Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li+].CC([N-][CH:23]([CH3:25])[CH3:24])C.Cl>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[C:15](=[O:17])[CH:14]([CH2:24][CH2:23][CH2:25][CH2:25][CH2:23][CH2:24][CH:14]1[CH2:13][C:5]3[C:4](=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[C:15]1=[O:17])[CH2:13]2
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OC)C(=O)C(CCCCCCC1Cc3cc(OC)c(OC)c(OC)c3C1=O)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3,4,5-trimethoxyphenyl)propionic acid (12 g) in THF (200 ml) was dropwise added LDA (1.9 M/THF solution; 60 ml) while temperature of the reaction mixture was kept under −10° C. After being stirred at 0° C. for 3 hr, the reaction mixture was acidified to pH3 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated in vacuo. Polyphosphoric acid (100 ml) was added to the residue and the reaction mixture was stirred at 60° C. for 4 hr. After being cooled, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then water, dried and concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with crystallization from ethyl acetate-hexane to yield the entitled compound (4.5 g). The compound recrystallized from ethanol gave following melting point.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC(C)C)s1
Yield: 51 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (42 mg, 51%) which was obtained as a white solid. MS: m/e=375.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>O1CCOCC1>[S:17]1[CH2:18][CH2:19][N:14]([C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([Cl:13])[N:3]=2)[CH2:15][CH2:16]1
Reactant: C1CSCCN1
Reactant: Cc1cccc2c(Cl)nc(Cl)cc12
Solvent: C1COCCO1
Product: Cc1cccc2c(N3CCSCC3)nc(Cl)cc12

Procedure:
A mixture of 23.3 gm (0.11 mol) of 1,3-dichloro-5-methyl-isoquinoline [prepared according to G. Simchen et al, Chem. Ber. 102, 3666 (1969); m.p. 120°C], 28.3 gm (0.275 mol) of thiomorpholine and 110 ml of dry dioxane was refluxed for 4 hours. The mixture was then evaporated, the residue was taken up with a mixture of tolune and water, and the toluene phase was isolated, dried and evaporated. The residue was recrystallized from 100 ml of ethyl acetate, yielding 22.7 gm (72% of theory) of the desired compound, m.p. 134°-136°C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:2]2([CH3:1])[CH2:7][CH2:6][C:5]3[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=3[O:3]2)[CH2:18][CH2:19]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCNCC1)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCN(C(=O)c3ccccc3)CC1)O2
Reaction time: 1 h

Procedure:
To stirred solution of 3,4-dihydro-2,5,7,8-tetramethyl-2-(1-piperazinylmethyl)-2H-1-benzopyran-6-ol (EXAMPLE 126, 0.3 g, 1.0 mmol), triethylamine (0.11 g, 1.1 mmol) and methylene chloride (3 ml) is added dropwise over 1-2 min a solution of benzoyl chloride (0.16 g, 1.1 mmol) in methylene chloride (2 ml). The mixture is stirred at 20°-25° for 1 hr and diluted with methylene chloride (20 ml), washed with water (20 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue. The residue is flashed chromatographed on silica gel (25 g) eluting with ethyl acetate/hexane (1/1) to give the product as an oil that is crystallized from ether to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH:23]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NC1Cc2ccccc2C1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNC1Cc2ccccc2C1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-aminoindan in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=419.
Reaction SMILES: Cl.CN.N1C=CC=C[CH:5]=1.Cl[NH:11][C:12](=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH3:5][NH:11][C:12](=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(NCl)Oc1ccccc1
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Oc1ccccc1
Temperature: 5 °C
Yield: 65.4 %

Procedure:
A mixture of commercially available methylamine hydrochloride (50 g, 0.74 mol), pyridine (124 mL, 1.53 mol), and N,N-dimethylformamide (500 mL) was stirred at 5° C., and commercially available phenyl chlorocarbamate (94 mL, 0.75 mol) was added dropwise over 2 hours. After the dripping was complete, the mixture was stirred under nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was added to ice water (2 L) and extracted with ethyl acetate (1.5 L) twice. The organic layer was washed with water (1 L) and a saturated saline solution (300 mL). The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated. n-Heptane and ethyl acetate were added to the concentrated residue and the precipitate was collected by filteration and washed with n-heptane and tert-butyl methyl ether to obtain the title compound (74.2 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>COCCOC>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 120 °C
Yield: 81.2 %

