Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)C.[OH-].[K+].Cl>C1(C)C=CC=CC=1.O>[CH2:20]([N:19]1[C:18]2[CH:17]=[CH:16][NH:15][C:14]=2[C:7](=[S:8])[NH:6][C:4]1=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNc1cc[nH]c1C(=O)OCC
Reactant: CCOC(=O)N=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]ccc21
Temperature: 90 °C
Yield: 6.5 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.13 ml, 1.1 mmol) was added to 3-(butylamino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.23 g, 1.1 mmol) in toluene (5 mL) and the mixture was heated at 90° C. for 1 h. The precipitate was filtered off and washed with hexane. The intermediate product was treated with potassium hydroxide (0.55 g, 9.9 mmol) in water (9 mL), and heated to reflux for 15 h. After cooling to ambient temperature, the pH was adjusted to pH 5 with 12 M HCl. The resultant precipitate was collected by filtration and washed with water. The crude product was purified using preparative HPLC to give the title compound (16 mg, 6%) as a solid.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:18])=[C:13]([CH3:22])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)O
Reactant: C1COCCN1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCC(=O)N1CCOCC1
Yield: 93.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone as a white solid (0.228 g, 92.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:11][C@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:6][CH2:7]2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: O[C@@H]1CCc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O[C@@H]2CCc3ccc(Cl)cc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of (R)-6-chloroindan-1-ol (0.45 g, 2.67 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (112 mg, 2.8 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (0.41 g, 2.94 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred, filtered, and dried to yield 450 mg of 2-fluoro-5-((R)-6-chloroindan-1-yloxy)benzonitrile.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@@H:2]([F:1])[CH2:3][O:4]1)=[O:47]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid (Example 7) gave 186 as the hydrochloride salt as a white solid (38 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.60-8.40 (m, 3H), 8.19-8.13 (m, 1H), 7.71 (s, 1H), 7.49-7.35 (m, 3H), 5.40-5.23 (m, 1H), 4.87 (d, J=10.5 Hz, 1H), 4.28 (ddd, J=32.0, 14.5, 4.7 Hz, 1H), 4.07 (ddd, J=23.4, 14.5, 2.8 Hz, 1H), 3.80 (s, 3H), 3.78-3.60 (m, 1H), 2.19-1.82 (m, 4H). LCMS (ES+) m/z 449 (M+1). Alkyl NH2 not observed.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (S)-1,1-diethoxypropan-2-amine (Compound XIV-1) 682 mg (3.55 mmol) in tetrahydrofuran 2 ml, benzaldehyde 337 mg (3.55 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 3 ml and sodium triacetoxyborohydride 829 mg (3.91 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate aq. 50 ml twice, water 50 ml twice and brine 50 ml twice. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 826 mg (98%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][Si](C(C)(C)C)(C)C)=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:34].O.[OH-].[Li+]>C1COCC1.O>[OH:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[C:16]([CH2:15][N:8]1[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:7]1=[O:34])=[CH:17][CH:18]=[CH:19]2
Reactant: COC(=O)CCn1c(=O)n(Cc2cccc3cc(O[Si](C)(C)C(C)(C)C)ccc23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCn1c(=O)n(Cc2cccc3cc(O)ccc23)c2ccccc21
Yield: 10.1 %

Procedure:
To a stirred solution of 3-{3-[6-(tert-Butyl-dimethyl-silanyloxy)-naphthalen-1-ylmethyl]-2-oxo-2,3-dihydro-benzimidazol-1-yl}-propionic acid methyl ester (200 mg, 0.41 mmol) in THF (7 ml) and water (1 ml) was added lithium hydroxide monohydrate (26 mg, 0.61 mmol) at ambient temperature. Upon complete consumption of the starting material the reaction was diluted with water, ethyl acetate and 6N HCl (adjusted to pH=2). The layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was diluted with acetonitrile (3 ml) and allowed to stand over night. The resulting precipitated product was collected via filtration, washed with acetonitrile and dried on house vacuum to give 15 mg (10%) of the desired product. LCMS (ESMS): m/z 363.38 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([N+:24]([O-])=O)[CH:16]=1.N[CH:28]([CH3:32])[CH2:29][C:30]#[N:31]>C(#N)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:16][C:17]=1[NH:24][CH:28]([CH3:32])[CH2:29][C:30]#[N:31])([O-:23])=[O:22]
Reactant: CC(N)CC#N
Reactant: CC(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c(Cl)c1
Solvent: CC#N
Product: CC(CC#N)Nc1cc(Oc2ccc(S(=O)(=O)C(C)C)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 4.0 g of 2-chloro-4-isopropylsulphonyl-(3,4-dinitrophenoxy)benzene and 2,5 g of 3-aminobutyronitrile in 30 ml of acetonitrile was refluxed for 13 hours. After evaporation the residue was recrystallized from methanol. The desired product was obtained in a yield of 3.3 g; m.p. 132° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])=O>>[C:30]([C:29]1[CH:28]=[C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)[CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Product: N#Cc1cccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)c1
Yield: 56 %

