Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C@H:8]1[CH2:13][N:12]2[C:14]3[N:20]=[C:19]([CH3:21])[CH:18]=[C:17](Cl)[C:15]=3[N:16]=[C:11]2[CH2:10][C@@H:9]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:32])[NH:7][C@H:8]1[CH2:13][N:12]2[C:14]3[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=3[N:16]=[C:11]2[CH2:10][C@@H:9]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)c2nc3n(c2n1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](c1cc(F)c(F)cc1F)C3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc3n(c2n1)C[C@H](NC(=O)OC(C)(C)C)[C@@H](c1cc(F)c(F)cc1F)C3
Reaction time: 1 h

Procedure:
To 19 mg (0.04 mmol) of the product from Step A in 4 mL of methanol was added 10 mg of 20% palladium hydroxide on carbon. The reaction mixture was purged with hydrogen gas and held under 1 atmosphere of hydrogen for 1 h. The mixture was filtered through a pad of Celite and the filter cake was successively washed with three 4-mL portions of methanol. The combined filtrate and washings were concentrated and used without further purification. LC/MS 433.1 (M+1).
Reaction SMILES: [SiH3]Cl.[C:3]([C:7]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=1[O:9][Si:10]([CH3:13])([CH3:12])Cl)([CH3:6])([CH3:5])[CH3:4].[S-:23][C:24]#[N:25].[NH4+]>C1(C)C=CC=CC=1>[C:3]([C:7]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=1[O:9][Si:10]([N:25]=[C:24]=[S:23])([CH3:13])[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: N#C[S-]
Reactant: Cc1cc(C(C)(C)C)c(O[Si](C)(C)Cl)c(C(C)(C)C)c1
Agent: [NH4+]
Agent: [SiH3]Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O[Si](C)(C)N=C=S)c(C(C)(C)C)c1
Yield: 48 %

Procedure:
A mixture of the silyl chloride prepared in (a) above (78 g, 0.25M), ammonium thiocyanate(26 g,0.28M) and toluene was refluxed for 48 hours. The mixture was filtered and the filtrate evaporated; recrystallisation of the residue from acetonitrile gave the title compound (40 g, 48%) m.p. 83°-4°. (Found: C, 64.8; H, 9.0; N, 4.05. C18H29
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][N:15]([C@@H:16]([C:28](=[O:43])[N:29]([CH3:30])[C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:14]([CH:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)=[O:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(N)CC1
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
To a solution of (4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)-ethyl}-carbamoyl]cyclohexyl)carbamic acid tert-butyl ester (240 mg, 0.38 mmol) in 1 ml dichloromethane was added 0.5 ml trifluoroacetic acid and the mixture was stirred for 5 min. Sodium bicarbonate was added until gas evolution has ceased, and the mixture was extracted with dichloromethane (3×15 ml). The combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (16 g) with dichloromethane/methanol (4:1). The obtained product was dissolved in 3 ml of methanol and added 40 ml of water and 0.5 ml of acetic acid and lyophilized to give 99 mg of the title compound.
Reaction SMILES: C1(N)CCCCC1.[C:8]([O:12][C:13](/[C:15](/[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:16]/[C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C1(P(C2C=CC=CC=2)C[C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C)C=CC=CC=1>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[C:8]([O:12][C:13]([C@H:15]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:16][C:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: COCCOC/C(=C\C1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C@H](CP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1=CCCC=CCC1
Solvent: NC1CCCCC1
Product: COCCOC[C@H](CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
(E)-1-[2-(tert-Butoxycarbonyl)-3-(2-methoxyethoxy)prop-1-enyl]-1-cyclopentanecarboxylic acid cyclohexylamine salt (50 mg, 0.11 mmole), chloro(1,5-cyclooctadiene)rhodium(I)dimer (2.0 mg, 0.004 mmole) and (R)-(+)-1,2-bis(diphenylphosphino)propane (3.2 mg, 0.008 mmole) were charged to a glass vial and the top sealed with a rubber septum. The system was flushed with argon, methanol (0.5 mL) was added and the mixture hydrogenated in a steel bomb at 345 kPa (50 p.s.i.) and room temperature for 4 hours. The crude product was purified by chromatography on silica by eluting with diethyl ether/1% acetic acid to give, after combination and evaporation of appropriate fractions, the title compound as an oil, (22 mg, 61%) (ratio S:R 54.46), Rf =0.3 (ethyl acetate/hexane, 1:1+1% acetic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 4-aminocinnamate, one equivalent of 15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[CH3:10][NH:11][CH2:12][CH2:13][NH:14][CH3:15].O(C(C)(C)C)[Na].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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]>[F:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[N:11]([CH3:10])[CH2:12][CH2:13][NH:14][CH3:15]
Reactant: CNCCNC
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNCCN(C)c1ccc(F)cc1F

