Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=[C:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][N:6]1[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C.[C:31](=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37]>C(OCC)(=O)C>[NH2:37][C:36]1[N:38]=[CH:31][C:8]2[CH2:7][N:6]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:5][CH2:10][C:9]=2[N:35]=1
Reactant: O=C(O)O
Reactant: N=C(N)N
Reactant: CN(C)C=C1CC(=O)CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: Nc1ncc2c(n1)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Yield: 80.8 %

Procedure:
2-[(Dimethylamino)methylene]-1-triphenylmethyl-4-piperidone (0.172 g, 0.434 mmol) was dissolved in ethyl acetate (4 ml) and treated with guanidine carbonate (47 mg, 0.260 mmol). The reaction mixture was heated to reflux for sixteen hours, and then concentrated in vacuo. Purification of the residue via flash column chromatography (eluant: 3.1 ethyl acetate: hexanes) yielded the title product as a yellow oil (83 mg, 0.21 mmol, 48% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:4]=[N:3]1.C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:4]=[N:3]1
Reactant: Cc1c(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cnn1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2cnn(C)c2C)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
tert-Butyl {[1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (290 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 178 mg, 71%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[O:29]=[C:7]([CH2:8][S:9][C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCNC(=O)Nc1ccccc1)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-amino-1-tritylsulfanyl-heptan-2-one (0.36 g, 0.86 mmol) in dichloromethane (10 mL) was added phenylisocyanate (0.10 ml, 0.92 mmol). The mixture was stirred at room temperature for 2 h. Solvent was then removed in vacuo and the crude product was purified by column chromatography (dichloromethane/MeOH=100/1 to 40/1) to provide 1-(6-Oxo-7-tritylsulfanyl-heptyl)-3-phenyl-urea (0.43 g, 93%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.Cl[CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH:14](O)[CH3:15].[OH-:17].[K+]>C(O)C>[OH:17][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1
Reactant: CC(O)OCCOCCCl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: OCCOCCOCCN1CCCC1
Yield: 76 %

Procedure:
A total of 295 g of pyrrolidone and 250 g of 2-chloroethoxyethoxyethanol in 750 ml of ethanol was refluxed for 5 hours. The reaction mixture was then treated with 106 g of KOH and refluxed for an additional hour. Filtration and distillation yielded 229 g of N-(hydroxyethoxyethoxyethyl)pyrrolidine (b.p.=145° C. at 3 mm).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[C:8]([CH2:13][C:14]([CH3:16])=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[CH:6]=[CH:5][N:4]3[CH3:3])[C:14](=[O:15])[CH3:16])=[CH:20][CH:19]=1
Reactant: CC(=O)Cc1cccc2c1ccn2C
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1cccc2c1ccn2C
Reaction time: 1.5 h

Procedure:
To a suspension of 135 mg (3.38 mmol) of sodium hydride in 8 mL dry THF, a solution of 605 mg (3.23 mmol) 1-(1-methyl-1H-indol-4-yl)acetone in 2 mL THF was added. The mixture was stirred for 45 min during which time the sodium hydride dissolved and a yellow orange solution resulted. The reaction was cooled in ice bath and 660 mg (3.24 mmol) 4-chlorobenzyl bromide in 1 mL THF was added. The cold bath was removed and the solution was stirred for 1.5 h. The reaction was quenched with 1.2 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc/hexane to isolate the desired product. 1H NMR: (500 MHz, CDCl3): δ 2.03 (s, 3H), 3.07 (m, 1H), 3.58 (m, 1H), 3.84 (s, 3H), 4.23 (t, 1H), 6.52 (d, 1H), 6.9-7.3 (m, 8H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]1[CH2:35][CH2:36][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][CH2:33]1
Reactant: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Temperature: 25 °C
Yield: 60.75 %