Procedure:
4-[4-(3-Cyano-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (150 mg, 56%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-(2-bromoacetyl)benzonitrile (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.59 (d, J=1.6 Hz, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 8.44 (d, J=7.7 Hz, 1H), 8.31 (dd, J=8.0, 1.6 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.64-7.88 (m, 4H), 7.43-7.49 (m, 2H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:20](=[O:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]([CH3:26])[C:16](=[O:27])[CH2:15]2)[CH2:9][CH2:8]1)=[O:6]>O1CCOCC1.O>[CH3:26][N:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20](=[O:21])[N:14]([CH2:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)[CH2:15][C:16]1=[O:27]
Reactant: COC(=O)[C@H]1CC[C@H](CN2CC(=O)N(C)c3ccccc3C2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc21

Procedure:
LiOH (0.77 mmol, 0.02 g) was added to a solution of trans-4-(1-Methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-ylmethyl)-cyclohexane carboxylic acid methyl ester (0.64 mmol, 0.22 g) in 1:1 dioxane/water (16 mL) at 0° C. After 1 h at 0° C. the ice bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was washed with DCM (1×20 mL). To the aqueous layer HCl 2N was added until acid pH, then extract with DCM (3×15 mL). The organic layer was washed with brine dried over Na2SO4 anhydrous and the solvent was removed under reduced pressure to obtain the titled compound (0.18 g, yield 85%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=O)[CH:10]=[CH:9]2>>[Cl:3][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH3:5])[CH:7]=2)[N:12]=[C:11]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]#[N:20])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2nc(-c3ccccc3C(N)=O)ccc2c1
Product: Cc1ccc2nc(-c3ccccc3C#N)cc(Cl)c2c1
Yield: 11 %

Procedure:
2.5 ml (34.2 mmol) of thionyl chloride were added to 1.28 g (4.88 mmol) of 2-(6-methylquinolin-2-yl)benzamide obtained in Reference Example 7 and the mixture was stirred. After heating the mixture under reflux for 3 hours, thionyl chloride was distilled off. The residue was dissolved in 100 ml of chloroform and poured into iced water. The organic layer was separated, neutralized with 150 ml of a saturated sodium bicarbonate solution, washed with a saturated sodium chloride solution and dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated and the concentrate was subjected to silica gel chromatography using a mixed solvent of hexane and ethyl acetate (10/1) to obtain 150 mg of 2-(4-chloro-6-methylquinolin-2-yl)benzo-nitrile.
Reaction SMILES: C1([C:7]2[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=2)C=CC=CC=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1B(O)O>>[CH:20]1[C:19]2[C:24](=[CH:15][C:16]([C:10]3[C:11]([CH:13]=[O:14])=[N:12][CH:7]=[CH:8][CH:9]=3)=[CH:17][CH:18]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)n1
Reactant: OB(O)c1ccc2ccccc2c1
Product: O=Cc1ncccc1-c1ccc2ccccc2c1

Procedure:
Precursor (D) was prepared following the same procedure as that used to prepare precursor (A) except that 206 mg (1.2 mmol) of 2-naphthylboronic acid were used as reagent. 190 mg of precursor (D) were obtained as colourless oil with a yield of 82%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li]CCCC.O1CCCC1.[CH:21]([N:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25](=[O:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)([CH3:23])[CH3:22]>C(OCC)C.C1COCC1.C(OCC)C>[CH:35]1([N:24]([CH:21]([CH3:23])[CH3:22])[C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([CH:30]([OH:31])[C:2]3[CH:7]=[CH:6][C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(C(O)c2ccc3c(c2)OCO3)cc1)C1CCCCC1
Temperature: -20 °C

Procedure:
To a stirred solution of 4-bromo-1,2-(methylenedioxy)benzene (1.00 g, 6.0 mmol) in ethyl ether (30 mL) at 0° under an argon atmosphere is added n-BuLi (3.75 mL of 1.6 M solution in hexane). Tetrahydrofuran (10 mL) is added. The reaction mixture is cooled to -20° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (0.82 g, 3.0 mmol) in THF: ethyl ether (4:3, 35 mL) is added rapidly. The reaction is followed by thin layer chromatography until complete. The reaction is quenched at -15° C. by adding water (50 mL) and 1N HCl(20 mL). The reaction is further diluted with water (300 mL) and extracted three times with EtOAc (50 mL portions). The combined extracts are washed twice with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.[O-:15][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:15])[CH2:8][CH:9]2[CH2:12][CH2:13][CH3:14]
Reactant: CCCC1CCc2ccc(OC)cc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCC1CC(=O)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 15.1 %

