Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[CH2:24]([N:27]=[C:28]=[S:29])[CH:25]=[CH2:26]>CN(C=O)C.[Cl-].[Na+].O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2[C:3]([C:21]([NH2:23])=[O:22])=[C:2]([NH:1][C:28]([NH:27][CH2:24][CH:25]=[CH2:26])=[S:29])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Reactant: C=CCN=C=S
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNC(=S)Nc1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C(N)=O
Temperature: 45 °C
Yield: 51.4 %

Procedure:
A mixture of 100 mg (0.286 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7) and 114 mg (1.15 mmol) of allyl isothiocyanate in DMF was warmed at 45° C. for 48 h. The reaction was diluted with 30 mL of brine and extracted with four 15 mL portions of EtOAc. The combined organic layers were washed with five 15 mL portions of brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel (MeOH-methylene chloride, first 2:98, then 4:96, then 5:95) to afford 66 mg (51%) of 2-(2,6-dichlorophenylamino)-3-methyl-5-(3-allyl-thioureido)-3H-benzimidazole-4-carboxylic acid amide.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[CH:4]1([CH2:3][CH2:2][O:30][C:23]2[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[C:27]3[C:22]=2[O:21][C:20](=[O:31])[CH:19]=[C:18]3[NH:17][C:16]2[C:15]([Cl:32])=[CH:14][N:13]=[CH:12][C:11]=2[Cl:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrCCC1CCCCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCC1CCCCC1

Procedure:
The title compound was prepared from (2-bromoethyl)cyclohexane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.82 (s, 2H), 7.95 (d, 1H), 7.21 (d, 1H), 4.64 (s, 1H), 4.02 (t, 2H), 3.92 (s, 3H), 1.80-1.50 (m, 8H), 1.70 (m, 3H), 0.90 (m, 2H); MS (ESI): 463.0.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.[C:33](Cl)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:33](=[O:35])[CH3:34])[CH2:30][CH2:31]3)=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(c2cnc3cc(CN)c(-c4ccc(Cl)cc4Cl)cn23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.7 %

