Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[C:7]([Cl:12])=[C:6]([Cl:13])[C:5]=1[C:14]#[N:15].O.[NH2:18][NH2:19].C(O)(=O)C>CO>[Cl:13][C:6]1[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]([Cl:10])=[C:4]2[C:5]=1[C:14](=[N:18][NH2:19])[NH:15][C:3]2=[O:16]
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: NN
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: NN=C1NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
119.6 g of 3,4,5,6-tetrachloro-2-cyanobenzoic acid methyl ester are dissolved in 600 ml of methanol and 70.6 g of a 30.6% strength methanolic solution of Na methylate. The solution is cooled to 10° C and is added dropwise at 10° C to a solution of 200 ml of hydrazine hydrate in 400 ml of methanol. A yellowish precipitate is formed. The reaction mixture is stirred at room temperature for 2 hours and is then warmed to 35° C over the course of 30 minutes and 200 ml of glacial acetic acid are added at this temperature. After stirring for 1 hour at room temperature, the product is filtered off and the filter residue is washed with methanol and water. The material filtered off is then extracted by boiling in 1 l of methylcellosolve for a further 2 hours, filtered off at room temperature and washed with methylcellosolve and methanol. After drying at 70° C, 98 g (82% of theory) of analytically pure 4,5,6,7-tetrachloro-isoindolin-1-on- 3-ylidene hydrazine of the formula ##STR31## are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NC4CCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and cyclobutylamine. ES-MS m/e (%): 440 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=O)[C:14]3[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:37])=O>ClC1C=CC=CC=1>[Cl:37][C:15]1[C:14]2[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:13]=2[N:12]2[C:18]([CH2:17][N:16]=1)=[C:9]([C:7]1[O:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:8]=1)[N:10]=[CH:11]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21
Solvent: Clc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: ClC1=NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21

Procedure:
3(-3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-8-bromo-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (1.1 g, 20.3 mmol) and N,N-dimethyl-p-toluidine (881 μL, 6.1 mmol) were mixed in chlorobenzene (8 mL) under Argon. Phosphorus oxychloride (279 μL, 3.1 mmol) was then added at room temperature and the resulting mixture heated under reflux for 2.5 h. After cooling, the mixture was evaporated and then extracted with CH2Cl2 (50 mL) and water (25 mL). The organic layer was separated, dried (Na2SO4) and evaporated. Chromatography on silica gel eluting with CH2Cl2: Acetone (30:1). Yield: 550 mg (67%). m/z 403/405 (M—H−).
Reaction SMILES: [CH3:1][SiH](C)OC.C([Si](C)(C)O[Si](C)(C)[CH:11]=[CH2:12])=C.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Pt]>[CH:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:11]=[CH2:12])=[CH2:1]
Reactant: Cc1ccccc1
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Reactant: CO[SiH](C)C
Agent: [Pt]
Product: C=Cc1ccccc1C=C
Temperature: 50 °C

Procedure:
Comparative Example 4. (Reaction between Divinyldisiloxane and Dimethylmethoxysilane) A glass tube was filled with 0.186 g of 1,3-divinyltetramethyl-1,3-disiloxane, 0.18 g of dimethylmethoxysilane, and 0.047 g of toluene. The contents were combined with 2 μL of a toluene solution of a complex of 1,3-divinyltetramethyldisiloxane and 0-valence platinum (platinum content: 0.4 Wt. %). The content was heated for 3 hours at 50° C. Gas chromatography analysis showed that the conversion of 1,3-divinyltetramethyl-1,3-disiloxane was 68% and that monosilyl and disilyl compounds of divinylbenzene were produced with the yields of 37% and 30%, respectively. The ratio of α-adducts to β-adducts was 6:1 and the ratio of α, α-adducts to α,β-adducts was 4.4:1.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:3]=1Br.[ClH:35]>O1CCOCC1>[Cl:35][C:3]1[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:5][C:6]2[N:7]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Reactant: Cl
Solvent: C1COCCO1
