Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](O)=[O:8].Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([N:15]([O:16][CH3:17])[CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
3-Bromocinnamic acid (15.3 g, 67.3 mmol), N,O-dimethylhydroxylamine hydrochloride (7.9 g, 80.8 mmol), HOBT (18.2 g, 134.7 mmol), EDAC (25.8 g, 134.7 mmol) and triethylamine (18.7 mL, 134.68 mmol) were added to dichloromethane (500.0 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane three times. The combined extract was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 14.8 g of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22](Cl)[N:21]=[C:20]([CH3:28])[CH:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[NH:9]([C:16]1[N:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:21]=[C:20]([CH3:28])[CH:19]=2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2c(c(OCC(F)(F)F)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Trifluoroethanol (0.08 mL, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0° C., and the mixture was heated at 60° C. for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2:1 EtOAc:Hex) to provide 2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-4(1H)-one (159 mg, 68%): LCMS RT: 2.65 min, MH+: 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28]([C:31](Cl)=O)([CH3:30])[CH3:29]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH:28]([C:31]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[C:13]4[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=4[C:11]3=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:27]=1)([CH3:30])[CH3:29]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(C)C)n3)c1)C2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (120 mg, 0.31 mmol) obtained in Step 1 was dissolved in pyridine (1.5 mL), and the mixture was stirred overnight at 90° C. after adding isopropylcarbonyl chloride (0.039 mL, 0.38 mmol) under ice-cooled conditions. The mixture was diluted with chloroform, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (149 mg, quantitative).
Reaction SMILES: CN(C)C(=O)C.C1(S([O-])(=O)=O)C=CC=CC=1.[CH3:17][S:18]([N:21]1[CH:25]=[C:24]2[CH2:26][NH2+:27][CH2:28][C:23]2=[N:22]1)(=[O:20])=[O:19].[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C@@H:37]1[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:41][C:40](=O)[CH2:39][O:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C@@H:37]1[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:41][C@@H:40]([N:27]2[CH2:26][C:24]3[C:23](=[N:22][N:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:25]=3)[CH2:28]2)[CH2:39][O:38]1
Reactant: CS(=O)(=O)n1cc2c(n1)C[NH2+]C2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A vessel was charged with N,N-dimethylacetamide (520.6 kg), 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate (intermediate 2, 30.0 kg, 86.8 mol), and tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl]carbamate (intermediate 1, 31.2 kg, 95.3 mol). After dissolving at room temperature, the solution was cooled to 0-10° C. and sodium triacetoxyborohydride (24 kg, 113 mol) was added in four equal portions every 40 min. The reaction was then allowed to warm to room temperature and stirred an additional 5 h. The solution was then cooled to 5-15° C. and water (672 kg) was added over 1-2 h. The resulting slurry was filtered and the cake washed sequentially with N,N-dimethylacetamide, twice with water, and then n-heptane. The solids were dried under vacuum at 40-60° C. to give tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>O.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 18.0 g. of p-chlorophenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. diethyl ether. The ethereal solution was extracted with 2×50 ml. 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave 4.7 g (29%) of analytically pure product which melted at 101°-104° C.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:26](/[S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:30])([F:15])[F:29])[CH:18]=1)(=[O:25])=[O:24])\[C:27]#[N:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=Cc1sccc1Oc1ccccc1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and 3-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-[3-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:3]1=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH2:60]>ClCCl.CO>[Cl:48][C:49]1[C:54]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH:60][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1C(=O)N(c2cccnc2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN1C(=O)N(c2cccnc2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.2 %

Procedure:
A mixture of crude 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylic acid (0.8 mmol), 1-hydroxybenzotriazole hydrate (147 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol), and N-ethyl morpholine (0.307 ml, 2.4 mmol) in dichloromethane (15 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (168 mg, 0.8 mmol) in dichloromethane (1 ml) was added and the reaction stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The solid was dissolved in methanol (5 ml) and anhydrous HCl in ether (1M, 0.5 ml) was added and the solution was evaporated. The resulting solid was collected, washed with ether and dried to give a pale yellow solid. The solid was dissolved in methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated and the resulting residue was triturated with ether, collected and dried to give N-{[2-Chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxamide (27 mg, 8%). LC/MS [M+H]+=413, retention time=1.96 minutes.