Procedure:
To a solution of [6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (0.5 mL) were added successively acetyl chloride (6 mg, 0.07 mmol), pyridine (0.015 mL, 0.19 mmol) and DMAP (1 mg, 0.006 mmol). The reaction mixture was stirred at RT for 14 h then evaporated to dryness. The resulting residue was dissolved in DCM (2 mL) then TFA (1 mL) was added and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 22 mg, 0.034 mmol, 57% for 2 steps) as a white solid. MS: 419 [M+1]+; HPLC: AtRet=1.00.
Reaction SMILES: I[CH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C([O-])(O)=O.[Na+]>[C:22]([O:21][C:20]([NH:19][CH2:18][CH:15]1[CH2:14][CH2:13][N:12]([CH2:2][C:3]2([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:17][CH2:16]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COC(=O)C1(CI)CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCCC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of Methyl 1-(iodomethyl)cyclopentanecarboxylate (5.52 g, 0.0206 mol, Step 1), tert-butyl (piperidin-4-ylmethyl)carbamate (8.83 g, 0.0412 mol) and iPr2NEt (10.76 mL, 0.0618 mol) in N-methylpyrrolidone (70 mL) was stirred at 120° C. for 24 h. After cooling, the reaction mixture was diluted with sat. NaHCO3 aq. (200 mL), extracted with AcOEt (200 mL) for three times, and the combined organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:1) to give 4.91 g (67%) of title compound as a yellow syrup.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH2:14][CH:15]([NH2:17])[CH3:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:31]Br>ClCCl>[ClH:1].[Br:31][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[C:5]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:6]=1
Reactant: BrBr
Reactant: COc1c(CC(C)N)ccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c(CC(C)N)cc(Br)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Example 4 (1.2 g, 4.78 mmol) and TEA (0.97 g, 9.56 mmol) in dichloromethane (100 ml) at 0° C. was added trifluoroacetic anhydride (1.2 g, 5.74 mmol). The reaction mixture was stirred at 0° C. for 1 h and evaporated to a residue, which was filtered through silica (ethyl acetate/hexane: 2/8). The fractions containing the protected amine were combined and concentrated to a residue that was dissolved in acetic acid (5 mL) and cooled to 0° C. Bromine (0.91 g, 5.74 mmol) was added and the reaction mixture stirred at this temperature for 30 min. The solid that formed was collected by filtration and dissolved in a mixture of methanol in water (1:1, 20 mL). To this solution was added 1 N aqueous sodium hydroxide (3 mL) and the mixture was stirred at room temperature overnight. Volatiles were evaporated and the desired compound was extracted with dichloromethane and transformed to hydrochloride salt, which was recrystallized from methanol-diethyl ether. Analysis. Calcd. for C14H16BrNO.HCl.0.2 CH3OH: C, 65.39; H, 7.21; N, 5.56. Found: C, 65.16; H, 7.07; N, 5.42.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][CH:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: CCCN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCN1CCC(Nc2cccc(OC)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 4.5 mL (30 mmol) of N-propyl-4-piperidone, 3.4 mL (30 mmol) of m-anisidine, and 1.7 mL (30 mmol) of glacial acetic acid was stirred in 120 mL of 1,2-dichloroethane (DCE) and 9.49 g (45 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at 25° C. for 3 h. The solution was washed with NaHCO3 solution and brine. It was dried and the solvent was evaporated. The m-anisidine excess was distilled off in a Kugelrohr at 100° C./0.05 Torr. There was obtained 3.5 g (47% yield) of N-(3-methoxyphenyl)-1-propyl-4-piperidinamine as a solid. MS m/z=249 (M++H). 300 MHz 1H NMR (CDCl3) δ7.1 (t, 1H); 6.15-6.35 (m, 3H); 3.75 (s, 3H ); 3.25 (m, 1H); 2.9 (m, 2H); 2.3 (m, 2H); 2.15 (m, 4H); 1.5 (m, 4H); 0.9 (t, 3H). Anal calcd. for C15H24N2O; C, 72.54; H, 9.74; N, 11.28. Found: C, 72.55; H, 9.51; N, 11.21.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:35])=[O:34])[CH2:12][C@@H:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH:15]=[CH:14]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:35])=[O:34])[CH2:12][C@@H:13]1[NH:19][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH:15]=[CH:14]1
Reactant: O=C1CN(c2ccc(C[C@H]3C=Cc4ccccc4C(=O)N3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CN(c2ccc(C[C@H]3C=Cc4ccccc4C(=O)N3)cc2O)S(=O)(=O)N1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-2,3-dihydrobenzo[c]azepin-1-one in methylene chloride (2 mL) at −10° C. is added 0.3 mL of BBr3. The mixture is stirred at −10° C. for 30 min and is quenched with water. The aqueous phase is separated and lyophilized to give the title compound: 1H NMR (DMSO-d6) δ 9.61 (br s, 1H), 8.30 (d, J=5.56 Hz, 1H), 7.84 (d, J=7.58 Hz, 1H), 7.52 (t, J=7.07 Hz, 1H), 7.40 (t, J=7.58 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.08 Hz, 1H), 6.71 (m, 3H), 6.17 (m, 1H), 4.30 (s, 2H), 3.64 (m, 1H), 2.68 (m, 1H), 2.77 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH3:15])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:17]=[CH:16][C:5]3[N:6]([C:15]4[CH:16]=[CH:17][CH:2]=[CH:3][CH:4]=4)[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:8][C:4]=3[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cn1c(-c2ccccc2)nc2cc(Br)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)cc1
Yield: 145.9 %

Procedure:
2.0 g (7.2 mmol) of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole, 1.2 g (7.9 mmol) of 4-chlorophenylboronic acid, and 0.17 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 20 mL of 1,2-dimethoxyethane. Then, 10 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. After the resultant had been stood to cool, an aqueous layer was removed and an organic layer was dried with magnesium sulfate. After the solvent had been distilled off under reduced pressure, the resultant solid was purified by means of silica gel column chromatography to obtain 2.0 g of 5-(4-chlorophenyl)-1,2-diphenyl-1H-benzimidazole (87% yield).
Reaction SMILES: I[C:2]1[N:3]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:5]2[C:10]=1[CH2:9][N:8]([CH3:11])[CH2:7][N:6]2[CH2:12][CH:13]([CH3:15])[CH3:14].[CH2:27]([OH:31])[CH2:28][C:29]#[CH:30]>>[OH:31][CH2:27][CH2:28][C:29]#[C:30][C:2]1[N:3]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:5]2[C:10]=1[CH2:9][N:8]([CH3:11])[CH2:7][N:6]2[CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2I
Reactant: C#CCCO
Product: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2C#CCCO

