Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([C:14]3[S:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:18]=3)=[N:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: C(#Cc1cnc(-c2cccs2)s1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ncc(C#Cc3ccccc3)s2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 0.80 gram (0.0030 mole) of 1-phenyl-2-[2-(thien-2-yl)thiazol-5-yl]ethyne in 20 ml of tetrahydrofuran was cooled to -78° C. A solution of n-butyllithium (1.4 ml of a 2.1M solution in hexane) was added, and the mixture was stirred at -78° C. for two hours. This mixture was transferred to another reaction flask containing a stirred solution of 0.65 gram (0.0060 mole) of ethyl chloroformate in 10 ml of tetrahydrofuran. This reaction mixture was allowed to warm slowly to room temperature and stir for approximately 18 hours. An aqueous, saturated ammonium chloride solution (20 ml) was added dropwise. The resultant mixture was extracted with diethyl ether. The organic extract was washed with water followed by an aqueous, saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:2), to yield 0.82 gram of ethyl [5-[5-phenylethynylthiazol-2-yl]thien-2-yl]carboxylate as a solid, m.p. 137°-141° C., Compound 30 of Table 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Clc1ccc(CCCBr)cc1Cl
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1ccc(Cl)c(Cl)c1
Yield: 46.8 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methypyridine and 4.05 g (15.1 mmol) of 1-bromo-3-(3,4-dichlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.18 g of the desired compound (yield: 46.9%). The resulting compound was identified as 1-(3,4-dichlorophenyl)-4-(3-ethyl-4-pyridyl)-butane (hereinafter referred to as compound 51) by the following analytical results.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22]N(C)C=O.P(OC)(OC)(OC)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:22])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: CN(C)C=O
Solvent: COP(=O)(OC)OC
Solvent: O
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 20 ml of dimethylformamide was added 4.2 g of trimethyl phosphate and the whole was refluxed for 5 hours. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue thus obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.4 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 241°-242° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH3:11]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCB(O)O
Reactant: O=Cc1ccc(Br)cc1
Product: CCc1ccc(C=O)cc1
Yield: 51.3 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and ethylboronic acid (165 mg, 2.23 mmol) in place of hexylboronic acid to give 4-ethylbenzaldehyde (93 mg, 51%). Used without further characterization.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=O)C.C(COC)OC.S(=O)(=O)(O)O.[Cl-].[Na+]>O>[OH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1ccc(O)cc1

Procedure:
A solution of 4.5 g (0.025 mole) of 4-acetoxybenzoic acid, 25 g of dimethoxyethane, 25 g of water, and 6.1 g of concentrated sulfuric acid was heated at reflux for 2 hours under a nitrogen atmosphere. The solution was cooled, saturated with sodium chloride, and extracted with 75 mL of ethyl acetate (3x). The organic fractions were combined, dried over anhydrous magnesium sulfate, and filtered. Rotary evaporation afforded a substantially quantitative yield of 4-hydroxybenzoic acid based on the 4-acetoxybenzoic acid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][C:15]([CH3:19])([NH2:18])[CH2:16][OH:17]>>[OH:13][CH2:14][C:15]([NH:18][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])([CH3:19])[CH2:16][OH:17]
Reactant: CC(N)(CO)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(CO)(CO)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 1,3-dihydroxy-2-methyl-2-amino-propane comparable as in Example A. A resin-like, colorless product was obtained.
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(O)=O.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:56])[CH2:43][O:44][C:45]1[C:54]2[CH2:53][CH2:52][CH2:51][C:50](=[O:55])[C:49]=2[CH:48]=[CH:47][CH:46]=1)([CH3:40])([CH3:39])[CH3:38]>O>[C:37]([O:41][C:42](=[O:56])[CH2:43][O:44][C:45]1[C:54]2[CH2:53][CH2:52][CH2:51][C@H:50]([OH:55])[C:49]=2[CH:48]=[CH:47][CH:46]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a flask containing 124 mg (0.203 mmol) of di-mu-chlorobis[(p-cymene)chlororuthenium(II) ([RuCl2(C10H14)]2, Strem Chemicals, Inc., CAS No. 52462-29-0) and 153 mg (0.416 mmol) of (1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylenediamine (Aldrich, CAS No. 167316-27-0) was added 50 mL of a pre-formed mixture of formic acid and triethylamine (in 5:2 molar ratio), and the resulting mixture was stirred at room temperature for 45 minutes (gas evolution was observed). Then 10 g (36.19 mmol) of (5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (V, prepared as described above) was added, and the reaction mixture was stirred at 42° C. internal temperature. Upon gas evolution and foaming, the reaction mixture was cooled to 33° C. internal temperature over 1 hour, and then stirred for an additional 24 hours at 33° C. The reaction mixture was then cooled in an ice-water bath, diluted with 50 mL of de-ionized water, and extracted with 100 mL of toluene. The organic layer was separated and washed with 1 M aqueous citric acid (50 mL), saturated aqueous sodium bicarbonate (50 mL), and water (50 mL). The organic phase was then dried over MgSO4, and concentrated azeotropically at 35° C./20 mmHg to a total volume of 30 mL. The resulting solution was co-evaporated with 2×100 mL of toluene to a total volume of 20 mL (product and toluene), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:14]([OH:18])(=O)[CH:15]=[CH2:16]>>[C:3]([O:12][CH2:11][CH2:10][O:9][CH2:8][C:2]([CH3:13])([CH3:1])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:14](=[O:18])[CH:15]=[CH2:16])(=[O:4])[CH:2]=[CH2:1]
Reactant: CC(C)(COCCO)COCCO
Reactant: C=CC(=O)O
Product: C=CC(=O)OCCOCC(C)(C)COCCOC(=O)C=C