Reaction SMILES: N([O-])=O.[Na+].[Br-:5].[K+].Br.N[CH:9]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11]>O>[Br:5][CH:9]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(CCCC(N)C(=O)O)cc1
Reactant: [Br-]
Agent: Br
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CCCC(Br)C(=O)O)cc1
Reaction time: 2 h

Procedure:
At −5° C., sodium nitrite (176 mg) was slowly added to a solution of potassium bromide (591 mg) in a 0.75M aqueous hydrobromic acid solution and then 2-amino-5-(4-methoxyphenyl)pentanoic acid (300 mg) was added thereto. After stirring at the same temperature for 2 hours, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (20 ml×twice). The organic layer was collected, washed with a saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate, and then concentrated under reduced pressure. 2-Bromo-5-(4-methoxyphenyl)pentanoic acid was obtained as 355 mg of a crude product.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=CC=C([F:39])C=2N=1>>[F:39][C:27]1[C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=[CH:2][CH:28]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Fc1cccc2sc(Cl)nc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)cccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-4-fluoro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.22 (m, 2H), 2.23-2.31 (m, 2H), 3.06-3.18 (m, 2H), 3.42 (d, J=12.1 Hz, 2H), 4.48-4.57 (m, 1H), 7.42-7.49 (m, 1H), 7.50-7.57 (m, 1H), 8.00-8.07 (m, 2H), 8.30 (br. s., 1H), 8.37 (br. s., 1H), 8.54 (s, 1H). MS (ES+): m/z=395.12 [MH+]. HPLC: tR=2.05 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]([NH2:9])=O)[N:6]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]#[N:9])[N:6]=1
Reactant: Cc1nc(C(N)=O)c(Nc2ccccc2[N+](=O)[O-])s1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
Combine 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylic acid amide (60 g, 215 mmol) and toluene and add POCl3 (40 mL, 430 mmol) and reflux the reaction mixture. After 2.5 h cool to 0° C. Add saturated NaHCO3 solution to quench the extra POCl3 (Caution!!) until the aqueous was around pH 8. Add ethyl acetate (2×2 L) to extract the product. Combined organic layer and wash with brine (2×1 L), dry over MgSO4. and evaporate to give a reddish solid which triturated with 25% ethyl acetate in hexane to give a reddish solid (36 g). Evaporate the filtrate to half volume to give second batch of compound (3.2 g). Total yield (39.2 g, 70%): mass spectrum (m/e): 261(M+1); 1HNMR(300 MHz, DMSO-d6, ppm): δ 2.70(s, 1H), 7.02(t, 1H), 7.22(d, 1H), 7.58(t, 1H), 8.25(d, 1H), 9.78(s, 1H): 13CNMR(75 MHz, DMSO-d6, ppm): δ20.4, 113.1, 116.2, 118.7, 121.2 127.0, 134.9, 136.6, 140.0, 148.6, 161.5. Formula: C11H8N4O2S
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[CH:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:25][N:26]([CH3:30])[CH2:27][C:28]#[C:29][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: C#CCN(C)C
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1cc(C#CCN(C)C)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 5.6 %

Procedure:
5-Bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50 mg, 0.125 mmol), 1-dimethylamino-2-propyne (194 μL, 0.14 mmol), trimethylacteylene (20 μL, 0.14 mmol), Pd(PPh3)2Cl2 (1.9 mg, 0.003 mmol) and copper iodide (1.0 mg, 0.006 mmol) were stirred together at 120° C. for 30 minutes. The reaction was cooled and partitioned between aqueous NaHCO3 and EtOAc, and the organic was washed with 1N HCl and then basified with 1N NaOH, extracting with EtOAc. The solvent was removed under reduced pressure and purified on silica (2% ammonia in MeOH/EtOAc) to afford 2.8 mg (6%) of a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.34 (d, 2H), 7.29 (d, 2H), 7.20 (d, 2H), 4.78 (s, 2H), 4.22 (s, 2H), 3.49 (s, 2H), 2.74 (s, 3H), 2.38 (s, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Cl.[F:13][C:14]([F:41])([F:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>COCCOC>[F:13][C:14]([F:41])([F:40])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Recrystallization from ether affords the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[C:24]1([C:30]#[C:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(=O)([O-])O.[Na+].N1C=CC=CC=1>[C:24]1([C:30]#[C:31][C:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C#Cc1ccccc1)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 17.6 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (18.6 mg, 0.060 mmol), 3-phenylprop-2-ynic acid (13.1 mg, 0.090 mmol), HATU (48.7 mg, 0.128 mmol), N,N-diisopropylethylamine (35.1 μL, 0.205 mmol) and pyridine (1.5 mL) was stirred at 80° C. for 13 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (4.6 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CC1CCCN(C)C1(C)C.[Li].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:29]([SnH:24]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC1CCCN(C)C1(C)C