Product: Nc1c(Cl)c(N2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (0.09 mmol) was charged to a 20 mL scintillation vial. To this vial was added 4N HCl in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and 6-chloro-5-(piperazin-1-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([CH2:15][C:16]#N)[CH2:9][CH2:8]2)(=O)C.[CH2:18]([OH:20])[CH3:19].CC[O:23]CC.C(O)(C)C.[ClH:30]>>[ClH:30].[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([CH2:15][C:16]([O:20][CH2:18][CH3:19])=[O:23])[CH2:9][CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CC#N)O2
Reactant: CCOCC
Reactant: CCO
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)CC1CCc2cc(N)ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A mixture of 1.5 g of 6-acetamido-2-cyanomethylchromane (Example 14) in 25 mL of concentrated hydrochloric acid is stirred vigorously at room temperature for about 6 h. Ethanol (50 mL) is added and the mixture allowed to stand overnight. The precipitate is filtered, rinsed with 50-mL aliquots of ether, and dried. Absolute ethanol (25 mL) and HCl (10 mL) are stirred with the precipitate for 2 h, followed by addition of 10 mL of concentrated HCl. The precipitate is recovered and recrystallized twice from ether/isopropanol affording about 1.3 g of ethyl 2-(6-aminochroman-2-yl)acetate hydrochloride (about 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[NH:5][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccc(O)c1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-hydroxyphenylalanine methyl ester (1 g) in CH2Cl2 (20 mL) at 0° C. was added triethylamine (2 mL) followed by DMAP (527 mg) and benzoyl chloride (1.1 mL). When addition was complete, the mixture was stirred for 17 hr at r.t. and then NH4OAc buffer was added. The aqueous phase was extracted with CH2Cl2 (3×) and the combined organics were washed with buffer, brine, dried (MgSO4) and concentrated. The residue was dissolved in MeOH (15 mL) and THF (1.5 mL) and NaOMe (1M in MeOH; 2.4 mL) was added at 0° C. After 2.5 hr, saturated aq. NH4Cl was added and the aqueous phase extracted with EtOAc (3×). The combined organics were washed with NH4OAc buffer (2×), H2O, brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (1:1)) provided N-benzoyl-3-hydroxyphenylalanine methyl ester as a foam. A portion of this material (1.25 g), K2CO3 (866 mg) and methyl iodide (312 μL) in DMF (12 mL) were stirred at r.t. for 18 hr and then H2O (150 mL) was added. The mixture was extracted with EtOAc (3×) and the combined organics washed with NH4OAc buffer, H2O (2×) and brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (55:45)) provided N-benzoyl-3-methoxyphenylalanine methyl ester as a gum. A portion of this material (950 mg) was dissolved in refluxing xylene (25 mL) and P2O5 (10.9 g) was added periodically over 5 hr. After refluxing for 5.5 hr, the mixture was cooled to r.t. and the xylene was decanted. The residual solid was dissolved in cold H2O (600 mL) and neutralized with solid NaHCO3. The aqueous mixture was extracted with EtOAc (3×) and the combined organics were washed with NH4OAc buffer (2×), brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/EtOAc (3:2)) provided the title compound as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)(=[O:14])=[O:13])[N:4]=1.[C:24](O)(=[O:26])C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>CN(C=O)C.[Fe]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([N:11]2[C:24](=[O:26])[NH:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]2(=[O:14])=[O:13])[N:4]=1
Reactant: CC(=O)O
Reactant: COc1cnc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1OC
Agent: [Fe]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cnc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1OC

Procedure:
The title compound was prepared in two steps from N-(4,5-dimethoxypyrimidin-2-yl)-2-nitrobenzenesulfonamide (231 mg, 0.68 mmol), Fe powder (380 mg, 6.8 mmol) and acetic acid (5 mL); followed by 1,1′-carbonyldiimidazole (396 mg, 2.44 mmol) and triethylamine (0.17 mL, 1.22 mmol) in DMF (4.0 mL) using the methods of (IntA17), step 2 and (IntA14), step 3. The residue from step 3 was triturated with Et2O to yield the title compound (104 mg, 0.31 mmol).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][C:2]1=[O:13].[F-].[CH2:15]([N+](CCCC)(CCCC)CCCC)[CH2:16][CH2:17][CH3:18].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1>[OH:32][CH2:36][CH:35]1[CH:17]2[CH2:18][CH:33]([CH2:15][CH2:16]2)[CH:34]1[N:1]1[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][C:2]1=[O:13]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2[nH]1
