Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]([C:16]2[C:24]3[C:19](=[C:20](Cl)[N:21]=[CH:22][C:23]=3[O:25][CH3:26])[NH:18][CH:17]=2)=[O:15])[CH2:9][CH2:8]1.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[Sn](CCCC)(CCCC)CCCC>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]([C:16]2[C:24]3[C:19](=[C:20]([C:30]4[S:29][CH:33]=[CH:32][N:31]=4)[N:21]=[CH:22][C:23]=3[O:25][CH3:26])[NH:18][CH:17]=2)=[O:15])[CH2:9][CH2:8]1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4ccccn4)CC3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: COc1cnc(-c2nccs2)c2[nH]cc(C(=O)C(=O)N3CCN(c4ccccn4)CC3)c12

Procedure:
Example 50, was prepared from 1-(pyridin-2-yl)-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine and thiazol-2-yl tributyltin, Precursor 14a-21, according to the general method above to provide 1-(pyridin-2-yl)-4-[(4-methoxy-7-(thiazol-2-yl)-6-azaindol-3-yl)-oxoacetyl]piperazine MS m/z: (M+H)+ Calc'd for C24H25N6O4S: 477.13; found 477.22. HPLC retention time: 0.98 minutes (column A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[C:22](Cl)(Cl)=[O:23]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22](=[O:23])[NH:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)Cl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2

Procedure:
0.15 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine is dissolved in 10 ml of pyridine and treated with 1.44 ml of a 14.3% solution of phosgene in toluene. The mixture is heated to 60° for 5 minutes and then evaporated in vacuo. The residue is partitioned between benzene and water. The benzene phase is washed successively with water, with sodium hydrogen carbonate solution and with water. The solvent is evaporated in vacuo. The residue is chromatographed on 15 g of silica gel while eluting with benzene/ethyl acetate (19:1 and 9:1). After recrystallization from ether/hexane, there is obtained pure 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 223°-225°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:11][S:10][C:9](=[S:12])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20]Br)=[CH:17][CH:16]=1.[I-:25].[Na+]>CC(C)=O.C(Cl)Cl>[I-:25].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=[O:22])[CH2:20][S:12][C:9]2[S:10][S:11][C:7](=[N+:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: S=c1cc(N2CCOCC2)ss1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)CSc2cc(=[N+]3CCOCC3)ss2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A suspension of 5-morpholino-1,2-dithiol-3-thione (2.62 g), 4-methoxyphenacyl bromide (4.12 g) and sodium iodide (3 g) in acetone (60 cc) is heated to the reflux temperature and maintained there for 2 hours. After cooling to a temperature of about 20° C., the insoluble product is filtered off and washed successively with acetone (30 cc), distilled water (2×40 cc) and acetone (2×30 cc). The product thus obtained is suspended in methylene chloride (110 cc). After stirring for 1 hour at a temperature of about 20° C., the insoluble product is separated by filtration. N-[5-(4-Methoxyphenacylthio)-1,2-dithiol-3-ylidene]-morpholinium iodide, melting at 152°-155° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].N1C=CC=CC=1>CCOCC>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(O)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 3-chloro-4-methylphenol (500 mg) in ether (5.0 ml) were added acetic anhydride (430 mg) and pyridine (416 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was washed with 1N hydrochloric acid (once) and saturated brine (twice), dried over magnesium sulfate and concentrated to dryness under reduced pressure to give the objective compound (645 mg) as a pale-yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:22]=2[Cl:21])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1Cl)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 2-chloro-3-trifluoromethyl-benzoic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:20][C:21]#[N:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29]>O1CCOCC1>[CH3:24][C:23]([CH3:26])([CH3:25])[CH:19]([NH:18][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)[N:4]=1)[CH2:20][C:21]1[N:27]=[N:28][NH:29][N:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)C(CC#N)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Solvent: C1COCCO1
Product: CC(C)(C)C(Cc1nn[nH]n1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 130 °C