Procedure:
The compound 2 (0.31 g, 0.8 mmol), 4-phenylpiperidine (0.2 g, 1.2 mmol) and K2CO3 (0.166 g, 1.2 mmol) were added to 50 mL CH3CN, and the solution was refluxed under argon atmosphere for 16 h. After cooling to room temperature, the solvent was evaporated to dryness. Purification was carried out on a silica gel TLC plate that was developed in 4% methanolic NH3 (7 M NH3 in methanol)/96% CH2Cl2. The product was obtained as pale yellow oil (60.75%). 1H NMR (CDCl3) δ 8.489 (dd, 1H, Ar), 7.624 (ddd, 1H, Ar), 7.572 (d, 1H, Ar), 7.497 (dd, 1H, Ar), 7.290 (t, 2H, Ar), 7.203 (m, 4H, Ar), 7.106 (m, 1H, Ar), 6.936 (ddd, 1H, Ar), 6.836 (d, 1H, Ar), 3.792 (s, 3H, —OCH3), 3.763 (s, 2H, —CH2—), 3.667 (s, 2H, —CH2—), 3.063 (m, 2H, —CH2—), 2.486 (t, 3H, —CH—CH2—), 2.336 (s(br), 2H, —CH2—), 2.041 (s(br), 2H, —CH2—), 1.836 (s(br), 4H, —CH2—CH2—), 1.543 (m, 4H, —CH2—CH2—), 1.300 (m, 2H, —CH2—), 1.238 (m, 2H, —CH2—). Mass Spect.=471.68 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:10][C:4]1[C:5]([O:9][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1cc(Cl)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
A solution of 4-amino-2-chloro-5-fluorophenol (6.0 g, 37 mmol), 2,4-dichloro-pyridine (5.3 g, 37 mmol) and K2CO3 (5.2 g, 37 mmol) in DMSO (100 mL) was heated at 80° C. under nitrogen overnight. The mixture was cooled to RT, poured into water (300 mL), and extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3×100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to give 5-chloro-4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine as a white solid (3.0 g, 32% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.33 (d, J=5.7 Hz, 1 H), 7.34-7.31 (m, 1 H), 7.01-6.82 (m, 3 H), 5.63 (br s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:28]=[CH:29][C:20]=3[CH3:19])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1ccc2ccccc2c1B(O)O
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2ccccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 150 °C

Procedure:
In a 2-5 mL Smith Process Vial, 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg, 0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) and Cs2CO3 (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture was suspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N2. The mixture was heated at 150° C. for 75 min using microwave reactor (Biotage Optimizer). After an aqueous work up, the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 20:80) to give 6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]=1[N+:13]([O-])=O.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]=1[NH2:13]
Reactant: COCCOc1cccc(F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCOc1cccc(F)c1N
Yield: 99.8 %

