Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[C:14](=[O:15])[N:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:11]=[N:12]2)=[CH:21][CH:20]=1
Reactant: O=c1n(CCCC2CCCCC2)nnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2nnn(CCCC3CCCCC3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-(3-cyclohexyl-propyl)-4-(4-nitro-phenyl)-1,4-dihydro-tetrazol-5-one (69.6 g, 210 mmol) in a mixture of absolute ethanol (220 mL) and ethyl acetate (300 mL) was added to a 2 L Parr hydrogenation vessel containing Degussa 10% Pd/C (3.48 g). The Parr vessel was shaken at room temperature under a hydrogen atmosphere maintained at 20 psi for 4.5 hours. The mixture was filtered through Celite and concentrated in vacuo to a light yellow oil which spontaneously crystallized to afford a light brown crystalline solid (63.5 g, 98%). Mp 64-69° C.; 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 8.8 Hz, 2 H), 6.78 (d, 9.2 Hz, 2 H), 3.98 (t, 7.0 Hz, 2 H), 1.88 (m, 2 H), 1.72-1.63 (m, 5 H), 1.29-1.11 (m, 6 H), 0.94-0.84 (m, 2 H); MS (EI) m/z 302.2 (MH+); Anal. calcd for C16H23N5O: C, 63.76; H, 7.69; N, 23.24. Found: C, 64.00; H, 7.78; N, 22.87; Rf =0.67 (B).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(S)cc1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
324 mg of said di(3-chloro-4-methoxyphenyl)disulfide was dissolved in 10 ml of ethanol, followed by addition of 106 mg of sodium borohydride. The mixture was stirred over 2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with ethyl acetate. The organic layer was washed with saturated salt water and then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column chromatography (hexane: ethyl acetate =15:1), whereby 239 mg of 3-chloro-4-methoxybenzenethiol was obtained. 231 mg of the resulting 3-chloro-4-methoxybenzenethiol was dissolved in 4 ml dichloromethane, followed by cooling to 0° C. 4 ml of boron tribromide in dichloromethane was added dropwise under stirring. The mixture was stirred for 2 hours under cooling on ice and then for 20 hours at room temperature. Subsequently, under cooling on ice, water was added to the solution thus reacted, and the product was extracted twice with chloroform. The organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out, whereby 208 mg of crude 3-chloro-4-hydroxybenzenethiol was obtained.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
A solution of (2-fluoro-3-methylphenyl)-(4-methoxy-phenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) in pyridine was heated at 100 C for 24-48 hrs. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The resulting residue was purified by flash chromatography to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC2CCCCO2)cc1
Yield: 99.9 %

Procedure:
In a manner similar to Preparation 5 stir 4-methoxyphenol (0.161 mol), 3,4-dihydro-2H-pyran (0.193 mol), CH2Cl2 (50 mL), p-TsOH (0.161 mol) at 0° C. for 10 minutes, then add triethylamine (1.77 mol). Evaporate, add diethyl ether (Et2O), and extractively work up to give 33.5 g (100%) of 2-(4-methoxyphenoxy)tetrahydro-2H-pyran as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.06-6.95 (m, 2H), 6.89-6.77 (m, 2H), 5.31 (t, J=3.3 Hz, 1H), 4.00-3.89 (m, 1H), 3.78 (s, 3H), 3.64-3.56 (m, 1H), 2.07-1.93 (m, 1H), 1.88-1.83 (m, 2H), 1.65 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 154.49, 151.09, 117.78, 114.49, 97.31, 62.11, 55.67, 30.50, 25.27, 18.95.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][OH:33]>C(#N)C>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][OH:33])[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: OCCBr
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N(CC1CCN(CCO)CC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 56 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) in acetonitrile (10 mL) was added potassium carbonate (76 mg, 0.552 mmol) followed by 2-bromoethanol (29.9 mg, 0.239 mmol). The reaction mixture was heated in the seal tube at 80° C. for 4 hours. The reaction mixture was then filtered and evaporated. 2,2,2-Trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide (40 mg, 0.103 mmol, 55.8% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.07-7.37 (m, 5H), 3.75-3.87 (m, 2H), 3.57-3.66 (m, 1H), 3.49-3.57 (m, 1H), 3.46 (t, J=6.06 Hz, 1H), 3.36-3.41 (m, 3H), 3.19 (t, J=3.79 Hz, 1H), 2.78-3.04 (m, 2H), 2.56-2.76 (m, 1H), 2.48 (ddd, J=3.54, 6.51, 10.17 Hz, 1H), 1.96-2.15 (m, 1H), 1.87 (td, J=2.91, 10.80 Hz, 2H), 1.63 (dt, J=5.24, 10.23 Hz, 1H), 1.39-1.57 (m, 3H); LC-MS Rt=0.76 min; MS (ESI): 371.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.