Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[C:12]1[N:13]([CH3:31])[C:14](=[O:30])[CH:15]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:17]=1[C:18]([O-:20])=O.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][OH:44]>C1COCC1>[F:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:16]1[C:17]([C:18]([NH:41][CH2:42][CH2:43][OH:44])=[O:20])=[CH:12][N:13]([CH3:31])[C:14](=[O:30])[CH:15]=1
Reactant: Cn1c(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)[O-])c(Nc2ccc(I)cc2F)cc1=O
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
2,3,4,5,6-Pentafluorophenyl-4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (600 mg, 1.08 mmol) was dissolved in THF (15 mL) to which was added DIEA (697 mg, 5.40 mmol), followed by 2-aminoethanol (132 mg, 2.17 mmol). This mixture was stirred at R.T. for 2 h., then the reaction solvent removed under reduced pressure and the resulting white solid suspended in Et2O. The solid was collected by filtration, then recrystallised from EtOAc/MeOH to give 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (394 mg, 85%) as a white solid, m.p. (EtOAc/MeOH) 205-208° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.10 (s, 1H), 8.43 (br s, 1H), 8.28 (s, 1H), 7.72 (dd, J=10.2, 1.8 Hz, 1H), 7.56 (br d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 5.58 (s, 1H), 4.76 (br t, J=5.2 Hz, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.36 (s, 3H), 3.32-3.26 (m, 2H). Anal. Calcd for C15H15FIN3O3: C, 41.8; H, 3.5; N, 9.8. Found: C, 4.19; H, 3.2; N, 9.7.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.O/[N:23]=[C:24](/[C:26]1[CH:27]=[CH:28][C:29]([CH3:40])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:31]=1)\[NH2:25]>CN1C(=O)CCC1>[F:21][C:14]1([F:13])[CH2:15][CH:16]([C:18]2[O:20][N:23]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH3:40])=[C:30]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH:31]=3)[N:25]=2)[CH2:17]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: Cc1ccc(/C(N)=N/O)cc1NC(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
CDI (1.2 g, 7.34 mmol) was added portion-wise to a stirred solution 3,3-difluorocyclobutanecarboxylic acid (1 g, 7.34 mmol) in NMP (10 mL). After 30 minutes, (Z)-tert-butyl 5-(N′-hydroxycarbamimidoyl)-2-methylphenylcarbamate (35) (1.8 g, 7.34 mmol) was added in one portion and stirred for another hour at room temperature. The solution was then heated via microwave at 120° C. for 20 minutes. The solution was partitioned with EtOAc and water. The organic phase was separated, dried over MgSO4 and purified over silica gel to afford tert-butyl (5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (36) (1.2 g, 45% yield). MS m/z 366.1 (M+1)+.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C([Mg]Cl)(C)C.[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:15]=[C:4]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.16 g, 5 mmol) in THF (10 mL) was cooled to −15° C. and slowly charged with isopropylmagnesium chloride (2.0M, 2.37 mL, 0.95 eq). After a clear solution was obtained, benzylmagnesium chloride (1.0M, 4.99 mL, 1.0 eq) was added dropwise with stirring at rt overnight. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (10 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate before being filtered, concentrated to give a white solid as (S)-tert-butyl 3-oxo-4-phenylbutan-2-ylcarbamate. Mass Spectrum (ESI) m/e=264 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
A solution containing the product from Example 8B (5.67 g, 12.5 mmol) in THF (124 mL) was treated with the product from Example 7B (3.8 g, 12.5 mmol), DEPBT (5.59 g, 18.7 mmol), and N,N-diisopropylethylamine (10.8 mL, 62.0 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with acetone to give the title compound (4.42 g, 48% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.25 Hz, 3 H), 0.82 (m, 14 H), 0.92 (m, 1 H), 1.30 (m, 1 H), 1.50 (m, 2 H), 1.79 (m, 1 H), 2.43 (m, 3 H), 2.68 (m, 3 H), 2.89 (m, 1 H), 3.10 (m, 3 H), 3.57 (m, 3 H), 3.89 (m, 2 H), 4.13 (m, 2 H), 4.34 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.56 Hz, 1 H), 7.11 (m, 12 H), 7.50 (d, J=8.82 Hz, 1 H), 7.66 (t, J=7.54 Hz, 1 H), 7.83 (d, J=9.19 Hz, 1 H).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C=C(C)C)cc1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A round bottom flask equipped with a stir bar and nitrogen inlet was charged with veratrole (2.5 mL, 20 mmol), 3,3-dimethyl acryloyl chloride (2.2 mL, 20 mmol) and dry CH2Cl2, (100 mL). The solution was cooled to 0° C. and AlCl3 (2.6 g, 20 mmol) was added portionwise. On completion of addition, the cooling bath was removed and the reaction was allowed 3 h. TLC showed consumption of SM. It was added to saturated NH4Cl (100 mL) and stirred vigourously for 15 min. The phases were separated and the CH2Cl2 phase was washed with saturated Na2CO3 (100 mL), washed with brine, (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was used as is in the next step. Amount obtained: 4.3 g, 19.5 mmol, 98% yield. LC-MS (ESI) m/e 221 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02 (s, 3H) 2.20 (s, 3H) 3.96 (s, 6H) 6.73 (s, 1H) 6.89 (d, J=8.20 Hz, 1H) 7.53-7.60 (m, 2H). Step 2
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2CC[C@@H](CO)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CC[C@@H](COS(C)(=O)=O)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Reaction time: 1.75 h