Procedure:
A mixture of ethyl 6-chloronicotinate (2.67 g, 14.4 mmol), tert-butyl piperazine-1-carboxylate (2.5 g, 13.4 mmol) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) in DME (15 mL) was heated at 120° C. for 12 hours. The mixture was then cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The organic layer was washed twice with 10% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using 3:1 hexanes:ethyl acetate to 100% ethyl acetate afforded tert-butyl 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (3.65 g). 1H NMR (400 MHz, CDCl3): 8.81 (s, 1H), 8.04 (d, 1H), 6.58 (d, 1H), 4.33 (q, 2H), 3.70-3.67 (m, 4H), 3.56-3.53 (m, 4H), 1.49 (s, 9H), 1.37 (tr, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([OH:28])=O)=[O:22])=[N:15]1.[NH3:36]>C(Cl)Cl.CN(C=O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([NH:23][C@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][C:26]([NH2:36])=[O:28])=[O:22])=[N:15]1
Reactant: COc1cc(C(=O)N[C@@H](CC(=O)O)c2ccccc2C)nn1-c1ccccc1F
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H](CC(N)=O)c2ccccc2C)nn1-c1ccccc1F
Reaction time: 16 h
Yield: 34 %

Procedure:
DMF (1.8 mg, 25 μmol) and oxalyl chloride (160 mg, 1.26 mmol) were added to a solution of (S)-3-{[1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl]-amino}-3-(2-methyl-phenyl)-propionic acid (500 mg, 1.26 mmol) in DCM (5 ml) at room temperature. After 16 h at room temperature a 33% aqueous solution of ammonia (649 mg, 12.6 mmol) was added and the mixture was stirred for further 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 170 mg (34%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCN(CC)CCSc1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a solution of 7.4 g (29 mmol) of N,N-diethyl-2-[(4-nitrophenyl)thio]ethanamine in 150 mL of ethanol add 32.8 g (140 mmol) of tin(II) chloride dihydrate. Reflux the reaction mixture for about 5 h. After this time, cool the reaction mixture to room temperature and carefully add the mixture to a solution of 75 g (0.54 mol) of potassium carbonate in 500 mL of water. Extract the mixture with 3×500 mL of ethyl acetate. Combine the organic extracts and wash with 2×350 mL of saturated aqueous sodium chloride solution. Dry the organic extracts over anhydrous sodium sulfate. Remov the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:21])[CH3:20])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:20])[CH3:21])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:14][CH:13]=2)=[N:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
To a mixture of methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.50 g, 4.99 mmol) in pyridine (1.21 mL) and dichloromethane (20 mL) was added benzyl chloroformate (1.07 mL, 7.49 mmol). After stirring for 14 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The remaining residue was chromatographed on silica gel (NH silica gel, hexane/ethyl acetate 2:1) to give methyl[2-(4-{[(benzyloxy)carbonyl]amino}-benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.99 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[N:23]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:23][C:11](=[O:25])[C:12]3[S:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[CH:14][C:13]2=3)=[CH:6][CH:7]=1
Reactant: ON=C1CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Reactant: [OH-]
Agent: [Na+]
Product: O=C1NCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 130 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
In a 100 mL round bottomed flask was placed stereo isomeric mixture of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6-dihydro-1-benzothiophen-7(4H)-one oxime prepared above and then was added polyphosphoric acid (11 g, 46 mmol) and the mixture was stirred for 6 h at 130° C. During this period, the mixture was occasionally mixed by hand. The mixture was allowed to cool to ambient temperature and then was added crushed ice (ca 20 ml) while the reaction mixture is hot. The mixture was stirred for 30 min at rt. A dark brown suspension was obtained, which was basicified by the addition of 5N NaOH (30 mL, pH ca 12). The mixture was extracted with a 1:1 mixture of CH2Cl2 and THF (30 mL×3). The combined organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain title compound (230 mg; 68%) as a yellowish off-white powder, which was only one isomer.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CCCCC2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 1) was reacted with aminomethylcyclohexane according to the procedure described in EXAMPLE 11, Step C to afford the title compound. Mass Spectrum (ESI): 308.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H); 8.39 (br s, 1H); 8.23 (br s, 1H); 7.87 (m, 1H); 7.41 (m, 2H); 6.78 (d, J=5.5 Hz, 1H); 5.50 (br s, 1H); 3.39 (t, J=6.3 Hz, 2H) 1.70-1.93 (m, 6H); 1.18-1.38 (m, 3H); 1.02-1.12 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:18][NH2:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[N:19][NH:18][C:16]([C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])=[CH:22][CH:23]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Solvent: CCO
