Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[C:18]([C:22]1[C:23]([SH:30])=[CH:24][C:25]([CH3:29])=[C:26]([OH:28])[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:18]([C:22]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a round bottom flask equipped with a magnetic stirrer and addition funnel were added tosyl bromide (30.6 g, 130 mmol), CCl4 (150 mL), and pyridine (10.51 mL, 130 mmol), respectively. This slurry was cooled to 0° C. and treated dropwise a solution of 24.3 g (124 mmol) of 5-tert-butyl-4-mercapto-2-methyl-phenol (prepared in Example QQQ) in CCl4 (150 mL). The mixture was diluted with CHCl3, washed with brine, and dried (MgSO4). The solvent was evaporated to give a solid which was washed and filtered with hexanes:Et2O (4:1) to give the title compound. 1H NMR (CDCl3) δ 1.22 (s, 9 H), 2.11 (s, 3 H), 2.42 (s, 3 H), 6.87 (s, 1 H), 7.16 (s, 1 H) 7.26 (d, 2 H), 7.49 (d, 2 H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[S:4].[IH:15].[CH3:16]I>CO>[IH:15].[IH:15].[CH3:1][NH:2][C:3](=[N:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[S:4][CH3:16]
Reactant: CI
Reactant: CNC(=S)NCCCCc1nccs1
Agent: I
Solvent: CO
Product: CNC(=NCCCCc1nccs1)SC

Procedure:
N-Methyl-N'-[4-(2-thiazolyl)butyl]thiourea was converted into its hydriodide salt with 66% hydriodic acid. This salt was dissolved in methanol, methyl iodide added and the solution heated under reflux for 2 hours. Concentration and crystallisation of the resultant oil gave N,S-dimethyl-N'-[4-(2-thiazolyl)butyl]isothiourea dihydriodide. Reaction of this isothiourea with hydroxylamine by the procedure of Example 1(ii) gave the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH3:18][Si](C=[N+]=[N-])(C)C>CO>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([O:16][CH3:17])[C:13]([O:14][CH3:15])=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Solvent: CO
Product: COC(=O)c1cc(CCCO)c(OC)c(OC)c1
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a stirred solution of 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (Example 10, Step 1, 3.53 g, 14.7 mmol) in MeOH (37 mL) at 0° C. was slowly added trimethylsilyldiazomethane (TMSCHN2) (2.0 M, 37 mL, 73.5 mmol) over the course of 5 min. After stirring for 10 min the reaction mixture was concentrated. The crude product was purified by flash column chromatography on silica gel using 67% EtOAc in hexanes as an eluent to furnish 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid methyl ester (2.76 g).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([F:33])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:32]2[CH:31]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[C:8]([F:33])=[CH:7][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3F)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(N)nc4cc3F)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Potassium thiocyanate (500 mg, 5.12 mmol) was suspended in acetic acid (10 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a solution of N-[3-(4-amino-2-fluorophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (500 mg, 1.28 mmol) in acetic acid (10 mL), and the mixture was further stirred at room temperature for 15 min. To the obtained solution was added dropwise slowly a solution of bromine (0.225 g, 1.41 mmol) in acetic acid (7.0 mL) and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 14 hr. The resulting yellow insoluble material was filtrated, and washed with acetic acid. The filtrate and washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (200 mL×2), water (200 mL) and saturated brine (200 ml), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.32 g, 57%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: Cn1ccnc1S
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1SCCCOC1CCCCO1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Sodium hydride (0.95 g of a 50% suspension in mineral oil, 20 mmol) was added to a solution of 2-mercapto-1-methylimidazole (2.26 g, 19 mmol) in DMF (100 ml) and the mixture stirred for 30 minutes. 2-(3-Bromopropoxy)tetrahydropyran (5.0 g, 22.5 mmol), (J. Chem. Soc. 1963, 3440), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 1-methyl-2-(3-(2-tetrahydropyranyloxy)propylthio)imidazole (2.5 g, 55%). 1H NMR Spectrum: (DMSOd6) 1.38-1.72(m, 6H); 1.80(m, 2H); 3.0(t, 2H); 3.36-343(m, 2H); 3.58(s, 3H); 3.62-3.78(m, 2H); 4.50(s, 1H); 6.90(s, 1H); 7.21(s, 1H)
