Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH:19](Br)[C:20]([OH:22])=[O:21]>CS(C)=O.O>[CH3:9][C:5]1[C:4]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)=[CH:3][C:2]2[O:1][CH:19]([C:20]([OH:22])=[O:21])[O:8][C:7]=2[CH:6]=1
Reactant: Cc1cc(O)c(O)cc1C(=O)c1cccnc1
Reactant: O=C(O)C(Br)Br
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1C(=O)c1cccnc1)OC(C(=O)O)O2

Procedure:
By reaction of 17.3 g (0.075 mol) of (3,4-dihydroxy-6-methylphenyl)-(3-pyridyl)-methanone with 16.5 g (0.075 mol) of dibromoacetic acid, analogously to Example 3, there is obtained 5-methyl-6-nicotinoyl-1,3-benzodioxole-2-carboxylic acid as sand-coloured crystals, m.p. 250°-232° C. (from dimethyl sulfoxide/water).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14]([NH:16][CH2:17][C:18]([O:20]C1C(F)=C(F)C(F)=C(F)C=1F)=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[N:33](C)C=O>O>[NH:16]([C:14]([O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([NH2:33])=[O:20]
Reactant: CN(C)C=O
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The amine trifluoroacetate from Example 4 (215 mg, 0.180 mmol) is dissolved in N,N-dimethylformamide (2 ml). To this solution 1M sodium bicarbonate (200 μl, 0.200 mmol) and pentafluorophenyl N-benzyloxycarbonylglycinate (106 mg, 0.270 mmol) is added. After 1 h, the reaction mixture is diluted with water (2×). Isolation by reverse-phase (C18) flash column chromatography eluting with acetonitrile/water gives, after lyophilization of the product-containing fractions, the N-CBZ glyamide: C61H92N10O19, formula weight=1269.47.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.[CH2:21]([O:23][C:24](=[O:38])[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:27]Br)[CH3:22]>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:27][C:26]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[CH:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1ccc(OC)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=C(CN[C@@H](CC(C)C)C(=O)OC)Oc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.64 g, 3.56 mmol) in acetonitrile (8.9 mL) was treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol) and acetonitrile (8.9 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.02 g, 3.23 mmol) in acetonitrile (8.09 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 20-30% ethyl acetate/hexanes) afforded (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.84 g, 68%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.63-1.81 (m, 1H), 3.60 (s, 3H), 3.77 (s, 3H), 3.88 (dd, J=6.5, 3.2 Hz, 1H), 3.96 (d, J=6.9 Hz, 1H), 4.01 (d, J=6.9 Hz, 1H), 4.61 (s, 1H), 7.02 (s, 4H).
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C:10]4[CH2:16][CH2:15][CH2:14][C:11]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][C:2]1=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>[CH:1]1[N:12]2[C:13]3[C:9]([C:10]4[CH2:16][CH2:15][CH2:14][C:11]=42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH:2]=1
Reactant: O=C1Cn2c3c(c4cccc(c42)CN1)CCC3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C1=Cn2c3c(c4cccc(c42)CN1)CCC3
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a suspension of 3,4,9,10-tetrahydro-8H-cyclopenta[b][1,4]diazepino[6,7,1-hi]indol-2(1H)-one (67 mg, 0.30 mmol) in Et2O (7 mL), LAH power (28 mg, 0.74 mmol) was added slowly at rt under Ar. After 16 h, additional Et2O (5 mL) was added followed by dropwise addition of a sat'd Na2SO4 solution (0.1 mL). H2 gas evolved upon addition. Additional Et2O (8 mL) was added, dried over Na2SO4, filtered and concentrated in vacuo to give 44 mg (70%) of the title compound as a yellow syrup.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:20]1[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
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: [Cs+]
Product: Cc1ccc(-c2c(C(C)O)oc(=O)c3ccccc23)cn1
Yield: 29 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.55 g, 2.04 mmol), 6-methylpyridin-3-ylboronic acid (0.550 g, 2.0 mmol), Pd(PPh3)4 (0.118 g, 0.102 mmol) and Cs2CO3 (1.06 g, 3.27 mmol) to afford the title compound (0.163 g, 28%)
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[Cl-].[Na+].[CH2:15](O)[CH3:16]>>[CH3:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:15][CH3:16])=[O:4]
Reactant: CCO
Reactant: CC[C@H](C)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)CC
Temperature: 25 °C
Yield: 822.7 %

