Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[CH3:47][C:48]1[C:57]([CH3:58])=[C:56](OS(C(F)(F)F)(=O)=O)[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:67]([O:69][CH2:70][CH3:71])=[O:68])[CH:54]=2)[N:49]=1>[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[F:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:13])[C:12]=1[C:56]1[C:55]2[C:50](=[CH:51][CH:52]=[C:53]([C:67]([O:69][CH2:70][CH3:71])=[O:68])[CH:54]=2)[N:49]=[C:48]([CH3:47])[C:57]=1[CH3:58]
Reactant: CCOC(=O)c1ccc2nc(C)c(C)c(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: Fc1cncc(F)c1
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(C)c(C)c(-c3c(F)cncc3F)c2c1
Reaction time: 1 h
Yield: 18.7 %

Procedure:
Under argon gas atmosphere, n-butyllithium (1.6 M THF solution, 1.3 mL) was added dropwise to a mixture of 3,5-difluoropyridine (238 mg) and THF (4 mL) at −78° C., followed by stirring at the same temperature for one hour. Then, zinc chloride (0.5 M THF solution, 3.8 mL) was slowly added stirried at the same temperature for 30 minutes and further for an additional hour at room temperature. Tris(dibenzylideneacetone)dipalladium (73 mg), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (148 mg), and ethyl 2,3-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}quinoline-6-carboxylate (300 mg), were added to the reaction mixture and heated under stirring in an oil bath at 70° C. for 15 hours. The reaction mixture was returned to room temperature, and the insoluble materials were separated by filtration. Then, the precipitate was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl 4-(3,5-difluoropyridin-4-yl)-2,3-dimethylquinoline-6-carboxylate (51 mg).
Reaction SMILES: FC1C=CC(C)=CC=1CO.[F:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH:14]=[O:15]>>[F:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1cc(Cl)ccc1F
Agent: Cc1ccc(F)c(CO)c1
Product: OCc1cc(Cl)ccc1F

Procedure:
The title intermediate was prepared essentially as was 2-fluoro-5-methylbenzyl alcohol, supra, except that an equimolar amount of 2-fluoro-5-chlorobenzaldehyde was employed instead of the 2-fluoro-5-methylbenzaldehyde employed therein.
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[CH3:9][O:10][C:11]([C:13]1[N:17]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]2([CH3:28])[CH3:27])[C:16](S)=[N:15][CH:14]=1)=[O:12].[OH-].[Na+]>O>[CH3:9][O:10][C:11]([C:13]1[N:17]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C:19]2([CH3:28])[CH3:27])[CH:16]=[N:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cnc(S)n1C1c2ccccc2CC1(C)C
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
2 g of sodium nitrite and 17.4 ml of nitric acid are solved in 140 ml of deionisized water. Within 20 min. 28 g of 1-(2,2-dimethyl-indan-1-yl)-2-mercapto-5-imidazolecarboxylic acid methyl ester are added portionwise at a temperature between 30° C. and 50° C. The reaction mixture is treated with conc. aqueous sodium hydroxide solution. Extracting the aqueous phase with chloroform, and evaporating the organic solvent yields 24.2 g of 1-(2,2-dimethyl-indan-1-yl)-5-imidazolecarboxylic acid methyl ester as a colourless product (m.p. 96°-97° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[C:17]([F:20])=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.[C:37](O)([C:39]([F:42])(F)F)=O>C(Cl)Cl>[F:42][C:39]1[CH:37]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K85) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (37 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=[C:34](Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.CN(C)C1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([N:33]([CH3:34])[CH3:32])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N,N-dimethylpyrrolidin-3-amine. MS (m/e): 414.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][O:45]C(=O)C3C=CC=CC=3)[C@@H:32]([O:33]C(=O)C3C=CC=CC=3)[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:43][C@@H:42]([CH2:44][OH:45])[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:54][CH:55]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](OC(=O)c3ccccc3)[C@H](COC(=O)c3ccccc3)O2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](CO)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 98.4 %

