Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:17][C:18]1[O:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1)[C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12]C)=[O:11])(=[O:3])[CH3:2].O[Li].O>CO>[C:1]([N:4]([CH2:17][C:18]1[O:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:22]=1)[C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cccc(N(Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)C(C)=O)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(=O)N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
A mixture of methyl [3-[N-acetyl-[(4,5-diphenyl-2-oxazolyl)methyl]amino]phenoxy]acetate (0.58 g, 1.3 mmol), LiOH.H2O (0.05 g, 1.3 mmol) and MeOH (30 mL) was stirred at room temperature for about 15 hours before adding LiOH.H2O (0.05 g, 1.3 mmol). After about 1 hour, the solvent was evaporated, the residue diluted with 1N HC1 solution and extracted with CH2Cl2. The combined extracts were washed with saturated NaCl solution, dried over MgSO4 and concentrated in vacuo to leave [3-[N-acetyl-[(4,5-diphenyl-2-oxazolyl) methyl]amino]phenoxy]acetic acid (0.51 g, 91%), mp 75-80° C. IR (KBr) 2500 (CO2H), 1740 (CO2H), 1660 (NCOCH3) cm-1 ; 1H NMR (CDCl3) δ1.95 (3H, s, COCH3), 4.55 (2H, s, OCH2), 5.11 (2H, s, NCH2) 6.70-6.95 (3H, m, aromatic H) , 7.25-7.40 (7H, m, aromatic H) , 7.45-7.65 (4H, m, aromatic H); MS m/z 443 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:8][N:7]1[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[C:3]([CH:12]=[O:13])[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(c3ccccc3)CC2)c(C=O)c(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
To an ice-cooled, stirred solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.600 g, 2.96 mmol) and triethyl-amine (0.45 ml, 3.26 mmol) in dichloromethane (20 ml), a solution of N-phenylpiperazine (0.49 ml, 3.26 mmol) in dichloromethane (10 ml) was added dropwise. The resulting suspension was stirred at room temperature until the starting material was consumed (3.5 h, monitored by TLC). Then the reaction mixture was washed with water (3×10 ml), and the organic phase was dried over 20, anhydrous MgSO4. The solvent was evaporated in vacuo, and the brown oily crude product was purified by column chromatography with a mixture of dichloromethane:ethyl acetate (1:1) as the eluent and crystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl.[N:33]1([C:38](=N)[NH2:39])C=CC=N1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:38]([NH2:39])=[NH:33])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: N=C(N)n1cccn1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=N)N)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.193 g, 0.65 mmol) in dichloromethane (10 mL) and Hunig's Base (0.34 mL, 1.95 mmol) was added 1H-pyrazole-1-carboximidamide hydrochloride (0.100 g, 0.69 mmol). The reaction mixture was stirred at room temperature for 2 hours. A white precipitates was formed, which was filtered, washed with dichloromethane and hexane to give the desired product, 3-(4-methoxy-benzyl)-3,6,8,9-tetrahydro-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamidine as a white solid (0.088 g, 40%). M.p.=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.35 (s, 1H), 8.26 (s, 1H), 7.63 (s, 4H), 7.22-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.60 (s, 2H), 4.75 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.69 (s, 3H), 3.21 (t, J=6 Hz, 2H); LCMS [M+H]: 337.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.18 g of 1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.18 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-trifluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (1)) (optical purity: 99% ee).