Procedure:
One mole of neopentyl glycol (viz., 2,2-dimethylpropane-1,3-diol) is reacted with two moles ethylene oxide to produce 5,5-dimethyl-3,7-dioxanonane-1,9-diol. One mole of 5,5-dimethyl-3,7-dioxanonane-1,9-diol is reacted with two moles acrylic acid to produce 1,9-diacrylyloxy-5,5-dimethyl-3,7-dioxanonane.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O-:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([NH:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:2]2=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=[C:7]2[C:8](=[O:10])[NH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncc(C(=O)[O-])c(Cl)n1
Reactant: NNCc1ccccc1
Product: CSc1ncc2c(=O)[nH]n(Cc3ccccc3)c2n1

Procedure:
Prepared as described above in Example 1 starting with 4-chloro-2-methylthio-5-pyrimidinecarboxylate and benzylhydrazine to give the intermediate pure 1-benzyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one. The synthesis then follows as in Examples 2 and 3 to give 1-benzyl-3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. To a solution of 1-benzyl-3-bromo-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine (334 mg, 1 mmol) in chloroform (15 mL) was added 3-chloroperoxybenzoic acid (549 mg, 3 mmol, 3 eq) and the reaction mixture was allowed to stir for 5 hours at room temperature. To the reaction mixture were then added 10 mL of 1 M Na2CO3 solution and the layers were separated. The organic layer was washed with water, dried over MgSO4 and evaporated to give 1-benzyl-3-bromo-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidin-3-one (291 mg, 78% yield); LC/MS (m/e)=369.0 (MH+), Rt=1.95 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:32])[CH2:16][N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:11][C:10]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1)[OH:32]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (1.03 g, 2 mmol) which was obtained in Example 7) and 10% palladium on carbon (Pd/C) (0.4 g) in methanol (100 mL) at room temperature was added anhydrous ammonium formate (HCO2NH4) (1.26 g, 20 mmol) under a nitrogen atmosphere. The resulting mixture was refluxed for 2 hours. After cooling to room temperature the catalyst was removed by filtration through a celite pad and washed with methanol. The filtrate is evaporated under reduced pressure to give the titled compound (Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75 (dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H), 6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1 Hz, 1 H), 8.44 (s, 1H); MS (ES) m/z: 246.7 (MH+); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([O:27]CC)=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].O.Cl>O1CCCC1>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[N:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C#N)cc3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(Cn3nc(CC(=O)O)c4ccccc43)cc2)cc1
Yield: 60.9 %

Procedure:
Ethyl 2-[1-[4-(4-cyanobenzamido)benzyl]-1H-indazol-3-yl]acetate (121 mg, 0.276 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried, and the resulting solid was recrystallized from ethyl acetate to obtain a white solid 69 mg, at a yield of 60.9%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[N:11][C:10]([C:41]1[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
Following general procedure II, tert-butyl 4-{[trans-4-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)cyclohexyl]methyl}piperazine-1-carboxylate (150 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (130 mg, 0.45 mmol) to afford the product (170 mg) which was carried forward without any purification: ESI MS m/z 628 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (+/−)-pyrrolidin-3-yl-carbamic acid tert butyl ester by a method analogous to Example 1B. MS: 382/384 (MH+); HPLC Rf: 5.21 min.; HPLC purity 99%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][C:20]=1[F:21])=[N:16][N:15]([CH3:22])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC.CC(O)C>CCCCCC.CC(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][C:20]=1[F:21])=[N:16][N:15]([CH3:22])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Yield: 48 %

Procedure:
Trans-tert-butyl{[2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (735 mg) was fractionated by high performance liquid chromatography (instrument: K-Prep (manufactured by YMC), column: CHIRALPAK AS (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) 2-propanol 100%, mixing ratio: A/B=900/100, flow rate: 80 mL/min, column temperature: 25° C., sample concentration: 21 mg/mL (hexane/2-propanol=900/100), injection amount: 735 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (353 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AS (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/2-propanol=90/10), injection volume: 10 μL).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:4][C:3]=1[O:17][CH3:18].Br.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:24][NH2:25].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH2:24][NH:25][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[CH:10]/[C:5]1[CH:4]=[C:3]([O:17][CH3:18])[C:2]([OH:1])=[C:7]([O:8][CH3:9])[CH:6]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1O
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C=C/C(=O)NCc2ccc(O)c(O)c2)cc(OC)c1O

