Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH2:30][C:31]#[N:32])[CH:3]=1.Br[CH:34](C)C#N.C1(O)C=CC=CC=1>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH:30]([C:31]#[N:32])[CH3:34])[CH:3]=1
Reactant: N#CCOc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: CC(Br)C#N
Solvent: Oc1ccccc1
Product: CC(C#N)Oc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 14 %

Procedure:
This compound was made in an analogous fashion to 1-(4-bromo-2-(cyanomethoxy)-5-fluorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide via Method 166 except employing 2-bromopropanenitrile in the first step to alkylate the phenol. The yield of the desired product after HPLC purification was 5.3 mgs (14% yield). 1H NMR (500 MHz, DMSO-d6) □=ppm 1.36 (d, J=6.62 Hz, 2 H) 3.02-3.11 (m, 1 H) 3.17 (s, 1 H) 5.43-5.51 (m, 1 H) 6.16-6.22 (m, 1 H) 6.72 (d, J=9.73 Hz, 2 H) 7.67-7.78 (m, 2 H) 7.84-7.94 (m, 1 H) 8.15-8.24 (m, 2 H) 8.35 (br. s., 1 H). m/z (ESI) 530.9 (M−H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]=[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH:30]=3)[C:25](=[O:37])[NH:24][C:23]2=[O:38])=[CH:16][CH:15]=1)=O)(C)(C)C.OP(O)(O)=O.CC#N.[OH-].[Na+]>C(Cl)Cl.O>[NH:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([NH:20][CH:21]=[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH:30]=3)[C:25](=[O:37])[NH:24][C:23]2=[O:38])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1c1ccc(NC=C2C(=O)NC(=O)c3ccc(-c4ccsc4)cc32)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccc(-c3ccsc3)cc2C1=CNc1ccc(C2CC=CCN2)cc1
Yield: 78 %

Procedure:
2-{4-[(1,3-Dioxo-6-thiophen-3-yl-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (230 mg, ˜60-70% pure, ˜0.26-0.31 mmol) is mixed with H3PO4 (1 mL) in CH2Cl2 (1 mL) at room temperature. The resulting mixture is stirred until no starting material is detected by TLC. CH3CN and H2O and ice were then added to dilute the sample. The mixture is neutralized by NaOH and extracted with EtOAc. The EtOAc layer is washed with brine and dried. After removal of EtOAc, the residue is purified by flash chromatography to provide the title compound (80 mg, 78% for two steps). 1H NMR (400 MHz, DMSO) δ 12.53 (1H, d, J=12.8 Hz), 11.30 (1H, s), 9.02 (1H, d, J=12.4 Hz), 8.34 (1H, s), 8.21 (1H, s), 8.05 (1H, d, J=7.6 Hz), 7.44-7.85 (7H, m), 5.76-5.84 (2H, m), 3.77-3.81 (1H, m), 3.31-3.50 (2H, m), 2.09-2.21 (2H, m). MS (ESI): 428.1 (M+1)−1.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (150 mg, 0.78 mmol) was coupled to aniline (60) (150 mg, 0.78 mmol) using Method C to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH:12](Br)[CH3:13])[N:3]=1.[OH:15][CH2:16][C:17]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>>[Br:1][C:2]1[N:3]=[C:4]([CH:12]([O:15][CH2:16][C:17]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(Br)n1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(Br)n1

Procedure:
This compound was prepared according to the experimental condition of Intermediate 2 from 2-bromo-6-(1-bromoethyl)-4-(trifluoromethyl)pyridine and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate to afford the titled compound. 1HNMR (CDCl3 400 MHz) δ7.41 (m, 3H), 7.36 (m, 4H), 5.07 (q, 1H), 4.34 (m, 2H), 3.80 (m, 2H), 3.05 (m, 2H), 2.25 (m, 2H), 1.96 (m, 2H), 1.55 (s, 9H), 1.43 (d, 3H). Mass Spec.: 544.44 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
To a solution of 1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-one (4.96 g, 0.020 mol) in dichloroethane (50 ml) is added N-methylpiperazine (2.7 ml, 0.024 mol) at 0° C. and the mixture is stirred at room temperature. After 4 h, sodium triacetoxy-borohydride (5.04 g, 0.024 mol) is added and the mixture is further stirred at room temperature for 24 h. After addition of 1N sodium hydroxide at 0° C., the mixture is poured into water and extracted three times with dichloromethane. The organic layer is combined and extracted three times with 1N hydrochloride. The water layer is basified with 2N sodium hydroxide and extracted three times with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound as yellow solids (6.04 g) in 91% yield.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[C:13]([C:14]#[N:15])=[C:12]([NH2:16])[N:11]([CH3:17])[N:10]=1.Cl>N1C=CC=CC=1>[NH2:16][C:12]1[N:11]([CH3:17])[N:10]=[C:9]([NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:13]=1[C:14]#[N:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1nc(N)c(C#N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)C(C)(C)C)c(C#N)c1N
Temperature: 0 °C
Yield: 59 %