Product: COc1ccc(C=NNC(=O)c2[nH]c3ccccc3c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 1C (1.76 g, 7.0 mmol) and p-anisaldehyde (894 mL, 7.35 mmol) in ethanol (120 mL) was refluxed for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:9].C(O)(=O)C>C(O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:9]=1)[CH3:7]
Reactant: CCC(=O)CC#N
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
To an ice-cold solution of 3-oxopentanenitrile (14.6 g, 150 mmol) and 2-hydrazinopyridine (13.6 g, 125 mmol) in ethanol (150 mL), acetic acid (14.3 mL, 250 mmol) was added and the resulting mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature, and concentrated under reduced pressure, and water was added to the residue. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (21.1 g, 90% yield). NMR (CDCl3) δ: 1.25 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 5.38 (1H, s), 5.90 (2H, br s), 7.04 (1H, ddd, J=1.2 Hz, 5.0 Hz, 7.4 Hz), 7.75 (1H, ddd, J=2.0 Hz, 7.4 Hz, 8.4 Hz), 7.94 (1H, ddd, J=0.8 Hz, 1.2 Hz, 8.4 Hz), 8.29 (1H, ddd, J=0.8 Hz, 2.0 Hz, 5.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].N>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:11]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:10]=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Br)c3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(-c4ccc(F)cc4)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 4, starting with 2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 166) in place of 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting cesium fluoride for sodium carbonate (yield: 0.62 g, 62%). mp 222-225° C. 1H NMR (300 MHz, DMSO d6) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.36 (m, 3H), 7.53 (m, 2H), 7.64 (m, 2H), 7.73-7.81 (m, 3H), 7.93 (m, 3H), 8.27 (s, 1H). MS (DCI/NH3) m/z 515 (M+H)+, 532 (M+NH4)+. Anal. calc. for C29H20F2N2O3S.0.25H2O: C, 67.10; H, 3.98; N, 5.35. Found: C, 66.93; H, 3.99; N, 5.17.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[NH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(Cl)Cl>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: NC1CCOCC1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(NC1CCOCC1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (prepared according to method B, step 1, 2.0 g, 6.92 mmol) in anhydrous THF (40 mL) are added 4-aminotetrahydropyran (0.70 g, 6.92 mmol) and Cs2CO3. The reaction is heated to 60° C. for 48 h. After cooling the reaction mixture is partitioned between DCM (100 mL) and water (100 mL). The organic layer is separated and dried over Na2SO4. Filtration and concentration of the filtrate gives a yellow oil. The oil is dissolved in DCM and extracted with 1M aqueous HCl solution. The acidic aqueous extract is basified with 5M aqueous NaOH solution and extracted with DCM (3×100 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to give N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-2-(tetrahydro-pyran-4-ylamino)-propionamide (0.89 g, 42%). m/z 310 [M+H+]. Conversion into its hydrochloride salt is achieved upon treatment with 1M HCl solution in diethyl ether (2.89 mL).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 90.3 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 4-aminobutyric acid (97 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 109 mg (0.28 mmol) in 89% yield. LC-MS ESI−: 390.04 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([O:7][C:6]4[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-methoxy-phenoxy)-1H-indazole (0.25 grams, 1.0 mmol), 4-fluorobromobenzene (0.23 mL, 0.36 grams, 2.08 mmol), cuprous oxide (0.15 grams, 1.0 mmol), potassium carbonate (0.29 grams, 2.08 mmol) and N,N-dimethylacetamide (0.25 mL) was stirred at 160° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (0-100%), affording 1-(4-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-1H-indazole as a colorless solid. MS: 335.3 [M+H]+