Procedure:
A mixture of 1-fluoro-3-(2-methoxy-ethoxy)-2-nitro-benzene (675 mg) and Pd/C (10%, 30 mg) in ethanol was shaken under 50 psi of hydrogen for 4 hours. The reaction mixture was filtered through celite and concentrated to afford 580 mg of 2-fluoro-6-(2-methoxy-ethoxy)-phenylamine: 1H NMR (300 MHz, CDCl3) δ 6.8-6.7 (m 3H), 4.2 (t, 2H), 3.9 (bs, 2H), 3.8 (t, 2H), 3.5 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>[Cu]=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nc(Cl)cc(-c2ccccn2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 0.22 ml of 2-(tributylstannyl)pyridine, mg of copper oxide and 81 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed toluene, and the mixture was stirred at 110° C. for 4 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 63 mg of the objective compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH2:22])[CH2:19]2)=[N:14]1.[C:23]1([CH2:29][CH2:30][CH:31]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClC(Cl)C.C(O)(=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)=[N:14]1
Reactant: O=CCCc1ccccc1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NCCCc3ccccc3)C4)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a stirring solution of 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (50 mg, 0.17 mmol) and 3-phenylpropionaldehyde (20 mg, 0.2 mmol) in dichloroethane (2 mL) was added NaB(OAc)3H (37 mg, 0.17 mmol) and acetic acid (2 drops). The reaction mixture was stirred overnight at RT. Water (5 mL) was added, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude material was purified on SiO2 (0-5% CH3OH/CH2Cl2) to give 24 mg (36%) of the title compound as a clear oil. MS (ESI): exact mass calculated for C25H27N5O, 413.22; m/z found, 414.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.07 (s, 1H), 8.72-8.70 (m, 1H), 8.25-8.23 (m, 1H), 8.08-8.07 (m, 1H), 7.30-7.21 (m, 5 H), 7.18-7.16 (m, 1H), 4.09 (s, 3H), 3.06-2.90 (m, 3H), 2.80-2.68 (m, 5H), 2.46-2.40 (m, 1H), 2.19-2.16 (m, 1H), 1.93-1.86 (m, 2H), 1.77-1.67 (m, 1H).
Reaction SMILES: ClCCCCS[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1.[Cl:17][C:18]1C=C[CH:21]=[C:20](C(OO)=O)[CH:19]=1.[S:28]([O-:32])([O-])(=[O:30])=S.[Na+].[Na+]>ClCCl.ClC1C=CC=C(C(OO)=O)C=1>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][S:28]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[CH:15][N:16]=2)[CH:13]=1)(=[O:32])=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCCSCc1ccc2nccn2c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCCCCl)Cc1ccc2nccn2c1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
11.79 g of the 6-((4-chlorobutyl)thiomethyl)imidazo[1,2-a]pyridine prepared in the Preparative Example 7 was dissolved in 160 ml of dichloromethane. The obtained solution was cooled with ice, followed by the addition of 7.99 g of m-chloroperbenzoic acid in about 40 minutes. The obtained mixture was stirred. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was further added thereto. The obtained mixture was additionally stirred for one hour, followed by the addition of an aqueous solution of sodium thiosulfate. The obtained mixture was vigorously stirred at room temperature for 30 minutes and extracted with chloroform. The organic phase was washed with an aqueous solution of potassium carbonate, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1 to 10:1)] to give 9.51 g of the title compound as a dark-creamy oil (yield: 76%).
Reaction SMILES: [F:1][CH:2]([C:21]1[O:22]CC(C)(C)N=1)[CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(Cl)(Cl)Cl.[OH2:32]>Cl>[F:1][CH:2]([CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:21]([OH:22])=[O:32]
Reactant: CCCCCC=CCCCCC#CCC#CCCC(F)C1=NC(C)(C)CO1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\CCCCC#CCC#CCCC(F)C(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A suspension of 2-(1-fluorononadec-13-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole (86 mg) in 3 ml of 3N HCl was refluxed with stirring under argon for 15 min. It was cooled to about 23° C., diluted with 3 ml of water, and extracted three times with ether. The ether extracts were combined, washed with brine, and dried over MgSO4. Concentration of ether at 35° C./35 mm Hg gave the crude acid which was purified by flash chromatography on silica gel (8 g, 230-400 mesh). Elution with HOAc--CH3OH--CHCl3 under nitrogen afforded 49 mg (66% yield by weight) of (Z)-2-fluoro-14-eicosene-5,8-diynoic acid as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:24])(=[O:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=2[CH3:25])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:33]1([CH2:36][NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:35][CH2:34]1>C(O)C>[CH:38]1([N:37]([CH2:36][CH:33]2[CH2:34][CH2:35]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])(=[O:24])=[O:23])=[CH:13][C:12]=3[CH3:25])=[O:9])[CH:3]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: C1CCC(NCC2CC2)CC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: COCCNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C
Yield: 84.3 %

