Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C@H:11]([CH3:22])[NH:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)=[O:14])[CH3:2].C(O)C(O)C.[S:30]([O-])([O-])(=O)=S.[Na+].[Na+]>O>[CH2:1]([O:3][C:4](=[O:24])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:23])[C@H:11]([CH3:22])[NH:12][C:13]([C:15]1[CH:20]=[CH:19][NH:18][C:17](=[S:30])[CH:16]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1ccnc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(O)CO
Product: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)c1cc[nH]c(=S)c1
Yield: 85 %

Procedure:
To a solution of 4.5 g (0.013 mol) of N-[(2-Chloro-4-pyridinyl)carbonyl]-L-alanyl-L-proline ethyl ester (Compound No. 3) in 45 ml of a 10:1 mixture of 1,2-propyleneglycol:water, 15.2 g of sodium thiosulfate are added, and the mixture is heated under reflux for 15 hours. The resulting reaction mixture is diluted with 100 ml of water and extracted with four 100 ml portions of methylene chloride. The organic layer is washed three times with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off at reduced pressure. The residue obtained is purified by crystallisation from a mixture of acetone:petroleum ether, to give the title product as a yellow solid (yield: 85%).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[C:14]2[C:6](=[N:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][N:4]=1.S(Cl)([Cl:18])=O>>[ClH:18].[Cl:18][CH2:2][C:3]1[CH:15]=[C:14]2[C:6](=[N:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:5][N:4]=1
Reactant: OCC1=NCC2=Nc3ccccc3C2=C1
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCC1=NCC2=Nc3ccccc3C2=C1
Temperature: 25 °C
Yield: 100 %

Procedure:
To thionylchoride (50 mL) was added 3-(hydroxymethyl)-1H-β-carboline (2.60 g, 13.12 mmol) and the reaction mixture was refluxed for 1 hour. After cooling down to room temperature the mixture was evaporated in the vacuum and treated with ether (300 mL). The gray solid was collected by filtration, washed with ether and dried in the vacuum to give 3-(chloromethyl)-1H-β-carboline hydrochloride (3.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([OH:16])(=[O:15])=O)=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=1[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]([NH:21][C:22]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:23]=3[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])(=[O:16])=[O:15])=[CH:11][C:10]([C:17]([F:19])([F:20])[F:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)NC(C)C)c1NS(=O)(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 9 h
Yield: 9.8 %

Procedure:
To 2.84 g (10.2 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-sulfonic acid (i.e. the title material from Step C) in 70 mL of dichloromethane was added 1.96 g (10.2 mmol) of 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. the title compound of Step E) 1.78 mL (10.2 mmol) of diisopropylethylamine and approximately 5 mg of 4-(dimethylamino)pyridine. The reaction mixture was stirred for 9 hours, then washed with water and dried (sodium sulfate). The solvent was removed with a rotary evaporator. The residue was purified by MPLC (20–40% ethyl acetate in hexanes as eluant) to afford 0.50 g of the title compound as a foamy white solid melting at 69–72° C. 1H NMR (CDCl3) δ 0.1.12 (d, 6H), 2.32 (s, 1H), 3.85 (m, 1H), 5.96 (brd, 1H), 7.07 (s, 1H), 7.35 (m, 3H), 7.39 (dd, 1H), 7.89 (dd, 1H), 8.20 (dd, 1H), 9.26 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.F[C:39](F)(F)[C:40]1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=[CH:44][CH:45]=1>>[CH:11]1([CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13](=[O:15])[NH:35][C@@H:32]2[C@@H:30]3[C@@H:29]([CH2:28][N:27]([S:24]([C:21]4[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:36])[F:37])=[CH:23][CH:22]=4)(=[O:25])=[O:26])[CH2:31]3)[CH2:34][CH2:33]2)[CH2:12][CH2:44][CH2:45][CH2:40][CH2:39]1
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
tert-Butyl(S)-3-cyclohexyl-1-oxo-1-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)propan-2-ylcarbamate was prepared by substituting (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 256 Step A for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.76 (s, 1H), 8.13 (d, J=8.1, 2H), 8.01 (d, J=8.3, 1H), 7.90 (d, J=8.3, 2H), 4.74-4.65 (m, 1H), 4.31-4.19 (m, 1H), 3.85-3.78 (m, 1H), 3.21-3.10 (m, 2H), 3.01-2.93 (m, 1H), 2.64-2.51 (m, 2H), 1.96-1.74 (m, 6H), 1.69-1.60 (m, 1H), 1.60-1.45 (m, 13H), 1.32-1.18 (m, 1H), 1.16-0.96 (m, 3H), 0.94-0.81 (m, 1H), 0.79-0.67 (m, 1H); MS (ESI+) m/z 605 (M+NH4)+.
Reaction SMILES: NC([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:23][CH2:22]3)=[O:20])=[C:13]([F:34])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)=O.O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C[N:52](C)C=O>>[NH2:52][C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19]([C:21]3([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH2:22][CH2:23]3)=[O:20])=[C:13]([F:34])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: O
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Benzyl 1-{[(4-{[2-(aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)amino]carbonyl}cyclopropanecarboxylate (1.55 g) was dissolved in N,N-dimethylformamide (33 ml). Water (0.299 ml) and iodobenzene diacetate (1.18 g) were added at room temperature, and the mixture was stirred for 15 hours and 20 minutes. Iodobenzene diacetate (215 mg) was added again and the mixture was stirred for 2 hours and 20 minutes. Water (150 ml) was added to the mixture, and the mixture was stirred for 1 hour, and partitioned after the addition of a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and ethyl acetate (300 ml). The organic layer was washed with water (200 ml, twice) and brine (150 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (1.217 g, 83%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][O:9][CH2:10][CH2:11][Cl:12]>C1(C)C=CC=CC=1>[Cl-:12].[CH3:8][O:9][CH2:10][CH2:11][P+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: COCCCl
Reactant: CCP(CC)CC
Solvent: Cc1ccccc1
Product: CC[P+](CC)(CC)CCOC
Product: [Cl-]

