Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([F:17])=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:17])=[C:6]([F:16])[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)c(F)c1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (6-Amino-2,3-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.22 (s, 9H), 7.31 (d, 2H, J=8.4 Hz), 7.40-7.47 (m, 3H), 7.55 (d, 2H, J=8.4 Hz), 7.59 (m,1H), 8.69 (b,1H), 8.82 (d, 2H, J=6.0 Hz). MS: m/z 431.0 (M++1).
Reaction SMILES: Br[C:2]1[N:20]=[C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:7][C:8]([CH:10]3[CH2:12][CH2:11]3)=[CH:9][N:4]2[N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[CH:23]=1.[O-]C1C=CC=CC=1.[Na+].C(Cl)(Cl)Cl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([C:24]5[CH:23]=[C:22]([CH3:21])[N:27]=[CH:26][N:25]=5)[CH2:29][CH2:30]4)[N:20]=3)[CH:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:7]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: Clc1ccc(-c2cc(C3CC3)cn3nc(Br)nc23)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(Cl)cc5)cc(C5CC5)cn4n3)CC2)ncn1
Temperature: 160 °C
Reaction time: 15 h

Procedure:
A solution of 2-bromo-8-(4-chloro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (50 mg, 0.14 mmol), 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-ylamine (see example 94a, 23 mg, 0.12 mmol) and sodium phenoxide (21 mg, 0.2 mmol) in dry 1,4-dioxane (3 mL) in a sealed tube was purged with argon for 10 minutes. Pd2(dba)3.CHCl3 (8 mg, 0.01 mmol) and xanthphos (2 mg) were added to the solution and stirred at 160° C. for 15 hours. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a light brown solid (5 mg, 8%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S-:9][C:10]#[N:11].[Na+].BrBr.C([O-])(O)=O.[Na+]>CO.[Na+].[Br-].CO.O>[F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#[N:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#C[S-]
Reactant: Nc1ccccc1F
Agent: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c(F)c1
Yield: 86.2 %

Procedure:
2-Fluoroaniline (9.8 mL, 0.1 mol) and sodium thiocyanate (24.9 g, 0.3 mol) in MeOH (55 mL) were treated with a cold solution of bromine (5.7 mL, 0.11 mol) in saturated NaBr-MeOH solution (50 mL) added dropwise at −5-0° C. over 2 hours. After the addition, the reaction mixture was poured into cold water (200 mL) with stirring, adjusted to pH 8-9 with NaHCO3 (10 g), and stirred at 5° C. for 30 minutes. The resulting crystals were collected by filtration, washed with cold water, and dried at room temperature overnight in vacuum to give crude product 2-fluoro-4-thiocyanatoaniline (14.5 g) as slightly brown crystal. A mixture of the crude 2-fluoro-4-thiocyanatoaniline (14.5 g) and concentrated hydrochloric acid (58 mL) in EtOH (15 mL) was refluxed for 8 hours. The reaction mixture was cooled and stirred at room temperature overnight. The resulting crystals were collected by filtration, washed with cold EtOH and i-Pr2O, dried at room temperature overnight in vacuum to give the title compound as its hydrochloride salt (pale yellow crystal, 10.1 g, 56%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[BH4-].[Na+]>Cl>[OH:28][CH:17]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Product: CCCCCCCCCCC(O)c1ccc(CC(=O)OCC)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of ethyl phenylacetate (13.1 g, 0.08 mol) and aluminium chloride (24.5 g, 0.18 mol) was added undecanoyl chloride (20 ml) at -10° C. The reaction mixture was stirred for 20 minutes at room temperature and further for 4 hours at 50° C., and then poured into the mixture of concentrated hydrochloric acid (40 ml) and ice (160 g). The resultant precipitate was extracted with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (100 ml), to which was added sodium borohydride (1.18 g, 0.03 mol). The reaction mixture was stirred at room temperature, to which was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: hexane:ethyl acetate=5:1) to obtain ethyl 4-(1-hydroxyundecyl)phenylacetate (3-v, 10.9 g, 41%) as oil.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccccc1
Yield: 95 %