Reactant: C1CCOC1
Agent: [F-]
Product: O=c1[nH]c2cnc3[nH]ccc3c2n1C1C2CCC(C2)C1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{[(triisopropylsilyl)oxy]methyl}bicyclo[2.2.1]hept-2-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (45 mg) in tetrahydrofuran (0.15 ml) was added 1M tetrabutylammoniumfluoride/tetrahydrofuran solution (297 μl), and the mixture was stirred overnight at ambient temperature. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol) to obtain 1-[3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2(1H)-one (14.8 mg) as a white solid. To a solution of rel-4-{[(1R,2R,3S,5s)-5-hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carbohydrazide in 1-methyl-2-pyrrolidone (1 ml) were added triethyl orthoformate (340 μl) and p-toluene sulfonic acid monohydrate (5.6 mg). After stirring at 120° C. for 30 minutes, triethyl orthoformate (340 μl) and p-toluene sulfonic acid monohydrate (5.6 mg) were added. After the mixture was stirred at 120° C. for 40 minutes, the reaction solution was extracted with 20% chloroform/methanol solution, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol) to obtain rel-(1s,3R,4R,5S)-4-{[1-(diethoxymethyl)-5-(1,3,4-oxazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]amino}adamantan-1-ol (28 mg) and rel-(1s,3R,4R,5S)-4-{[5-(1,3,4-oxazole-2-yl)-1H-pyrrolo[2,3-b]pyridine-4-yl]amino}.adamantan-1-ol (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].Cl>O1CCOCC1>[O:14]=[C:13]1[C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:10][N:9]1[CH2:8][C:7]1[CH:6]=[C:5]([CH:35]=[CH:34][CH:33]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.19 g, 0.4 mmol) was added 4M solution of HCl in dioxane (2 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo to obtain methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Clc1ccnc2ccc(Br)cc12
Product: Brc1ccc2nccc(N3CCOCC3)c2c1

Procedure:
122 mg 6-bromo-4-chloroquinoline and 0.13 mL morpholine were reacted by the same method as in Production Example 74 to give 68 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]\[C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(/C=C/C2N=C(NC(=O)C)SC=2)=CC=1)#N.CO.[H][H]>[Pd].C(O)(=O)C.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(=O)Nc1nc(/C=C\c2ccc(C#N)cc2)cs1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)Nc1nc(/C=C/c2ccc(C#N)cc2)cs1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(C#N)cc2)cs1

Procedure:
A mixture of N-{4-[(Z)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide and N-{4-[(E)-2-(4-cyanophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (Z:E=3:1) (1.5 g), 10% palladium on carbon (323 mg), methanol (20 ml), tetrahydrofuran (10 ml) and acetic acid (5 ml) were combined. The reaction mixture was stirred under 4 atm hydrogen at ambient temperature for 9 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:1)→chloroform/methanol (30:1) as an eluent, and triturated with ethyl ether to give N-{4-[2-(4-cyanophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (1.18 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)oc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)oc2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 29.9 %

Procedure:
A mixture of 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (450 mg, 1.32 mmol), (1R,2R)-2-aminocyclohexanol (228 mg, 1.98 mmol) and DIEA (341 mg, 2.64 mmol) in DMA (10 mL) was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to rt and poured into water (30 mL) and the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a white solid (155 mg, 29.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.16-7.08 (m, 3H), 6.82 (dd, J=2.4, 8.7 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J=4.5 Hz, 1H), 3.75 (s, 3H), 3.35 (br s, 2H), 1.90 (m, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: I[C:2]1[NH:3][C:4]2[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]=2[C:10](=[O:12])[CH:11]=1.[C:21](=O)([O-])[O-].[Na+].[Na+].O.[CH2:28]([CH2:31][O:32][CH3:33])OC>>[O:32]1[CH:31]=[CH:28][C:21]([C:11]2[C:10](=[O:12])[C:9]3[C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=4[CH:6]=[C:5]([O:17][CH2:18][CH2:19][CH3:20])[C:4]=3[NH:3][CH:2]=2)=[CH:33]1