Procedure:
Pivaloyl chloride (2,2-dimethylpropionyl chloride) (3.6 g) was added cautiously to a suspension of 3,5-diamino-4-cyano-1-methylpyrazole (4.1 g) in pyridine (25 ml). The temperature of the mixture rose to about 60°. The mixture was left to cool overnight and was then poured into a mixture of ice (60 g) and concentrated HCl (40 ml). The precipitate was filtered off, washed and dried, to give 3.9 g of crude 5-amino-4-cyano-3-(2,2-dimethylpropanoylamino)-1-methylpyrazole. Recrystallisation from a 70:30 ethanol/water mixture gave 3.1 g of pure product, mp 245°-247° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH2:16][CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=1[O:24]COC.COC1C=C(OCOC)C(OC)=C(CCCCCCCCCC#C)C=1OCOC>>[CH3:14][O:13][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:24])[C:5]=1[CH2:15][CH2:16][CH2:17][C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC#CCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Agent: C#CCCCCCCCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Product: CCCCC#CCCCC1=C(OC)C(=O)C=C(OC)C1=O

Procedure:
1.0 Gram of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(4-nonynyl)benzene prepared in the abovementioned process (1) was treated for the removal of methoxymethyl group and was oxidized by employed procedures similar to those described in Example 30 (4), there was obtained 530 mg of 2,5-dimethoxy-3-(4-nonynyl)1,4 -benzoquinone. Yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][NH:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][NH:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CNCc2cc(Br)ccc2OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a mixture of ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)-aminomethyl]benzoate (1.4 g) in methanol (25 ml) was added 2N sodium hydroxide solution (7.7 ml). The mixture was heated at reflux for 30 minutes, left to stand for 2 hours at ambient temperature, the solvent evaporated and the residue mixed with water (20 ml). The mixture was acidified with acetic acid, the precipitate filtered off and crystallised form ethyl acetate to give the title compound (800 mg) mpt 209° C. The starting material was prepared as follows:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1.C(O)C.O.[Fe]>[NH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[C:5]1[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(F)cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc(CN(Cc2cccc(N)c2)c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a slurry of the product from Example 143A (0.450 g, 1.180 mmol) in THF (4 mL), ethanol (1.00 mL) and water (4.00 mL) at rt was added ammonium chloride (0.189 g, 3.54 mmol) followed by iron (0.329 g, 5.90 mmol) and the mixture heated to 80° C. After 3 h, the mixture was filtered through Celite, concentrated and the residue partitioned between water and 25% isopropyl alcohol-CHCl3. The organic phase was dried (Na2SO4) and concentrated. The solid was dried in a vacuum oven to provide 321 mg (85%) of the title compound. MS (ESI; M+H) m/z=322.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:31])([CH3:30])[CH2:22][NH:23][S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:29][N:27]([CH3:28])[S:24]([NH:23][CH2:22][C:21]([F:31])([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:10]=2)=[CH:20][CH:19]=1)[CH3:30])(=[O:25])=[O:26]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)N(C)C)cc2)c1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 356 mg of 2-propanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:29](OC(N1CC(=C)CC1C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:29])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1

Procedure:
This compound was prepared using the procedure used to prepare (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8]CC1C=CC=CC=1.C(O)C>[Pd].OCC(CO)O>[CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[OH:8]
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: OCC(O)CO
Product: Cc1[nH]ccc(=O)c1O
Reaction time: 24 h
Yield: 71 %

Procedure:
4.2 g (14.5 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of glycerol is put into the mixture of 54 mL ethanol—6 mL H2O, and 0.11 g of Pd/C at 10% is added. The reaction medium is subjected to catalytic hydrogenolysis under agitation at room temperature for 24 hours. At the end of this hydrogenolysis, the reaction medium is filtered. The filtered Pd/C is washed with EtOH; then the filtrate is evaporated under reduced pressure. The solid residue is re-crystallized in a MeOH-ethyl acetate mixture to obtain 2.05 g (10.3 mmol) of 2-methyl-3-hydroxypyridine-4(1H)-one of glycerol, which is pure at chromatographic and NMR analyses. Yield: 71%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)([N:31]1C=CN=C1)=O.CN>O1CCCC1>[CH3:29][NH:31][C:26]([C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][N:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[CH:21][CH:22]=1)=[O:28]
Reactant: O=C(O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
2.00 g of 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.03 g of 1,1′-carbonylbis-1H-imidazole was then added thereto. The obtained mixture was stirred at room temperature for 1.5 hours, and 4.11 ml of a 40% methylamine aqueous solution was added thereto. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, a saturated ammonium chloride aqueous solution, and a saturated sodium chloride solution. Thereafter, the organic layer was dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, and the residue was then purified by NH silica gel column chromatography (ethyl acetate) and silica gel column chromatography (hexane/ethyl acetate), so as to obtain 1.77 g of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[C:14]([CH:15]([CH2:38][CH2:37][CH3:41])[C:16]([O:18][CH3:19])=[O:17])=[C:13]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:12]2[C:11]3[CH2:10][CH2:9][O:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Yield: 29.8 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate (0.270 g; 0.73 mmol), LHMDS 1N in THF (0.8 mL; 0.8 mmol), 1-iodopropane (0.122 mL; 1.09 mmol) in DMF (3 mL) for 19 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.089 g (30%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]12([CH2:32][CH2:33]O)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][CH2:33][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]3[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][N:15]=3)[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCC12CC3CC(CC(C3)C1)C2
Yield: 75 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 1-adamantaneethanol (27 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 58 mg (75%) of the titled compound. ESI-MS m/z 454 (MH+), 452 (M−H−).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][S:7]([C:10]1[N:14]=[CH:13][NH:12][N:11]=1)(=[O:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:32])[S:28](Cl)(=[O:30])=[O:29].O>C(#N)C>[CH3:26][N:27]([CH3:32])[S:28]([N:12]1[CH:13]=[N:14][C:10]([S:7]([O:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=2)(=[O:8])=[O:9])=[N:11]1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Oc1cccc(C(F)(F)F)c1)c1nc[nH]n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1cnc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)n1
Yield: 97.4 %

