Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:17]1([N:7]2[C:6]3[N:22]=[C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])[N:3]=[CH:4][C:5]=3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]2[CH2:9][CH2:10][CH2:11]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C2CCCC2N(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Yield: 34.1 %

Procedure:
A mixture of 0.580 g (0.0018 mole) of (rac)-6-chloro-4-cyclopentyl-9-methyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraazabenzo[f]azulen-10-one (VII-68), 0.372 g (0.0022 mole) of 4-amino-3-methoxybenzoic acid, 36.97 mL of ethanol and 0.468 mL of hydrochloric acid was heated at reflux overnight. Additional ethanol and hydrochloric acid were added and the mixture heated at reflux overnight. The mixture was then cooled, made basic to dissolve solids by the addition of sodium hydroxide solution, transferred to a separatory funnel with ethyl acetate. The aqueous layer was washed twice with ethyl acetate, and then acidified by the addition of 1 M hydrochloric acid. The acidified aqueous layer was extracted twice with ethyl acetate and these extracts were combined, washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.277 g of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-benzoic acid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)CN
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of 2,6-dichloro-3-cyano-5-fluoropyridine (1.0 g, 5.23 mmol), neopentylamine (530 mg, 6.0 mmol) and triethylamine (1 mL) in acetonitrile (20 mL) was stirred at room temp for 4 h. After the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to afford the product (1.11 g, 87%). C11H13ClFN3 MS m/e=242 (M+H).
Reaction SMILES: [CH:1]([NH:14][S:15]([CH2:18][CH2:19][CH2:20]Cl)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C>CN(C)C=O>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[NH:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(CCCCl)NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
In a three-neck round bottom flask equipped with argon inlet was charged with anhydrous dimethylformamide and 3-chloro-propane-1-sulfonic acid benzhydryl-amide (893 mg, 2.76 mmol). 1-Boc-piperazine (771 mg, 4.14 mmol, Aldrich) was added, followed by triethylamine (0.77 mL, 5.52 mmol). The mixture was stirred at 60° C. overnight. It was then heated at 120° C. for 10 min and at 180° C. for 15 min using the microwave synthesizer. Upon cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, and concentrated. Purification of the crude residue by flash column chromatography gave 4-[3-(benzhydryl-sulfamoyl)-propyl]-piperazine-1-carboxylic acid tert-butyl ester as yellow oil (688 mg).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:21][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:30]=[CH:29][C:27]=1[OH:28]
Reactant: C1CCNC1
Reactant: COc1cc(C=O)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(CN2CCCC2)ccc1O
Yield: 74.6 %

Procedure:
NaB(OAc)3H (8.7 g, 0.041 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.4 mL, 0.041 mol) and vanillin (5 g, 0.033 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 2 h and cooled. Then 10 N NaOH (4.1 mL) and water (30 mL) were added. The organic layer was separated; the aqueous one was extracted with chloroform (2×50 mL). The organic fractions were evaporated. The residue was distributed between water and CH2Cl2. Concentrated HCl (2.98 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 6 and extracted with chloroform (2×100 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.1 g, 75%) was obtained as white crystals. 1H-NMR (400 MHz)-data (dmso-d6): 8.72 (s, 1H ArOH), 6.81-6.84 (m, 1H, Ar—H), 6.64-6.70 (m, 2H, Ar—H), 3.74 (s, 3H, ArOCH3), 3.43 (s, 2H, ArCH2), 2.36-2.41 (m, 4H, pyrrolidine (CH2)2N), 1.64-1.70 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][Br:44])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=3[O:40][CH2:41][CH3:42])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.2 %

Procedure:
To a cooled (0° C.) solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxy methyl-piperidin-1-yl]-methanone (60 mg, 0.096 mmol) in methylene chloride (2 mL) was added carbon tetrabromide (70 mg, 0.210 mmol) followed by triphenyl phosphine (55 mg, 0.21 mmol). The reaction mixture was stirred at ambient temperature for 2.5 h. The reaction was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, brine, and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-bromomethyl-piperidin-1-yl]-methanone (50 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4Cl)[O:13]2)[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]2[CH:19]3[CH:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]3)[CH:14]([N:22]3[CH:30]=[N:29][C:28]4[C:23]3=[N:24][CH:25]=[N:26][C:27]=4[N:42]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:41])[O:13]2)[CH:6]=1)=[O:4]
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1cc(OCC2OC(n3cnc4c(Cl)ncnc43)C3OC(C)(C)OC23)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2OC(n3cnc4c(N(C)Cc5ccccc5)ncnc43)C3OC(C)(C)OC23)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (0.106 g, 0.23 mmol) in tetrahydrofuran (1.2 mL) was added polymer-bound diisopropylethylamine (PS-DIEA; Argonaut Tech., 3.83 mmol/g, 0.190 g, 3 eq), followed by addition of 0.040 mL of N-methyl-N-benzylamine (1.2 eq). The resulting mixture was stirred at room temperature overnight. The PS-DIEA resin was washed three times with dichloromethane and the solution obtained from the washes was concentrated to yield 3-{6-[6-(N-Benzyl-N-methyl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethoxy}-isoxazole-5-carboxylic acid methyl ester as yellow oil. This material (0.23 mmol) was dissolved in 1,4-dioxane (1.2 mL) and 0.250 mL of an aqueous 2M lithium hydroxide solution added. The mixture was stirred at room temperature for 4 h. The crude product, isolated after acid workup, was used without further purification in the following step. MW calculated for C25H26N6O7 (MH+): 523, found 523 by LCMS.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C(CO)=CC=CC=1>[C:7]1([N:5]2[CH:6]=[C:2]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[CH:3]=[N:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1cnn(-c2ccccc2)c1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cc(-c3cccs3)cn2)cc1
Temperature: 80 °C
Yield: 27.6 %

