Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]1=[O:12].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=[C:20]2[N:19]=1>O1CCOCC1>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[C:26]([CH2:2][N:3]3[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]3=[O:12])=[C:20]2[N:19]=1
Reactant: O=C1CC(C=C(F)F)CN1CCl
Reactant: Clc1ccn2nc(C3CC3)cc2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nn2ccc(Cl)nc12
Yield: 69 %

Procedure:
To a solution of 1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one x276 (2.55 mmol, 2 eq, 500 mg) in 15 ml of dioxane at 0° C. are added successively AlCl3 (5.1 mmol, 2 eq, 680 mg) and 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 (2.55 mmol, 1 eq, 495 mg). The mixture is stirred at reflux for 1 hour, then quenched with an aqueous saturated NH4Cl solution and the resulting mixture extracted with AcOEt. The cumulated organic layers are washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/2/0.2), followed by a crystallization step in hexane. 1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 219 is obtained as a solid (623 mg).
Reaction SMILES: Br.Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccccn3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 10.6 parts of 1-(4-methoxyphenyl)piperazine dihydrobromide, 7.9 parts of 2-bromopyridine, 8.4 parts of potassium carbonate and 90 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is diluted with water and the product is extracted twice with benzene. The combined extracts are dried, filtered and evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 8 parts (74%) of 1-(4-methoxyphenyl)-4-(2-pyridinyl)piperazine; mp. 125.6° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([F:18])=[C:12]([CH:14]=[CH:15][C:16]=1[F:17])[NH2:13].CCCCCC.O>CN(C)C=O>[Br:1][C:14]1[CH:15]=[C:16]([F:17])[C:10]([Cl:9])=[C:11]([F:18])[C:12]=1[NH2:13]
Reactant: Nc1ccc(F)c(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(F)c(Cl)c1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
18.9 g of N-bromosuccinimide was gradually added to a stirred solution of 17.4 g of 3-chloro-2,4-difluoroaniline in 150 cm3 of dry dimethylformamide, cooled to a temperature in the region of −20° C., while this temperature was maintained. After stirring for 1 hour, the temperature was brought to the region of 20° C. and then the mixture was concentrated under reduced pressure (5 kPa), at a temperature in the region of 60° C. The residue obtained was supplemented with 400 cm3 of hexane and 200 cm3 of water. The mixture was stirred and the aqueous phase decanted off. The latter was extracted three times with successively 200, 200, and 100 cm3 of hexane. The extracts were combined, washed twice with 200 cm3 of water and twice with 200 cm3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 19.2 g of 2-bromo-5-chloro-4,6-difluoroaniline was obtained in the form of a white solid, which melted at 62° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[S:30][C:31]([CH2:34]Cl)=[CH:32][N:33]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[S:30][C:31]([CH2:34][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])=[CH:32][N:33]=2)[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: FC(F)(F)c1cc(-c2ncc(CCl)s2)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-[3,5-bis(trifluoromethyl)phenyl]-5-(chloromethyl)-1,3-thiazole (Example 321B): 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 2H), 7.89 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 6.67 (s, 1H), 5.58 (s, 2H), 2.57 (s, 3H): MS (ES) m/z 532 (M−1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[I-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C(=CC(=C(C=1)C)C)C)C>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[C:1]1([O:7][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cc1cc(C)c(C)cc1C
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Phenol (2.836 g, 30 millimoles, Aldrich, 99+%), sodium hydroxide (1.411 g, 35 millimoles, Merck, 97%), and sodium iodide (0.433 g, 3 millimoles, Aldrich, 98%) were dissolved in water (299.19 g). The excess molar concentration of sodium hydroxide of was 0.166. The aqueous phase was introduced into a 3-neck 500 mL reactor immersed in the water bath at 50° C. The mixture consisting of benzyl chloride (3.930 g, 31 millimoles, Aldrich, 97%), Aliquat 336 (2.597 g, 6 millimoles, Aldrich), durene (0.693 g, 5 millimoles, Aldrich, 98%), and toluene (15.02 g, J. T. Baker, ultra-pure). The organic phase:aqueous phase weight ratio was 1:14. The two phase mixture was stirred mechanically (600 rpm) at 50° C. for 90 minutes. The aliquot of the reaction mixture was centrifuged, the phases were separated and the organic phase was injected into a GC column. The yield of benzyl phenyl ether based on the limiting reactant (phenol) was 70%. No byproducts could be detected in the chromatograms representing the reaction mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.[BH3-]C#N.[Na+]>CO>[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:11][C:10]1[CH:9]=[CH:8][NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=Cc1ncc[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1ncc[nH]1
Yield: 98.5 %

