Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(4-nitrophenoxy)isobutyrate was dissolved in methanol (50 mL) and water (50 mL). Sodium hydroxide (5 g) was added. The solution was stirred at rt for 30 min, then acidified with 1N HCl aq. to pH ˜3. The aq. Solution was extracted with ethyl acetate (2×100 mL). The organic layers were evaporated to give 2-(4-nitrophenoxy)isobutyric acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:10]([C:31]#[N:32])[N:9]=1>CCCCO.C(Cl)(Cl)Cl>[F:30][C:26]1[CH:25]=[C:24]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:13]=3)[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:9][C:10]=2[C:31]#[N:32])[CH:29]=[CH:28][CH:27]=1
Reactant: C1COCCN1
Reactant: N#Cc1nc(Cl)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: N#Cc1nc(N2CCOCC2)c2ccc(-c3ccccn3)cc2c1-c1cccc(F)c1
Temperature: 220 °C

Procedure:
Morpholine (36 mg, 0.42 mmol) was added to a solution of 1-chloro-4-(3-fluorophenyl)-6-pyridin-2-ylisoquinoline-3-carbonitrile (15 mg, 0.04 mmol) in n-BuOH (1.0 mL) in a microwave tube. The tube was sealed and heated to 220° C. for 1 h in the microwave. The reaction was diluted with CHCl3 and washed with sat'd NaHCO3, brine, dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (1:3-1:1 EtOAc/hexanes) to yield the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:33][CH2:32][CH2:31][NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:20]([OH:22])=[O:21])=[CH:6][N:7]2[CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2C1CCOCC1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-3-quinolinecarboxylic acid (45.0 mg, 0.139 mmol), 2-(2-pyridylamino)ethylamine (29.0 mg, 0.211 mmol), and triethylamine (0.029 mL, 0.209 mmol) in DMSO (1.0 mL) was stirred at 120° C. for 3 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water, and the washing was extracted with 10% MeOH in CHCl3 two times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave 5-Amino-6-fluoro-1,4-dihydro-4-oxo-1-(tetrahydropyran-4-yl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic Acid (54.0 mg, 88%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[C:6](=[N:7][C:8](O)=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=3)[N:5]2[N:21]=1.CN(C=O)C.C(Cl)(Cl)[Cl:28]>>[Cl:28][C:8]1[N:7]=[C:6]2[C:11]([CH:12]=[N:13][C:4]3[N:5]2[N:21]=[C:2]([CH3:1])[CH:3]=3)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2ncc3nc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C

Procedure:
A 40 mL scintillation vial containing Compound [CCXXX] (220 mg, 0.8 mmol, 1 eq.), CHCl3 (12 mL), DMF (12 mg, 0.16 mmol, 2 eq.), and SOCK (0.56 g, 3.2 mmol, 4 eq.) was heated at 70° C. under nitrogen for 1.5 hours. Then the mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CHCl3 (20 mL) and washed with saturated NaHCO3 (5 mL). The water solution was extracted with CHCl3 (2×5 mL). The combined organic phases were dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography using EtOAc and heptanes as the mobile phases to furnish Compound [CCXXXI] as a yellowish solid: LCMS (m/e) 296 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 6.71 (s, 1H) 7.46-7.52 (m, 3H) 7.79 (dd, J=6.61, 3.00 Hz, 2H) 9.02 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:35])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)[CH:19]=2)=[CH:14][CH:13]=1.Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:7][O:8][C:9](=[O:35])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:20]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)[CH:19]=2)=[CH:16][CH:17]=1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(-c2ccc(OCCN3CCOCC3)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
K2CO3 (265 mg, 1.92 mmol) was added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (250 mg, 0.64 mmol) in DMF (2.5 ml) and the mixture was stirred at RT for 30 min. 4-(2-Chloroethyl)-morpholine hydrochloride (155 mg, 0.83 mmol) was added and the solution was heated to 60° C. for 14 h. The reaction was quenched by addition of water and was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, water and brine, dried over Na2SO4 and evaporated under reduced pressure to obtain (E)-3-[3′-adamantan-1-yl-4′-(2-morpholin-4-yl-ethoxy)biphenyl-4-yl]-acrylic acid methyl ester (193 mg, 60%) after purification on silica gel (EtOAc:hexane 50:50).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S([O-])(=O)=O.[N:25]1([S:30](N2C=C[N+](C)=C2)(=[O:32])=[O:31])[CH:29]=[CH:28][N:27]=[CH:26]1>CC#N>[F:2][C:3]1([F:7])[CH2:6][N:5]([S:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:32])=[O:31])[CH2:4]1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(N1CC(F)(F)C1)n1ccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A solution of 3,3-difluoroazetidine hydrochloride (1.00 g, 7.72 mmol) and DIEA (1.5 mL, 8.6 mmol) in MeCN (5 mL) was stirred for about 5 min and then was added to a solution of 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.20 g, 11.6 mmol) in MeCN (10 mL) at about 0° C. The reaction mixture was stirred at about 0° C. for about 1 h, and then warmed to ambient temperature and stirred for about 16 h. The reaction mixture was then concd under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 5-100% EtOAc in DCM to give 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.95 g, 55%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.16 min; MS m/z 224 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:14][CH2:15]1
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CCC(Nc3nc4ccccc4[nH]3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.223 ml) was added to a stirred suspension of the product from step (ii) (0.2 g) in dimethylformamide. After 5 min 3,4-dichlorobenzaldehyde (0.175 g) then sodium triacetoxyborohydride (0.212 g) was added and the mixture stirred at room temperature for 3 h. The mixture was partitioned between 2M hyrochloric acid and ether, the aqueous layer was basified with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/ether and the solid collected. Yield 0.045 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(C#N)c1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C#N)c1-n1cncn1
Temperature: 140 °C
Yield: 24.2 %

