Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[N:18]([CH3:22])[CH3:17])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)N(C)C)ccc1Br
Yield: 36.2 %

Procedure:
4-Bromo-3-methylaniline (5.00 g, 27 mmol), triethylamine (3.9 ml, 28 mmol), 4-(dimethylamino)pyridine (0.5 g, 4 mmol) and dimethylcarbamyl chloride (2.6 ml, 28 mmol) were mixed in dichloromethane (100 ml), and left to stand for 2 weeks. The solution was then washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to give a solid. This was triturated with ether, and the solid was filtered off and dried, affording the title compound (2.51 g, 36%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[N:12]=[C:11]2[CH2:13][N:14]([C@@H:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:18]O)[C:15](=[O:16])[C:10]2=[CH:9][CH:8]=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:28])[C:6]=1[C:7]1[N:12]=[C:11]2[CH2:13][N:14]([C@@H:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:18][N:33]3[C:29](=[O:39])[C:30]4[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:32]3=[O:34])[C:15](=[O:16])[C:10]2=[CH:9][CH:8]=1
Reactant: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of 2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-6-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (0.065 g, 0.16 mmol) and phthalimide (0.029 g, 0.19 mmol) in tetrahydrofuran (5 mL) at 25° C. was added diethyl azodicarboxylate (0.096 mL, 0.24 mmol) and triphenylphosphine (0.055 g, 0.21 mmol). The reaction mixture was stirred at room temperature for 2 hr. After concentration, the residue was purified by pH=2 Prep.—HPLC to give 0.020 g (23% yield) of the desired product as white powder. LC/MS found: 530.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:21]([O:28][C:29]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)OCc1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a stirred solution of 0.83 g (4-6 mmol) of 5-fluorotryptamine and 0.48 g (0.55 mL, 5 mmol) of n-methylmorpholine in 10 mL of DMF at 0° C. was added dropwise 0.72 mL (5 mmol) of benzylchloroformate. The reaction mixture was allowed to stir at 0° C. under argon. After 1.5 hours of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash chromatography using hexane:ethyl acetate (2:1) as an eluent to yield 1 g (68%) of N-(Benzyloxycarbonyl)-5-fluorotryptamine as a white solid. mp 104°-105° C.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=3)[CH2:6][C:5]=12
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Reactant: c1nnc2n1CCNC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCn5cnnc5C4)cc23)c1
Temperature: 80 °C
Reaction time: 36 h
Yield: 20.5 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.17 g) in DMF (8 mL) was added Ag2CO3 (1.29 g) and a solution of 6-(3-chloropropoxy)-N-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine (0.45 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (114 mg, 20.50%), HPLC: 90.63%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 456.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 3.99 (s, 1H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-bromobenzoyl chloride (5 g, 22.78 mmol) was taken up in THF (75 mL) and cooled to 0° C. A solution of morpholine (2.084 mL, 23.92 mmol) and DIPEA (4.38 mL, 25.06 mmol) in THF (25 mL) was added dropwise and the resulting mixture stirred at 0° C. for 3 hours. Water as added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 4-(4-bromobenzoyl)morpholine as a pale yellow gum.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)[CH3:11])=[O:8])[CH2:3]1.[C:28](O)(=[O:30])[CH3:29].C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:23]([O:22][C:21](=[O:27])[NH:20][C@H:9]([C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]1)=[O:8])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:28](=[O:30])[CH3:29])[CH3:19])[CH2:14][CH2:13]1)[CH3:11])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)O