Procedure:
Compound 5 (0.95 g, 1.30 mmol) was treated with a solution (saturated at −10° C.) of methanolic ammonia (40 mL), at room temperature overnight. After concentration, the residue was dissolved in dichloromethane (60 mL) and washed with water (30 mL). The aqueous layer was extracted twice with dichloromethane (10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give pure 6 (0.67 g, 98%) as a foam: 1H NMR (CDCl3): δ 2.6-2.9 (m, 2H, H-2′ and H-2″), 3.5 (br s, 1H, OH-5′), 3.55 (s, 3H, OCH3), 3.9-4.0 (m, 3H, H-4′, H-5′ and H-5″), 4.5-4.6 (m, 1H, H-3′), 6.03 (dd, 1H, H-1′, J1′,2′=4.0 Hz, J1′,2″=8.8 Hz), 7.0 (br s, 1H, NH-6), 6.7-6.8 and 7.1-7.4 (2m, 14H, MMTr), 7.40 (d, 1H, OH-3′, JH,OH=10.6 Hz), 7.80 and 7.99 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 524 [M+H]+, 408 [BH2]+, (FAB−) m/z 1045 [2M−H]−, 522 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 275 nm (ε 12300), λmin 247 nm (ε 3600); [α]D20=+28 (c 0.94, DMSO).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-trifluoromethoxybenzene boronic acid. The title compound was obtained in 84% yield as white foam. MS (m/e): 566.4 (MH+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]CCCC.[Br:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[N:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[Br:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)([OH:26])[C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: O=C1CCCc2c(Br)cncc21
Reactant: Cc1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCCc3c(Br)cncc32)cc1C
Temperature: 0 °C
Yield: 63.8 %

Procedure:
A solution of 4-bromo-1,2-dimethylbenzene (78.6 mg, 425 μmol) in THF (1.3 mL) was cooled (−78° C.) and treated with n-BuLi (1.6 M in n-hexane, 265 μL, 425 μmol). After 15 min a solution of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate A-1[C]) (80 mg, 354 μmol) in THF (1.3 mL) was added and after 1 h the brown suspension was warmed up 0° C. The mixture was poured on aq. sat. NH4Cl-solution and extracted with EtOAc (3×). The organic layers were washed with aq. sat. NaHCO3 and aq. sat. NaCl solution, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 2%)) gave the title compound (75 mg, 64%) as off-white foam. MS: 332.1 (M+H+, 1 Br).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](S(C)(=O)=O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:29].[Na+].O.Cl>O1CCOCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:28])([CH3:27])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([OH:29])=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Temperature: 80 °C
Yield: 37 %

Procedure:
7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (800 mg, 1.92 mmol) was dissolved in 1,4-dioxane (5.00 mL) and 5.00 M sodium hydroxide in water (5.00 mL, 25.0 mmol) was added. The reaction was heated at 80° C. for 2 hours and then acidified to pH 6 with conc. HCl. The product was then extracted with DCM (100 mL) and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as a yellow solid (252 mg, 37%). m.p.=194-195° C.; LCMS (m/e) 356 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.27 (d, 1H, J=7.7 Hz), 8.07 (s, 1H), 7.52-7.44 (m, 1H), 7.40 (d, 1H, J=7.6 Hz), 7.17 (d, 1H, J=5.1 Hz), 7.05 (d, 1H, J=5.1 Hz), 4.84 (s, 2H), 0.97 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH3:16])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O1CCCC1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH:22]1([CH2:28][NH:29][C:5](=[O:6])[C:4]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 200 mg of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of tetrahydrofuran was added dropwise under ice cooling to a mixture of 5 ml of tetrahydrofuran, 93 mg of cyclohexylmethylamine and 100 mg of triethylamine. Then, the mixture obtained was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 223 mg of N-cyclohexylmethyl-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 45 of the present invention) represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11](O)[C:12]=1[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7].[CH:16]1([CH:19]([OH:22])[C:20]#[CH:21])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH:16]1([CH:19]([O:22][C:11]2[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=2[O:13][CH3:14])[C:6]([O:8][CH3:9])=[O:7])[C:20]#[CH:21])[CH2:18][CH2:17]1
Reactant: COC(=O)c1cc(O)c(OC)c(OC)c1
Reactant: C#CC(O)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C#CC(Oc1cc(C(=O)OC)cc(OC)c1OC)C1CC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
63.6 g of methyl 3,4-dimethoxy-5-hydroxy-benzoate [E. Spath and H. Roder, Monatsh. fur Chemie, 43, 93 (1923)], 38.5 g of (RS)-1-cyclopropyl-prop-2-yn-1-ol and 118 g of triphenylphosphine were dissolved in 600 ml of toluene under argon and cooled to 5° C. A solution of 70 ml of diethyl azodicarboxylate in 150 ml of toluene was slowly added dropwise thereto at 5° C. over 90 min. The mixture was stirred at 5° C. for a further 1 hr. and at 20° C. for 3 hrs. Then, 300 ml of toluene were distilled off on a rotary evaporator and the suspension obtained was stirred in an ice bath for 30 min. The separated triphenylphosphine oxide was filtered off and the filtrate was evaporated. The resulting oil was chromatographed on silica gel with hexane/ethyl acetate 4:1, then 3:1. Crystallization was effected from diethyl ether and hexane. There was obtained methyl (RS)-3-(1-cyclopropyl-prop-2-ynyloxy)-4,5-dimethoxy-benzoate as white crystals.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:24][N:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28]>C1COCC1>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1.[CH3:24][N:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28]
Reactant: c1ccc(COc2ccc3cnn(C4CCCCO4)c3c2)cc1
Agent: CCC(=O)N(C)C
Solvent: C1CCOC1
Product: Oc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
5% palladium on carbon-STD-type-50% wet with water (224 mg; manufactured by N.E. Chemcat Corp.), and a THF solution of 3-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-N,N-dimethylpropanamide that can be produced by the method described in Reference Example 51 or the like [6.3 mL; prepared by dissolving 3-(6-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-N,N-dimethylpropanamide (596 mg) in dehydrated THF (7.3 mL)) were mixed, and the reaction system was purged with hydrogen. Under a hydrogen atmosphere, the reaction solution was stirred overnight at room temperature. The reaction solution was purged with nitrogen, and then was filtered. The solvent was evaporated under reduced pressure from the filtrate, and thus the title compound (383 mg) was obtained.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][C@H:19]([C:21]([F:24])([F:23])[F:22])[O:18][C@H:17]([CH3:25])[CH2:16]1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+].F[C:42]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:43]=1[CH:44]=[O:45].CN(C)CCNC>C(Cl)Cl>[CH3:25][C@H:17]1[O:18][C@@H:19]([C:21]([F:23])([F:22])[F:24])[CH2:20][N:15]([C:42]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:43]=2[CH:44]=[O:45])[CH2:16]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H](C(F)(F)F)O1
Agent: CC(Cl)OC(=O)Cl
Agent: CNCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C(F)(F)F)O1
Temperature: 25 °C

