Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:33]1[CH2:3][CH:2]1[CH2:1][N:4]([CH:17]([CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: C=CCN(C(C)c1ccccc1)S(=O)(=O)c1ccc(CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1ccc(S(=O)(=O)N(CC2CO2)C(C)c2ccccc2)cc1
Yield: 91 %

Procedure:
A solution of 3.27 g (0.01 mole) of N-allyl-N-α-methylbenzyl-4-propylbenzenesulfonamide in 30 ml of chloroform was admixed with 4.31 g (0.02 mole) of metachloroperbenzoic acid for reaction under reflux for 2 hours. Thereafter, an aqueous sodium sulfite solution was added to decompose the excess of the peroxide. After washing with an aqueous sodium bicarbonate solution and water, the chloroform solution was dried over anhydrous magnesium sulfate, concentrated and purified by the silica gel chromatography to obtain the intended product (Compound No. 14). The yield was 91% and the nD25.0 value was found to be 1.5445. The elemental analysis of the product was effected with the results shown below.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].P(Cl)(Cl)(Cl)=O.[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=C[CH:25]=2.[CH2:33]([O:35]C(=O)C)C>ClCCCl>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:21]2[CH:22]=[CH:23][C:4]([CH:2]=[O:3])=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[C:29]([CH:33]=[O:35])[CH:28]=2
Reactant: CC(C)=O
Reactant: CCOC(C)=O
Reactant: COCCOCCOCCn1c2ccccc2c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COCCOCCOCCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Under nitrogen atmosphere, 191 g (2.61 mol) of dimethylformaldehyde and 100 ml of 1,2-dichloroethane were put in a 1 L three-hole flask provided with an agitator, a thermometer, and a reflux condenser, and after cooling the mixture sufficiently to the temperature of 0° C., 197.6 g (1.29 mol) of phosphorous oxychloride was dropped down slowly thereto. The temperature of the reactant was raised to room temperature, and then the reactant was agitated for 1 hour, recooled to 0° C. and 21.0 g (0.067 mol) of N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}carbazole diluted with 30 ml of 1,2-dichloroethane was added slowly thereto. After 1 hour, the reaction temperature was raised to 90° C. and the reaction was carried out for 24 hours. After reaction, the temperature was dropped to room temperature, and the reactant was diluted with 1.5 L of ice water, and then was extracted three times with 200 ml of dichloromethane. The extracted organic solutions were combined, and then washed consecutively with water, saturated NaHCO3 aqueous solution, and salt water. The resultant solution was dried with anhydrous magnesium sulfate, and after filtering and evaporating the solvent, a yellow viscous liquid was obtained. Such liquid was recrystallized three times with a small amount of ethylacetate, and 11.1 g (yield: 45%) of a light yellow solid having the melting point of 108° C. to 109° C. was obtained. [1H-NMR (CDCl3), δ 3.48-3.56(m, 11H, OCH2 and OCH3), 3.98(t, 2H, OCH2), 4.61(t, 2H, NCH2), 7.62(d, 2H, aromatic), 8.13(d, 2H, aromatic), 8.68(s, 2H, aromatic), 10.15(s, 2H, CHO)].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[CH:21]2>>[ClH:1].[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([N:12]5[CH2:16][CH2:15][CH2:14][CH2:13]5)[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Clc1ncnc2ccc(N3CCCC3)cc12
Product: Cl
Product: c1nc(Nc2ccc3[nH]ncc3c2)c2cc(N3CCCC3)ccc2n1
Yield: 78 %

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-6-(1-pyrrolidinyl)quinazoline was reacted with 5-amino-1H-indazole to give 4-(1H-indazol-5-ylamino)-6-(1-pyrrolidinyl)quinazoline hydrochloride in 78% yield, m.p. 271°-273° C.;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1Br.[CH3:18][N:19]1CCCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F
Reactant: CN1CCCC1=O
Product: N#Cc1cc(-n2cnnc2)cc(C(F)(F)F)c1N

