Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[C:26]([O:25][C:23]([C:8]1[NH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:4](=[O:3])[C:6]=2[C:7]=1[CH3:30])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1c(CCCNCCN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 61 %

Procedure:
3-Methyl-5-[3-(2-morpholin-4-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10a (2.238 g, 5.29 mmol) was dissolved in 50 ml of toluene under stirring, and added slowly with a solution of trimethyl aluminum in toluene (3.9 ml, 2 mol/L, 7.9 mmol) under an argon atmosphere. The reaction system was stirred for 30 minutes at room temperature until no white smoke was released, and refluxed for another 3 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the oil bath was removed, and the reaction mixture was quenched with a little water, adjusted to pH 8-10 with dilute sodium hydroxide solution (2 mol/L), added with saturated brine (50 ml) and extracted with ethyl acetate (50 ml×3). The combined organic extracts were filtered through a pad of Celite, concentrated under reduced pressure to obtain the title compound 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 10b (1.218 g, yield 61%) as a light yellow solid
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>O>[C:16]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1ccccc1
Reaction time: 8 h

Procedure:
A 500 ml, round-bottom, three-neck flask was charged with 300 ml of water, 33.55 g (0.40 mole) of sodium bicarbonate, and 19.33 g (0.14 mole) of p-aminobenzoic acid (PABA). The resultant solution was stirred mechanically as 25.0 ml (30.0 g, 0.18 mole) of carbobenzoxy chloride was added dropwise over a period of one hour. Once addition was complete, the thick, white suspension which had formed was allowed to stir overnight. This suspension was suction filtered, and further work-up of both the filtrate (A), and the filtered solid (B) afforded the desired product. The filtrate (A) was acidified with concentrated hydrochloric acid to pH 1, and the white precipitate which formed was isolated by filtration and washed with water until the filtrate was neutral. This precipitate was dissolved in 1N NaOH and extracted with 100 ml of ether. The ether layer was back extracted twice with 60 ml of 1N NaOH and these extracts were pooled with the first aqueous layer. Acidification of the pooled basic layer to pH 1 yielded a copious white precipitate which was collected on a filter and washed with water until the filtrate was neutral. The moist solid was freed of water by dissolving it in ethyl acetate (EtOAc, 200 ml), draining off the several milliliters of water which rapidly settled out, drying over magnesium sulfate, and taking the colorless solution to dryness in vacuo. Yield 6.05 g of Z-PABA-OH as a white powder.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C@H:13]([C:26]([O:28]C)=[O:27])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Li+].Cl>O1CCCC1.O>[CH2:19]([O:18][C:16]([N:14]1[CH2:15][C@@H:11]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH2:12][C@H:13]1[C:26]([OH:28])=[O:27])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H]1C[C@H](N2CCN(S(C)(=O)=O)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of the compound prepared in Example 3 (0.90 g, 2.11 mmol) in tetrahydrofuran (20 mL) and water (20 mL) at 0° C. was added lithium hydroxide (0.203 g, 8.4 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction mixture was carefully acidified to pH 5 with 2 M hydrochloric acid. The aqueous solution was extracted with ethyl acetate (2×300 mL) and the combined organic extracts were dried and concentrated to give the title compound (0.565 g, 65%) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>C(Cl)Cl.C(OCC)(=O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([C:19]1[NH:18][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Aluminum chloride (2.6 g, 20 mmol) was added to a mixture of 2-chloro-5-nitro-benzoyl chloride (5 g, 20 mmol) and pyrrole (4 g, 30 mmol) in DCM (100 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins. The reaction was diluted with ethyl acetate, washed with brine, water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give 1.5 g (30%) of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[C:27]1(C)C=CC=CC=1.C(OC(OCC)OCC)C>C(O)(C)C.[Pt]>[N:14]1([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:27]1
Reactant: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: Cc1ccccc1
Agent: [Pt]
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: O=C(NCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (1.0 g, 2.8 mmol) in isopropyl alcohol (120 mL) was warmed to dissolve some of the material. A catalytic amount of platinum on carbon was added and the reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 3 hours the reaction mixture was filtered to remove catalyst. The filtrate was concentrated under vacuum to provide crude N1-{3-[(3-aminoquinolin-4-yl)amino]propyl}benzamide as an oil. Toluene (100 mL) was added to the oil followed by the addition of triethylorthoformate (0.8 g, 5.6 mmol). The reaction mixture was heated on a steam bath overnight. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 0.53 g of N1-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as an off white solid, m.p. 188-190° C. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (t, J=5.5 Hz, 1H), 8.50 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.17 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (d, J=7.0 Hz, 2H), 7.71 (dt, J=7.5, 1.5 Hz, 1H), 7.56 (dt, J=7.5, 1.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.0 Hz, 2H), 4.78 (t, J=7.0 Hz, 2H), 3.38 (q, J=6.0 Hz, 2H), 2.18 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)CS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)CS(=O)(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cn1
Yield: 79.9 %