Procedure:
Combine 1-bromo-2,4-difluorobenzene (1.00 g, 5.18 mmol), N,N′-dimethylethylenediamine (2.74 g, 31.1 mmol), NaO-t-Bu (0.70 g, 7.2 mmol), Pd(dba)2 (0.060 g, 0.10 mmol) and (+)-BINAP (0.19 g, 0.31 mmol) in toluene (10 ml). Heat at 110° for 18 h, allow to cool, and extract with 1N HCl. Basify the aqueous solution with NaOH and extract with CH2Cl2. Dry, concentrate, and purify by PLC to give N-(2,4-difluorophenyl)-N,N′-dimethylethylenediamine.
Reaction SMILES: [C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]#[C:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C.O.CO.[Zn]>[C:1](=[O:25])([O:23][CH3:24])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]#[C:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][C:4]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCC(C)C)cc1C1CCCC1
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(N)c(C#CCC(C)C)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-Cyclopentyl-4-(4-methylpent-1-ynyl)-5-nitrophenyl methyl carbonate (75 mg, 0.22 mmol) was dissolved in a mixture of glacial acetic acid (940 μL) and water (235 μL). Zn dust (71 mg, 1.09 mmol) was added at room temperature and the reaction stirred for 10 min. The reaction was diluted with methanol (5 mL), filtered and concentrated. The product was brought up in dichloromethane, washed with 50% saturated NaHCO3, dried over Na2SO4, filtered, and dried down to provide 5-amino-2-cyclopentyl-4-(4-methylpent-1-ynyl)phenyl methyl carbonate as a clear orange oil (68 mg, 99% yield). LC/MS m/z 316.2 [M+H]+.
Reaction SMILES: C([O:3][C@@H](CC1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1)C(O)=O)C.C([C@H]1COC(=O)N1C(=O)[C@@H](OC)[C@H](O)C1C=CC(OCCC2N=C(C3C=CC=CC=3)OC=2C)=C2C=1CCC2)C1C=CC=CC=1.C([SiH](CC)CC)C.C([C@H]1COC(=O)N1[C:96](=[O:125])[C@@H:97]([O:123][CH3:124])[CH2:98][C:99]1[CH:107]=[CH:106][C:105]([O:108][CH2:109][CH2:110][C:111]2[N:112]=[C:113]([C:117]3[CH:122]=[CH:121][CH:120]=[CH:119][CH:118]=3)[O:114][C:115]=2[CH3:116])=[C:104]2[C:100]=1[CH2:101][CH2:102][CH2:103]2)C1C=CC=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O.C1COCC1>[CH3:124][O:123][C@@H:97]([CH2:98][C:99]1[CH:107]=[CH:106][C:105]([O:108][CH2:109][CH2:110][C:111]2[N:112]=[C:113]([C:117]3[CH:122]=[CH:121][CH:120]=[CH:119][CH:118]=3)[O:114][C:115]=2[CH3:116])=[C:104]2[C:100]=1[CH2:101][CH2:102][CH2:103]2)[C:96]([OH:3])=[O:125]
Reactant: CCO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)O
Reactant: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC[SiH](CC)CC
Agent: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2c1CCC2)C(=O)O