Procedure:
1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of 4-benzyl-cis-2-methyl-6-(trifluoromethyl)morpholine (324 mg, 1.25 mmol) in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 16 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 4 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (0.261 mL, 1.5 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (254 mg, 1.5 mmol, Oakwood) are added and the mixture is heated at 60° C. for 36 hours. N,N,N′-trimethylethylenediamine (2.3 mL) is added and the reaction is stirred an additional 2 hours @60° C. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is taken up in EtOAc (100 mL) and washed 2× with 1.0 M HCl, 1× with saturated NaHCO3 and 1× with brine (75 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 25M+ using 20% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 100° C. yielding a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:29][CH3:28])[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: CN
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)c(N)c2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Amino-1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (23 mg) and a 40% aqueous solution (60 mg) of methylamine were added to pyridine (240 mg), and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (6 mg) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([F:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)c(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a stirred suspension of zinc powder (0.54 g, 8.13 mmol) in THF (20 mL) was slowly added TiCl4 (0.45 mL, 4.07 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of (4-bromophenyl)(3-fluoro-4-hydroxyphenyl)methanone (82) (0.30 g, 1.02 mmol) and cycloheptanone (0.35 g, 3.05 mmol) in THF (6 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (20 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 20:1) to give 0.30 g (79%) of compound 133 as a yellow solid. mp 102-104° C. 1H NMR (400 MHz, CDCl3): δ 1.56 (br s, 8H), 2.20-2.35 (m, 4H), 4.96 (br s, 1H), 6.75-6.86 (m, 2H), 6.90 (t, J=8.6 Hz, 1H), 7.00 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H). LCMS (ES): m/z 373 (M−H)−.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:25]([SH:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C(O)C>[CH2:25]([S:37][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C=CC(=O)OC(CSCc1ccccc1)CSCc1ccccc1
Reactant: CCCCCCCCCCCCS
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCC(=O)OC(CSCc1ccccc1)CSCc1ccccc1

Procedure:
A solution of 16.5 grams of 1,3-bis-(benzylthio)-2-propyl acrylate, 9.45 grams of dodecanethiol, and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 11 hours. The reaction mixture was allowed to cool and was then poured into water. The oil which precipitated was separated by extraction with hexane and the hexane solution was stripped on a rotary evaporator. The residue, which weighed 22.5 grams, was identified as 1,3-bis-(benzylthio)-2-propyl 3-(dodecylthio)propionate by means of its NMR spectrum.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:23])[CH:16]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Cc1cccc(O)c1
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(OC(c2ccccc2)C(O)C(=O)NC(C)C)c1

Procedure:
This compound was prepared as in Example 12 from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (6.16 g.), m-cresol (3.3 g.), sodium hydride (50% oil dispersion, 1.5 g.), 18-crown-6 (0.9 g.), and acetonitrile (250 ml.). The product which was recrystallized from ether melted at 158°-159°, and weighed 3.2 g.