Procedure:
Dissolve 7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (142 mg, 0.27 mmol) in methanol (5 mL). Add lithium hydroxide hydrate (23 mg, 0.54 mmol) and stir for 1 h. Mix with silica gel (1 g), concentrate in vacuo, and purify by chromatography on silica gel (12 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH) (1:0 to 9:1 gradient) to give 7-chloro-6-{[6-(2,2-dimethylpropane-sulfonyl)-pyridin-3-yl-methyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (91 mg, 78%). MS (APCI) m/z: 422 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:20]=1[F:33].[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:20]=1[F:33]
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2C)c(F)c(-c2cccc(F)c2)c1
Reaction time: 2 h
Yield: 9.8 %

Procedure:
To a stirred solution of isopropyl 2-[4-fluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (100 mg, 0.22 mmol, 1.0 eq) in a mixture of THF (10 mL) and H2O (10 mL) was added NaOH (17 mg, 0.44 mmol, 2.0 eq). The reaction was stirred for 2 h then acidified to pH 4 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 20:1) to give a partially purified material. Further purification by preparative HPLC provided the title compound as yellow solid (9 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:28][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH2:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>CN(C=O)C>[CH3:30][C:29]([N:37]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([CH2:48][N:49]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:50][C@H:51]([OH:61])[C@@H:52]([NH:60][C:11](=[O:13])[C@H:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:44][CH:43]=2)=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
With the exclusion of air, 868 mg (4.59 mmol) of N-methoxycarbonyl-(L)-tert-leucine (Example 2e), 1.64 g (8.58 mmol) of EDC and 773 mg (5.72 mmol) of HOBT are dissolved in 24.5 ml of DMF. After 15 min, 2.39 ml (17.2 mmol) of TEA and 1.64 g (2.86 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 12 ml of DMF are added. After 20 hours, the mixture is concentrated by evaporation, and water and methylene chloride are added to the residue; the aqueous phase is separated off and extracted 2× more with methylene chloride. The organic phases are washed with 10% citric acid solution, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Digestion from DIPE yields the title compound: HPLC20-100: tRet=18.6; FAB MS (M+H)+=743.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH:7]([CH3:36])[C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClCl>[CH3:36][CH:7]([C@H:8]([C:13](=[O:35])[NH:14][C@H:15]1[CH2:32][C:31]2=[CH:33][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=32)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:34])[CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([OH:37])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C)C(=O)OC(C)(C)C
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C)C(=O)O

Procedure:
Alternatively, the less polar stereoisomer of (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester prepared in Example 5D above (15 mg) was taken up in CH2 Cl2 (2.4 mL) and TFA (0.6 mL) and the resulting mixture was stirred at room temperature for 4 hrs. The solvent was removed under reduced pressure at 35° C. Then ethyl acetate was added and the solution was washed with water (3×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate/petroleum ether gave (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a white solid (7 mg), MS: 456.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1B(O)O>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:16]2[CH:15]=[CH:14][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCCNC(=O)c1cccc(Br)c1
Product: CCCNC(=O)c1cccc(-c2ccc3ccccc3c2)c1
Yield: 57 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A was reacted with 2-naphthylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum ether 80:20 to CH2Cl2/AcOH 80:20 to give a white solid (57%). NMR 1H (ppm, CDCl3): 8.12 (t, J4=1.65 Hz, 1H), 8.06 (s, 1H), 7.91 (t, J3=8.37 Hz, 2H), 7.83 (d, J3=7.81 Hz, 2H), 7.73 (td, J3=8.51 Hz, J4=1.79 Hz, 2H), 7.55-7.46 (m, 3H), 6.18 (br. s., 1H), 3.49-3.43 (m, 2H), 1.67 (sext., J3=7.31 Hz, 2H), 1.00 (t, J3=7.37 Hz, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)=[O:13]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([CH:14]3[CH2:8][CH2:9][CH2:10][CH2:11][S:12]3=[O:13])[CH:16]=[CH:17][C:18]=12
Reactant: O=S(CCCCCl)Cc1ccc2nccn2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=S1CCCCC1c1ccc2nccn2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
8.68 g of potassium t-butoxide was added to 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture, followed by the cooling with ice. A solution of 9.51 g of the 6-((4-chlorobutyl)sulfinylmethyl)imidazo[1,2-a]pyridine prepared in the Preparative Example 8 in 30 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture was dropped into the obtained mixture. The obtained mixture was stirred for one hour. Followed by the addition of ice-water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained oil was solidified by allowing to stand, followed by the addition of ether. The obtained mixture was filtered to give 5.84 g of the title compound as a dark-creamy powder (yield: 71%). The NMR spectroscopic analysis of this powder revealed that the powder was a mixture comprising two diastereomers at a ratio of about 2:1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:28])=[O:27].CCN(CC)CC.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:25])[S:44]([C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.7 %