Reaction SMILES: [F:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@:13]2(O)[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1>C(Cl)Cl>[F:1][C@H:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@]12CCC(=O)C=C1[C@H](F)C[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1[C@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
6β-Fluoro-9α-hydroxyandrost-4-ene-3,17-dione (III, Example 8 21.2 g) is dissolved in methylene chloride (1000 ml) and the mixture dried over magnesium sulfate for 1 hr. After suction filtration (the magnesium sulfate cake is washed with methylene chloride) the filtrate is cooled on an ice bath and chlorosulfonic acid (8.3 ml) is added dropwise keeping the temperature at 0°. The reaction mixture is quenched with water (20 ml) 20 min after the addition of the chlorosulfonic acid is completed. The reaction mixture is transferred to a separatory funnel. The phases are separated. The organic phase is washed repeatedly with water until the pH becomes greater than 5. The organic phase is then dried over sodium sulfate concentrated under reduced pressure to give the title compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1.Cl>CS(C)=O>[CH:18]1([CH2:17][N:16]2[C:2]3[C:3](=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=3[F:8])[CH2:12][C:13]2=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: NCC1CC1
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CC1CC1
Temperature: 45 °C
Reaction time: 20 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.50 g, 11.5 mmol) and (aminomethyl)cyclopropane (6 eq., 5.98 ml, 0.0691 mol) are mixed in DMSO (10 ml) and stirred at 45° C. for 20 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and ether, and dried under vacuum to give the title compound as a yellow solid. HPLC r.t. 4.91 min; MS for C12H11FN2O3 m/z 251.2 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=O)C.C(=O)(O)[O-].[Na+].C(O)(=O)C>CO>[C:25]([O:24][C:15]12[O:23][N:10]([CH2:11][CH:12]3[CH:14]1[N:13]3[C:28](=[O:30])[CH3:29])[C:9]1[C:17](=[C:5]([OH:4])[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=1)[CH:16]2[CH2:18][O:19][C:20](=[O:22])[NH2:21])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC12ON(CC3C1N3C(C)=O)c1cc(C=O)cc(O)c1C2COC(N)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (52 mg) in methanol (5 ml) was added sodium bicarbonate (10 mg) in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and for additional 2.5 hours at ambient temperature. To the reaction mixture was added acetic acid to adjust the pH value to about 6 in an ice-water bath and the mixture was evaporated in vacuo. The residue was extracted with a mixture of chloroform and methanol (5:1, v/v) (5 ml×3). The extracts were combined and evaporated in vacuo. The residue was subjected to silica gel column chromatography and elution was carried out with a mixture of chloroform and methanol (50:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-9-yl acetate (26 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:15](N)=[NH:16]>C(OCCO)C>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[N:16][CH:15]=1
Reactant: N=CN
Reactant: Nc1ncccc1C(=O)O
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Oc1ncnc2ncccc12
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 2-aminonicotinic acid (880 mg, 6.4 mMol) and formamidine acetate (2.0 g, 19.1 mMol) in 2-ethoxyethanol (25 mL) was heated at reflux overnight. The solution was allowed to come to room temperature and stand for 2 hours, then the resulting precipitate was collected by filtration, rinsed with 2-ethoxy ethanol (2×5 mL), diethyl ether (20 mL), and air dried to yield 525 mg of a gray powder as product. MS (ES+)=148 (M+H)+. Yield=56%.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C:16]1[C:10]2[O:9][C:8]([CH:5]3[CH2:6][CH2:7][O:3][CH2:4]3)=[CH:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Oc1cccc2cc(C3CCOC3)oc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2cc(C3CCOC3)oc12
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
Sodium hydride (80 mg, 60% dispersion in mineral oil) was added to a stirred solution of 2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (0.37 g) in dry tetrahydrofuran (10 ml) at room temperature under a dry nitrogen atmosphere. After stirring for 10 minutes tert-butyldimethylsilyl chloride (0.27 g) was added and the reaction stirred for 90 minutes. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (2×25 ml). The combined aqueous washings were extracted with ethyl acetate (30 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (0.58 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
(7-Fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (0.50 g, 2.41 mmol) (for a preparation see Example 88(a)) was combined with 1,1-dimethylethyl 4-piperidinylcarbamate (0.48 g, 2.41 mmol) in 1:1 MeOH/DCM (20 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (1.53 g, 7.23 mmol) was added and the reaction was stirred an additional 2 h. The solution was concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as a yellow solid (0.678 g, 72%).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]1=[O:30])C1C=CC=CC=1>C1COCC1.[Pd]>[CH:27]1([CH2:26][N:11]2[C:12]3[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:13]=3)[C:18](=[O:19])[N:9]([OH:8])[C:10]2=[O:30])[CH2:29][CH2:28]1
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(CC2CC2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CC2CC2)c(=O)n1O
Yield: 48.2 %

Procedure:
Using the method of Example 56, 20% Pd/C (25 mg), 3-benzyloxy-1-cyclopropylmethyl-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example V-4, 0.16 g, 0.39 mmol) were combined in 25 mL of THF, to give 0.06 g of the title compound as a solid, mp 211-213° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N+:13]([C:16]1[C:21]([O:22][CH3:23])=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=[C:18]([C:27]([F:30])([F:29])[F:28])[C:17]=1Cl)([O-:15])=[O:14]>>[Cl:8][C:7]1[C:2]([NH:1][C:17]2[C:18]([C:27]([F:30])([F:29])[F:28])=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21]([O:22][CH3:23])[C:16]=2[N+:13]([O-:15])=[O:14])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[CH:6]=1