Procedure:
A reaction mixture with 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.2 g, 1.30 mmol), 2-imidazolecarboxaldehyde (0.15 g, 1.53 mmol), NaCNBH3 (0.082 g, 1.30 mmol) and OHAc (0.15 mL, 2.60 mmol) in methanol (5 mL) was stirred at r.t. for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Washed with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.30 g (99%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: O=Cc1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(Cc3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
80 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. To the mixture were added 73 mg of benzaldehyde, 97 mg of triacetoxy sodium borohydride and 41 mg of acetic acid, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate. Then the mixture was evaporated, and the residue was purified by NH silica gel chromatography (hexane/ethyl acetate system), to give 80 mg of the title compound.
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:21][C:22]1[CH2:27][CH2:26][CH2:25][C:24]([CH3:29])([CH3:28])[C:23]=1/[CH:30]=[CH:31]/[C:32](/[CH3:61])=[CH:33]/[CH:34]=[CH:35]/[C:36](/[CH3:60])=[CH:37]/[CH:38]=[CH:39]/[CH:40]=[C:41](/[CH:43]=[CH:44]/[CH:45]=[C:46](/[CH:48]=[CH:49]/[C:50]1[C:55]([CH3:57])([CH3:56])[CH2:54][C@H:53]([OH:58])[CH2:52][C:51]=1[CH3:59])\[CH3:47])\[CH3:42]>O1C(CC)C1.CC1C[C@@H](O)CC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)/C=C/C1C(C)(C)C[C@H](O)CC=1C>[CH3:59][C:51]1[CH2:52][C@@H:53]([OH:58])[CH2:54][C:55]([CH3:56])([CH3:57])[C:50]=1/[CH:49]=[CH:48]/[C:46](/[CH3:47])=[CH:45]/[CH:44]=[CH:43]/[C:41](/[CH3:42])=[CH:40]/[CH:39]=[CH:38]/[CH:37]=[C:36](/[CH:35]=[CH:34]/[CH:33]=[C:32](/[CH:31]=[CH:30]/[C@@H:23]1[C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][CH:27]=[C:22]1[CH3:21])\[CH3:61])\[CH3:60]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1
Agent: CCC1CO1
Agent: [Br-]
Product: CC1=CCCC(C)(C)[C@H]1/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C[C@@H](O)CC1(C)C

Procedure:
The ketone 1 prepared from isophorone is reacted with a Grignard reagent prepared from but-3-yn-2-ol to give the diol 2, from which the dihydroxyketone 3 is formed by eliminating the ethylenedioxy protective group. The dihydroxyketone 3 can be reduced with lithium aluminum hydride to the triol 4, which can be reacted with acetic anhydride in pyridine to give the acetate 5. Dehydration of 5 with phosphoryl chloride in pyridine gives the enyne diacetate 7, which can be reduced with lithium aluminum hydride to the enynediol 6 and, when the reaction is carried out under more stringent conditions, to 3-hydroxy-β-ionol. Selective oxidation of 8 with manganese dioxide gives 3-hydroxy-β-ionone 9. Reaction of the latter with vinyl magnesium bromide gives the vinyl alcohol 10, which, when treated with triphenylphosphonium bromide, forms the Wittig reagent 11. When the latter is heated with the dialdehyde 12 in 1,2-epoxybutane, zeaxanthin 14 is obtained in good yield. Condensation of the Wittig salt 11 with (C25 -)-β-apo-12'-carotenal 16 in 1,2-epoxybutane gives β-cryptoxanthin 18, or condensation of 11 with racemic (C25 -)-α-apo-12'-carotenal gives zeinoxanthin 17. Equation 1 below illustrates the synthetic route described:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16](O)=[O:17].Cl[Si](C)(C)C.Cl>CCOCC.C1COCC1>[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=1[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: Brc1ccccn1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 2-bromopyridine (5 ml, 52 mmol) in Et2O (60 ml) was added 40 ml of a n-butyllithium (1.6M in hexane, 64 mmol) drop wise at −40° C. over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 1 hr at −50° C. to −30° C. In a separate flask, a solution of 2-amino-5-chlorobenzoic acid (2.05 g, 12 mmol) in dry THF (90 ml), under nitrogen atmosphere and with ice-cooling, was added in one portion to the solution prepared as described above. The reaction mixture was stirred for 2 hrs at 0° C. and then chlorotrimethylsilane (30 ml) was added at 0° C. with stirring. The reaction mixture was allowed to warm to room temperature and 1 N HCl aq (100 ml) was added. The resulting two-phase system was separated. The aqueous phase was adjusted to pH12 with 6N NaOH solution and extracted with ethyl acetate (2×150 ml). The combined organic extractions were dried over Na2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1:4) as eluent. Crystallization of the product from Et2O/hexane mixture gave 1.26 g (45%) of desired product as yellow solid. 1H-NMR (DMSO-d6, 500 MHz): δ 6.90 (1H, d, J=9 Hz), 7.31 (1H, dd, J=9 and 2.5 Hz), 7.40 (2H, br), 7.53 (1H, d, J=2.5 Hz), 7.61 (1H, m), 7.79 (1H, d, J=8 Hz), 8.03 (1H, m), 8.69 (1H, m). MS: (ESI+): 233.2 (M+1).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][S:18]C(=O)C)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.Cl>O.N>[SH:4][CH2:5][CH:6]([CH2:17][SH:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CS)CS