Procedure:
A solution of 6-chloro-N-(4-(N-(2-methoxyethyl)sulfamoyl)-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 38, 100 mg; 0.26 mmol) and diisopropylamine (91 mL; 0.52 mmol) in ethanol (2.5 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (54.4 mg; 0.33 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (110 mg, 84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:22][C:23]([F:28])([F:27])[C@@H:24]1[CH2:26][O:25]1>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:10][N:11]([CH2:26][C@H:24]([OH:25])[C:23]([F:28])([F:27])[F:22])[CH2:12][CH2:13][O:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: Clc1cccc([C@@H]2CNCCO2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of (R)-2-(3-chloro-phenyl)-morpholine hydrochloride (45 mg, 192 μmol) and triethylamine (134 μL, 961 μmole) in 4 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (43.1 mg, 384 μmol). The mixture was stirred at 50° C. for 3 h, followed by evaporation in vacuo to afford (S)-3-((R)-2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (59.5 mg), which was used directly for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=O)=[CH:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])=[CH:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2cc(=O)n(Cc3ccc(Cl)cc3)c3ccccc23)S1
Yield: 50.5 %

Procedure:
1.50 g of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-carboxaldehyde and 0.826 g of 2,4-thiazolidinedione were suspended in 30 ml of toluene. Five drops of piperidine and five drops of acetic acid were added, followed by heating and refluxing for 6 hours. The resultant was allowed to cool to precipitate a solid, and the precipitated solid was collected by filtration and dried, giving 1.01 g (50% yield) of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-4-ylmethylidene]thiazolidine-2,4-dione as a light-brown powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](CC)C(C(F)(F)F)=[CH:10][C:9]=1[NH:20][C:21](=[O:40])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][C:34](C3CC3)=[CH:35][CH:36]=2)[CH:26]=1)=O)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O.[CH2:49](Cl)Cl>>[CH3:49][C:36]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:27]1[CH:26]=[C:25]([C:23]2[CH2:22][C:21](=[O:40])[NH:20][C:9]3[CH:10]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M206) (266 mg, 0.518 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (162 mg, 79%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:28]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC[C@H](N(C)C)C3)cn2)c1O
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50.0 mg, 0.156 mmol), (S)—N,N-dimethylpyrrolidin-3-amine (26.7 mg, 0.234 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44.9 mg, 0.234 mmol) in DMF (1561 μl). HOBT (35.9 mg, 0.234 mmol) and DIPEA (136 μl, 0.781 mmol) were added. The reaction was allowed to stir overnight. Then 1N aqueous hydrochloric acid (21 ML) was added and reaction mixture was then purified using preparative HPLC eluting with 0.1% formic acid in water and 5-30% acetonitrile to give the title compound (30 mg, 0.072 mmol, 46.1%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.88 (m, 1 H) 2.24 (br. s., 3 H) 2.36 (br. s., 3 H) 2.42 (s, 3 H) 2.88-3.05 (m, 2 H) 3.59-3.81 (m, 4 H) 7.58 (d, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.95 (d, J=7.83 Hz, 1 H) 8.01 (s, 1 H) 8.11 (d, J=9.09 Hz, 1 H) 8.43 (d, J=8.84 Hz, 1 H) 8.62 (s, 1 H); ESI-MS m/z (M+H)+ calc'd for C23H24N6O2, 417.20; found 417.5.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.CCOCC>C(O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: [C-]#N
Reactant: Cc1cc(Cl)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(Cl)cc(CC#N)c1
Temperature: 70 °C
Yield: 75.5 %

Procedure:
To a flask equipped with additional funnel, was placed potassium cyanide (29.6 g, 0.45 mol) and distilled water (55 ml). The mixture was heated up to 70° C. in an oil bath. With stirring, 1-Bromomethyl-3-chloro-5-methyl-benzene (46) (35 g, 0.16 mol) in ethanol (180 ml) was then dropwise added over 1 hr through the addition funnel. After completion of addition, the mixture was refluxed for 8 hr. After cooling to room temperature, ether was added to the mixture. The mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 20 g (77%) of a pale brown oil. 1H NMR (200 MHz, CDCl3) δ: 2.31 (3H, s), 3.66 (2H, s), 7.02 (1H, s), 7.09 (2H, s).