Reactant: O=C([O-])[O-]
Reactant: CCCOc1cc2ccccc2c2c(=O)cc(I)[nH]c12
Reactant: COCCOC
Agent: [Na+]
Solvent: O
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccoc3)c[nH]c12
Temperature: 95 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
3-Iodo-5-propoxy-4H-benzo[f]quinolin-1-one (1.06 g, 2.79 mmol) was suspended in dimethoxyethane (20 ml). Furan-3-boron acid (354 mg, 3.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane complex (PdCl2(DPPF).CH2Cl2, 123 mg, 0.11 mmol) and a 2N aqueous sodium carbonate solution (4.0 ml) were sequentially added to the suspension. The mixture was stirred at 90 to 100° C. under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, water was added thereto, and the resulting mixture was subjected to extraction using dichloromethane. The thus-obtained organic layer was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=80:1). The purified product was concentrated under reduced pressure, the residue was washed with ethyl acetate and then dried, giving a pale brown powder of 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (430 mg, yield: 48%).
Reaction SMILES: [H-].CCCCCC.[CH:8]1([CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][C:17]#N)[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:20]S(O)(=O)=O>CC(OC)(C)C.CO>[CH:8]1([CH:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH:17]=[O:20])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(CCCC#N)C1CCCC1
Reactant: O=S(=O)(O)O
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: CC(CCCC=O)C1CCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Diisobutylaluninum hydride (60 ml of 1.0 M solution in hexane) was added at −65° C. to a hexane (50 ml) solution of 5-cyclopentylhexanenitrile (5.0 g; 30 mmol; from example 11). After stirring at −70° C. for 0.5 hour, and at room temperature for 3 hours, methanol (1.8 ml) was added, and the stirring continued for 20 minutes. 10% H2SO4 (48 ml) was added, and the reaction mixture was diluted with MTBE (150 ml). The organic layer was separated, washed with saturated sodium bicarbonate solution (300 ml) and brine (3×300 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (100° C./0.2 torr) to give 2.6 g (51.5% yield) of 5-cyclopentylhexanal.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:41])[CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:29])[S:14][N:13]=1
Reactant: NCCC(O)CCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCl, m/z): 498 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4](/[CH:5]=[CH:6]/[CH3:7])[C@@H:3]1[C:8]([OH:10])=[O:9].Br[CH2:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([CH3:22])=[C:16]([F:23])[C:15]=1[F:24].CN(C)C=O.C(N(CC)CC)C>O>[CH3:11][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]/[CH3:7])[C@@H:3]1[C:8]([O:10][CH2:13][C:14]1[C:15]([F:24])=[C:16]([F:23])[C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])=[O:9]
Reactant: C/C=C/[C@H]1[C@H](C(=O)O)C1(C)C
Reactant: Cc1c(F)c(F)c(CBr)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C/C=C/[C@H]1[C@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a mixture solution of 0.50 g of (1RS)-trans-2,2-dimethyl-3-((E)-1-propenyl)cyclopropanecarboxylic acid, 0.72 g of 1-bromomethyl-2,3,5,6-tetrafluoro-4-methylbenzene and 8 ml of dimethylformamide, 1.0 g of triethylamine was added and the mixture was stirred at 80° C. for 4 hours. After the mixture was cooled to room temperature, water was poured into the mixture and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.83 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1RS)-trans-2,2-dimethyl-3-((E)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[N:30]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 45.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.400 g), tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.400 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.250 g of the desired product.