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]1([CH2:10][N:11]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH2:14][CH2:13][C:12]2=[O:24])[CH2:9][CH2:8]1.II.BrBr.[N-:29]=[N+]=[N-].[Na+].[Br-]>ClCCl.CN(C)C=O>[NH2:29][C@@H:13]1[CH2:14][CH2:15][C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:17][N:11]([CH2:10][CH:7]2[CH2:9][CH2:8]2)[C:12]1=[O:24]
Reactant: O=C1CCCC(c2ccccc2)CN1CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H]1CC[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (1.99 g, 9.57 mmol) was added to a solution of 1-(cyclopropylmethyl)-6-phenylazepan-2-one (2.33 g, 9.57 mmol) in dichloromethane (55 mL) at 0° C. After 1 h, iodine (0.024 g, 0.096 mmol) and a solution of bromine (0.49 mL, 9.57 mmol) in dichloromethane (5 mL) were added sequentially and the mixture was allowed to warm to ambient temperature. After 18 h, the reaction was quenched with aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Sodium azide (5.60 g, 86.2 mmol) was added to a solution of the crude bromide in N,N-dimethylformamide (50 mL) and the mixture heated to 50° C. After 4 h, the reaction was allowed to cool to ambient temperature, concentrated, and diluted with water. The mixture was extracted with ethyl acetate, washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. 10% palladium on carbon (0.50 g) was added to a solution of the crude azide in ethanol (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the racemic amine. The cis and trans enantiomers were both separated using a Chiralcel OD column eluting with 5% 2-propanol/90% (hexanes with 0.1% diethyl amine)/5% methanol to give the title compound (247 mg). MS 259 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.34 (t, J=7.6 Hz, 2H), 7.26–7.23 (m, 1H), 7.17 (d, J=7.6 Hz, 2H), 3.86–3.81 (m, 2H), 3.62 (dd, J=13.9, 6.8 Hz, 1H), 3.32 (d, J=11.1 Hz, 1H), 3.08 (dd, J=13.9, 7.3 Hz, 1H), 2.79–2.74 (m, 1H), 2.14–2.12 (m, 1H), 2.02–1.97 (m, 2H), 1.77–1.67 (m, 1H), 1.03–0.99 (m, 1H), 0.55–0.49 (m, 2H), 0.28–0.25 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]([CH2:14][CH3:15])[C:11](Cl)=[S:12])[CH3:9].[F:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([N:10]([CH2:14][CH3:15])[C:11]([O:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[CH:20][CH:21]=1)=[S:12])[CH3:9]
Reactant: Oc1cccnc1F
Reactant: CCN(CC)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=S)Oc1cccnc1F
Temperature: 75 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
36.2 g (358 mmol) of triethylamine and 54.3 g (358 mmol) of diethylthiocarbamoyl chloride are added in succession to a suspension of 36.7 g (325 mmol) of 2-fluoro-3-hydroxypyridine in 150 ml of toluene at room temperature, and the reaction mixture is heated at 75° C. After the reaction mixture has been stirred at this temperature for 1 hour, it is cooled to room temperature, diluted with ethyl acetate, washed 3 times with water, dried over Na2SO4 and concentrated in vacuo at 60° C.; 80 g of brown oil which, after recrystallization from Et2O/hexane, gave 64.2 g (86%) of brown crystals of m.p. 52°-54° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:27])=[O:26])=[C:14]([OH:19])[CH:15]=2)[CH:10]=1)C.[OH-].[K+]>CO.O>[OH:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[N:20]1[CH2:24][C:23](=[O:25])[NH:22][S:21]1(=[O:27])=[O:26])[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])[CH:18]=[CH:17]2