Procedure:
The following compound, m.p. 283°, was similarly prepared to the previous Preparation using 4-(4-amino-3-bromo-5-trifluoromethylphenyl)-1,2,4-triazole, cuprous cyanide and 1-methyl-2-pyrrolidone as the starting materials: ##STR148##
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[N+:5]([C:8]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])=[C:9](Cl)Cl)([O-:7])=[O:6].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>C(O)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:9]([S:24][C:21]2[CH:22]=[CH:23][C:2]([CH3:3])=[CH:19][CH:20]=2)=[C:8]([N+:5]([O-:7])=[O:6])[C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])C(=C(Cl)Cl)C(Cl)=C(Cl)Cl
Reactant: Cc1ccc(S)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(SC(Sc2ccc(C)cc2)=C(C(Cl)=C(Cl)Cl)[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.05 g (75 mmol) of sodium ethoxide in 10 ml of ethanol are added dropwise over a period of 10 min to a solution of 10.00 g (36.9 mmol) of 2-nitropentachloro-1,3-butadiene and 9.3 g (75 mmol) of 4-methylthiophenol in 50 ml of ethanol. After 2 h of stirring at 0° C., the precipitate is separated off, washed with water and cold methanol (2×20 ml) and dried under reduced pressure, yield 14.5 g (88%), Rf=0.68 (Et2O: petroleum ether=1:3), m.p. 117-118° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:42]2[O:41][CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 2-furansulfonyl chloride (132 mg) under ice-cooling and the mixture was stirred for 1 hr and half. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 243 mg, 87%).
Reaction SMILES: I[C:2]1[C:6]2[C:7]([NH:11]C(=O)OCC)=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>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.O1CCOCC1.O>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:6]3[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=3[NH:4][CH:3]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)Nc1nccc2[nH]cc(I)c12
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: C1COCCO1
Product: Nc1nccc2[nH]cc(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 80 °C
Yield: 25.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol, 0.1 eq) was added to ethyl 3-iodo-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (0.031 g, 0.094 mmol, 1.0 eq), sodium carbonate (0.07g, 0.66 mmol, 7.0 eq) and 4-nitrophenyl boronic acid (0.055g, 0.33 mmol, 3.5 eq) in a degassed solution of 1/1 dioxane/water (1 mL) at room temperature. The reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and the pH adjusted to 7.0 with dilute aqueous HCl. The solution was extracted with 10/1 CHCl3/MeOH, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by loading it onto a 1.5 g Varian SCX cationic exchange cartridge (eluting sequentially with 1/1 DCM/MeOH, MeOH, 0.1N NH3 in MeOH, and to elute the product 1.0 N NH3 in MeOH) and the appropriate fractions were isolated and concentrated in vacuo to afford the product (0.006 g, 26%) as a solid. MS(ESI+) m/z 255 (M+H)+. Calculated: 255.0882, found: 255.0887.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]=[C:12]([CH3:21])[CH2:13][C:14]([O:16][CH:17]1[CH2:20][O:19][CH2:18]1)=[O:15]>N1CCCCC1.C(O)(=O)CCCCC.C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([C:12](=[O:11])[CH3:21])[C:14]([O:16][CH:17]1[CH2:20][O:19][CH2:18]1)=[O:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OC1COC1
Solvent: C1CCNCC1
Solvent: CCCCCC(=O)O
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)OC1COC1
Temperature: 25 °C
Yield: 121.1 %

Procedure:
A solution of 2,3-dichlorobenzaldehyde (1.33 g, 7.6 mmoles), 3-oxetanyl 3-oxobutanoate (1.2 g, 7.6 mmoles), piperidine (6 drops) and hexanoic acid (8 drops) in dry benzene (80 ml) was heated at reflux using a Dean and Stark apparatus. The solution was allowed to cool to room temperature and the solvent removed in vacuo to leave the sub-title compound as an oil 2.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 62.1 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and toluene (50 g) was heated under reflux for 12 hours. Analysis by high speed liquid chromatography revealed the presence of 20% of the compound (II) as unreacted. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the compound (I) (10.9 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C(O[CH2:17][CH3:18])(=O)C.[C:19](=[O:22])([O-])[O-].[Na+].[Na+]>C(OC(=O)C)(=O)C.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:19](=[O:22])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:17][CH:18]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2[nH]cc(C(=O)Cc3cccnc3)c2c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 3-pyridylacetic hydrochloride reduced in powder (2.36 g, 13.6 mmol, 1.0 eq.) in acetic anhydride was heated in a sealed tube at 85° C. for 60 minutes and then, 5-methoxyindole (2 g, 13.6 mmol, 1.0 eq.) was added. The whole was heated at 85° C. for 20 minutes and then, 105° C. for 30 minutes. The reaction was allowed to cool to room temperature and then ethyl acetate and water were added. The pH was adjusted to 7 with saturated aqueous sodium carbonate. The aqueous layer was extracted with ethyl acetate and then, the organic layer was dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 96/4 to 94/6). The product impure was triturated with ethanol and diethyl ether to afford 1-(5-methoxy-1H-indol-3-yl)-2-pyridin-3-yl-ethanone as a beige powder (1.74 g, 48%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=[O:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:16])[C:7](=[O:15])[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C1=CC(C(C)(C)C)=C([N+](=O)[O-])C(=O)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 mL) was slowly added HNO3 (15 mL). The mixture was heated at 60° C. for 40 min before it was poured into H2O (50 mL). The mixture was allowed to stand at room temperature for 2 h, then was placed in an ice bath for 1 h. The solid was collected and washed with water to provide 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24%). 1H NMR (400 MHz, DMSO-d6) δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[ClH:1].[C:21]([O:20][C:19]1[C:2]([Cl:1])=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][C@@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:18]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@H](c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1CCc2cc(Cl)c(OC(=O)c3ccccc3)cc2[C@H](c2ccccc2)C1
Product: Cl