[C:11]([NH:19][C:20]1[CH:21]=[C:22]([CH:40]=[CH:41][C:42]=1[C:43]([O:45]C(C)(C)C)=[O:44])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29](C(OC(C)(C)C)=O)[CH:28]=[CH:27]2)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:11]([NH:19][C:20]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:40]=[CH:41][C:42]=1[C:43]([OH:45])=[O:44])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)cc1NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3[nH]ccc3c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 mL of trifluoroacetic acid was added to 4.0 mL of methylene chloride solution containing the obtained tert-butyl 5-(3-(benzamido)-4-(tert-butoxycarbonyl)phenoxy)-1H-indole-1-carboxylate while ice-cooled and stirred at the same temperature for 2 hours and 30 minutes. After the reaction mixture was warmed to room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added. The aqueous layer was separated and washed with ethyl acetate after adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid and allowed to stand still for 17 hours. A solid substance was separated by filtration to obtain 10 mg of 2-(benzamido)-4-(1H-indol-5-yloxy)benzoic acid as white solid.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].N1C=CC=CC=1.[O:36]1CC[CH2:38][CH2:37]1.C(OC(=O)C)(=O)C>O.C(#N)C>[C:37]([N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)(=[O:36])[CH3:38]
Reactant: C1CCOC1
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg), pyridine (0.022 ml), tetrahydrofuran (2 ml) and acetonitrile (1 ml) was slowly added acetic anhydride (0.022 ml) at 0° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (Na2SO4), and concentrated. The obtained crystals were recrystallized from tetrahydrofuran-heptane to give the title compound (88 mg, yield 82%) as colorless crystals. melting point 216-218° C.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1.O>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mm ol) in THF (5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring for 3 h at ambient temperature. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at 60° C. for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 392 (M+H)+, m/z: 322 M+H−C5H11)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([O:19]CC)=[O:18].[Li+].[OH-].Cl>C1COCC1.CO.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1CCCOC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)O
Reaction time: 5 h
Yield: 99.5 %

Procedure:
Ethyl 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (26.3 g, 76.1 mmol) was dissolved in THF/MeOH (1:1, 300 mL) and a solution of LiOH (3.6 g, 152 mmol) in H2O (75 mL) was added. The reaction was stirred for ˜5 h and the pH adjusted to ˜3 by the addition of 3N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated to give 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylic acid (21 g, 99% yield) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.C[O:29][B:30](OC)[O:31]C.Cl>C1COCC1>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([B:30]([OH:31])[OH:29])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
In an argon atmosphere, 10 g (29 mmol) of 5-bromo-1,2-diphenyl-1H-benzimidazole were dissolved into 100 mL of dehydrated THF, and the temperature of the solution was cooled to −78° C. Then, 20 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 9.7 mL (87 mmol) of trimethoxyborane were dropped. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 100 mL of 10-mass % hydrochloric acid were added, and the whole was stirred for 1 hour, followed by filtration. The organic layer of the filtrate was washed with a saturated sodium chloride solution and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography to obtain 3.2 g of 1,2-diphenyl-1H-benzimidazole-5-boronic acid (35% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:12][C:13](=[CH2:36])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH2:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28].O.Cl>O1CCCC1.ClCCl>[CH2:12]=[C:13]1[CH2:36][CH:26]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:17]2[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][C:16]=2[O:15][CH2:14]1
Reactant: C=C(CCl)COc1ccc(C(=O)OC)cc1CS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
1.33 ml of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added to 478 mg (1.21 mmol) of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-[(phenylsulfonyl)methyl]benzoate dissolved in 39 ml of tetrahydrofuran. The solution is stirred for 5 minutes and then water, 1N hydrochloric acid and dichloromethane are added to the reaction medium. After separating, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, dried and then concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to provide 259 mg (60%) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a white solid; 1H NMR (300 MHz, CDCl3): 2.98 (dd, J=13.9 and 7.1 Hz, 1H), 3.21 (dd, J=13.9 and 7.1 Hz, 1H), 3.86 (s, 3H), 4.20 (d, J=13.4 Hz, 1H), 4.45 (t, J=7.35 Hz, 1H), 4.73 (d, J=13.4 Hz, 1H), 4.99 (s, 1H), 5.09 (s, 1H), 6.98 (d, J=8.28 Hz, 1H), 7.43 (m, 2H), 7.62 (m, 3H), 7.76 (d, J=2.07 Hz, 1H), 7.94 (dd, J=8.46 and 2 Hz, 1H).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([NH:23][CH3:24])[CH2:14]1.Cl[C:30]1[N:35]=[C:34]([NH2:36])[N:33]=[C:32]2[NH:37][N:38]=[CH:39][C:31]=12.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([N:23]([CH3:24])[C:30]2[N:35]=[C:34]([NH2:36])[N:33]=[C:32]3[NH:37][N:38]=[CH:39][C:31]=23)[CH2:14]1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: CNC1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(c1nc(N)nc2[nH]ncc12)C1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 120 °C