Procedure:
The mixture of indans from step 2 (1.287 g, approx. 6.1 mmol) in CH2Cl2 (50 mL) was treated with a finely ground mixture of KMnO4 (7.00 g) and CuSO4.xH2O. The resulting mixture was heated at reflux for 89 hours, then cooled to room temperature and filtered through a celite pad. The filtrate was dried over MgSO4, filtered and evaporated under vacuum to an oil (1.155 g). The crude product was purified by chromatography on a Biotage FLASH 12M column, eluting with 10% EtOAc in hexanes, to afford 5-methoxy-3-propyl-1-indanone (0.188 g) as an oil. Other column fractions afforded 6-methoxy-3-propyl-1-indanone, the indan starting materials, and 5-methoxy-1-indanone.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>>[CH3:22][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([N:32]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=[C:31]4[CH3:30])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)([CH3:23])[C:19]([NH2:21])=[O:20]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1

Procedure:
2-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide (0.15 g) was reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling to give 29.3 mg 192 following reverse phase purification. MS (Q1) 535.2 (M)+.
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)ON=C(CBr)C(=O)OCC
Yield: 83.7 %

Procedure:
Ethyl 3-bromo-2-(hydroxyimino)propanoate (4.0 g, 19 mmole) and methacryloyl chloride (2.18 g, 20.8 mmole) in methylene chloride (100 ml) were treated with dry pyridine (1.66 g, 21 mmole). After a workup as in Example 1, 4.42 g (84% yield) of ethyl 3-bromo-2-(methacryloyloximino)propanoate was obtained as an oil. NMR and IR spectra confirm the structure.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 25 mg of 2-bromoacetophenone was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 33 mg of white crystals.
Reaction SMILES: [OH-].[K+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)(=O)C>CO>[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:38])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2C(C)=O)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Yield: 76.5 %

Procedure:
A solution of potassium hydroxide (0.22 g) in methanol (4 ml) was added at room temperature to tert-butyl 5-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (1.00 g) obtained in Reference Example 47, and heated at reflux for 2 hours with stirring. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (700 mg).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1>>[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:12]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)=[CH:11][CH:10]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Product: O=C1C=C(c2cccc3c2oc2ccccc23)CCC1
Yield: 83 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and dibenzofuran-4-boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 20% ethyl acetate/hexanes) yielded the product (141 mg, 83%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.91 (d, J=6.9 Hz, 2H), 7.30-7.58 (m, 5H), 6.90 (s, 1H), 2.97 (t, J=4.7 Hz, 2H), 2.56 (t, J=6.1 Hz, 2H), 2.21 (quintet, J=5.8 Hz, 2H). 13C (75 MHz, CDCl3): 200.1, 156.2, 155.9, 153.3, 128.6, 127.7, 125.6, 125.3, 124.0, 123.5, 123.2, 123.0, 122.0, 120.7, 111.9, 37.7, 29.0, 23.2. HRMS (LCT Electrospray): mass calcd for (C18H14O2+Na) m/z 285.0891; measured [M+Na]+: m/z 285.0895.
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.Cl.[F:9][C:10]([F:24])([F:23])[CH2:11][CH:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[C@@H:13]([C:15](O)=[O:16])[NH2:14]>C1COCC1.[OH-].[Na+]>[NH2:14][C@@H:13]([CH:12]([CH2:11][C:10]([F:9])([F:23])[F:24])[CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:15][OH:16]
Reactant: N[C@H](C(=O)O)C(CC(F)(F)F)CC(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: N[C@H](CO)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of LiBH4 (0.35 mL, 0.71 mmol) in THF (5 mL) at 0° C. was added chlorotrimethylsilane (0.112 mL, 0.885 mmol). The reaction mixture was warmed to 25° C. and, after 30 min, added dropwise to a 0° C. suspension of crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-L-norvaline hydrochloride salt (0.045 g, 0.177 mmol) in THF (1 mL). The mixture was warmed to 25° C. and, after 21 h, quenched with MeOH. The volatiles were removed in vacuo to give a residue, which was dissolved in 1N aqueous NaOH (5 mL) and extracted with CH2Cl2 (4×10 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentan-1-ol as a crude light yellow oil (0.046 g, 100%). The crude amino alcohol was used in the next step without further purification. Mass Spectrum (+ESI): 240 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30])#[N:22]>>[CH3:15][N:13]([CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]#[N:22])(=[O:31])=[O:30])[CH3:14]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2C#N)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.2 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-cyanobenzenesulphonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (6 mg, 22%) as a white solid. MS (ESI+) for C19H19N3O3S m/z 370 (M+H)+.