Procedure:
To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>>[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C:31]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:32]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc2ccccc2c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-naphthoyl chloride, there is obtained ethyl N-(2-naphthylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 420 (7), 391 (8), 194 (100), 155 (28), 127 (28);
Reaction SMILES: C([O:4][C:5]1[C:6]([C:12]#[N:13])=[N:7][C:8]([F:11])=[CH:9][N:10]=1)C=C.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[F:11][C:8]1[N:7]=[C:6]([C:12]#[N:13])[C:5](=[O:4])[NH:10][CH:9]=1
Reactant: C=CCOc1ncc(F)nc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
In 5 mL of toluene was dissolved 1.0 g of 3-(allyloxy)-6-fluoro-2-pyrazinecarbonitrile. After adding 0.82 g of aluminum chloride, the mixture was stirred at room temperature for 1.5 hours. Water (5 mL) was added to the reaction mixture, the aqueous layer was separated, and the organic layer was extracted first with 3 mL of water and then with 2 ml of water. The aqueous layers were united and washed with 5 mL of toluene, and extracted with 15 mL of ethyl acetate. The organic layer thus obtained was washed with 3 mL of water and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.45 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:16][C:17]([F:33])([F:32])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:9]1[CH2:14][CH2:13][CH:12]([NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:32])[F:33])=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of ethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A4) (25.6 g, 1.2 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (31.1 g, 1.0 equiv), DCE (400 ml) and acetic acid (6.3 ml, 1.1 equiv) was stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (33.5 g, 1.5 equiv) was added and stirring continued for 19 hours. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 1.5 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, filterered through a pad of silica gel, dried over sodium sulfate and evaporated in vacuo. The desired product was obtained as a white solid (44.2 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])c(Br)c2)C1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A solution of 2-bromo-4-fluoro-1-nitrobenzene (1.5 g, 6.8 mmol), (S)-tert-butyl pyrrolidin-3-ylcarbamate (1.9 g, 10 mmol), and sodium bicarbonate (1.7 g, 20 mmol) in DMSO (40 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature, poured into excess water and the resulting precipitate was filtered. The solids were washed with aqueous ammonium chloride, brine and water to afford the desired product (2.5 g, 96%) as a yellow solid: 387 [C15H20BrN3O4+H]+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]#[N:29])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:30].[K+]>CC(O)(C)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:29])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: [OH-]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4F)cc23)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4F)cc23)CC1
Yield: 25.1 %

Procedure:
The mixture of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluorophenyl)-1H-indazole-7-carbonitrile (Intermediate 12) (0.102 mmols) and potassium hydroxide (26 mg, 0.51 mmol) in 2-methyl-2-propanol (4 mL) was heated overnight. The reaction mixture was concentrated. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (11 mg, 25% for 2 steps)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[B-](F)(F)(F)F.[N:22]([OH:24])=[O:23]>C(#N)C>[N+:22]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[NH:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)[C:13]#[N:14])([O-:24])=[O:23]
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Reactant: O=NO
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(Nc2nccc(Cl)n2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.1 %