Procedure:
To a solution of racemic 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanenitrile, 165a, (0.150 g, 0.420 mmol) in 10 mL of dioxane was added azido-tributylstannane (0.221 g, 0.668 mmol). The reaction vessel was sealed and warmed to 130° C. for 12 hours. Upon cooling, the reaction was concentrated to dryness and the resulting residue was purified by silica gel chromatography to afford 48 mg of desired product: 1H NMR (300.0 MHz, d6-DMSO) δ 12.23 (s, H), 8.49 (d, J=9.6 Hz, H), 8.26-8.05 (m, H), 4.03 (d, J=7.1 Hz, H), 3.48-3.35 (m, H), 3.17 (s, H), 2.50 (s, H), 1.99 (s, H), 1.13 (dt, J=25.1, 8.0 Hz, H), 1.01 (s, H), 0.96 (s, H) and 0.87 (d, J=6.6 Hz, H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.94 minutes (M+H) 400.46.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[NH:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.C[Al](C)C.[CH3:24][C:25]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2=[O:36])[CH:28]=[CH:27][C:26]=1[C:37]1[CH:42]=[CH:41][C:40]([C:43](OC)=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]3[N:18]([C:43]([C:40]4[CH:39]=[CH:38][C:37]([C:26]5[CH:27]=[CH:28][C:29]([N:31]6[CH2:35][CH2:34][CH2:33][C:32]6=[O:36])=[CH:30][C:25]=5[CH3:24])=[CH:42][CH:41]=4)=[O:44])[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CN(C)CCN1CCOc2cc3c(cc21)NCCC3
Reactant: COC(=O)c1ccc(-c2ccc(N3CCCC3=O)cc2C)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)N(CCN(C)C)CCO4)cc1
Temperature: 82.5 °C
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
A stirred solution of 4-(2-dimethylaminoethyl)-2,3,6,7,8,9-hexahydro-4H-pyrido[2,3-g][1,4]benzoxazine (D5, 130 mg, 0.49 mmole) in toluene (4 ml) under argon was treated with trimethylaluminium (0.27 ml of 2M in toluene, 0.54 mmole) and stirred for 20 mins. Methyl 2'-methyl4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylate (D29, 154 mg, 0.50 mmole) was added and the mixture heated at 80-85° C. for 6 h, then further trimethylaluminium (0.45 ml) was added and the mixture heated under reflux for 6 h. The reaction mixture was allowed to cool, poured into a slurry of silica gel (4 g) in dichioromethane (10 ml), then loaded onto a chromatography column and eluted with 0-16% methanol/dichloromethane. The product obtained was further purified by prep. plate TLC on silica gel eluting with 10% methanol/dichloromethane to afford the title compound as a light green semi-solid (16 mg). This was converted to it hydrochloride salt as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[CH:4]1[O:6][CH2:5]1.[CH3:15][Al](C)C.Cl>ClCCl.CCCCCC>[F:1][C:2]1[C:3]([CH:4]([CH3:15])[CH2:5][OH:6])=[C:7]([F:14])[C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Reactant: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F

Procedure:
A solution of 10.5 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 50 ml of dichloromethane was added dropwise to 100 ml of a 1.0M solution of trimethylaluminum in hexane, and was reacted for 40 hours at room temperature. This reaction mixture was poured into 100 ml of 1N hydrochloric acid. After the aqueous layer was extracted with ether, the total organic solution was dried over magnesium sulfate. The solvent was distilled out under reduced pressure, and the subsequent distillation under reduced pressure gave 10.6 g of (+)-2-(pentafluorophenyl)-1-propanol having the aforementioned physical properties.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9]2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I>[CH2:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:3][C:4]=2[CH3:19])[CH2:10][CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)ccc1C1(OCc2ccccc2)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1C1(OCc2ccccc2)CC1
Yield: 89.7 %

Procedure:
Using General Procedure D; 4-bromo-1-(1-benzyloxycyclopropyl)-2-methyl-benzene (Intermediate 74, 320.0 mg, 1.00 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (19.0 mg, 0.1 mmol) and then sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(I) (70.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound (300.0 mg, 89%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.O.[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:23]([N:1]1[CH2:2][CH2:3][C:4](=[C:7]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:5][CH2:6]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29]
Reactant: c1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C2c3ccccc3CCc3cccnc32)CC1

Procedure:
Dissolve 13.8 g of 11-(4-piperidylidene)-6,11 dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (Compound IC) prepared according to Villani et. al., J. Med. Chem. 15, 750 (1972) in 250 ml of dry tetrahydrofuran. With stirring, add in one portion 12 g of di-t-butyl carbonate and stir at room temperature overnight. The mixture is poured into water, is extracted with ether, is washed with water and the solvent removed. Recrystallize the residue from isopropyl ether. The melting point is 144°-145° C.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]3)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.720 g, 3.86 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.60 g (97% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 430 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([C:9](C(O)=O)=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH3:15]>C(O)C>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])(=[O:10])[NH2:15]
Reactant: CNc1ccccc1C(=O)C(=O)O
Reactant: N
Solvent: O
Solvent: CCO
Product: CNc1ccccc1C(N)=O
Temperature: 80 °C
Yield: 84.8 %