Procedure:
9 g (88 mmol) of the (S)-(+)-2-methylbutyric acid obtained by the method of the above Referential Example 1 was mixed with 20.24 g of 99.5% by vol. ethanol containing 0.4 g of conc. sulfuric acid and heated under reflux for 4 hours. After the completion of the reaction, the mixture was cooled to room temperature and poured into 150 ml of a saturated aqueous solution of sodium chloride. The oily layer was extracted with n-hexane and thus separated from the aqueous layer. Then it was further washed with a saturated aqueous solution of sodium chloride twice and dehydrated over calcium chloride. After distilling off the n-hexane under atmospheric pressure, the temperature was further elevated. Thus 9.3 g of (S)-(+)-ethyl 2-methylbutyrate (boiling point: 135° C./760 mmHg) was obtained (yield: 81.3%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.CCN(CC)CC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:4][C:3]=1[CH3:9]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1nc(Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN[C@H](C)C2)ccc1Br
Temperature: 165 °C
Yield: 35.6 %

Procedure:
In a 10 mL microwave vial equipped with a magnetic stir bar were mixed 3-bromo-6-chloro-2-methylpyridine (515 mg, 2.496 mmol), (R)-2-methylpiperazine (250 mg, 2.496 mmol), and Et3N (1.044 mL, 7.49 mmol) in DMF (4 mL). The resulting yellow suspension was heated in a microwave reactor to 165° C. for 4 hours. The reaction mixture was subsequently partitioned between 0.25N HCl (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (40 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified using flash chromatography (12 g column) eluting with a gradient of 0-100% EtOAc in heptanes and then 0-20% MeOH in DCM. The pure fractions were combined and concentrated to give the title compound as a clear syrup (240 mg, 35.6%).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>O1CCOCC1.CCOCC.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[Cl:13][C:12]([Cl:15])([Cl:14])[CH:7]1[CH:8]2[CH:3]([C:9]2([CH3:11])[CH3:10])[C:4](=[O:5])[O:6]1
Reactant: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1(C)C2C(=O)OC(C(Cl)(Cl)Cl)C21
Yield: 56.5 %

Procedure:
To a refluxing solution of cupric acetylacetonate (0.07 g, 0.27 mole) in 70 ml of dioxane was added drop-dropwise over a 31/2 hour period, under an argon atmosphere, a solution of (±)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (1.09 g, 0.004 moles) and cupric acetylacetonate (0.007 g, 0.027 mmole) in 10 ml of dioxane. The reaction mixture was then heated under reflux for one hour and evaporated to dryness, yielding a residue which was dissolved in ether. The ethereal solution was washed successively with two portions of aqueous 1N hydrochloric acid, two portions of aqueous sodium bicarbonate, and twice with saturated aqueous sodium chloride. After drying the solution over magnesium sulfate, the ether was evaporated to afford a pale yellow oil, which was purified by column chromatography on a silica gel column using a 9/1 mixture of n-hexane/ethyl acetate as the eluent, to give (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.55 g, 53% yield).
Reaction SMILES: [Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]12)=[O:9].C(N(CC)CC)C.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.Cl>CN(C)C=O>[Na+:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][C@@H:11]1[C:23](=[O:24])[N:13]2[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][O:19][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid sodium salt (3.86 g) and, at -5° C., triethylamine (1.40 ml) and diketene (1.50 ml) were added. The reaction was carried out at -5°-0° C. for 1 hour, after which time the reaction mixture was poured in ice-water (200 ml). The mixture was adjusted to pH 2.0 with 4 N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was rinsed with water, diluted with water, brought to pH 7.0 with 5% aqueous sodium hydrogen carbonate solution and separated. The water layer was taken, concentrated and subjected to column-chromatography on Amberlite XAD-2, elution being carried out with water-methanol. The eluate was lyophilized. The above procedure provided 7β-(2-thienylacetamido)-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid sodium salt (4.48 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][N:3]=[C:4]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3nnc(N(C)C)s3)CS[C@H]12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3nnc(N(C)C)s3)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A mixture of 0.11 g of benzhydryl 7-(2-methoxyimino-2-phenylacetamido)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 48), 2 ml of anisole and 4 ml of trifluoroacetic acid is stirred for 30 minutes at room temperature. After removal of the solvent under reduced pressure, the residue is triturated with the addition of absolute ether. The precipitates are filtered, and washed with ether to give 0.058 g of 7-(2-methoxyimino-2-phenylacetamido)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][OH:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: OCc1ccccn1
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Product: O=C(O)c1ccc(Br)c(OCc2ccccn2)n1