Procedure:
Cyclohexylamine (3.41 mL, 29.64 mmol) was added to a solution of Compound 15 (5.0 g, 14.82 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.5 g (95%) of white solids. M.P. 87° C. 1H NMR (DMSO-d6): δ 1.22 (m, 1H), 1.36 (m, 4H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.51 (s, 2H), 7.14-7.33 (m, 6H), 7.47 (d, J=8.6 Hz, 1H), 7.90 (s, 1H), 10.44 (s, 1H). EIMS m/z 391 (M+1).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>C(OCC)(=O)C.[Cu]>[CH:1](/[C:9]1[N:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Brc1nccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1nccs1)\c1ccccc1
Yield: 65.6 %

Procedure:
A stirred mixture of 2-styryl-1H-benzimidazole (220 mg, 1 mmol), 2-bromothiazole (328 mg, 2 mmol), potassium carbonate (138 mg, 1 mmol), copper bronze (20 mg) and nitrobenzene (10 ml) was heated to reflux under a nitrogen atmosphere for 7 h. The cooled reaction mixture was diluted with ethyl acetate (150 ml) and filtered through a pad of celite. The filtrate was washed consecutively with water (50 ml), and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 100 g; n-hexane/ethyl acetate (9/1 to 3/1)) gave 199 mg of the titled compound as an orange oil, which was solidified on standing at room temperature. Recrystallization from isopropyl ether gave 117 mg (39%) of the titled compound as colorless crystals. MW: 303.39; mp: 99.0-99.5° C.; 1H-NMR (CDCl3) δ: 8.01 (1H. d, J=15.8 Hz), 7.91 (1H, d, J=3.7 Hz), 7.85-7.80 (1H, m), 7.69-7.64 (1H, m), 7.59-7.54 (2H, m), 7.51 (1H, d, J=3.7 Hz), 7.40 (1H, d, J=15.8 Hz), 7.42-7.29 (5H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:33])[C@@H:28]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:29]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC[C@@H](N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07-2.22 (m, 1H) 2.33 (s, 4H) 2.70-2.95 (m, 6H) 3.71 (d, J=5.05 Hz, 3H) 3.83-4.01 (m, 2H) 7.64 (br. s., 1H) 7.68-7.80 (m, 1H) 8.05-8.61 (m, 3H) 8.67 (s, 1H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[CH:12]1([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:38]([O:40][C:41](=[O:51])[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)=O)[CH3:39].Cl>C1COCC1.O>[CH2:38]([O:40][C:41](=[O:51])[C:42]([C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)=[CH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:39]
Reactant: CCOC(=O)C(=O)c1ccc(Br)cc1
Reactant: c1ccc([P+](CC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC1CCCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add LHMDS in THF (451 mL, 1.0 M, 451 mmol) to a slurry of cyclohexylmethyl-triphenyl-phosphonium bromide (207.5 g, 472 mmol) in THF (500 mL) maintained at 0 ° C. and stir the mixture for 1 h. Dissolve (4-bromo-phenyl)-oxo-acetic acid ethyl ester (prepared as described by Hu, Shengkui; Neckers, Douglas C. J. Org. Chem. 1996, 61, 6407-6415.) in THF (40 mL) and add the resulting solution to the reaction mixture. Stir the reaction mixture for 60 h at room temperature. Dilute the mixture with water and neutralize with 1 N HCl. Evaporate the THF and add ether (700 mL). Stir at room temperature for 30 minutes and filter through celite®. Separate the layers and extract the aqueous layers with ether. Dry the combined organic layers over magnesium sulfate, filter, and concentrate. If large amounts of triphenylphosphine oxide are present, add ether (1 L), filter through celite® and concentrate the filtrate. Dissolve the brown oil in CH2Cl2 (50 mL) and filter through a pad of silica gel, eluting with a gradient of 0-5% EtOAc in hexanes to obtain the title compound (109.7 g) as an E/Z mixture (E/Z ratio: 2/1). MS (m/e): 337 (+H).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH3:12].S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccccc1OCCO
Product: CSc1ccccc1OCCCl