Procedure:
The title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl )-1 H -pyrrolo[3,4-d]pyrimidine-2,4(3 H, 6 H)-dione and 3-butyn-1-ol in a manner analogous to the method of Example 13 above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[CH2:33][CH2:34][NH2:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:34][CH2:33][C:32]4[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=4)[N:22]=3)[CH:16]=2)[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(F)c1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 68 was coupled with 3-flourophenethylamine following procedure F. LC-MS showed the product had the expected M+H+ of 506. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (m, 2H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 5.3 (m, 1H) 3.9 (m, 4H) 3.7 (m, 4H) 3.0 (m, 4H) 1.6 (m, 3H) 1.4 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)c(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,4-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0505.
Reaction SMILES: [OH-].[K+].FC(F)(F)C([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:22][O:23]C(=O)C)=[C:13]([CH2:17][O:18]C(=O)C)[CH:14]=2)[CH2:9]1)=O>O.CO>[NH2:7][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][OH:18])=[C:12]([CH2:22][OH:23])[CH:11]=2)[CH2:16]1
Reactant: CC(=O)OCc1cc2c(cc1COC(C)=O)CC(NC(=O)C(F)(F)F)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1Cc2cc(CO)c(CO)cc2C1

Procedure:
A solution of potassium hydroxide (10.10 g, 0.180 mol) in water (35 ml) was added to a solution of 2-(trifluoroacetylamino)-5,6-bis(acetoxymethyl)indane 47 (20.1 g, 53.8 mmol) in methanol (200 ml) at room temperature, and the mixture was heated to reflux for 2.5 hours. The solvent was removed under vacuum to leave 2-amino-5,6-bis(hydroxymethyl)indane (48) as a semisolid. The crude product was mixed with 1-bromopropane (27.1 g, 0.220 mol) and potassium carbonate (22.32 g, 0.162 mol) in acetonitrile (100 ml), and the mixture was stirred mechanically at reflux on the steam bath for 17 hours. 1-Bromopropane (6.8 g, 0.055 mol) was added, and the reflux was continued for 4 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave a brown oil (15.75 g). Purification by flash chromatography (230-400 mesh silica gel, ethyl acetate to 30% tetrahydrofuran in ethyl acetate) gave the title compound (49) as a solid (12.1 g, 81%). A sample (0.50 g) was crystallized from ethyl acetate/hexane to give white crystals (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH3:26]
Reactant: CCI
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.100 g, 0.390 mmol) in DMF (3 mL), was added K2CO3 (0.080 g, 0.58 mmol) and stirred at 25° C. for 10 minutes. To the reaction mixture, ethyl iodide (0.0913 g, 0.58 mmol) was added slowly and stirred at 25° C. for 1 hour. DMF was removed under vacuum, and the reaction mass was quenched by water, extracted with ethyl acetate (3×10 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 8% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:20]([CH3:21])([CH3:19])[CH2:1][C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)=[CH:23]1
Reactant: CC(C)=C1C=Cc2ccccc21
Reactant: Cc1csc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1csc(CC(C)(C)C2=CCc3ccccc32)n1
Temperature: -78 °C
Reaction time: 14 h

Procedure:
A solution of 2,4-dimethyl-1,3-thiazole (3.2 g, 28.1 mmol) in 20 ml of tetrahydrofuran was cooled to −78° C. and 15% n-butyl-lithium in hexane (17.5 ml, 28 mmol) was added during 15 min with stirring. The resulting yellow suspension was stirred for 20 min and then a solution of 1-(1-methylethylidene)-1H-indene (4.6 g, 29 mmol) in 5 ml of tetrahydrofuran added with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature and for 14 h. The resulting mixture was hydrolyzed with a saturated ammonium chloride solution.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=3[F:33])[N:23]=[C:22]3[NH:34][N:35]=[C:36]([CH3:37])[C:21]=23)[C:13]([CH3:39])([CH3:38])[CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[F:33][C:27]1[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:23]=[C:22]2[NH:34][N:35]=[C:36]([CH3:37])[C:21]2=[C:20]([CH2:19][N:14]2[CH2:15][C:16]([CH3:17])([CH3:18])[N:11]([CH2:10][CH2:9][OH:8])[CH2:12][C:13]2([CH3:39])[CH3:38])[CH:25]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(CCOCc4ccccc4)CC3(C)C)c12
Agent: [Pd]
Solvent: CO
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CC(C)(C)N(CCO)CC3(C)C)c12
Reaction time: 5 h