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-carbaldehyde (example 91 b]) was reacted with (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy[-indan-4-yl}-propionyl]-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionyl]oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-(2(S)-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-indan-4-yl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-in dan-4-yl}-propionic acid as colorless solid after crystallization from AcOEt/hexane. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 97.7%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]=[C:22]3[C:25]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27][CH2:26]3)=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C>[CH2:36]([NH:43][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]=[C:22]3[C:25]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH2:28]3)=[CH:17][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)nc1
Solvent: CCO
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(NCc2ccccc2)nc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloro-N-(2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethyl)pyridine-3-sulfonamide (70.0 mg, 0.132 mmol) and benzylamine (14.2 mg, 0.133 mmol) were dissolved in dry ethanol (3 ml) and stirred in a microwave oven at 150° C. for 1 h. The solvent was reduced under vacuo and the residue was purified by column chromatography using silica gel and heptan/ethyl acetate (3:7->7:3) as the eluent. The product was obtained as a white solid (79 mg, 0.132 mmol, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([CH:17]=O)[C:6]=2[C:19]=1[F:20].[CH2:21]([NH2:24])[CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+].II>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[NH:23][CH2:22][CH2:21][N:24]=3)[C:6]=2[C:19]=1[F:20]
Reactant: NCCN
Reactant: O=Cc1c(-c2ccc(F)cc2)oc2ccc(Cl)c(F)c12
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A mixture of 5-chloro-4-fluoro-2-(4-fluorophenyl)benzofuran-3-carbaldehyde (1.2 g, 4.10 mmol) and ethylenediamine (0.277 m, 4.10 mmol) in t-BuOH (15 ml) under a N2 atmosphere in a 50 ml RB flask was stirred at room temperature for 30 minutes. Potassium carbonate (0.567 g, 4.10 mmol) followed by iodine (1.041 g, 4.10 mmol) were then added and the reaction mixture was heated at 70° C. for 2 hours. The solvent was removed and the residue diluted with ethyl acetate. The mixture was washed with 10% sodium thiosulfate solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by using combiflash silica column using 8% methanol in chloroform as an eluent. The desired fractions were collected and concentrated to give the titled product (0.7 g, 52%). 1H NMR (400 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.37-7.34 (m, 1H), 7.27-7.16 (m, 3H), 3.90 (s, 4H).
Reaction SMILES: [H-].[Na+].F[C:4]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:4]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1)[CH3:23]
Reactant: CCO
Reactant: O=Cc1cc(Oc2ccccc2)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc([N+](=O)[O-])c(C=O)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60%, 400 mg, 10 mmol) was added to ethanol (10 mL) and stirred at room temperature for 30 min. Then, 4-fluoro-2-nitro-5-phenoxy-benzaldehyde (520 mg, 2 mmol) was added. The resulting mixture was stirred at room temperature overnight and ten concentrated. The resulting crude mixture was purified by chromatography (silica gel, 20-50% methylene chloride in heptane) to yield a slightly yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[Cl:21][C:22]1[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:14]([CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[N:29][N:28]=2)[N:27]=1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cnc2ccc(Cc3nnc4ccc(Cl)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.05 g, 0.2 mmol), 1-(6-chloropyridazin-3-yl)hydrazine (0.04 g, 0.3 mmol), water (0.5 mL) and hydrochloric acid (0.05 ml, 0.5 mmol). The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 10 min. at 100° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH—brown ppt. was generated. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=75%:20%:5%, Flow=30 mL/min). A peak at 25 min was collected. The solvent was removed in vacuo to afford the desired product as light yellowish solid. Wt: 20.0 mg. MS (ESI pos. ion) m/z: 326.53. Calc'd exact mass for C16H12ClN5O: 325.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[CH:9][C:8]=1[C:13]#[N:14]
Reactant: COc1ccc2c(=O)c(C#N)c[nH]c2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)c(C#N)cnc2c1
Temperature: 165 °C

Procedure:
A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxo-3-quinolinecarbonitrile and 8.3 g (40 mmol) of phosphorous pentachloride was heated at 165° C. for 3 hours. The mixture was diluted with hexanes and the solid was collected. The solid was mixed with brine and dilute sodium hydroxide solution and extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered through a pad of silica gel giving 3.7 g of 4-chloro-7-methoxy -3-quinolinecarbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 218.9.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[CH:17][CH:16]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:19][CH:20]=1
Reactant: CCOC(=O)/C=C/C=C/c1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/C=C/CO)cc1