Procedure:
1-[(2-Acetylthiomethyl-3-(acetylthio)propanoyl]-L-proline (1.2 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under an atmosphere of argon. After twenty minutes, the mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate 1-(2-mercaptomethyl-3-mercaptopropanoyl)-L-proline is filtered and dried, yield 0.63 g., m.p. 138°-140°.
Reaction SMILES: [CH3:1][C:2]1[C@@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[OH:7][C@@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][CH:13]=[CH2:14])=[C:2]1[CH3:1]
Reactant: C=CCC1=C(C)[C@@H](O[N+](=O)[O-])CC1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)[C@H](O)CC1=O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of 0.99 g of purified (S)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one prepared in Example 6, 0.50 g of calcium carbonate and 30 ml of water was stirred at a temperature of 85°-90° C. for 2 hours. Thereafter, with the same operations as in Example 3, 0.72 g of (R)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one (chemical purity: 94.2%, [α]D24 : -6.64° (C=1.18, in chloroform), (R)-isomer/(S)-isomer=76.2/23.8) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([Cl:17])=[O:15])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C

Procedure:
To an oven-dried round bottom flask containing 1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-8) (618 mg, 3.0 mmol) and CH2Cl2 (3 mL) was added thionyl chloride (1.07 g, 9.0 mmol) and N,N-dimethylformamide (0.1 mL). The reaction mixture was stirred at ambient temperature under an Ar atmosphere until the gas evolution ceased (2-3 h). The excess thionyl chloride was removed under vacuum and the resulting residue dissolved in CH2Cl2 (3 mL). The mixture was used without further manipulation.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:4]([C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:50][CH2:51][CH3:52]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-chloro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.26-1.36 (m, 2 H) 1.69-1.76 (m, 2 H) 2.50 (s, 3 H) 4.17 (t, 2 H) 6.29 (s, 1 H) 7.69-7.76 (m, 1 H) 7.77-7.82 (m, 2 H); MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH2:18](O)[C:19]([F:22])([F:21])[F:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (111 g, 0.35 mol) was dissolved in tetrahydrofuran (1600 mL). To the solution were added trifluoroethanol (38 mL, 0.53 mol), triphenylphosphine (117 g, 0.42 mol) and diisopropyl azodicarboxylate (89.4 mL, 0.42 mol) at 0° C. The mixture was stirred for 30 min at 0° C., for 1 h at room temperature and for 18 h at 50° C. The mixture was cooled, poured into n-heptane (3.8 L) and extracted with 80% methanol (2×3.8 L). The methanol phase was extracted with another 3.8 L of n-heptane, the n-heptane phases were combined and dried with MgSO4. The solvent was removed in vacuo to give the title compound (121.5 g) as yellowish oil.
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH2:3][NH2:4].O=S(Cl)Cl.[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[S:23]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)(O)CN
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)(C)S1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-5,5-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]3)[CH:13]=2)OC1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=2[N:35]=1>[Pd]>[F:27][C:11]1[CH:10]=[C:9]([F:28])[C:8]([C:31]2[O:32][C:33]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:13][C:12]=1[C@:14]1([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:23])([CH3:24])[O:18][CH2:17][C:16](=[O:25])[NH:15]1
Reactant: CC1(C)COB(c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)OC1
Reactant: FC(F)(F)c1ccc2nc(Cl)oc2c1
Agent: [Pd]
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 73 %

Procedure:
In a manner analogous to that described in Example 19a), the palladium-catalyzed coupling of (R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate D1.1) and 2-chloro-6-(trifluoromethyl)benzo[d]oxazole yielded the title compound (73% yield) as a white solid. MS (ISP): m/z=491.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([OH:33])[C:31]#[CH:32].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:32]#[C:31][CH2:30][OH:33]
Reactant: C#CCO
Reactant: Fc1ccc(I)c(F)c1F
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCC#Cc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2,3,4-trifluoroiodobenzene (5.00 g), copper(I) iodide (73.9 mg), triphenylphosphine (254 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (402 mg), propargyl alcohol (1.26 ml), diisopropylethylamine (13.5 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 17 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue 5 was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.14 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1[C:24](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:23](OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH2:25][CH2:24][CH3:23])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Product: CCC/C(=C\c1c(C)c(OC)c(OC)c(OC)c1OC)C(=O)OCC

Procedure:
Compound 8d was prepared from 7 (0.437 g, 1.82 mmol) as described above for 8a to give 0.275 g (0.780 mmol, 43%) of the product as a colorless oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.O.[NH2:35][NH2:36]>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:36][N:35]=2)=[CH:22][CH:23]=1)=[O:29])[CH3:32]
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 90.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-ethoxycarbonylmethylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (128 mg, 0.29 mmol, prepared in Synthetic Example 26) in DMF (3 ml) was added hydrazine monohydrate (80%, 34 μl, 0.87 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (115 mg, 91%).