Procedure:
o-(β-Hydroxyethoxy)-thioanisole (0.1 mole) is refluxed in excess thionyl chloride and evaporated to dryness to yield o-(β-chloroethoxy)-thioanisole.
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([OH:21])[C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1C1C=CC=C(Cl)C=1)(=O)=O.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[CH3:36][S:37]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([OH:21])[C:15]3[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:22]=[CH:27][CH:26]=[C:25]([Cl:28])[CH:24]=2)=[CH:6]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)cc(-c1cccc(Cl)c1)n2S(C)(=O)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cn2S(C)(=O)=O

Procedure:
Alternatively, the compound of Example 2, (±)-1-methylsulfonyl-(3-chlorophenyl)-5-[(4-chlorophenyl) hydroxyl (1-methyl-1H-imidazol-5-yl) methyl] indole was also made analogously to the method described for making Example Y, using methanesulfonyl chloride in place of 4-morpholinecarbonyl chloride. Yield: 77%. MS (Calc.): 526.46, MS(ES): 526.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.BrBr.[NH2:17][C:18]([NH2:20])=[S:19].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CCCCC>[NH2:20][C:18]1[S:19][C:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=2[N:17]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a solution of compound tert-butyl 4-oxopiperidine-1-carboxylate (24.0 g, 120.6 mmol) in dry CHCl3 (500 mL) at 0-5° C., was slowly added a solution of Br2 in CHCl3 (100 mL) over 1.5 hours. The reaction mixture was warmed to RT and stirred for 3 hours. The reaction mixture was concentrated to obtain solid, which was thoroughly washed with Et2O. The resulting intermediate tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate was used immediately in the next reaction. Accordingly, this intermediate (20 g, 72 mmol) was suspended in pentane, filtered, washed with pentane, and the solid so obtained dried in vacuo and dissolved in EtOH (100 mL). Thiourea (5.46 g, 72.0 mmol) was added and the reaction mixture heated for 4 hours at 70-75° C. The reaction mixture was concentrated to yield a residue, which was treated with aq. Na2CO3 solution, adjusted to pH=10, extracted with EtOAc, washed with water, washed with brine solution, dried (Na2SO4), filtered, and concentrated. The residue washed with pentane to obtain tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (8.7 g, 28% yield)
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19]C[CH2:17][C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.C(OC1C=CC(C2C=C3N=C4C(=CN3N=2)CCCC4)=CC=1)C1C=CC=CC=1.[H][H]>[Pd]>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:17][CH2:19][CH2:20][CH2:21]3)=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: [Pd]
Agent: c1ccc(COc2ccc(-c3cc4nc5c(cn4n3)CCCC5)cc2)cc1
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1