Procedure:
1.0 g of 3-(3-trifluoromethylphenoxysulfonyl)-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 1 was dissolved in 10 ml of acetonitrile. Then, 0.57 g of potassium carbonate was added, and 0.59 g of dimethylsulfamoylchloride was gradually added at room temperature while stirring them. Then, they were refluxed for one hour, and the reactant solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvent was removed by distillation and the residue was purified by silica gel chromatography. As a result, 1.33 g of the titled compound was obtained.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=O>COCCO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: Cc1ccc(C(=O)/C=C/N(C)C)cc1
Agent: Cl
Solvent: COCCO
Product: Cc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (124 mg, 0.6 mmol, PREPARATION 3) and (2E)-3-(dimethylamino)-1-(4-methylphenyl)prop-2-en-1-one (95 mg, 0.5 mmol) in 2-methoxyethanol (3 mL) was stirred at 100° C. for 2 h. The reaction mixture was cooled, concentrated, and dissolved in EtOAc and then washed with water and brine. The organic phase was dried, concentrated, triturated with EA/PE (1:10, 5 mL), filtered, and dried to give the title compound (120 mg, 92%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 6.49 (1H, d, J=1.6 Hz), 7.16 (4H, s), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.76 (1H, d, J=1.2 Hz), 7.90 (1H, s,), 8.44(1H, d, J=5.2 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:20][CH:19]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2([S:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:23]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2(Sc3ccc(C(=O)CCC(=O)OC)cc3)CCCCC2O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCC2(Sc3ccc(C(=O)CCC(=O)O)cc3)CCCCC2O)ccc(C(C)=O)c1O

Procedure:
The isomer of the title compound of Step A of Example 2 was treated with sodium hydroxide as described in Step E of Example 1 to afford the title compound, m.p. 65°-67°, remelts at 125°-127° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[NH:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=O)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[NH:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]#[N:27])[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(-c2n[nH]c([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cccc(-c2n[nH]c([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1

Procedure:
1.3 mmol (R)-3-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-1H-[1,2,4]triazol-3-yl}-benzamide were treated with neat trifluoroacetic anhydride at room temperature overnight. The reaction was quenched with aqueous NaHCO3 and product extracted with ethylacetate twice. The organic layers were washed with water/NaCl, combined, dried over Na2SO4 and the solvent evaporated. The product was purified via preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:20][CH2:17][CH2:18][CH3:19])[C:2]([NH2:1])=[N:3][C:4]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CSc1nc(N)c(C=O)nc1Cl
Reactant: CCCN
Product: CCCN=Cc1nc(Cl)c(SCC(=O)OC)nc1N

Procedure:
Following the procedures described above in Example 6, Step B, but employing instead 2-amino-5-chloro-3-formyl-6-(methoxycarbonylmethylthio)pyrazine (100 mg; 0.382 mMol) prepared in Step A, and n-propylamine (27 mg; 0.382 mMol and 20% excess), the title compound was prepared (80 mg). Elemental Analysis for C11H15N4O2ClS:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:20][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(-c3ccncc3)cc2)nc1CCN1CCCC1
Yield: 82.6 %

Procedure:
2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) (7.23 g, 21.57 mmol), 4-pyridylboronic acid (3.98 g, 32.35 mmol), [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.616 g, 0.755 mmol), and aqueous sodium carbonate (2M, 40 mL) are dissolved in 200 mL of dioxane and heated to reflux for 1.5 hours. The mixture is concentrated to a dark residue and purified by flash silica gel chromatography (gradient: 3-6% 2M NH3 in MeOH/dichloromethane) to provide the titled compound (5.94 g, 82.5% yield). MS (m/e): 334.2 (M+1)