Procedure:
The title compound was synthesized in analogy to Example 9 d, using 5-bromo-6-chloro-pyridine-2-carboxylic acid and 2-pyridinemethanol (CAN 586-98-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 308.9876 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11](=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:13])[CH:8]=2)[O:3]1.[H-].[Na+].[CH3:17][CH2:18][O:19][C:20]([CH2:22]P(OCC)(OCC)=O)=[O:21].P([O-])([O-])([O-])=O>O1CCCC1>[CH2:18]([O:19][C:20]([CH2:22][C:11]1[C:2]([CH3:14])([CH3:1])[O:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:13])=[CH:6][CH:5]=2)=[O:21])[CH3:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC1(C)Oc2ccc(F)cc2CC1=O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1=Cc2cc(F)ccc2OC1(C)C
Reaction time: 0.5 h

Procedure:
While stirring at from 0° to 5°, a solution of 5.7 g (29 mmol) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in 100 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 1.69 g (35 mmol) of sodium hydride dispersion (55% in mineral oil), which has been substantially freed of mineral oil beforehand by repeated washing with n-hexane, in 100 ml of absolute tetrahydrofuran. The mixture is then stirred at from 0° to 5° for 30 minutes and then a solution of 7.9 g (35 mmol) of phosphonoacetic acid triethyl ester of the formula (H5C2O)2P(=O)CH2C(=O)OC2H5 in 70 ml of absolute tetrahydrofuran is added dropwise thereto within a period of 30 minutes at from 0° to 5°. The reaction mixture is stirred for a further 30 minutes at from 0° to 5° and then for 16 hours at room temperature and then poured into 700 ml of cold phosphate buffer solution (pH=6). The resulting mixture is extracted with diethyl ether. The combined organic phases are washed in succession with phosphate buffer solution (pH=7) and water, dried over sodium sulfate and concentrated by evaporation. The resulting red oil is chromatographed on 400 g of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 5.76 g (75% of the theoretical yield) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromene in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:1][C:2]3[CH:23]=[CH:22][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCOCC1
Reaction time: 4 h
Yield: 53.6 %

Procedure:
Morpholine-4-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (121 mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (92.0 mg) were dissolved in N,N-dimethylformamide (4 ml), and diisopropylethylamine (0.358 ml) and HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate; 213 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring for 4 hr. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (131.9 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration, and dried under aeration to provide a titled compound as pale yellow powder (107.1 mg, 55.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:29]([C:31]3[NH:32][C:33]4[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=3)=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:43]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:28])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][N:19]=3)=[O:17])[CH2:13][CH2:12][N:11]([C:29]([C:31]3[N:32]([CH3:43])[C:33]4[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=3)=[O:30])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CN(C(=O)c1ccc(C(F)(F)F)cn1)[C@@H]1CCN(C(=O)c2cc3c([nH]2)C(=O)CCC3)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(C(F)(F)F)cn1)[C@@H]1CCN(C(=O)c2cc3c(n2C)C(=O)CCC3)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of the compound (0.060 g) obtained in Example 642 in DMF (1 mL) was added sodium hydride (0.005 g) and the mixture was stirred for 10 min. Methyl iodide (0.020 mL) was added at 0° C. and the mixture was stirred at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→70% ethyl acetate/hexane) to give the title compound (0.020 g, 33%) as a white powder.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[S:33][C:32]([CH:34]=[O:35])=[N:31][CH:30]=1)[OH:28].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:34]([C:32]3[S:33][C:29]([CH:27]([OH:28])[C:26]([F:36])([F:25])[F:37])=[CH:30][N:31]=3)=[O:35])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ncc(C(O)C(F)(F)F)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(C(O)C(F)(F)F)s1
Yield: 93.4 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.30 g), 5-(2,2,2-trifluoro-1-hydroxyethyl)-1,3-thiazole-2-carbaldehyde (0.20 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (23 mg), triethylamine (0.05 mL), tetrahydrofuran (4 mL) and ethanol (2 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.45 g, yield 90%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 560 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12](Cl)[C:11]([CH:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=[O:38]>C(#N)C>[NH:19]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]([CH2:15][C:11]2[C:12]([OH:38])=[N:13][C:8]([NH:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[CH:18]1
Reactant: OC(c1ccc(NCc2ccc(Cl)cc2)nc1Cl)c1c[nH]c2ncccc12
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: Oc1nc(NCc2ccc(Cl)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 85 °C
Yield: 78.3 %

Procedure:
To (6-(4-chlorobenzylamino)-2-chloropyridin-3-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanol (P-0050, 0.028 g, 0.000070 mol) dissolved in acetonitrile (1 mL) was added triethylsilane (42.6 uL, 0.000266 mol) and trifluoroacetic acid (28.4 uL, 0.000368 mol). The reaction was heated at 85° C. overnight. The reaction was extracted with ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane, 3%, 5% and finally 10% methanol in dichloromethane to give the compound as a white solid (P-0051, 20 mg, 78%). MS (ESI) [M+H+]+=365.3.