Procedure:
4-Bromo-1-phenyl-1H-pyrazole (150 mg, 0.672 mmol), thiophen-2-ylboronic acid (296 mg, 2.31 mmol), PEPPSI-iPr (13.6 mg, 0.062 mmol), and K2CO3 (480 mg, 3.48 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80° C. for 10 minutes. The reaction mixture was then filtered and washed with toluene-methanol (5 ml), and the filtrate was concentrated. The crude mixture was then column purified using 15-20% ethyl acetate/hexane to yield 1-phenyl-4-(thiophen-2-yl)-1H-pyrazole (42 mg, yield 27%). The HPLC purity of the final product was 99.32%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7].C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7])=[O:27]
Reactant: COCC(O)(CCN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(O)(CCNC(=O)CCl)c1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-methoxybutan-2-ol (3.00 g) and triethylamine (1.60 mL) in THF (50 mL) was added dropwise chloroacetyl chloride (0.91 ml) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (2.13 g).
Reaction SMILES: [NH2:1]/[C:2](=[N:30]\[S:31]([C:34]1[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]2[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=2[C:44]=1[CH3:45])(=[O:33])=[O:32])/[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:8](=[O:15])[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.Cl[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(Cl)(Cl)Cl>[CH2:61]([O:60][C:58]([N:12]1[CH2:11][CH2:10][N:9]([C:8](=[O:15])[C@@H:7]([NH:16][S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][NH:3]/[C:2](/[NH2:1])=[N:30]/[S:31]([C:34]2[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]3[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=3[C:44]=2[CH3:45])(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:59])[CH3:62]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of compound D (8.0 g, 11.1 mmol) in CHCl3 (50 ml) was added DIEA (4.1 mL, 23.3 mmol) at room temperature and stirred for 15 min. The mixture was cooled to ˜5° C., ethyl chloroformate (1.06 mL, 11.1 mmol) was added drop wise. After stirring at room temperature overnight (˜18 h), solvent removed in vacuo. The residue was dissolved in MeOH (˜25 ml) and Et2O (˜500 mL) was added. The precipitated crude product was filtered off, washed with Et2O and dried under vacuo to afford compound E (8.5 g, 11.1 mmol). LC-MS [M+H] 757.6 (C36H48N6O8S2+H, calc: 757.9). Compound E was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5].[Cl:23]C(Cl)C>>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:23])=[O:12])=[CH:9][C:8]=1[O:16][CH3:17])=[O:5]
Reactant: CC(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)c1cc(F)ccc1Cl
Product: COc1cc(C(=O)Cl)ccc1NC(=O)c1cc(F)ccc1Cl

Procedure:
In a manner analogous to the process outlined in Example 12, 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid was suspended in dichloroethane and reacted to yield the 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoyl chloride as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:5][N:4]=[N:3]1.OO.S([O-])(O)=[O:18].[Na+].C(OO)=O>C(O)=O.O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)=[O:18]
Reactant: Cn1nnnc1SCc1ccccn1
Reactant: O=S([O-])O
Agent: O=COO
Agent: OO
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cn1nnnc1S(=O)Cc1ccccn1
Reaction time: 5 h