Reactant: CNC1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step C (0.020 g, 0.052 mmol) in DMF (1 mL) was added acetic acid (0.003 mL, 0.06 mmol), N,N-diisopropylethylamine (0.045 mL, 0.26 mmol), HOAT (0.095 mL of a 0.6 M DMF solution, 0.095 mmol), and HATU (0.022 g, 0.095 mmol). After 3 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate and washed with 0.5 M aqueous sodium bicarbonate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. Purification by reverse phase liquid chromatography (20%-60% acetonitrile in water gradient) afforded the title compound as a white solid. LC/MS 450.3 (M+Na).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:8]#[C:9][CH3:10].Cl.C[N:24]([CH3:27])C=O>C(OCC)(=O)C.O>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:24][C:27]2([C:1]([OH:2])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:8]#[C:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of cis-2-amino-1-cyclopentane (1.0 g, 7.74 mmol) in 1:1 water:dimethylformamide (10 mL) at 0° C. was added sodium carbonate (2.7 g, 25.5 mmol) followed by 4-(2-butynyloxy)phenyl sulfonyl chloride (2.08 g, 8.5 mmol). The reaction mixture was allowed to warm to room temperature. After stirring overnight water and ethyl acetate were added and the mixture acidified to pH=1 with 6N aqueous hydrochloric acid. The organic phase was washed with water and brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave (1R,2S)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}amino cyclopentanecarboxylic acid (1.58 g) as a white solid, mp 105-135° C. Electrospray Mass Spec 336.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:29])=[O:3])[CH2:7][CH2:8]2)=[C:13]([NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:14]=1
Reactant: CCOC(=O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 0.590 g (1.35 mmol) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester in a mixture of tetrahydrofuran (10 mL) and methanol (4 mL) is added water (2 mL) followed by 0.16 g (6.8 mmol) of lithium hydroxide. The mixture is stirred overnight at room temperature. The mixture is concentrated under reduced pressure to remove volatile organics and the pH of the resulting solution is adjusted to approximately pH 4 by the addition of concentrated hydrochloric acid. A green oil forms at the bottom of the mixture. The aqueous layer is removed by decanting and the green oil is concentrated under reduced pressure to provide 0.46 g (83%) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid as a green solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[CH2:15][OH:16].F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1.[Cl-].[Na+]>C1COCC1>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:16][CH2:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH3:3])[N:19]=1
Reactant: Cc1cccc(F)n1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(OCc2c(-c3ccccc3)noc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 48 mg, 1.1 mmol) in THF (1.5 mL) was added a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (189 mg, 1.0 mmol) in THF (3 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of 2-fluoro-6-methylpyridine (122 mg, 1.1 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound (135 mg, 48%) which was obtained as a yellow oil. MS: m/e=281.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2[C:39](=[O:40])[N:38]([CH2:41][CH3:42])[C:30]3[N:31]=[C:32](S(C)=O)[N:33]=[CH:34][C:29]=3[CH:28]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([C:27]2[C:39](=[O:40])[N:38]([CH2:41][CH3:42])[C:30]3[N:31]=[C:32]([NH:1][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[CH:3]=4)[N:33]=[CH:34][C:29]=3[CH:28]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: COc1cc(N)cc(OC)n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3cc(OC)nc(OC)c3)nc21
Temperature: -10 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a −78° C. solution of 3.0 g (19.5 mmol) of 4-amino-2,6-dimethoxypyridine in 75 mL of THF was added dropwise 10.6 mL (17.0 mmol) of 1.6 M n-butyllithium in hexanes. The reaction solution was stirred for 15 minutes at which time 1.8 g (4.9 mmol) of 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was added in small portions as a solid. The reaction mixture was allowed to warm slowly to −10° C. then remain at −10° C. overnight. The reaction mixture was poured into ethyl acetate/water/3.5 mL 6N HCl. The mixture is shaken and separated. The organic phase was washed with a saturated solution of sodium bicarbonate, twice with water, and brine, then dried over magnesium sulfate, filtered, and concentrated to a solid yellow residue. The solid was triturated under 25 mL of 1:15:10 methanol/chloroform/ethyl acetate and filtered to give a yellow solid that is crystallized from 300 mL of acetonitrile to give 1.15 g (51%) of the titled compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([OH:28])=O)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C([N:32]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]([NH2:32])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.2 %