Procedure:
The compound was prepared based on the methodology in Example 5 using 38 mg (0.15 mmol) of 5-(4-hydroxy-3,5-dimethoxyphenyl)-penta-2E,4E-dienoic acid [Example 4], 67 mg (0.30 mmol) of 3,4 dihydroxybenzylamine hydrobromide, 153 μl (1.5 mmol) of triethylamine, and 100 mg (0.23 mmol) of BOP reagent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:19][N:20]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]1=[O:26]>C(O)(=O)C>[CH3:19][N:20]1[C:24](=[O:25])[CH2:23][CH:22]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([NH:10][C:11](=[O:18])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:21]1=[O:26]
Reactant: O=C(Nc1ccc2cc[nH]c2c1)c1ccccc1
Reactant: CN1C(=O)C=CC1=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3cc(NC(=O)c4ccccc4)ccc23)C1=O
Yield: 45.1 %

Procedure:
Compound 114 (3.5 g, 14.813 mmol) and N-methylmaleimide (4.07 g, 37.033 mmol) in glacial acetic acid (100 mL) was refluxed for 56 h. The reaction was brought to room temperature and acetic acid was evaporated. The crude solid was taken into ethyl acetate (100 mL), washed with sat. NaHCO3 solution (3×20 mL), brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 1:3 to 1:1) to obtain compound 115 (2.32 g, 45%) as a foam. 1H NMR (DMSO-d6) δ 2.80 (dd, 1H, J=5.1, 18.0 Hz), 2.92 (s, 3H), 3.23 (dd, 1H, J=9.3, 18.0 Hz), 4.34 (dd, 1H, J=5.1, 9.3 Hz), 7.26-7.36 (m, 2H), 7.45-7.60 (m, 4H), 7.95-7.98 (m, 2H), 8.07 (s, 1H), 10.17 (s, 1H), 11.02 (s, 1H); ESI-MS (m/z, %) 370 (M+Na, 100), 348 (MH+, 58).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1)#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:8])[CH:21]=1)#[N:29]
Reactant: CC1(C)OB(c2cnccc2C#N)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 100 mg, 0.224 mmol) was dissolved in DMF (1.5 mL). 4-Cyanopyridine-3-boronic acid pinacol ester (77 mg, 0.336 mmol), K2CO3 (0.224 mL, 0.448 mmol) and Pd(PPh3)4 (12.95 mg, 0.011 mmol) were added at RT. The vial was evacuated/purged with argon and sealed. The light yellow solution was stirred at 130° C. for 4 h. The yellow reaction solution was diluted with EtOAc (50 mL) and washed with water (3×30 mL). the combined extracts were dried over Na2SO4, filtered, the solvent was evaporated off under reduced pressure to give a crude that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 95:5). The fractions containing product were evaporated to dryness under reduced pressure and the residue was dissolved in hot MeOH (2 mL). The yellow solution was allowed to cool down to RT under stirring and the resulting suspension was stirred at RT for 1 h then filtered. The solid was washed with MeOH (1 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=5.91 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=470 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.97 (m, 2H) 2.84 (d, J=10.95 Hz, 1H) 3.07-3.18 (m, 1H) 3.19-3.30 (m, 1H) 3.32-3.45 (m, 1H) 4.21 (br. s, 1H) 4.82-5.00 (m, 1H) 7.36 (d, J=8.99 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 7.94-8.05 (m, 1H) 8.12 (d, J=6.26 Hz, 1H) 8.80-8.90 (m, 2H) 9.03 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].N1C=CC=CC=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1>[CH3:2][O:3][N:4]([CH3:5])[C:12](=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CNOC
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)N(C)OC
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
O,N-dimethylhydroxylamine hydrochloride (74.6 g, 765 mmol) was dissolved in THF (1 L) and pyridine (123 ml, 1531 mmol) was added and stirred for 30 minutes. Methacryloyl chloride (37.4 ml, 383 mmol) was added slowly and stirred overnight. The solids were filtered and concentrated. The residue was partitioned between water and CH2Cl2, washed with water, dried over sodium sulfate, filtered and concentrated to afford N-methoxy-N-methylmethacrylamide (56.5 g, 335 mmol, 87.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]=[C:6]([S:9][CH3:10])[S:7][CH3:8].CC([O-])(C)C.[K+].[CH2:18]([N:20]=C=S)[CH3:19]>C1COCC1>[CH3:10][S:9][C:6]1[S:7][C:8]([NH:20][CH2:18][CH3:19])=[C:4]([C:3]([O:2][CH3:1])=[O:11])[N:5]=1
Reactant: CCN=C=S
Reactant: COC(=O)CN=C(SC)SC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1sc(SC)nc1C(=O)OC
Reaction time: 0.5 h

Procedure:
A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous TKF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C, 29.99; H, 4.12; N, 8.74. Found: C, 29.71; H, 4.10; N, 8.60.