Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
α-Hydroxypalmitic acid (3.2 g) was dissolved in pyridine (15 ml), and palmitoyl chloride (3.3 g) was added thereto at 0° C. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water and the aqueous solution was stirred at room temperature for 1 hour, followed by acidification with 1N hydrochloric acid, and extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give a residue which was recrystallized from petroleum ether to afford crystals of 2-hexadecanoyloxyhexadecanoic acid (5.4 g). M.p. 55°-56° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S([O-])(=O)=O.[F:26][C:27]([F:49])([F:48])[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:10]1[CH:11]=[C:12]([CH:13]=[CH:28][C:27]([F:49])([F:48])[F:26])[CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: FC(F)(F)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)C=Cc1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
A solution of 4-benzyloxy-3-chlorobenzaldehyde (0.25 g, 2.0 mmol), 2,2,2-trifluoroethyltriphenylphosphonium trifluoromethanesulfonate (0.49 g, 1.0 mmol) and CsF (0.76 g, 5.0 mmol) in DMF (10 mL) was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate, washed with water and dried. Removal of the solvent gave a residue which was purified by preparative TLC to give 1-(3-chloro-4-benzyloxyphenyl)-3,3,3-trifluoropropene. This product (65 mg, 0.2 mmol) was dissolved in ethyl acetate (2 mL) and hydrogenated (1 atm) in the presence of 10% palladium on carbon for 1 hr. Removal of the catalyst and solvent give 2-chloro-4 (3,3,3-trifluoropropyl)phenol as an oil.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.[Li]CCCC.[C:13](=[O:15])=[O:14]>C1COCC1>[CH3:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: O=C=O
Reactant: Cc1cscc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cscc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromo-4-methylthiophene (2.7 g, 15.6 mmol) in THF (35 mL) was added n-BuLi (1.6 M in hexane, 14.6 mL, 23.3 mmol) at −78° C. dropwise over a period of 15 min and the mixture was stirred at −78° C. for 30 min. The CO2 (gaseous) was passed through the reaction mixture for 10 min and the mixture was stirred at the same temperature for 20 min. Thereafter, the reaction mixture was warmed to 0° C., quenched with aqueous 1 M NaOH (60 mL) and washed with EtOAc (2×50 mL). The aqueous layer was acidified to pH ˜5 and extracted with DCM (2×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 8% MeOH/DCM as eluent) to provide compound A56-1 (1.5 g, 70%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I:11]Cl>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: ClI
Reactant: O=C(O)c1cccc(O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
30.0 g (217 mmol)) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the solution at room temperature. After stirring at 45° C. for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and 500 ml of water twice, and then dried at 80° C. under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH:4]([OH:7])[C:5]#[CH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:17]([Si:14]([O:7][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5]#[CH:6])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC(CC(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of 5-methyl-hex-1-yn-3-ol (5.0 g, 0.045 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 2.5 h and then treated with saturated NH4Cl (25 mL) and EtOAc (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.84 g, 97.5%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.10 (s, 3H), 0.13 (s, 3H), 0.90-0.88 (m, 15H), 1.53-1.46 (m, 1H), 1.65-1.58 (m, 1H), 1.87-1.77 (septet, J=6.6 Hz, 1H), 2.36-2.35 (t, J=1.84 Hz, 1H), 4.39-4.37(m, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=2)=[CH:6][C:5]=1[F:33])[CH3:2].[C:34]1([CH3:43])[CH:39]=[CH:38][CH:37]=[C:36]([N:40]=[C:41]=[O:42])[CH:35]=1>N1C=CC=CC=1>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH3:43])[CH:35]=4)=[O:42])=[C:5]([F:33])[CH:6]=3)[C:18]=12
Reactant: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Reactant: Cc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: CCN(C(=O)Nc1cccc(C)c1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
cis-3-[4-(Ethylamino)-3-fluorophenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.177 mmol) was dissolved in pyridine (3 mL) then cooled to 0° C. m-Tolylisocyanate (26 mg, 0.194 mmol) was added to the reaction and stirring was continued at 0° C. for 2.5 hours. The reaction mixture was warmed to room temperature and stirred overnight. Additonal m-tolylisocyanate (13 mg, 0.101 mmol) was added to the reaction mixture and stirring was continued for 1 week. The reaction mixture was concentrated under reduced pressure to give the crude product as a light yellow oil (110 mg). Purification was achieved by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300 A, 15 μm, 40×100 mm column). cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-ethyl-N′-(3-methylphenyl)urea was collected as a white solid (10 mg). HPLC-RT: 13.18 min. (flow rate: 1 mL/min λ=254 mn Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=586.5.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[NH2:40]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:40][NH:39][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:19])=[CH:15][CH:14]=2)=[O:10])=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Into a solution of 4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoic acid (1.0 g, 3.19 mmol) and N-methyl morpholine (420 μL, 3.83 mmol) in anhydrous THF (25 mL) at 0° C. was added isobutyl chloroformate (455 μL, 3.51 mmol) then tert-butyl hydrazine carboxylate (1.12 mg, 7.66 mmol). After stirring at 0° C. for 1 hr and overnight at rt, the reaction mixture was quenched with HCl (1N, 25 mL). Extraction with EtOAc (2×25 mL), drying over MgSO4 and evaporation under vacuo gave a residue. Purification by flash chromatography (SiO2, EtOAc) gave the title compound (773 mg, 55%) as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:11]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[CH:33]=[C:34]([O:39][CH3:40])[C:35]([O:37][CH3:38])=[CH:36][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2nc(CC3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(CC3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclohexylmethyl-5,6-dimethoxy-benzimid-azol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH3:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].C(O)C.[NH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH3:15])[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([NH2:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)propan-1-one (compound 49b, 3.0 g, 8.81 mmol) in a mixture of toluene:ethanol (15 ml:45 ml) were added 4-aminosulfonylbenzene boronic acid (1.947 g, 9.69 mmol) and potassium carbonate (2.43 g, 17.61 mmol) at 25° C. in a sealed tube and a nitrogen gas was bubbled through it for 15 minutes. To the reaction mixture was the added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) under nitrogen atmosphere and reaction mixture was heated at about 90 to about 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane. The combined filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.22 g, 33.2%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].N#N.[O:7]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:8]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:8][CH:9]([OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: NCCO
Reactant: OCCCCCCCCCCCCCCC1CO1
Agent: N#N
Solvent: CCO
Product: OCCCCCCCCCCCCCCC(O)CNCCO
Yield: 66.7 %