Reactant: CCOC(=O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[6-hydroxy-7-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid ethyl ester (Example 8, 0.025 g, 0.053 mmol) in MeOH/H2O (3 mL) is added KOH (0.009 g, 0.159 mmol). This is stirred at 50° C. for 18 h. LC/MS reveals the desired product, so the reaction solution is acidified using 1 N HCl, extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 5-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-pentanoic acid as a white solid: 1H NMR (MeOD) δ7.88 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.31 (dd, J=8.46, 1.64 Hz, 1H), 7.21 (s, 1H), 4.61 (s, 2H), 2.75 (t, J=7.33 Hz, 2H), 2.32 (t, J=7.07 Hz, 2H), 1.61 (m, 4H). Retention time=0.87 min (Method A); (M−H)−=377.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH3:10])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(OCC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:32])[CH3:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1ccc(C#N)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(Br)c1ccc(C#N)cc1

Procedure:
To a solution of 1-(4-Cyanophenyl)ethanol 1.01 g, 6.84 mmol), in diethyl ether (15 ml) and triphenylphosphine (2.14 g, 8.17 mmol), was added carbon tetrabromide (2.82 g, 8.50 mmol) in dieathylether (20 ml) at room temperature. After 30 min the reaction was filtered through celite and evaporated to dryness. The residue was purified by chromatography (SiO2, 5% EtOAc in hexanes) to afford the title compound as an oil
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.Cl[C:40]1[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([NH2:47])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:40]5[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([NH2:47])[N:41]=5)[CH:6]=4)[C:2]([CH3:38])([CH3:1])[CH2:3]3)=[C:21]([CH3:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3c(c2)N(c2c(C)c(-c4ccccn4)nc4cc(F)ccc24)CC3(C)C)nc(N)n1
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (70 mg, 0.14 mmol) (described herein), 4-chloro-6-methylpyrimidin-2-amine (21.7 mg, 0.15 mmol), bis(triphenylphosphine)palladium(ii) chloride (9.6 mg, 0.014 mmol), and sodium carbonate (43.7 mg, 0.41 mmol) in 1,4-dioxane (3.1 mL) and water (0.79 mL), and heating in a microwave at 120° C. for 60 min. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-6-methyl-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, d, J=4.3 Hz), 7.76-7.96 (4H, m), 7.34-7.46 (2H, m), 7.28 (1H, br. s.), 7.21-7.26 (1H, m), 6.66-6.76 (1H, m), 6.58 (1H, d, J=1.2 Hz), 5.19 (2H, br. s.), 3.74-3.90 (2H, m), 2.35-2.41 (3H, m), 2.28-2.35 (3H, m), 1.55-1.61 (3H, m), 1.49-1.55 (3H, m). Mass Spectrum (ESI) m/e=491 (M+1).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(Cl)cc1
Product: Clc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-chloroaniline by Procedure A. The product was isolated by filtration and recrystallisation to give the title compound as a hydrochloride salt (white solid, mp 238-240° C.). MS(ES+) m/z 244 ([M+1]+, 100).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[C:14](C)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: COc1cccc(-c2nc3cnc(C4CCNC(C)C4)[nH]c-3c2C)c1
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC(c2ncc3nc(-c4cccc(O)c4)cc-3[nH]2)CCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.7 %

Procedure:
To a −78° C. solution of 1-[2,7-dimethyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]-3-methoxybenzene (Example 139) (0.89 g, 2.76 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (5.50 mL, 5.50 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (2 mL). CH2Cl2 (60 mL) added and the resulting mixture was stirred at room temperature for 2 h. The mixture was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 0.90 g (100%) of 3-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]phenol as a beige colored solid. This compound (0.90 mg, 5.00 mmol) was dissolved in 5:1:1 EtOAc/MeOH/CH2Cl2 (40 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (5.00 mL, 5.00 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×5 mL) and dried under vacuum at 60° C. to give 525 mg (55%) of the title compound as white colored crystals. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.48 (s, 3), 3.97 (br s, 4), 6.73 (s, 1), 6.84-6.87 (m, 1), 7.24 (br s, 1), 7.27-7.28 (m, 2), 9.75 (s, 1), 11.61 (s, 1), 13.87 (s, 1). MS m/z: 309 (M+1 for free base). Anal. Calcd for C18H20N4O.HCl.1.3H2O: C, 58.70; H, 6.46; N, 15.22; Cl, 9.63. Found: C, 59.09; H, 6.11; N, 14.91; Cl, 9.30.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN1C(=O)CCC1>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(Cc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1