Procedure:
10.0 g of N-methylisatic acid are added gradually to 140 ml of water at a room temperature and 9.6 g of aqueous ammonia are added dropwise thereto. The mixture is warmed to a temperature of 80° C. during 45 minutes and ethanol is added thereto until the reaction mixture becomes colorless. Then, the reaction mixture is cooled to a room temperature and the precipitated crystals are collected by filtration to obtain 7.11 g of 2-carbamoyl-N-methylaniline as colorless crystal.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10](=O)([O:13]C)[O:11][CH3:12].C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][C:10]([O:11][CH3:12])=[O:13])[CH2:5][CH2:6]1
Reactant: COC(=O)OC
Reactant: CC(=O)C1CCOCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 80.5 %

Procedure:
In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of 4-acetyltetrahydropyran synthesized in the same manner as in Reference example 2, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C([O-])(=[S:15])C.C(O)(=S)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:15]
Reactant: C=CCCCCCCCCCBr
Reactant: CC([O-])=S
Agent: CC(O)=S
Solvent: Cc1ccccc1
Product: SCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
11-Bromo-1-undecanethiol was synthesized in two steps (see FIG. 11). First, 11-bromo-1-undecene (5.0 g) was converted to a thioacetate by reacting with AiBN (1.5 g) and thioacetic acid (10 mL) in toluene (50 mL). The reaction was run under Ar and refluxed for 2 h. The solution was washed with excess water and the toluene removed by rotary evaporation. The thioacetate was converted into a thiol by exposing the 11-bromo-1-undecanethioacetate to dry HCl. Acetyl chloride (6 mL) was added dropwise to dry methanol in an ice bath under Ar. The solution was allowed to warm to room temperature and the reaction progressed for approximately 6 h. Methylene chloride and water were added and the methylene chloride layer was washed several times with water. The solvent was removed by rotary evaporation.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[S:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccsc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. thiophene-3-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 25 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-3-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[NH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([CH2:31][NH:30][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:33][CH2:34]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NC[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC[C@H]3CC[C@H](O)CC3)ccc21
Yield: 62.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide (60 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), trans-4-aminomethyl-cyclohexanol hydrochloride (34 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 521.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.47-8.35 (m, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.49 (s, 1H), 3.63 (s, 3H), 3.11 (t, 2H), 1.92-1.68 (m, 3H), 1.66-1.18 (m, 4H), 1.17-0.88 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([OH:21])[CH:13]=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=3[N:9]=2)=[C:14]([OH:21])[CH:13]=1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2nc(-c3ccc(N)cc3O)[nH]c2cc1C
Temperature: 130 °C
Yield: 28 %

Procedure:
To polyphosphoric acid at 130° C. were added 4,5-dimethylbenzene-1,2-diamine (500 mg, 3.67 mmol) and 4-amino-2-hydroxybenzoic acid (562 mg, 3.67 mmol), and the resulting mixture was then heated to 130° C. for 16 h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na2CO3. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 260 mg (28%) of the title compound (LCMS RT=6.14 min, MH+ 254.1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:38][C:39]1[C:40]([CH2:51][S:52]([C:54]2[NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[N:55]=2)=[O:53])=[N:41][CH:42]=[CH:43][C:44]=1[O:45][CH2:46][C:47]([F:50])([F:49])[F:48].[H-].[Na+].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([N:55]3[C:56]4[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=4[N:58]=[C:54]3[S:52]([CH2:51][C:40]3[C:39]([CH3:38])=[C:44]([O:45][CH2:46][C:47]([F:48])([F:49])[F:50])[CH:43]=[CH:42][N:41]=3)=[O:53])(=[O:34])=[O:33])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
6-[2-(4-chlorosulfonyl-phenoxy)-acetylamino]-n-hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 19, 1.0 g, 1.73 mmol, 1.27 eq) in CH2Cl2 (5 mL) was added to a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) and NaH (40 mg, 1.65 mmol) at room temperature, and the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried and concentrated under reduced pressure. The residual oil was purified by column chromatography (CH2Cl2 to 3% MeOH in CH2Cl2) to yield 6-[2-(4-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-phenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 20, 1.15 g, 94%) as an off-white foam.