Procedure:
Methanesulfonyl chloride (0.483 mL, 6.20 mmol) was added to a solution of (7S)-7-(hydroxyl methyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (1.3 g, 3.10 mmol) and triethylamine (1.296 mL, 9.30 mmol) in DCM (30 mL). The mixture was stirred at room temp. for 105 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic extract was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-75% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:30]2[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[CH:23][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:21][CH2:22]3)=[O:19])[N:16]=2)[N:13]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1ccc(Cl)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Yield: 91.6 %

Procedure:
Using N-[6-(5-amino-2-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (131 mg, 0.382 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (91 mg, 0.573 mmol), triethylamine (116 mg, 1.15 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (163 mg, 92%) was obtained as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccn3)CC2)cc1
Yield: 152.3 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g) in dimethylformamide (20 ml) was stirred at 60-70° C. for 2.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil. The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow oil (2.5 g). The obtained pale-yellow oil was crystallized from ethyl acetate and the crystals were recrystallized from ethyl acetate to give the title compound (1.4 g) as white crystals, m.p.=100-101° C.
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:13]=[N:14][OH:15].C=C.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:13]2[CH2:4][CH2:3][O:15][N:14]=2)[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Reactant: O=C1CCC(=O)N1Cl
Agent: C=C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOCC1
Reaction time: 0.5 h

Procedure:
At 60° C., a small amount of N-chlorosuccinimide is added to a solution of 50 g (171 mmol) of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime in 200 ml of dimethylformamide. Once the reaction has started, a total of 23.3 g (171 mmol) of N-chlorosuccinimide are metered in at 40-50° C. The reaction mixture is stirred for another 30 minutes, until conversion is complete according to HPLC. The reaction mixture is then poured onto ice-water and the solid is filtered off with suction, washed three times with water and twice with n-pentane. The hydroxamic acid chloride is used moist and without further purification for the next reaction. The solid is dissolved in 250 ml of dichloromethane, and ethylene is passed through the solution. With continued introduction of ethylene, 20.3 q (200 mmol) of triethylamine are added dropwise. The reaction mixture is stirred at room temperature for about 72 hours, with repeated introduction of more gaseous ethylene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=O)=[CH:29]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH:35]=[C:9]2[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[CH:4]4[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]4)[NH:11][C:10]2=[O:16])=[CH:29]3)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with (5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde (60 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: CO.[C:3]([O:7]OC(C)(C)C)(C)(C)C.[C:13]([CH:17]=[C:18]([F:20])[F:19])([F:16])([F:15])[F:14]>>[C:13]([CH2:17][C:18]([CH2:3][OH:7])([F:20])[F:19])([F:16])([F:15])[F:14]
Reactant: FC(F)=CC(F)(F)F
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: OCC(F)(F)CC(F)(F)F
Yield: 934.5 %

Procedure:
Under nitrogen, into a quartz tube equipped with a dry-ice condenser was added anhydrous methanol (20 g, 0.62 mol) and di-tertiarybutylperoxide (.79 g, 0.003 mol). The quartz tube was placed in a Rayonet UV photochemical reactor and HFC 1225, CF3CH═CF2 (7 g, 0.05 mol) was added drop-wise via a dry-ice condenser (−78° C.) over a period of ˜30 minutes while being irradiated at 254 nm. After complete addition, the reaction mixture was irradiated for ˜30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was extracted in diethyl ether (˜50 mL), washed with 20 mL aq. Na2SO3 (20%) and brine (10 mL). The ether layer was then concentrated to afford 7 g of the crude material which was distilled under reduced pressure (24-28 mm Hg) to afford CF3CH2CF2CH2OH (4.6 g, mol) as a colorless liquid. Yield=52% based on HFC 1225. Boiling point, 62° C./24-28 mm Hg. GC-MS: m/e 164 (C4H5F5O) for M+;19F and 1H NMR spectra are consistent with the structure. 19 F NMR (CDCl3)δ=−62.4 (3F, tt overlaps), −106.5 (2F, m) ppm; 1H NMR (CDCl3)δ=2.7 (1H, t), 2.9 (2H, m), 3.8 (2H, m) ppm.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.N1C=CC=CC=1.P(Br)(Br)[Br:17]>C(OCC)C>[Br:17][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: C[Si](C)(C)C#CCCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Si](C)(C)C#CCCBr
Yield: 117 %