Procedure:
1-Methyl-5-(2-pyridyl)methylthio-1,2,3,4-tetrazole (2.0 g) is dissolved in formic acid (20 ml), and thereto is added with stirring 30% hydrogen peroxide (1.3 g) at room temperature, and the mixture is stirred for 5 hours. Sodium hydrogensulfite is added to the mixture under ice-cooling in order to decompose excess performic acid. Water is added to the mixture and it is extracted with chloroform. Chloroform solution is washed with water and saturated aqueous sodium bicarbonate and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography [Wakogel C-200, eluting agent, chloroform-methanol (50:1)] to give 1-methyl-1,2,3,4-tetrazol-5-yl 2-pyridylmethyl sulfoxide as brown liquid, nD26.5 =1.5810.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH:14]=[N:13]1.O>N1C=CC=CC=1>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:21]([C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[NH:12][N:13]=[CH:14]4)(=[O:23])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OC2)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.385 g, 2.07 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 1H-indazole-5-sulfonyl chloride (0.45 g, 2.07 mmol) and the resulting orange solution stirred at room temperature for 0.5 h. The reaction was warmed to 50° C. for 2 h and then the pyridine was removed under reduced pressure to afford a sticky residue. This was treated with water (40 mL) and sonicated for 5 h at 70° C. The fine precipitate that formed was collected by filtration, washed with water and dried in vacuo generating 0.402 g (59%) of the title compound as a yellowish orange solid. mp 222° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.19 (s, 1H), 8.24 (s, 2H), 7.67 (s, 2H), 7.48 (d, J=1.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 4.84 (s, 2H); MS (ESI) m/z=330 (M+1, positive); HPLC purity: 97.30% (MaxPlot 200-400 nm), 97.30% (220 nm).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:5]=1[O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:13]2[CH2:16][CH3:17])=[CH:9][N:8]=1.Br[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>C1COCC1.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]([C:12]1[N:13]([CH2:16][CH3:17])[C:14]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([O:6][C:5]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:4]=1[F:3])[N:15]=2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34]
Reactant: CCn1c(Nc2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reactant: CNC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(N(CC(=O)NC)c2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reaction time: 1 h
Yield: 38 %

Procedure:
Sodium hydride (60% in oil, 0.010 g, 0.25 mmol) is added to a solution of [2-(2,6-difluorophenoxy)-9-ethyl-9H-purin-8-yl]-(2-chlorophenyl)-amine, 14, (0.1 g, 0.25 mmol) in THF (3 mL). After 5 minutes at room temperature 2-bromo-N-methyl-acetamide (0.06 mL, 0.37 mmol) is added and stirring is continued for 1 hour. The mixture is diluted with H2O (25 mL) and extracted three times with EtOAc (50 mL). The combined organic layers are washed with brine, dried over MgSO4, concentrated in vacuo and the residue purified by HPLC to afford 45 mg (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 7.54-7.59 (m, 2H), 7.15-7.36 (m, 4H), 7.04 (t, J=7.8 Hz, 2H), 4.53 (s, 2H), 3.61 (q, J=7.2 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H); ESI/MS: 473 (M+H).
Reaction SMILES: [CH:1]1([CH:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11](=[O:22])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:28]([Si:32]([O:35][CH2:36][CH2:37][CH2:38]I)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([Si:32]([CH3:34])([CH3:33])[O:35][CH2:36][CH2:37][CH2:38][CH:10]1[O:9][CH2:8][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:11]1=[O:22])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1ccc(CN2C(=O)COCC2C2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(CCCO[Si](C)(C)C(C)(C)C)OCC2C2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (700 mg, 2.3 mmol, 1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (1.58 mL, 1.6 M in heptane, 2.54 mmol, 1.1 equiv). The resulting solution was stirred at −78° C. for 30 minutes, after which it was added a solution of tert-Butyl-(3-iodo-propoxy)-dimethyl-silane (693 mg, 2.3 mmol, 1.0 equiv) in THF (1.0 mL). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 480 mg (yield 44%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14]OS(C)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH2:26]([N:33]1[CH2:6][CH2:7][C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCCc1ccoc1CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(CN2CCc3ccoc3CC2)cc1
Temperature: 102 °C

Procedure:
A solution of 2,3-di(2-methanesulfonyloxyethyl)furan (114 mmol) in dioxane (168 mL) is treated with potassium carbonate (337 mmol) and benzyl amine (70.1 mmol) and heated to 102° C. for 18 hours. The reaction is cooled, the precipitate removed by filtration, and the mother liquor concentrated to give a crude oil which is purified by silica chromatography (EtOAc/hexanes eluant) to provide 6-benzyl-5,6,7,8-tetrahydro-4H-furo[3,2-d]azepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23](O)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(CC)CC>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)N3CCOCC3)c3[nH]ncc3c2)ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A capped vial containing a stir-bar, was charged with 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylic acid (100 mg, 0.28 mmol), HBTU (140 mg, 0.36 mmol), morpholine (29 mg, 0.03 mL, 0.34 mmol), NEt3 (57 mg, 0.08 mL, 0.57 mmol) and acetonitrile (3 ml) successively and stirred the contents at room temperature. After 12 h, the reaction mixture was concentrated and diluted with EtOAc (15 mL)/H2O (5 mL). Organic layer was separated, washed with brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC. Product fractions were concentrated, diluted with water and neutralized with aq. Na2CO3 solution. The resulting white precipitate was filtered and dried to obtain (5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazol-7-yl)(morpholino)methanone. 1H NMR (DMSO-d6): δ 13.27 (s, 1H), 8.66 (d, 1H, J=4.7 Hz), 8.17 (s, 1H), 7.97-7.92 (m, 2H), 7.48 (dd, 1H, J=4.9 and 7.6 Hz), 7.33 (d, 1H, J=7.8 Hz), 6.97-6.88 (m, 3H), 3.62-3.42 (m, 8H), 2.10 (s, 3H).19F NMR (DMSO-d6): δ −118.69 (s).LCMS: rt 4.45 min (A), purity 97%, MS (m/e) 417 (MH+)