield: 47.3 %

Procedure:
A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL) was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and (S)-3-hydroxypyrrolidinol (350 mg, 4.04 mmol). The mixture was heated in a sealed tube at 85° C. for 21.5 h then cooled and partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes to 0-30% THF in EtOAc gradient to afford the product, as a yellow solid (200 mg, 47% yield). HRMS m/z calcd for C9H11N3O3 [M+H]+: 210.0873; Found: 210.0873.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[CH2:12][C:13]([O:15]CC)=O.IC1C=CC=C2C=1CCN/C/2=C\C([O:32][CH2:33][CH3:34])=O.[BH3-]C#[N:37].[Na+].C([O-])(O)=O.[Na+]>CCO.CC(O)=O>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:33](=[O:32])[CH2:34][NH:37][C:13](=[O:15])[CH:12]=[C:7]12
Reactant: CCOC(=O)CC1NCCc2c(I)cccc21
Reactant: CCOC(=O)/C=C1\NCCc2c(I)cccc21
Reactant: [BH3-]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
ethyl 2-(5-iodo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A solution of (Z)-ethyl 2-(5-iodo-3,4-dihydroisoquinolin-1(2H)-ylidene)acetate (40.0 g, 116 mmol) in dry EtOH (430 mL) was treated with AcOH (33 mL) and NaBH3CN (9.63 g, 146 mmol) portionwise at RT under Ar. The mixture was stirred at RT for 1.5 h, and another load of NaBH3CN (3.85 g, 58 mmol) was then added portionwise. The mixture was stirred for another 1.5 h, and then poured onto a saturated aq. solution of NaHCO3. The pH was adjusted to 8, and the mixture was then extracted with AcOEt. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (39.5 g) as an orange oil that was used as it is in the next step. UPLC-MS: MS 346.1 (M+H+); UPLC rt 0.66 min.
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[ClH:8].[ClH:8].[Cl:8][C:6]1[CH:7]=[C:2]([NH:11][C:12]2[CH:13]=[C:14]3[C:18]4=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]4[C@H:16]4[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]34)[CH:20]=2)[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: N#Cc1ncc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Cl
Product: N#Cc1ncc(Cl)cc1Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Following the procedures described in Example 176 and using 3-bromo-5-chloro-2-cyanopyridine, tert-butyl (7bR,11aS)6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from Example 56, Part B was converted into the title compound of Example 177. ESI MS m/z 382.3/384.3 [C20H20CIN5O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19](OCC)[O:20]CC)[NH:11][CH:10]=[C:9]1[C:26]([O:28][CH3:29])=[O:27].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]=[O:20])[NH:11][CH:10]=[C:9]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC=C(C(=O)OC)C1c1ccccc1Cl
Yield: 27.2 %

Procedure:
To a mixture of a yellow oil (360 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (10 ml) was added 6 N hydrochloric acid (0.3 ml) and the resultant mixture was stirred for 1.5 hours at room temperature, and the acetone was removed. Water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The resultant orange oil (0.26 g) was crystallized and the crystals were washed with n-hexane to give yellowish-orange powder (80.7 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[C@@H:11]([OH:28])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:36]N(C)C=O.CI>C(#N)C.[Ag]=O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=3)[C@@H:11]([O:28][CH3:36])[CH2:10]2)=[CH:34][CH:33]=1
Reactant: CN(C)C=O
Reactant: O=C(N[C@@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@@H]1O)c1ccc(OC(F)(F)F)cc1
Agent: O=[Ag]
Solvent: CI
Solvent: CC#N
Product: CO[C@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@H]1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51 %

Procedure:
To a solution of (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (75.6 mg, an optical isomer of the compound obtained in Example 2) in acetonitrile (8 mL)/dimethylformamide (2 mL) was added successively methyl iodide (233 μL) and silver oxide (216.8 mg) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered through Cerite, washed with acetonitrile and evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→2:1) to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine (39.5 mg; yield: 51%) as an amorphous powder.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:74]([CH:75]([CH3:77])[CH3:76])=[CH:73][C:72]([Cl:78])=[C:71]([CH3:79])[C:69]=2[N:70]=1>>[Cl:78][C:72]1[CH:73]=[C:74]([CH:75]([CH3:76])[CH3:77])[C:68]2[O:67][C:66]([S:65][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([N:50]5[CH2:51][CH2:52][CH2:53][CH2:54]5)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=4[N:44]4[CH2:45][CH2:46][CH2:47][CH2:48]4)=[O:36])[CH2:32][CH2:33]3)=[N:70][C:69]=2[C:71]=1[CH3:79]
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Reactant: Cc1c(Cl)cc(C(C)C)c2oc(S)nc12
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4c(C)c(Cl)cc(C(C)C)c4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methyl-3-pyridyl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercapto-5-chloro-7-isopropyl-4-methylbenzoxazole, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Reactant: Nc1cnccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnccn1)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 23.7 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.095 mL, 0.75 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (250 mg, 0.65 mmol) in DCM (6 mL) and stirred at RT for 30-40 minutes. 2-Aminopyrazine (125 mg, 1.31 mmol) and pyridine (0.106 mL, 1.31 mmol) were added and the reaction stirred at RT for 2 hours. The solvent was removed in vacuo, water (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organic extracts were combined and washed with 2N hydrochloric acid (20 mL), a saturated solution of sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound (71 mg).
Reaction SMILES: CS[CH:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6]C)=[O:5].[OH-].[K+].O.S(=O)(=O)(O)O.[CH3:21]OCCOC>>[CH3:21][CH:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5]
Reactant: COCCOC
Reactant: COC(=O)C(SC)c1cccs1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Methyl α-methylthio(2-thienyl)acetate (1.956 g) was dissolved in 20 ml of 1,2-dimethoxyethane, and 10 ml of a 2N aqueous solution of potassium hydroxide was added. The mixture was stirred at room temperature for 2 hours and 50 minutes. Water (20 ml) and 10 ml of 3N sulfuric acid were added. The mixture was extracted four times with 50 ml of diethyl ether. The ethereal layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.668 g of α-methyl(2-thienyl)acetic acid as pale yellow crystals. Recrystallization from diethyl ether/n-hexane afforded crystals having a melting point of 75 to 75.5° C.