Procedure:
Ethyl (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2,4pentadienoate was reduced with diisobutylaluminum hydride in the same manner as in Reference Example 22 to yield (E,E)-5-[4-[2-(5-methyl-2-phenyl4-oxazolyl)ethyl]phenyl]-2,4-pentadien-1-ol, which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 117°-118° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:19][C:20]([O:22][CH:23]([CH:80]([CH3:90])[CH2:81][O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[CH:24]([CH3:79])[CH:25]([O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:74])[CH3:73])[CH:26]([CH3:70])[CH2:27][C:28]([CH3:69])=[CH:29][CH:30]([CH3:68])[CH:31]([O:60][Si:61]([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62])[CH:32]([CH3:59])[CH:33]=[CH:34][CH:35]([OH:58])[CH2:36][C:37](=[O:57])[CH:38]([CH3:56])[CH:39]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH:40]([CH3:47])[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:21].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(Cl)Cl>CC#N.CC(O)=O.CC#N>[NH2:19][C:20]([O:22][C@@H:23]([C@@H:80]([CH3:90])[CH2:81][O:82][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C@@H:24]([CH3:79])[C@H:25]([O:71][Si:72]([C:75]([CH3:78])([CH3:77])[CH3:76])([CH3:73])[CH3:74])[C@@H:26]([CH3:70])[CH2:27]/[C:28](/[CH3:69])=[CH:29]\[C@H:30]([CH3:68])[C@@H:31]([O:60][Si:61]([C:64]([CH3:65])([CH3:66])[CH3:67])([CH3:63])[CH3:62])[C@@H:32]([CH3:59])/[CH:33]=[CH:34]\[C@@H:35]([OH:58])[CH2:36][C@H:37]([OH:57])[C@H:38]([CH3:56])[C@H:39]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:50])[CH3:51])[C@@H:40]([CH3:47])[C:41]([N:43]([O:45][CH3:46])[CH3:44])=[O:42])=[O:21]
Reactant: CON(C)C(=O)C(C)C(O[Si](C)(C)C(C)(C)C)C(C)C(=O)CC(O)C=CC(C)C(O[Si](C)(C)C(C)(C)C)C(C)C=C(C)CC(C)C(O[Si](C)(C)C(C)(C)C)C(C)C(OC(N)=O)C(C)COCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: CON(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)[C@@H](O)C[C@H](O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OC(N)=O)[C@@H](C)COCc1ccccc1
Temperature: -30 °C
Reaction time: 14 h
Yield: 75.1 %

Procedure:
A solution of tetramethylammonium triacetoxyborohydride (263 mg, 1 mmol, 10 eq) in MeCN/HOAc(1:1, 1.1 mL) is stirred for 1 h at 23° C. and cooled to −30° C. A solution of (2R,3S,4R,7S,8Z,10S, 11S,12S,13Z, 16S,17R,18R, 19S,20S)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-5-oxo-21-(phenylmethoxy)-8,13-heneicosadienamide (103 mg, 0.1 mmol)in MeCN (1 mL) is added dropwise. The mixture is stirred for 14 h at −30° C. Saturated Rochelle's salt solution is added and the resultant stirred for 30 min. Then the mixture is warmed to 23° C. CH2Cl2 (5 mL) is added to the mixture. The organic layer is separated, washed with brine and dried over MgSO4. The solvent is removed. The crude product is chromatographed (20% EtOAc in hexane) to give 80 mg (80%) of the desired compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.N12CCCN=C1CCCCC2>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:3]=1
Reactant: O=C1CCc2c(cc(Br)nc2-c2ccc(F)cc2Cl)N1c1c(Cl)cccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-1,6-naphthyridin-2(1H)-one (2.33 g, 4.65 mmol) in 75 mL of CCl4 was added recrystallized N-bromosuccinimide (993 mg, 5.58 mmol) and 2,2′azobis(2-methylpropionitrile) (76.4 mg, 0.465 mmol). The resulting reaction mixture was evacuated and flushed with argon 3 times, then heated and maintained at reflux for 2.5 h. 1,8-diazabicyclo[5.4.0]undec-7-ene (695 μL, 4.65 mmol) was added and the reaction mixture was cooled to rt, washed with 140 mL of half-saturated aqueous NaHCO3, and the aqueous layer was back-extracted with 2×70 mL of ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash chromatography on Biotage 40M column, eluting with a gradient system of 90:10 hexanes-ethyl acetate to 80:20 hexanes-ethyl acetate to yield 7-bromo-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one as an off white solid. Mass spectrum (ESI) 497 (M+1). 1H NMR (500 MHz, CDCl3): δ 6.64 (s, 1H); 6.79 (d, J=10.1 Hz, 1H); 7.21 (m, 1H), 7.31 (m, 1H); 7.54 (m, 3H); 7.65 (m, 2H),