Procedure:
A 50-ml two-necked flask equipped with a stirrer, dropping funnel and N2 inlet tube was charged with 4.14 g (68 mmol) of ethanolamine and 0.8 g of ethanol. While heating and stirring the mixture at 80° C. in an N2 atmosphere, an ethanol solution of 0.87 g (3.4 mmol) of 1,2-epoxy-16-hexadecanol was added dropwise over 1.5 hours. The resultant mixture was stirred further for 2 hours at 80° C. After completion of the reaction, ethanol and excess ethanolamine were distilled off under reduced pressure, and the resultant residue was purified by flash column chromatography on silica gel, thereby obtaining 0.72 g (yield: 68%) of the title compound (IId-1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(OCC(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 42.7 %

Procedure:
A stirred mixture of 4-isobutoxybenzene-1-sulfonyl chloride (0.060 g, 0.24 mmol), 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.050 g, 0.22 mmol), and 4-(dimethylamino)pyridine (DMAP, 0.025 g, 0.20 mmol) in pyridine (2 mL) was heated at 80° C. for 2 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 2-5% methanol in dichloromethane), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.041 g, 0.094 mmol, 43%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.23 (d, J=4.0, Hz, 1H), 7.21 (d, J=4.0, Hz, 1H), 7.15 (dd, J=1.2, 7.2 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.25 (s, 1H), 3.72 (dd, J=2.0, 6.4 Hz, 2H), 2.33 (s, 3H), 2.13 (hept, J=6.4 Hz, 1H), 1.08 (dd, J=2.4, 6.4 Hz, 6H); MS: (ES) m/z calculated for C23H25N4O2S [M+H]+ 437.2. found 437.0.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11](=O)[CH3:12])[CH:8]=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[N:10]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1cccc(OCC(F)(F)F)n1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OCC(F)(F)F)n1
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield (0.35 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanone (0.48 g, 2.17 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([OH:8])(=O)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH2:24][CH2:23]1
Reactant: CC=CC=CC(=O)O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C=C/C=C/C(=O)NC1CC1
Yield: 51 %

Procedure:
2,4-Hexadienoic acid 1 eq, ethyl chloroformate 1.05 eq, triethylamine 1.2 eq, cyclopropylamine 1.3 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=51%. 0.54 ppm (m, 2H), 0.79 ppm (m, 2H), 1.82 ppm (d, 3H, J=5.93 Hz), 2.80 ppm (m, 1H), 5.72 ppm (d, 1H), 6.00 ppm (br. s, 1H), 6.03-6.15 ppm (m, 2H), 7.18 ppm (d, 1H, J=14.98 Hz, of d, J=10.02 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:3][CH:2]=1.C(O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])CCC>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-pyridylacetate (Step A, 2.5 g, 16 mmol) and benzyl alcohol (3.4 mL, 33 mmol) in anhydrous tetrahydrofuran (10 mL) at −10° C. was added butyllithium (2 M in cyclohexane, 16 mL, 33 mL), and the reaction was allowed to warm to room temperature overnight. The volatile materials were removed on a rotary evaporator, and the residue was diluted with methylene chloride (50 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography eluted with 30% ethyl acetate in hexane to give the title compound. 1H NMR (400 MHz, CD3OD): δ 8.43 (d, 2H), 7.38 (d, 2H), 7.32 (m, 5 H), 5.16 (s, 2H), 3.99 (s, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:9][C:8](=[CH:10][C:11]([O:13]CC2C=CC=CC=2)=[O:12])[CH2:7]1)=[O:5]>[Pd].CCO>[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([OH:13])=[O:12])[CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1CC(=CC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CON(C)C(=O)C1CC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.2 %