Procedure:
To a solution of 5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrole-2-carboxylic acid (1.3 g) in N,N-dimethylformamide (15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (980 mg) and 1-hydroxybenzotriazole ammonium salt (926 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (910 mg, yield 70%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 403 (MH+).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]>O.CO>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:2])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(SC)nc1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.8 %

Procedure:
To a mixture of sodium metaperiodate (360 mg, 1.69 mmol) in water (10 ml) was added a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (300 mg, 0.56 mmol) in methanol (40 ml). The reaction mixture was stirred at 25° C. for 60 h. The suspension was filtered. The filtrate was concentrated and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 97%) as a solid which was used in the next step without further purification: LC/MS m/e calcd for C28H27N3O5S2 [M+H]+ 550.67, observed 549.9.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:38]([CH2:41]OC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([C:41]2[CH:38]=[CH:17][C:16]5[C:5](=[CH:4][CH:3]=[CH:2][CH:15]=5)[CH:6]=2)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2cc(-c3ccc4ccc5c(-c6ccc7ccccc7c6)ccc6ccc3c4c65)ccc2c1
Temperature: 90 °C
Yield: 99 %

Procedure:
Under an atmospheric argon gas flow, 1,6-dibromopyrene in an amount of 10.3 g (28.6 millimole), 2-naphthylboronic acid in an amount of 11.8 g (68.7 millimole), tetrakis(triphenylphosphine)palladium(0) in an amount of 0.66 g (2% by mole), sodium carbonate aqueous solution in an amount of 43 milliliter (59.4 millimole, 2M), dimethoxyethane (DME) in an amount of 100 milliliter and dried THF in an amount of 70 milliliter were placed into a three-neck flask equipped with a cooling pipe and having a capacity of 200 milliliter, and the resultant solution was stirred with heating at a temperature of 90° C. for 8 hours. After the completion of the reaction, adding 50 milliliter of water, precipitated crystal was separated by filtration and washed with the use of 50 milliliter of water and 100 milliliter of ethanol, and as a result, 13.2 g of 1,6-di(2-naphthyl)pyrene (pale yellow powder) was obtained (the yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](O)=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C[CH2:27][N:28](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:28][CH3:27])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:23]([O-:25])=[O:24])[C:13]([CH:20]4[CH2:22][CH2:21]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (vi) (15 g, unpurified from the previous step) in DMF (300 mL) was added DIPEA (27.7 mL, 0.16 mol), HATU (23.9 g, 0.06 mol) and methylamine (2.0M solution in THF, 60 mL, 0.12 mol). The reaction mixture was stirred for 2 h at RT and then poured onto the ice. The precipitate was then separated by filtration and the solid obtained was dissolved in DCM (300 mL), dried (Na2SO4) and the volatiles removed in vacuo to give (vii) (16.5 g with purity 86.5% by HPLC analysis), which was used unpurified in subsequent steps. ESI-MS m/z calculated for [M+H]+: 371.1. found: 371.0. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.74 (s, 1H), 7.62-7.45 (m, 4H), 5.91 (brs, 1H), 3.09-2.97 (m, 3H), 2.40-2.28 (m, 1H), 1.04-0.95 (m, 2H), 0.73-0.65 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.976 min, m/z=448; 1H NMR (CDCl3) 1.50 (d, 3H), 1.91 (m, 1H), 2.17-2.23 (m, 5H), 2.41 (m, 1H), 2.86 (m, 1H), 5.18 (m, 1H), 5.32 (m, 1H), 5.66 (m, 1H), 7.00 (m, 4H), 7.18 (m, 3H), 7.57 (d, 1H), 7.69 (m, 3H), 8.58 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[C:25]([Cl:28])(=[O:27])[CH3:26].Cl>CC(C)=O.O>[ClH:28].[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Yield: 45.5 %

Procedure:
0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under cooling with water, followed by allowing the mixture to stand under water-cooling for 30 minutes. 2 ml of 1 N hydrochloric acid was added thereto, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloroformmethanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247°-248° C. (with decomposition).