Yield: 59.3 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-N-methyl-1,2,3,4-tetrahydroquinolin-3-amine TFA salt (200 mg, 0.52 mmol) and 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (211 mg, 1.24 mmol) in dimethylacetamide (5 mL) was treated with diisopropylethylamine (0.327 ml, 3.5 eq). The mixture was heated at 120° C. for 22 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and dried. The residue was purified by flash column (eluted with ethyl acetate:hexane: 1:1 to 100% ethyl acetate) to give N4-(1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-N4-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine as a cream solid (140 mg). 1H NMR (DMSO) 400 MHz δ 12.52 (s, 1H), 7.84 (br, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.27 (dd, J=2.0 Hz and 8.4 Hz, 1H), 7.13 (brs, 1H), 6.98 (d, J=6.8 Hz, 1H), 6.94 (t, J=7.2 Hz, 1H), 6.55 (t, J=7.2 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H), 6.0 (brs, 2H), 5.48 (br, 1H), 4.51 (dd, J=17.2 Hz and 58.0 Hz, 2H), 3.59 (t, J=10.4 Hz, 1H), 3.30 (m, 1H), 3.18 (s, 3H), 2.79 (m, 1H). LCMS m/e 455 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N-:33]1.[K+]>CN(C=O)C.O>[CH:28]1([NH:27][C:25]([C:10]2[N:11]=[N:12][N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=3)[C:9]=2[CH2:8][CH2:7][CH2:6][N:33]2[C:34](=[O:41])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]2=[O:31])=[O:26])[CH2:29][CH2:30]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Reactant: O=C1[N-]C(=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (1.31 g, 3 mmol) obtained in Example 1201a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (556 mg, 3 mmol, 1.0 eq.) were dissolved in DMF (20 ml) and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.32 g, 90.4%).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29].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>CCOC(C)=O.CN(C=O)C>[CH3:26][N:27]([CH3:37])[S:28]([N:31]1[CH2:36][CH2:35][N:34]([C:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[N:14][CH:13]=2)=[O:16])[CH2:33][CH2:32]1)(=[O:29])=[O:30]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
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
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)N1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15 mmol), piperazine sulfonic acid dimethylamide hydrochloride (44 mg, 0.19 mmol), and HBTU (74 mg, 0.19 mmol) were weighed out and added to a 10 mL reaction flask. DMF (1.5 mL) and DIEA (65 μL, 0.38 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (5 mL) and quenched with saturated aqueous NH4Cl (5 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel (10% EtOAc and 1% MeOH in CH2Cl2) afforded 53 mg (67%) of the desired compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CNC)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.5 %

Procedure:
A mixture of 4-(diethoxymethyl)benzaldehyde (1.04 g, 5 mmol) and methylamine (27-32% solution in methanol, 2.3 g, 20 mmol) in methanol (20 mL) was stirred at room temperature for 40 mins. The mixture was cooled to 0° C., sodium borohydride (0.284 g, 7.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g) as a light yellow oil which was used in the next step without further purification. LC-MS (ESI) m/z: 224(M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:44][C:45](OC(C)=O)=[O:46].[ClH:51]>C(Cl)Cl>[ClH:51].[Br:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:45](=[O:46])[CH3:44])[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(C)=O)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A 20 mL vial was charged with 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (40 mg, 0.068 mmol), triethylamine (0.0190 mL, 0.14 mmol), and CH2Cl2 (2 mL). Ac2O (0.008 mL, 0.082 mmol) was added and the reaction was stirred at room temperature for 10 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (38.2 mg, 84.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.20 (bs, 1H), 8.17 (d, 1H), 7.74 (m, 1H), 7.31 (m, 2H), 7.21 (t, 1H), 6.93 (d, 1H), 6.78 (m, 1H), 6.74 (s, 1H), 6.71 (m, 2H), 4.43 (d, 1H), 3.87 (d, 1H), 3.69 (s, 3H), 3.14 (m, 1H), 2.86 (m, 1H), 2.64 (m, 1H), 2.01 (s, 3H), 1.95 (m, 2H), 1.58 (m, 1H), 1.45 (m, 1H). Mass spectrum (apci) m/z=631.4 (M+H—HCl).