Procedure:
Palladium on charcoal (10%, 0.1 g) was added to a solution of benzyl 2-{3-[methoxy(methyl)carbamoyl]cyclobutylidene}acetate (1.54 g, 5.32 mmol) in EtOH (20 ml) and stirred under an atmosphere of hydrogen at RT for 6 h. The reaction mixture was filtered through celite and evaporated to dryness to give a colorless oil (1.04 g, 89%); MS (ESI+) for C9H15NO4 m/z 202.00 [M+H]+; MS (ESI)− for C9H15NO4 m/z 200.05 [M−H]−; HPLC purity 92% (ret. time, 1.10 min); 1H NMR (500 MHz, MeOD) δH ppm 1.84-2.08 (2 H, m), 2.28-2.53 (4 H, m), 2.56-2.72 (1 H, m), 3.06-3.22 (3 H, m), 3.38-3.56 (1 H, m), 3.68 (3 H, d, J=8.04 Hz).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][Na]>CO>[CH3:10][O:11][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CO[Na]
Reactant: N#Cc1cccnc1Cl
Solvent: CO
Product: COc1ncccc1C#N

Procedure:
2-Methoxy-nicotinonitrile was prepared according to the literature by reaction of the 2-chloro-nicotinonitrile with MeONa in MeOH according to Dunn, A. D.; Norrie, R.; Heterocycl. Chem.; EN; 24; 1987; 85-89.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13](CC#N)=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:21][C:20]([OH:23])=[O:22])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)O
Reactant: N#CCc1ccc(-c2cn3ccccc3n2)cc1
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 2 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetonitrile, 10 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, and water is added to the residue. The mixture is alkalified with 10% sodium hydroxide, and then filtered. The filtrate is adjusted to pH 6 by addition of 10% hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 1.2 g of 4-(imidazo[1,2-a]-pyridin-2-yl)phenylacetic acid as colorless crystals melting at 220°-222°C with decomposition.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23](F)=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35][O-:36].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]([O:36][CH3:35])=[C:22]3[C:17]([C:18](=[O:31])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][N:21]3[CH:25]3[CH2:27][CH2:26]3)=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-(1-t-Butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (300 mg) was dissolved in 3 ml of DMF, followed by the addition of 32 mg of 55% sodium hydride under ice cooling. After the resultant mixture was stirred for 10 minutes, 72 mg of sodium methoxide was added. The mixture thus obtained was stirred further for 18 hours at room temperature. The reaction mixture was diluted with chloroform and then washed successively with 10% aq. citric acid solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness, whereby 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained. It was used directly in the reaction of the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:16][CH:17]([CH2:23][CH3:24])[C:18](=[O:22])[C:19](O)=[O:20]>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:19](=[O:20])[C:18](=[O:22])[CH:17]([CH3:16])[CH2:23][CH3:24])[CH3:9]
Reactant: CCOC(CN)(OCC)c1cccnc1
Reactant: CCC(C)C(=O)C(=O)O
Product: CCOC(CNC(=O)C(=O)C(C)CC)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with 3-methyl-2-oxopentanoic acid there is obtained rac-N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-methyl-2-oxovaleramide as an amorphous, colorless solid. Subsequent acidic hydrolysis to rac-3-methyl-2-oxo-N-[(3-pyridylcarbonyl)methyl]valeramide hydrochloride (beige, crystalline solid, melting point 158°-159°) and ring closure gives rac-3-(1-methylpropyl)-5-(3-pyridyl)-2(1H)-pyrazinone as a yellow solid, melting point 146°-148° (from acetonitrile). The conversion into rac-2-chloro-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine is also effected analogously to Example 1. Hydrazinolysis to rac-2-hydrazino-3-(1-methylpropyl)-5-(3-pyridyl)pyrazine in the form of beige crystals, melting point 166°-167° (from ethanol/water) and subsequent condensation with diethyl malonate gives ethyl rac-8-(1-methylpropyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 335 (M)+, which is converted by saponification into the above acid, MS: 267 (M-CO 2)+.