Procedure:
First, 200 ml of a toluene solution of triethylphosphine (triethylphosphine content, approx. 20%; product of Kanto Chemical) was mixed with 50 ml of 2-methoxyethyl chloride (Kanto Chemical) to effect a reaction, which was carried out under refluxing for 24 hours. The solvent was then distilled off at normal pressure, following which the remaining solvent and unreacted reagents were completed removed by distillation using a vacuum pump. The residue was recrystallized from an ethanol-THF system, yielding 45 g of 2-methoxyethyltriethylphosphonium chloride.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:10])[C:8]=1[OH:9])[CH3:2].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([O:9][C:8]1[C:7](=[O:10])[CH:6]=[CH:5][O:4][C:3]=1[CH2:1][CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: CCc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1occc(=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a suspension of 2-ethyl-3-hydroxy-4-pyrone (70 g, 0.5 mol) in methanol (650 ml) and sodium hydroxide solution (24 g, 0.6 mol of sodium hydroxide dissolved in 80 ml distilled water) was added benzyl chloride (90 ml, 0.75 mol) with stirring at room temperature. The reaction mixture was refluxed for 24 hours and then cooled. The solvent was removed by rotary evaporation and the residue was extracted into dichloromethane (500 ml). The organic layer was washed with 5% w/v sodium hydroxide solution (3×600 ml) and water (2×600 ml), dried over anhydrous sodium sulphate, filtered and rotary evaporated to give an oil. This oil was crystallized from diethylether in liquid nitrogen and the product recrystallized from diethylether to give the title compound (69 g, 65%) as colourless crystals, m.p. 33°-34° C.
Reaction SMILES: [OH:1][NH:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].Br[CH:9](C)[C:10](OC(C)(C)C)=[O:11].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:10]([N:2]([O:1][C:18](=[O:20])[CH3:19])[C@H:3]([C:5]([OH:7])=[O:6])[CH3:4])(=[O:11])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](NO)C(=O)O
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CC(=O)ON(C(C)=O)[C@@H](C)C(=O)O

Procedure:
17.7 g. of the tert-butyl ester of N-hydroxyalanine which was prepared from tert-butyl bromopropionate by the method of Newman et al. [J. Amer. Chem. Soc. 77, 2308 (1971)] was added to 40 ml. of acetic anhydride and the mixture was stirred for 30° minutes at 100° C. The reaction mixture was evaporated to dryness under reduced pressure to give the oily tert-butyl ester of N-acetyl-N-acetoxyalanine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl>C(O)(C)C.O1CCOCC1.C(Cl)Cl>[Cl:34][C:20]1[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[C:7]3[N:8]([CH3:15])[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(C)c2c(N)cccc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2N(C)CCN(C)C3=O)ncc1Cl
Temperature: 110 °C
Yield: 42 %