Reactant: COc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Product: COc1c([N+](=O)[O-])cc(C(F)(F)F)c(Nc2ncc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]

Procedure:
In accordance with the process of Preparation 8 except using 1.9 g. of 2-amino-3-chloro-5-trifluoromethylpyridine and 2.8 g. of 2,4-dinitro-3-methoxy-6-trifluoromethylchlorobenzene, the reaction was carried out for 3 hours. The reaction mixture was treated as the process of Preparation 6 to obtain 1.4 g. of the object oily compound.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]/[C:19]/3=[N:32]/[C:33]#[N:34])[CH:13]=[CH:14][CH:15]=1)#[N:9]>CO>[NH2:34][C:33]1[N:3]([CH3:2])[O:4][C:19]2([C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:12]4[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=4)[C:8]#[N:9])[CH:17]=3)[O:22][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:20]2)[N:32]=1
Reactant: N#C/N=C1/CC(c2ccccn2)Oc2ccc(-c3cccc(C#N)c3)cc21
Reactant: CNO
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CN1OC2(CC(c3ccccn3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 7.7 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (14 mg, 0.14 mmol) in MeOH (4 mL) was added MeONa (0.03 mL, 25% (Wt.) in MeOH), followed (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (50 mg, crude). After stirring for 10 minutes, the solvent was removed in vacuo to give a residue. The residue was purified by preparative TLC to give 3-(3′-amino-2′-methyl-2-(pyridin-2-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (4.3 mg, 8%). 1H-NMR (MeOD): 2.11 (m, 1H), 2.51 (m, 1H), 3.02 (s, 2H), 3.28 (s, 1H), 4.12 (m, 1H), 5.32 (m, 1H), 6.97 (m, 1H), 7.32 (m, 1H), 7.55 (m, 5H), 7.82 (m, 3H), 8.46 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=5)=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: COc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: COc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
2-Chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 8.1 mg of 335. MS (Q1) 444.2 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester 1 (5 g, 21.5 mmol) and triethylamine (4.56 g, 45.0 mmol) in dichloromethane (100 ml) was added 2,4-dichlorobenzoyl chloride (3.90 g, 19.4 mmol). The reaction mixture was stirred for 30 min a 0° C. and 16 h at room temperature. Then, the reaction mixture was partitioned between 25 ml of H2O, 50 ml sat. NaHCO3 and 50 ml of CH2Cl2. The organic layer was separated and the aqueous phase was washed twice with CH2Cl2 (2×50 mL). The combined dichloromethane layer was dried (MgSO4), concentrated and the residue was purified by recrystallization in CH2Cl2 to obtain 5.832 g (74%) as a white solid of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 8.30 ppm (s, 1H, Haro); 7.74-7.66 ppm (m, 3H, Haro); 7.51 ppm (d, 1H, Haro); 7.46-7.34 ppm (m, 4H, Haro); 3.91 ppm (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2.C(=O)(O)[O-:10].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][C@@H:2]1[O:10][C:7](=[O:8])[CH2:6][C@@H:5]2[C@H:3]1[O:4]2
Reactant: C[C@@H]1C(=O)C[C@H]2O[C@@H]12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1OC(=O)C[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5.6 g (50 mmol) of (1S,2S,5R)-2-methyl-6-oxabicyclo[3.1.0]hexan-3-one (4) in 400 ml of anhydrous methylene chloride was added 15 g of sodium bicarbonate and 12.9 g (64 mmol) of 85% m-chloroperbenzoic acid. The suspension was stirred at room temperature for 72 hr and filtered through Celite Filter-Aid. The filtrate was evaporated to dryness under reduced pressure, the residue was triturated with 40 ml of methylene chloride and insolubles were removed by filtration. The filtrate was washed twice with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness under educed pressure. Heating at 70° (0.1 mm) removed 0.95 g of volatile material. The oily residue slowly crystallized on standing to give (1S,2S,6R)-2-methyl-3,7-dioxabicyclo[4.1.0]heptan-4-one: mp 51°-52°. Recrystallization from 12 ml of ether yielded end product: mp 51° -52°. Several recrystallizations from ether gave analytically pure (1S,2S,6R)-2-methyl-3,7-dioxabicyclo-[4.1.0]heptan-4-one: mp 52.5°-53.5°; [α]25D +147.26 (c 0.995, MeOH).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[CH3:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=3)[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)c(C)c3)CC2)n(C(C)(C)C)n1

Procedure:
135 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(3,4-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].[OH-:26].[Na+].[BH4-].[Na+]>O.O1CCCC1>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:26])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-acetyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution is 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.4 g. of ethyl 8-acetyl-12-hydroxy-12-methylheptadecanoate as a yellowish oil used in the next step without further purification; pmr (CDCl3) δ 0.88 (3H,t), 1.13 (3H,s, CH3COH), 1.25 (3H,t, CH3CH2OCO--), 2.12 (3H,s, CH3CO), 4.12 (2H,q).
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:27]([SH:30])[CH2:28][SH:29].B(F)(F)F.CCOCC>C(Cl)Cl>[S:29]1[CH2:28][CH2:27][S:30][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: SCCS
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1SCCS1
Yield: 74.4 %

Procedure:
In 20 ml of anhydrous methylene chloride was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 300 mg of 1,2-ethanedithiol and 0.8 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 900 mg of the titled compound as a colorless crystal.