Procedure:
63 mg of 4-{4-[4-(2-Benzyloxy-ethyl)-2,2,5,5-tetramethyl-piperazin-1-ylmethyl]-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}-3-fluoro-phenol were dissolved in 5 ml of methanol. 2 mg of Pd/C (10%) were added and the mixture was hydrogenated for 5 h at 5 bar. Then 1 ml of hydrorchloric acid (1M in dioxane) was added and the mixture was again hydrogenated at 5 bar for 24 h. The reaction was filtrated and concentrated in vacuo. After purification by HPLC 1 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1>[C:36]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])(=[O:38])[CH3:37]
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in THF was added 21 μL (0.15 mmol) of triethylamine and 7 μL (0.10 mmol) of acetyl chloride. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 20-3 as a white solid. Data for 20-3: 1HNMR (500 MHz, d6-DMSO) δ 7.8 (m, 1H), 7.6 (m, 1H), 7.4-7.2 (m, 7H), 6.2 (s, 1H), 4.9 (m, 1H), 4.7 (m, 1H), 3.05 (m, 2H), 2.7 (s, 6H), 2.05 (m, 1H), 1.8 (s, 3H), 1.2-1.1 (m, 3H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O2: 444.1849. Found: 444.1847.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(N)cc2)OCCO1
Yield: 34.9 %

Procedure:
A mixture of 4′-aminoacetophenone (1.45 g, 10.7 mmol), ethylene glycol (2.00 g, 32.2 mmol), and p-TsOH.H2O (2.45 g, 12.9 mmol) in toluene (30 mL) were heated to reflux under a Dean-Stark trap for 3.5 h. Basic work-up and purification gave 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine as colourless crystals (0.67 g, 35%).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[S:14]([OH:16])=[O:15])(=[O:5])[CH3:4].I[CH2:18][C:19]#[N:20]>CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[C:8]([S:14]([CH2:18][C:19]#[N:20])(=[O:16])=[O:15])[CH:9]=1
Reactant: N#CCI
Reactant: CC(=O)Nc1ccc(Cl)cc1S(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Cl)cc1S(=O)(=O)CC#N
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.10 g, 60% dispersion in mineral oil) was added at ambient temperature under nitrogen in small portions to a stirred solution of 2-acetylamino-5-chloro-benzenesulfinic acid (0.55 g) in dry dimethylformamide. After stirring for 35 min iodoacetonitrile (0.18 ml) was added and the temperature was raised to 70° C. for 45 min. Then the solvent was removed in vacuo. The residue was triturated with water (30 ml) and filtered. The filter cake was dried, stirred with a mixture of ether (5 ml) and petroleum ether (10 ml) for 1 h, filtered off and dried to give the title compound as white needles. Yield 0.52 g (81%), mp 173.5-174° C., 1H-NMR(DMSO-d6) δ (ppm): 9.69 (s, 1H); 8.06-7.87 (m, 3H); 5.37 (s, 2H), 2.16 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 169.6, 136.6, 136.4, 130.5, 129.8, 129.5, 128.5, 112.0, 44.9, 24.3; IR(KBr) ν (cm−1): 3343(NH), 2258(CN), 1682(C═O), 1330(SO2), 1156 and 1140 (SO2).
Reaction SMILES: [NH2:1][C:2]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>O1CCOCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:2]([NH2:1])=[S:28])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: N#Cc1ccc(Cn2cncc2CC(N)=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Cn2cncc2CC(N)=S)cc1
Temperature: 80 °C

Procedure:
To a 50 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-[5-(aminocarbonyl-methyl)imidazol-1-ylmethyl]benzonitrile (0.36 g, 1.49 mmol), Lawesson's reagent (0.73 g, 1.8 mmol) and 1,4-dioxane (10 mL). This well stirred mixture was heated at 80° C. for 24 hours. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 10% 2-propanol in ammonia saturated CHCl3). The title compound was obtained as a yellow, crystalline solid.