Reaction time: 0.17 h

Procedure:
To a solution of (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (0.2543 g 1 equiv) in dry THF (2 ml) and NMP (0.2 ml) under Argon was added Fe(acac)3 (acac=acetylacetonate) (46.8 mg 0.15 equiv). The mixture was stirred for 10 min, and then Benzylmagnesium chloride (2M in THF, 0.792 ml 1.8 equiv) was added dropwise. The mixture was stirred at room temperature overnight. The product was purified by HPLC to give 11.5 mg of solid. LC-MS: m/e 345 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1ccccc1C=O
Reactant: COc1cccc(Cl)c1CCC#N
Product: COc1cccc(Cl)c1Cc1cc2ccccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C1COCC1.Cl[C:13]([O:15][CH2:16][Cl:17])=[O:14].N1C=CC=CC=1>CCCCCCC.C(OCC)(=O)C>[F:1][CH2:2][C:3]([O:5][C:13](=[O:14])[O:15][CH2:16][Cl:17])([CH3:6])[CH3:4]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)(O)CF
Solvent: c1ccncc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(CF)OC(=O)OCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen atmosphere, to a mixture of 1-fluoro-2-methylpropane-2-ol (THF solution, 5.25 g) [CAS No. 353-80-0](Biorg. Med. Chem., volume 19, page 1580, 2011), THF (95 ml) and chloromethyl chloroformate (7 ml), pyridine (6.4 ml) was added dropwise at −78° C. The resulting mixture was stirred overnight at room temperature, and then ethyl acetate (200 mL) and heptane (200 mL) were added to the mixture. The resulting mixture was sequentially washed with 0.5 N hydrochloric acid (300 mL), saturated aqueous sodium hydrogen carbonate solution (200 mL), water (200 mL), and saturated aqueous sodium chloride solution (200 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was distilled under reduced pressure to obtain the captioned compound (5.25 g).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:18]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:14]1[CH:13]=[C:12]([S:11][CH2:10][CH2:9][NH2:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(OC(c2cccc(SCCNC(=O)OC(C)(C)C)c2)c2nc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-tert-butoxycarbonyl-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine in dichloromethane (2 mL) is added trifluoroacetic acid (0.5 ml) at room temperature. The mixture is stirred at room temperature for 24 h. Water is added and the mixture is basified by adding a solution of sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is triturated in diisopropylether to give 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][C:2]([F:12])([F:13])[F:1])[CH:8]=[O:9])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Trifluoromethoxybenzaldehyde (1.9 g, 10 mmol) was dissolved in concentrated sulfuric acid (8 mL) at 0 ° C. followed by dropwise addition of 70 % nitric acid (1,1 mL). The reaction mixture was stirred at 0 ° C. for 2 hours, then poured onto ice water and extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate solution , dried (sodium sulfate), filtered and evaporated. The residue was chromatographed on silica gel, eluting with 20 % ethyl acetate/hexane to provide 1.55.g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[C:20](OC)(OC)(OC)[CH3:21]>C(O)C>[Cl:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[C:20]([CH3:21])[N:6]([CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:4]2=[O:5]
Reactant: COC(C)(OC)OC
Reactant: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(=O)n1CCCn1ccnc1

Procedure:
A mixture of 2.79 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)propyl]benzamide, 5 ml of trimethyl orthoacetate and 10 ml of ethyl alcohol was heated at reflux for 24 hours. The resulting solution was concentrated and the residue was triturated with ether and gave a solid. The ether was decanted and the solid was dissolved in ethyl acetate and allowed to stand. The precipitate was collected and gave 650 mg of the desired product as tan crystals, mp 190°-192° C.