Procedure:
9-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (50 mg, 0.24 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (#) (79 mg, 0.27 mmol) were combined in isopropanol (1 mL). 4 N HCl in dioxane (67 μL) was added, and the resulting mixture was heated to 110° C. in the microwave for 20 min. The resulting solution was diluted with CH2Cl2 (50 ml) washed with saturated aqueous NaHCO3 (2×50 ml), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(1,4-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an off-white solid (47 mg, 41%). mp 243-244° C.; LCMS: m/z=466.16 (M+H+); 1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 8.54 (m, 3H), 8.12 (s, 1H), 7.51 (m, 2H), 7.26 (m, 1H), 7.19 (dd, J=7.8 Hz, 1H), 7.09 (dd, J=7.8 Hz, 1H), 6.42 (d, J=4.5 Hz, 1H), 3.36 (m, 4H), 3.21 (s, 3H), 3.03 (d, J=4.8 Hz, 3H), 2.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C>COCCOC>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCN1CCCCC1
Solvent: COCCOC
Product: Clc1ccnc(N2CCCCC2)n1

Procedure:
A mixture of 2,4-dichloropyrimidine (1.0 g), 1-ethylpiperidine (1.099 mL) and 1,2-dimethoxyethane (10 mL) was refluxed for 6 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (553.1 mg).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10])[CH2:3][CH:4]=[CH2:5].[C:16](=O)(O)[O-].[Na+].CI>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([O:11][CH3:16])=[O:10])[CH2:3][CH:4]=[CH2:5]
Reactant: O=C([O-])O
Reactant: C=CCC(O)c1cc(C(=O)O)ccc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCC(O)c1cc(C(=O)OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Into a 100-mL round-bottom flask, was added a solution of 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoic acid (compound 4.2, 1.4 g, 6.79 mmol) in N,N-dimethylformamide (20 mL). Sodium bicarbonate (1.14 g, 13.6 mmol) and methyl iodide (0.847 mL, 13.6 mmol) were added and the resulting mixture was stirred overnight at 25° C. The reaction was quenched with saturated aqueous Na2S2O3 (50 mL) and diluted with EtOAc (150 mL). The organic layer was washed with brine (3×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as the eluent to yield the title compound as a light yellow oil (800 mg, 53%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:47]2[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([N:47]4[CH2:53][CH2:52][CH2:51][N:50]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(C)c(N4CCCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 100 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]hexahydro-1H-1,4-diazepin-1-yl}aniline (67 mg, 0.2 mmol), and p-toluenesulfonicacid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 24 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (94 mg, 0.12 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.36 (s, 1H), 8.44 (s, 1H), 8.22 (d, J=5.13 Hz, 1H), 8.04 (d, J=2.20 Hz, 1H), 7.74 (dd, J=8.62, 2.02 Hz, 1H), 7.69 (d, J=8.80 Hz, 1H), 7.41-7.48 (m, 2H), 7.32-7.41 (m, 1H), 7.26 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.94 (t, J=6.78 Hz, 1H), 6.79 (s, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.26 (q, J=6.97 Hz, 2H), 3.78 (s, 3H), 3.28 (t, J=7.15 Hz, 2H), 3.06-3.14 (m, 4H), 3.04 (s, 3H), 2.92 (t, J=6.78 Hz, 2H), 2.80 (t, J=5.68 Hz, 4H), 2.15 (s, 3H), 1.85 (qd, J=5.74, 5.50 Hz, 2H), 1.42 (t, J=6.78 Hz, 3H); MS (ESI): 811 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16].[H-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>CN(C=O)C>[CH3:1][C:2]1[C:15]2[N:14]([CH2:22][CH2:21][CH2:20][Cl:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1ccc2c(c1C)Nc1ccccc1S2
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1C)N(CCCCl)c1ccccc1S2
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 5.0 g of 1,2-dimethylphenothiazine in N,N′-dimethylformamide was added 970 mg of sodium hydride under stirring at room temperature. After stirring at room temperature for 30 min, 4.0 g of 1-chloro-3-iodopropane was added dropwise followed by stirring at room temperature overnight. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 3.4 g of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[CH2:23]=O>ClC(Cl)C.C(O)(=O)C>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH2:9][CH2:10][C:11]=3[CH:1]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: C=O
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc3c(c2)CCc2ccccc2N3)CC1
Reaction time: 6 h
Yield: 91 %

