Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-cyclopentyl]-methanol (319) (12 g, 56.95 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.90 mmol) followed by mesyl chloride (5.3 mL, 68.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, diluted with dichloromethane (50 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic part was dried, concentrated and purified by CombiFlash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 85%) as a light yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:4].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[N:12]([CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17]1)[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC1CC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CCCCCC1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude cis-2-(2-cyclopropyl-ethylamino)-cycloheptanecarboxylic acid methyl ester (260.5 mg, 1.09 mmol) was mixed with (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 399 mg, 1.2 mmol) and dissolved in N,N-dimethylformamide (9 mL). N-Methylmorpholine (264 μL, 2.4 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol). The resulting mixture was shaken at 25° C. overnight. A 1.0 M aqueous hydrochloric acid solution (11 mL) was added (pH=2) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was further dried in vacuo for 5.5 h to afford the crude product, 2-{(2-cyclopropyl-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cycloheptanecarboxylic acid methyl ester, containing 2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetylamino]-cycloheptanecarboxylic acid methyl ester as a side product, as a brown oil. This crude product was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H34N4O7S2 554.19, found 555.3 [M+H+] and LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.3 [M+H+]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: Clc1ccc(CCCCCCCCCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 13-(4-chlorophenyl)tridecyl bromide and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:46].[Li+]>O1CCCC1>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CO)c1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
To a solution of 4 g of N-[2-(hydroxymethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide in 75 ml of tetrahydrofuran is added 1.19 g of triethylamine and 1.34 g of methanesulfonyl chloride, followed by stirring at room temperature for 1.5 hours. Added 7.66 g of lithium bromide with stirring continued for an additional 2.5 hours. The solvent is evaporated and the residue partitioned between chloroform and saturated sodium bicarbonate. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 2.6 g of the desired product as a white solid, m.p. 103°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1Cl

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 2 mmol of phthalimide and 2 mmol of Cs2CO3 in DMF at room temperature for fourteen hours and then the reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The ethyl acetate layer was concentrated and then purified by trituration with diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=O)=[CH:17][CH:16]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[C:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:17][CH:16]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/C=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/C=C2OC(=O)NC2=O)cc1