Agent: Clc1ccc(Cl)nn1
Agent: [Li]
Solvent: C1CCOC1
Product: CCCC[SnH](CCCC)CCCC
Reaction time: 1 h

Procedure:
A THF solution (10 mL) of 3,6-dichloropyridazine (16.8 mmol, 2.5 g) was added dropwise to a solution of lithium tetramethylpiperidine (20.1 mmol) in 170 mL of THF at -78° C. After one hour at -78° C., tributyltin chloride (21.8 mmol, 5.8 mL) was added to the anion solution and the solution was allowed to warm slowly overnight.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3(O)[CH2:15][CH:14]=[CH:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].CO>[CH:11]1([CH:8]2[CH2:9][CH2:10][C:5]3([O:1][CH2:2][CH2:3][O:4]3)[CH2:6][CH2:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1(C2CCC3(CC2)OCCO3)CC=CC1
Agent: [Pd]
Solvent: CO
Product: C1CCC(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 1-(1,4-dioxaspiro[4.5]decan-8-yl)cyclopent-3-enol (218 mg, 0.972 mmol), prepared in the Example 28 Step B, and Palladium on Carbon (157 mg, 0.074 mmol) was carefully added methanol (24 mL). The reaction flask was evacuated, backfilled with hydrogen via balloon and stirred at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford the product.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:16][CH:17]([F:47])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39]OS(C)(=O)=O)=[N:37][CH:38]=3)=[CH:29][CH:28]=2)[O:22][C:21]1([CH3:46])[CH3:45])=[O:19]>C(#N)C>[F:47][CH:17]([F:16])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[N:37][C:36]([CH2:39][NH:6][CH2:5][CH2:4][CH2:3][F:2])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[O:22][C:21]1([CH3:45])[CH3:46])=[O:19]
Reactant: NCCCF
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CNCCCF)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 3-Fluoro-propylamine hydrochloride (0.072 g, 0.636 mmol) in acetonitrile (5 mL) is added diisopropylethylamine (0.082 mL, 0.636 mmol) at room temperature. After stirring for 30 minutes methane sulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.211 mmol) is added then the resulting mixture is stirred at room temperature for overnight. Solvent is evaporated under reduced pressure and the crude material is purified by combi-flash chromatography using 12% methanol in CH2Cl2 as an eluent to afford the title compound (0.093 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (s, 3H), 1.60 (S, 3H), 2.06-2.14 (m, 2H), 3.57-3.60 (m, 2H), 4.35 (s, 2H), 4.49-4.51 (m, 1H), 4.52-4.56 (m, 0.5H), 4.57-4.63 (m, 1H), 4.64-4.70 (m, 1H), 4.83-4.86 (m, 0.5H), 4.93-4.97 (m, 1H), 5.28 (d, J=3.48 Hz, 1H), 6.66 (t, J=52.3 Hz, 1H), 7.61-7.65 (m, 3H), 7.84 (d, J=8.2 Hz, 2H), 8.21-8.23 (dd, J1=3.04 Hz, J2=8.16 Hz, 1H), 8.97 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=454.1.
Reaction SMILES: [Cl-].[NH4+:2].[OH-].[NH4+].Cl[O-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=1.[H-].[Na+].NCl>C(OCC)C.CN(C=O)C>[NH2:2][N:12]1[CH:13]=[C:9]([F:8])[CH:10]=[C:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(F)c[nH]1
Agent: NCl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(F)cn1N
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
A mixture of ammonium chloride (6.0 g, 112 mmol) in diethyl ether (220 mL) was cooled to −5° C., and concentrated aq. ammonium hydroxide (9.4 mL) was added dropwise with vigorous stirring. After the addition was complete, commercial grade aq. sodium hypochlorite solution (145 mL) was added via addition funnel at a rate such that the internal temperature was maintained below 0° C. The mixture was then stirred for 15 min, then the layers were separated, and the organic layer was washed with brine and dried over anhyd. calcium chloride. The resulting solution of chloramine was used directly as follows: In a separate flask, containing a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (0.98 g, 6.85 mmol) in DMF (15 mL) at 0° C. was added 60% sodium hydride dispersion (0.329 g, 8.22 mmol) and the resulting mixture was allowed to warm to rt and stir for 45 minutes. At this time, a portion of the previously prepared chloramine solution (55 mL) was added via syringe over ˜1 minute. After stirring for an additional 1.5 h at rt, the reaction mixture was quenched by adding sat. aq. Na2S2O3 followed by diluting with water and extracting with diethyl ether (100 mL×2). The combined extracts were dried over anhyd. sodium sulfate, filtered and concentrated under vacuum to afford 0.98 g (91%) of the title compound as a light tan oil. HPLC (condition B): retention time=1.57 min. LCMS (condition B): m/z 159 +ve. 1H NMR (400 MHz, MeOD) δ ppm 6.86 (1 H, d), 6.51 (1 H, d, J=2.42 Hz), 3.85 (3 H, s).