Procedure:
Using the method described for the preparation of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol, (4-benzyloxy-phenyl)-5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazoline and hydrogen in the presence of 10% Pd/C provided the title compound.
Reaction SMILES: C(O)(=O)C.C([BH3-])#N.[Na+].O1CCCC1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:28][CH2:29][CH2:30][O:31][N:32]=[C:33]([CH3:35])[CH3:34])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CO>[CH:33]([NH:32][O:31][CH2:30][CH2:29][CH2:28][N:27]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:14])[C:24]=2[N:25]=[C:26]1[CH2:36][CH2:37][CH3:38])([CH3:34])[CH3:35]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCON=C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCONC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Acetic acid (10 mL) followed by 1 M sodium cyanoborohydride in tetrahydrofuran (11.05 mL, 11.05 mmol) was added to a stirred solution of acetone O-[3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]oxime (1.50 g, 4.42 mmol) in methanol (10 mL). The reaction was stirred overnight at room temperature and then was concentrated under reduced pressure. The residue was diluted with water (100 mL) and the pH was adjusted with solid sodium hydroxide to pH 6. The mixture was extracted with chloroform (2×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 1.31 g of 1-{3-[(isopropylamino)oxy]propyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:32]1[O:34][C@@H:33]1[CH2:35][OH:36].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@H:33]([OH:34])[CH2:35][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OC[C@@H]1CO1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (30 mg, 0.07 mmol) in EtOH (1.0 mL) was added (R)-(+)-glycidol (5 mg, 0.07 mL, 1.0 equiv) and triethylamine (0.34 mg, 0.0035 mmol, 0.05 equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 15 h and then cooled to rt. The solvents were removed in vacuo. The residue was purified by preparative HPLC to afford (2R)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol as a white solid (14.8 mg, 40%). 1H-NMR (CD3OD) δ 8.45 (s, 1H), 8.32 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.46 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.25 (dd, J=2.3, 9.0 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.05 (td, 1H), 5.22 (s, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.72 (m, 2H), LCMS RT=3.32 min, [M+H]+=526.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N:6]([Si:17]([CH3:19])([CH3:18])[CH3:16])[Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-2,6-dimethylaniline (commercially available) (40 g, 0.2 mol) in tetrahydrofuran (500 ml) under a nitrogen atmosphere was added a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol). During this operation, the internal temperature was kept between −70° C. and −78° C. After five minutes, trimethylsilyl chloride (25 ml, 0.2 mol) was added whilst the internal temperature was kept below −68° C. After five minutes, the cooling bath was replaced with a water bath and the internal temperature rose to 0° C. Then the cooling bath was put back and the reaction mixture was cooled to −78° C. To this solution, a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol) was added whilst keeping the internal temperature below −70° C., followed by addition of trimethylsilyl chloride (30 ml, 0.237 mol) whilst keeping the internal temperature below −68° C. The reaction mixture was gradually allowed to warm to 20° C. Hexanes (200 ml) and water (40 ml) were added and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was distilled under a high vacuum leading to the title compound as a colorless oil which crystallized on standing. M.p. 47-52° C. 1H-NMR (CDCl3, 400 MHz): 0.08 (s, 18H), 2.21 (s, 6H), 7.15 (s, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)C>C1C=CC=CC=1.CCO.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>[C:16]1([C:2]2[CH:3]([CH2:7][CH:8]=[O:9])[CH2:4][CH2:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: O=CCC1CCC=C1Br
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: CCO
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=CCC1CCC=C1c1ccccc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) (1.85 g, 9.32 mmol) in benzene (70 mL) was treated with Na2CO3 (14.0 mL, 2M in H2O.) and phenylboronic acid (2.27 g, 18.6 mmol) in EtOH (40 mL). Tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4 catalyst (1.61 g, 1.40 mmol) was added and the mixture was heated to 80° C. for 3.5 h. until no starting material remained. The benzene was replaced with diethyl ether and the mixture was filtered through celite. The filtrate was washed with sat. K2CO3, brine and dried over MgSO4. Pure (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) 1.07 g (62%) was isolated by chromatography on silica gel. Use of (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) in Method A (without formation of the fumarate) produced 4-[(2-phenylcyclopent-2-en-1-yl)methyl]-1,3-dihydro-2H-imidazole-2-thione (Compound 112).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)c(Br)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To 84A (9.8 g, 45 mmol) in trifluoroacetic acid (20 mL) was added triethylsilane (14.3 mL, 90 mmol). After stirring at 50° C. for 6 h, the reaction was quenched with 100 mL of saturated NaHCO3 solution and extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The resulting residue was distilled at 200° C. to give 84B (85% purity).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1ccc2oc(S)nc2c1
Reactant: CN1CCCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2oc(N3CCCN(C)CC3)nc2c1

Procedure:
5-Methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 5-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (124 mg).