Procedure:
Reflux for 5 hours with stirring a mixture of 1.20 g (0.00417 moles) of (S)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (obtained in step E of Example 1), 2.0 ml (0.017 moles ) of benzoyl chloride and 2.5 g of anhydrous sodium bicarbonate in 40 ml of dry acetonitrile. Evaporate to dryness on a steam bath under reduced pressure (about 100 mm). Dissolve the residue by stirring for 2 hours at 10° C. in a mixture of 50 ml each of water and ethyl ether. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to dryness. Redissolve the residue in 50 ml of anhydrous ethyl ether and precipitate (S)-8-benzoyloxy-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride with 1N ethereal hydrogen chloride. Obtain an analytical sample by crystallization from 2-propanol, m.p. 257°-258° C., [α]D26 =+10.0° (c=1, dimethylformamide).
Reaction SMILES: C([O:5][C:6](=O)[C@H:7]([O:10][C:11]1[CH:34]=[CH:33][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=[CH:26][N:27]=1)[N:16]=3)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[CH2:28][N:24]1[C:23]([C:17]2[N:16]=[C:15]3[C:14]4[CH:33]=[CH:34][C:11]([O:10][C@H:7]([CH2:8][CH3:9])[C:6]([NH2:44])=[O:5])=[CH:12][C:13]=4[O:22][CH2:21][CH2:20][N:19]3[CH:18]=2)=[N:27][CH:26]=[N:25]1
Reactant: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of (R)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 495 as a white solid (60 mg, 48%). LCMS: RT=3.78 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H, m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([OH:11])=O)[CH2:2]2.S(Cl)(Cl)=O.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9]([C@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)=[O:11])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)[C@@H]1CN2CCC1CC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1)[C@@H]1CN2CCC1CC2

Procedure:
6.6 g (about 34.4 mmol) of (S)-1-azabicyclo[2.2.2]octane-3-carboxylic acid are heated together with 106 ml of thionyl chloride under reflux for 1 h. The excess thionyl chloride is removed under reduced pressure, and residues are removed by azeotropic distillation together with toluene. The crude acid chloride obtained in this way is stirred together with 5.73 g (33.32 mmol) of 4-bromoaniline and 23.21 ml (133.27 mmol) of N,N-diisopropylethylamine in 30 ml of DMF at RT for 72 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/triethylamine 70:30:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 2.9 g (28% of theory) of the title compound are isolated in a purity of 76%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH2:16][NH:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CNCC2CCCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.6 %

Procedure:
A solution of 1-Boc-2-aminomethylpiperidine (429 mg, 2 mmol) and methyl 4-formylbenzoate (329 mg, 2 mmol) in dichloroethane (10 mL) was stirred as acetic acid (180 mg, 3 mmol) and sodium triacetoxyborohydride (487 mg, 2.3 mmol) were added sequentially. The reaction was stirred at ambient temperature for 17 hours. The reaction was poured into water and extracted with methylene chloride (2×). The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 0.7 g of 1,1-dimethylethyl 2-((4-(methoxycarbonyl)phenylmethylamino)methyl)-1-piperidinecarboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH:28]=O)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[NH2:42].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:31])[N:7]([CH3:8])[C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:42][C:33]1[CH:34]=[CH:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a stirred solution of {(S)-1-[(S)-1-((S)-2-formyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (30 mg, 0.07 mmol) in dry MeOH (1.0 mL) was added 2-napthylamine (20 mg, 0.14 mmol) was the reaction was stirred at rt for 18 h. Acetic acid was added to adjust to pH ˜4. NaCNBH3 (8.7 mg, 0.139 mmol) was added and the reaction was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (10 mL×2), water (10 mL×2) and brine (4 mL×2) and concentrated in vacuo. The crude material was purified by preparative HPLC (X Bridge Prep C18 (250×19 0 mm) 5μ, acetonitrile and 5 mM NH4OAc) to give methyl-((S)-1-{(S)-2-methyl-1-[(S)-2-(naphthalen-2-ylaminomethyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-propylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester (32 mg), m/z=560 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>O1CCCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of 1,3-dibromo-benzene (2.36 grams, 10 mmol) in tetrahydrofuran at -78° C. was added a 1.6M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane and stirred for 4 hours. Cyclobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at -78° C., the reaction was quenched with 2N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2.5 grams of crude product which was purified on silica gel eluting with 50% methylene chloride in hexane to give 1.5 grams of the titled compound.