Procedure:
To secondary amine 30 (150 mg, 0.35 mmol, 1 eq.) in dry DCM (15 mL) at 0° C. was added Et3N (3 mL) followed by dropwise addition of a DCM solution of 4-fluorobenzenesulfonyl chloride (90 mg, 0.42 mmol, 1.2 eq). After stirring at 0° C. for 20 min, the mixture was stirred at room temperature for 2 h. The reaction was extracted between DCM and water and the organic layer was washed with 1N HCl, saturated NaHCO3 solution, and brine, dried (Na2SO4), and concentrated in vacuo to give 150 mg (72%) of t-butyl 2-((4-fluoro-3-(methylsulfonyl)phenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (31) as oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CC(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)C2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CC(C(=O)N3CCCNCC3)C2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a stirred solution of tert-butyl 4-({1-[(6-methylpyridin-3-yl)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane-1-carboxylate (455 mg, 1.13 mmol) in DCM (10 mL) was added TFA (440 μL, 5.65 mmol) and stirred at room temperature for 24 hours. The reaction was re-charged with TFA (0.5 mL, 6.5 mmol) and the reaction stirred for a further 5 hours until consumption of starting materials seen by TLC. Volatiles were removed at reduced pressure and the crude product shaken with Ambersep 900-OH resin in DCM (20 ml) for 2 hours. The resin was removed by filtration and the washings concentrated at reduced pressure to give the title compound (302 mg, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].Br[CH2:40][CH:41]([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH2:40]([N:36]1[CH2:35][CH2:34][N:33]([C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)=[CH:8][CH:9]=3)=[O:32])[CH2:38][CH2:37]1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CBr
Reactant: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN1CCN(C(=O)c2cc3cc(Oc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cn4)ccc3n2C)CC1
Yield: 36.1 %

Procedure:
To a solution of N-{6-[1-methyl-2-(piperazine-1-carbonyl)-1H-indol-5-yloxy]pyridin-3-yl}-4-trifluoromethyl-benzamide (250 mg, 0.478 mmol) in acetonitrile (2 mL) were added 1-bromo-2-methylpropane (0.123 mL, 1.13 mmol), diisopropylethylamine (0.25 mL, 1.44 mmol) and sodium iodide (180 mg, 1.2 mmol). The reaction mixture was stirred under reflux for 14 hours. The solvent was removed under reduced pressure. Water was added to the residue and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) and solidified with EtOH (2 mL). The precipitate was collected by filtration and dried to give 100 mg of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][C:15]=2[F:22])[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:29].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:29])=[CH:16][C:15]=2[F:22])[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To 241 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone (Example 314) dissolved in 50 ml dichloromethane, was added 138 mg of 70% m-chloroperoxybenzoic acid. The mixture was stirred at 0° C. for 1.5 hours, which was followed by addition of 30 ml 5% aqueous sodium bicarbonate. Then the mixture was stirred for 10 minutes and the volatile material was removed in vacuo. The resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated under reduced pressure, and then was purified by column chromatographic separation (hexane/ethylacetate=1:1) to afford 187 mg of 2,2-dimethyl-5-{2-fluoro-4-(methylsulfinyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 149-150° C. NMR: δ1.55 (s, 6H), 2.78 (s, 3H), 7.26 (m, 5H), 7.47 (m, 2H), 7.69 (dd, J=8.4, 6.6 Hz, 2H). IR (cm−1): 1700, 1621, 1380, 1223, 1161, 1075.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:18]([O-])=[O:19].[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>Cl.O>[N:1]1([CH2:7][CH:8]2[N:13]([N:18]=[O:19])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][CH2:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NC(CN1CCOCC1)CO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=NN1c2ccccc2OCC1CN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (-)-3-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in 250 ml of 2N aqueous hydrochloric acid was cooled to 0° C. and treated with a solution of 4.8 g (0.070 mole) of sodium nitrite in 50 ml of water. The solution was stirred for one hour at 0° C., poured into a mixture of 1500 ml of water and 1 liter of ethyl acetate and neutralized carefully by the addition of solid sodium bicarbonate. The organic layer was separated, and the aqueous layer was extracted with an additional 400 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and taken to dryness to give (-)-3-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.