Procedure:
A mixture of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.005 mol) and nitryl tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) was stirred at room temperature for 4 h. The material was quenched with saturated bicarbonate (50 ml) on cracked ice. The mixture was allowed to reach room temperature, and the yellow solid was filtered off. The solid was adsorbed onto silica and purified by column chromatography (eluent: 30%, 50%, 60%, 70% CH2Cl2 in hexanes). The solvent of the desired fraction was evaporated and the residue was dried, yielding 0.89 g (64%) of 3-nitro-4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile.(interrn. 51)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[NH:9][C:8]=2[CH:7]=[N:6][C:5]=1[C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:39](=[N:43]O)([NH2:42])[CH2:40][CH3:41]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[NH:9][C:8]=2[CH:7]=[N:6][C:5]=1[C:24]1[O:25][N:43]=[C:39]([CH2:40][CH3:41])[N:42]=1
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(CN4CCOCC4)c3c12
Reactant: CCC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2ncc3[nH]c4cccc(CN5CCOCC5)c4c3c2COC)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
A solution of 0.36 g of 4-methoxymethyl-5-morpholinomethyl-beta-carboline-3-carboxylic acid (prepared according to example 4) in 10 ml of absolute dimethylformamide is mixed with 0.2 g of carbonyldiimidazole and stirred for 30 minutes at 60° C. Then 0.4 g of propioamidoxime in 2 ml of DMF is added and the reaction mixture heated to 100° C. for 3 hours. After distilling off of the solvent in a vacuum, the residue is mixed with 20 ml of xylene and refluxed for 3 hours on the water separator, the reaction mixture is filtered hot, the filtrate is concentrated and chromatographed on silica gel. 0.25 g (60%) of oxadiazole derivative is obtained. Melting point 161°-163° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][C:16]=1[CH3:27]
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Temperature: 85 °C
Yield: 24.4 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-chloro-2-thiophenecarboxylate (409 mg, 1.60 mmol) [prepared according to the procedure of Example 95], 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 1.75 mmol) [prepared according to the procedure of Preparation 17], K2CO3 (676 mg, 4.89 mmol) and Pd(PtBu3)2 (32 mg, 0.06 mmol) in 1,4-Dioxane (6 mL) and water (1.5 mL). The reaction was heated at 85° C. for 3 hours. The reaction was partitioned between CHCl3/H2O and the pH of the aqueous layer was adjusted to ˜3 with 6N HCl. The separated organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (10-65% EtOAc/Hexanes) affording the title compound (106 mg, 0.39 mmol, %); LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][O:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7]>CO.[Pd]>[NH2:1][C:2](=[O:25])[CH2:3][O:4][NH:5][C:6]([C@@H:8]1[CH2:14][CH2:13][C@@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7]
Reactant: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of (2S,5R)—N-(2-amino-2-oxoethoxy)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 54 (0.11 g, 0.40 mmol) and Pd/C (0.040 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 55 (0.10 g, 98%) as a white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].C1(O)C=CC=CC=1.[BrH:26]>C(O)(=O)C>[BrH:26].[CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2]
Reactant: CC[C@H]1COCCN1S(=O)(=O)c1ccc(C)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: CC[C@H]1COCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-ethyl-4-tosylmorpholine (220 mg, 0.82 mmol) and phenol (150 mg, 1.6 mmol) were dissolved in 4.1 M of hydrogen bromide in acetic acid (2.4 mL) and the solution was stirred at room temperature overnight. The reaction was poured on ether and the solid was collected by filtration and washed with ether to give (S)-3-ethylmorpholine hydrobromide (j-1) as a white solid: 1H NMR (400 MHz, CDCl3) δ 3.77-3.60 (m, 3H), 3.60-3.44 (m, 2H), 3.44-3.19 (m, 3H), 1.67 (dtd, J=28.6, 14.0, 7.4 Hz, 2H), 1.31-1.12 (m, 2H), 0.97-0.84 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][CH:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: CC(O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (bs, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (m 2H), 7.67 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H) 7.30 (m, 2H), 7.03 (d, J=9.1 Hz, 2H), 5.40 (s, 2H), 4.29 (m, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 1.83 (m, 1H), 1.28 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).