Procedure:
10,11-Dihydro-5H-dibenz [b,f]azepine (250 g) was suspended in a mixture of 600 ml of dichloroethane and 600 ml of acetic acid, and 155 ml of 1-methylpiperazine was added dropwise to the suspension. To the mixture was added 42 g of paraformaldehyde at 50° C. followed by stirring for 6 hours. The solvent was distilled off under reduced pressure and the residue was diluted with ethyl acetate. The solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the product (91%). The obtained product was subjected to the subsequent reaction without particular purification.
Reaction SMILES: [N:1]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:25]([NH:27][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35](N)[CH:36]=2)[CH2:31][CH2:30][C@H:29]1[O:39][C:40](=[O:42])[CH3:41])=[O:26]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:25]([NH:27][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:8][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:36]=2)[CH2:31][CH2:30][C@H:29]1[O:39][C:40](=[O:42])[CH3:41])=[O:26]
Reactant: CC(=O)O[C@@H]1CCc2ccc(N)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)N1CCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCc2ccc(NC(=O)N3CCCC3)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A solution of pyrrolidine carboxamide (1.5 mL) in CH2Cl2 (25 mL) was treated with POCl3 (0.23 mL). After 1.5 h, the solution was treated with triethylamine (1 mL) and 115 (0.5 g). After stirring over night, the solvent was evaporated, the residue was treated with ice-water, the mixture neutralized, and the mixture extracted with EtOAc. The extracts were washed with brine and the solvent was dried and evaporated to give a dark oil. The oil was purified by radial chromatography eluting with 5% EtOH—CHCl3 to give a tan solid that was recrystallized from EtOAc to give a white solid (0.18 g), m.p. 229° C., dec.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([NH:26][CH2:27][C@@H:28]([C:37]1[CH:48]=[CH:47][C:40]2[O:41][C:42]([CH3:46])([CH3:45])[O:43][CH2:44][C:39]=2[CH:38]=1)[O:29][Si](CC)(CC)CC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1.C(OCC)C>[CH2:19]([NH:26][CH2:27][C@@H:28]([C:37]1[CH:48]=[CH:47][C:40]2[O:41][C:42]([CH3:45])([CH3:46])[O:43][CH2:44][C:39]=2[CH:38]=1)[OH:29])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CNCc1ccccc1)c1ccc2c(c1)COC(C)(C)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Yield: 73.5 %

Procedure:
Tetrabutylammonium fluoride (395 ml, 1M in THF) was added dropwise to a stirred solution of N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine (129.9 g) in THF (900 ml) at 5° C. Upon complete addition the reaction mixture was maintained at this temperature for 15 min before water (600 ml) was added. The resulting slurry was diluted with diethyl ether (500 ml) and filtered. The filtrate was washed with water (2×500 ml) and brine (500 ml) before being dried over anhydrous Na2SO4. The resulting mixture was filtered and concentrated under reduced pressure to give a solid which was triturated with diisopropyl ether to give the title compound (70 g) as a solid, δ (CDCl3) 7.31 (5H, m), 7.09 (1H, d, J 8 Hz), 6.98 (1H, s), 6.77 (1H, d J 8 Hz), 4.82 (2H, s), 4.63 (1H, m), 3.83 (2H, d, J 4 Hz), 2.80 (2H, m), 1.52 (6H, s).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH:69]([O:72][CH3:73])[O:70][CH3:71])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[N:63]([CH3:67])[CH:64]=[CH:65][N:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:71][O:70][CH:69]([O:72][CH3:73])[CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[CH:53][C:52]=3[N:58]([CH3:68])[S:59]([C:62]2[N:63]([CH3:67])[CH:64]=[CH:65][N:66]=2)(=[O:61])=[O:60])=[N:46][CH2:45]1
Reactant: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3nccn3C)c2[nH]1)SCc1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(OC)C1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccn4C)c3[nH]2)S1
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
To a solution of triphenylphosphine oxide (2.41 g) in dichloromethane (15 mL) was slowly added trifluoromethanesulfonic anhydride (1.46 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-{methyl[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}-1H-indole-2-carboxamide (4.4 g) and thioanisole (1.4 mL) in dichloromethane (20 mL) was added dropwise, and the mixture was stirred under ice-cooling for 1 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-4:6) to give the title compound (1.7 g, yield: 48%) as a pale-yellow oil. MS: 450 (MH+).