Procedure:
A mixture of (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2,4-pentadien-1-al (2.3 g), 2,4-oxazolidinedione (2.0 g), piperidine (0.596 g) and acetic acid (50 ml) was refluxed under heating conditions for 15 hours. The reaction mixture was concentrated; water was added to the residue, followed by acidification with 2N HCl and subsequent extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to silica gel chromatography to yield 5-[(E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2,4pentadienylidene]-2,4-oxazolidinedione [mixture of the (E)- and (Z)-configurations](1.0 g, 33%) from the fraction eluted with chloroform-ethyl acetate (9:1, v/v), which was then recrystallized from chloroform-methanol to yield light yellow prisms having a melting point of 208°-210° C.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:11]=2[CH:24]=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C1COCC1>[CH2:16]1[C:10]2[CH:9]=[CH:8][C:7]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:11]=2[CH2:12][CH2:13][CH2:14][N:15]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)ccc2C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCN(C(=O)OC(C)(C)C)C2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a 50-mL round-bottom flask charged with THF (15 mL) cooled to −78° C. under an N2 atmosphere was slowly added tert-butyllithium (0.922 mL, 1.474 mmol, 1.6 M in pentane). At this temperature, tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (0.37 g, 1.134 mmol) in THF (4 mL) was added. The resulting solution was stirred at -78° C. for 10 min. To the reaction flask was quickly added methyl chloroformate (1.75 mL, 22.68 mmol), and the resulting mixture was stirred at −78° C. for 30 min then warmed to room temperature for 10 min. The solvent was evaporated under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (50 mL). After separation, the aqueous phase was extracted with EtOAc (2×15 mL), the combined organic phases were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated. Flash column chromatography (EtOAc:hexanes, 0-10%) provided 2-tert-butyl 7-methyl 1,3,4,5-tetrahydro-2H-2-benzazepine-2,7-dicarboxylate (0.142 g, 41%) as a slightly yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.83-7.80 (m, 2H), 7.24 (d, J=7.6 Hz, 1H), 4.45 (br, 0.7H), 4.40 (br, 1.3 H), 3.90 (s, 3H), 3.68 (br, 2H), 3.00 (br, 2H), 1.78 (m, 2H), 1.37 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC[C@H](O)CNCc1ccccc1
Reactant: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(C)N(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of 3-chloro-5-[methyl(1-methylpropyl)amino]pyrazine-2-carbaldehyde (342 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (351 mg) and acetic acid (258 μL) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (477 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added dropwise saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (389 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)=[C:25]([CH:28]=1)[CH:26]=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:26]1[C:25]1[CH:28]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1noc(-c2ccc(Cl)cc2C=O)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (25 mg, 0.10 mmol) and 5-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (27 mg, 0.12 mmol) in DMF (5.0 mL) is added oxone (60 mg, 0.10 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2) and dried with Na2SO4. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (30 mg, 45%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[C:16]#[N:17].[CH3:18][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:18])[N:7]=1
Reactant: C[O-]
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 210 mg (0.87 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.16 ml (0.87 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.11 ml (1.73 mmol) methyl iodide and stirring continued for 90 minutes at room temperature. The reaction mixture was then poured onto 100 ml ice-water and the resulting crystals collected by filtration and dried in vacuo to afford 135 mg (61%) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyridine-3,5-dicarbonitrile as a light brown crystalline solid. EI-MS m/e (%): 256 (M+, 49), 255 ([M—H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:20])[NH:13]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(-c2cccc3[nH]ccc23)c1
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cc(F)cc(F)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 4-(3,5-difluoro-phenyl)-1H-indole (13.52 g, 59 mmol) in t-BuOH:ethanol:acetic acid (375 mL:225 mL:115 mL) was added pyridinium tribromide (57 g, 177 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (286 mL). Zinc dust (19.25 g, 295 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), neutralized with 1N HCl, washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 9.88 g (68%) of 4-(3,5-difluoro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[NH:7][C:8]=1[Br:9].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:9][C:8]1[N:7]=[C:6]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:4]=1[Br:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(c2nc(Br)c(Br)[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(c2nc(Br)c(Br)n2COCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A 250 mL round-bottom flask was purged with N2 and charged with NaH (95%, 0.33 g, 13.1 mmol). THF (15 mL) added, and the mixture cooled to 0° C. After 5 minutes, a solution of 4,5-dibromo-2-(1-methylcyclopropyl)-1H-imidazole (3.0 g, 10.7 mmol) in THF (20 mL) was added dropwise from an addition funnel over 5 minutes. The light tan solution was stirred at 0° C. for 25 minutes and SEMCl (2.1 mL, 11.8 mmol) was then added dropwise over 2 minutes. After 5 minutes, ice bath was removed, and the reaction stirred at room temperature. After stirring 2 hours, LCMS indicated 90% conversion. Another 0.3 mL of SEMCl (0.3 mL, 1.7 mmol) was added. LCMS indicates that the reaction has not proceeded; additional NaH (95%, 51 mg, 2.0 mmol) was added with concomitant gas evolution. After 15 minutes, LCMS indicated complete reaction. The reaction was quenched with water (1 mL). Heptane (250 mL) was added and organic layer was washed with water (200 mL). The aqueous layer was extracted with heptane (100 mL), and the combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give 4.46 g of crude material. The crude material was purified by flash chromatography (SiO2; 0-25% EtOAc in heptane) to give the product (3.45 g) as a light yellow oil: LCMS(m/z) 409.0 (MH+), tR=1.27 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:14]2([O:18][C:17](=[O:19])[NH:16][CH:15]2[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1([CH2:34]Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([O:18][C:17](=[O:19])[N:16]([CH2:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:15]2[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCCCC1
Reactant: CCCCC1NC(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1N(CC2CCCCC2)C(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
To a solution of 5.0 g 4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester (14.4 mmol) in 50 mL DMF was added 994 mg of sodium hydride (21.6 mmol, 60% dispersion in mineral oil). The reaction mixture stirred for five minutes and 2.2 mL of cyclohexylmethyl bromide (15.8 mmol) was then added. The reaction mixture stirred under nitrogen for 18 h. The reaction mixture was heated to 70° C. for three h. The reaction mixture cooled to room temperature and was diluted with 500 mL EtOAc and washed twice with water, once with brine. The organics were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel utilizing a gradient elution (10% to 15% EtOAc/DCM) to provide 4.1 g (65%) of 4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester: ms [M]+=443.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([O:15][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g (0.0047 mol) of [bis(4-fluorophenyl)]hydroxy(1H-1,2,4-triazol-1-ylmethyl)silane in 20 ml of tetrahydrofuran was added 0.8 ml (0.0063 mol) of chlorotrimethylsilane. A solution of 0.8 ml (0.0057 mol) of triethylamine in 5 ml of tetrahydrofuran was added dropwise, giving a thick white precipitate. The mixture was stirred overnight at room temperature, then filtered and concentrated to an oil. The residue was taken up in ether, filtered, and the filtrate was evaporated to afford the title compound as a clear colorless oil: nmr (CDCl3) 0.1 (9H, s), 4.3 (2H, s), 7.2 (4H, t, J=9 Hz), 7.6 (4H, d of d, J=9,6 Hz), 8.0 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:14](=[O:15])[NH:13][C:12]3[N:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10]2(=[O:21])=[O:20])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([F:33])[C:24]=1[CH2:25][N:13]1[C:12]2[N:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10](=[O:20])(=[O:21])[N:9]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=2)[C:14]1=[O:15]
Reactant: Cc1ccc(N2C(=O)Nc3ncccc3S2(=O)=O)nc1C
Reactant: COc1cc(F)c(CBr)c(F)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(C)c(C)n3)S(=O)(=O)c3cccnc32)c(F)c1
Yield: 66.7 %

Procedure:
The title compound (182 mg, 0.40 mmol) was prepared from 2-(5,6-dimethylpyridin-2-yl)-2H-pyrido[2,3-e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (IntF1) (181 mg, 0.60 mmol), 2,6-difluoro-4-methoxybenzyl bromide (169 mg, 0.71 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMF (3 mL) using the methods of (115).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (1.0 g, 2.94 mmol), 3-[(methyloxy)-carbonyl]benzoic acid (0.58 g, 3.24 mmol), HBTU (1.34 g, 3.53 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (30 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and the solution extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using CombiFlash chromatography, eluting with 80% ethyl acetate in hexane. The product fractions were combined and concentrated to give methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoate as an oil (1.40 g, 99%). LC-MS m/z 467 (M+H)+.