Procedure:
4-Trimethylsilyl-3-butyne-1-ol (14.2 g, 0.1 mol) and 0.2 ml of pyridine were dissolved in 50 ml of diethyl ether under a nitrogen atmosphere. Phosphorus tribromide (3.8 ml, 0.04 mol) was slowly added and the mixture was heated under reflux for 2 hours. Isolation of the product by conventional means yielded 9.6 g of 4-bromo-1-trimethylsilyl-1-butyne as a clear liquid, bp 35°-38° C. at 1 mm Hg.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]1.Cl[CH2:20][C:21](=O)[CH3:22]>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][C:13](=[O:18])[C:14]2[C:21]([CH3:22])=[CH:20][O:17][C:15]=2[CH2:16]1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2F)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccc(F)cc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.6 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.39 g, washed with hexane thrice), and to the suspension was added 5-(2,4-difluorophenyl)cyclohexane-1,3-dione (2.0 g) and then was added chloroacetone (0.83 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 12 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 6-(2,4-difluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.13 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[CH3:17][C:18](=[O:23])[CH2:19][C:20](=[O:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=[C:19]([C:18](=[O:23])[CH3:17])[C:20](=[O:22])[CH3:21])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cc(F)c(F)c2c(=O)cc(C)oc12)C(C)=O

Procedure:
250 mg (1.12 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 0.14 ml (1.34 mmol) of 2,4-pentanedione and 212.1 mg (1.12 mmol) of para-toluenesulfonic acid are heated in 100 ml of toluene under reflux with a water trap for 10 h. After cooling, 100 ml of ethyl acetate are added, and the reaction mixture is washed with water and with brine. Drying of the organic phase and concentration result in 269.7 mg (79% of theory) of the title compound as beige-coloured crystals.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Br:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (10.02 g, 25.75 mol) in methanol (100 mL) and water (100 mL) was treated with lithium hydroxide (15.4 g, 515 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×400 mL). The organic layer was washed with water (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (9.58 g, 99%) as a white solid which was used without further purification: mp 149-150° C.; FAB-HRMS m/e calcd for C15H19BrO4S (M+H)+ 375.0266, found 375.0274.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[CH:27](N1C2C=CC=CC=2N=N1)=[O:28]>O1CCCC1.ClCCl>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:16]([C:15]2[C:10]([S:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:7]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH:24]=[C:23]([CH3:25])[CH:22]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC=O)c2)c1

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (the free base of Compound No. 3-1, 50 mg, 0.14 mmol) was dissolved in anhydrous tetrahydrofuran (0.20 mL), a solution of N-formylbenzotriazole (19 mg, 0.13 mmol) in anhydrous tetrahydrofuran (0.2 mL) was added thereto, and then the mixture was refluxed for 16 hours. The mixture was diluted with dichloromethane (15 mL), and then the whole was washed with 2 N aqueous sodium hydroxide solution (4.0 mL) twice and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 60 mg of the target compound quantitatively as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([N:31]=[C:32]=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(=O)c4ccccc4)cc3)c2cc1OC
Yield: 15 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, benzoyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 11 mg of the title compound (yield: 15%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@H:24]([C:25]([NH:27][C:28]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([S:39][CH2:40][C:41]([NH:43][CH:44]4[CH2:49][CH2:48][N:47]([CH2:50][C:51]5[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=5)[CH2:46][CH2:45]4)=[O:42])[S:37][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)=[O:26])[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[Cl:58][C:53]1[CH:52]=[C:51]([CH:56]=[CH:55][C:54]=1[Cl:57])[CH2:50][N:47]1[CH2:48][CH2:49][CH:44]([NH:43][C:41](=[O:42])[CH2:40][S:39][C:36]2[S:37][CH:38]=[C:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([NH:27][C:25]([C@@H:24]4[CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16][NH:15]4)=[O:26])[CH:29]=3)[N:35]=2)[CH2:45][CH2:46]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(CSc1nc(-c2cccc(NC(=O)[C@@H]3Cc4ccccc4CN3)c2)cs1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the product (667 mg) of Example 54, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with chloroform (100 mL), and the mixture was washed with 1 mol/L sodium hydroxide and saturated brine, and dried. The solvent was evaporated under reduced pressure to give the title compound (362 mg) as a white amorphous solid.