Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:5]2[CH2:6][N:7]([C:10](OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C@@H:4]2[O:3]1.O=C1N(C(OC(C)(C)C)=O)[C@@H]2CNCC[C@@H]2O1.ClC1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53].CCN(C(C)C)C(C)C>CCO.CCOC(C)=O.CC(O)C.[Pd]>[N+:52]([C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:10]=1[N:7]1[CH2:8][CH2:9][C@@H:4]2[O:3][C:2](=[O:1])[N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:5]2[CH2:6]1)([O-:54])=[O:53]
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]21
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCNC[C@H]21
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3[N+](=O)[O-])C[C@H]21
Temperature: 75 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of (3aR,7aS)-5-benzyl 3-tert-butyl 2-oxotetrahydrooxazolo[4,5-c]pyridine-3,5(2H,6H)-dicarboxylate in a mixture of EtOH and EtOAc (1:1, 0.07M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen balloon for 15 h. The solution was then filtered through a pad of Celite and the filtrate was concentrated to dryness to give a clear oil. To a solution of (3aR,7aS)-tert-butyl 2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate in i-PrOH (0.12 M) was added 4-chloro-3-nitropyridine (1.2 equiv.) and DIEA (4.0 equiv.) The reaction was heated to 75° C. for 2 h, then cooled to room temperature and concentrated under vacuo. The crude mixture was diluted with EtOAc, water was added, the organic layer was extracted, washed with brine, dried with Na2SO4, and concentrated. The crude was purified via silica gel column chromatography eluting with EtOAc (100%) to yield (3aR,7aS)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate as a yellow foam in 89% yield). LCMS (m/z): 365.1 (MH+), Rt=1.79 min.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[NH:8][C:9]1[C:10]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.Cl>O.CO>[C:18]([C:16]1[NH:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:7]3[CH:23]=[CH:24][CH:25]=[C:5]([Cl:4])[CH:6]=3)[C:10]=2[CH:17]=1)([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4.5 h

Procedure:
A solution of 25 mg (0.6 mmol) of LiOH.H2O in 0.4 ml of H2O is added dropwise to a suspension of 95 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine in 0.7 ml of methanol. The reaction mixture is heated at boiling for 4.5 hours, then cooled in an ice-bath and acidified with 0.6 ml of 1 N HCl solution. Filtering and washing with water yield the title compound; HPLC: tRet (Grad20)=8.7; FAB-MS: (M+H)+ =289.
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H](CC1N=CNC=1)C(N[C@@H](CC1CCCCC1)[C@@H](O)C(O)C(C)(C)C)=O)=O)(=O)=O)(C)(C)C.C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H](CC1N=CNC=1)C(N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C(C)C)=O)=O)(=O)=O)(C)(C)C.[C:90]([S:94]([CH2:97][C@@H:98]([CH2:130][C:131]1[CH:136]=[CH:135][CH:134]=[CH:133][CH:132]=1)[C:99]([NH:101][C@@H:102]([CH2:124][C:125]1[N:126]=[CH:127][NH:128][CH:129]=1)[C:103]([NH:105][C@@H:106]([CH2:117][CH:118]1[CH2:123][CH2:122][CH2:121][CH2:120][CH2:119]1)[C@@H:107]([OH:116])[C@H:108]([CH:110]1[CH2:115][CH2:114][CH2:113][CH2:112][CH2:111]1)[OH:109])=[O:104])=[O:100])(=[O:96])=[O:95])([CH3:93])([CH3:92])[CH3:91]>>[C:90]([S:94]([CH2:97][C@@H:98]([CH2:130][C:131]1[CH:132]=[CH:133][CH:134]=[CH:135][CH:136]=1)[C:99]([NH:101][C@@H:102]([CH2:124][C:125]1[N:126]=[CH:127][NH:128][CH:129]=1)[C:103]([NH:105][C@@H:106]([CH2:117][CH:118]1[CH2:123][CH2:122][CH2:121][CH2:120][CH2:119]1)[C@@H:107]([OH:116])[C@H:108]([OH:109])[C:110]1[CH:111]=[CH:112][CH:113]=[CH:114][CH:115]=1)=[O:104])=[O:100])(=[O:96])=[O:95])([CH3:93])([CH3:91])[CH3:92]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CCCCC1
Agent: CC(C)(C)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@H](O)c1ccccc1

Procedure:
(S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4,4-dimethylpentyl]imidazole-4-propionamide; (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide; (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-3-cyclohexyl-1-(cyclohexylmethyl)-2,3-dihydroxypropyl]imidazole-4-propionamide.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:30])=[CH:23][CH:24]=3)=[NH:29])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Cc1ccc(C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 0.61 g (4.0 mmol) of 1,4-benzodioxan-6-amine in 5 mL of tetrahydrofuran at ambient temperature was added 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with 25 mL of dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as brown crystalline solid, which was used without further purification. LC/MS 269.2 (M+1). Step B: Ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a yellow foam. LC/MS 365.3 (M+1). Step C: 1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.62 g (1.7 mmol) of the compound from Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 337.3 (M+1).
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].O1CCCC1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.[Cl-].[NH4+]>C(OCC)C>[C:1]([C:13]1([OH:16])[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)#[CH:2]
Reactant: O=C1CCOCC1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of ethynylmagnesium chloride in tetrahydrofuran (0.5 M, 12 ML, 6.0 mmol) was added with cooling in an ice-water bath to a solution of tetrahydro-4H-pyran-4-one (0.496 g, 5.0 mmol) in diethyl ether (300 mL) dropwise over 15 min. The mixture was stirred at room temperature for 1 h. Aqueous saturated ammonium chloride solution (10.0 mL) was then added and mixture extracted with ether (2×20 mL). The ether layers were washed with saturated aqueous sodium chloride solution (20 mL), then combined, dried over MgSO4, filtered and concentrated to give 4-ethynyl-tetrahydro-pyran-4-ol as a colorless oil that solidified on standing. (0.60 g, 96.2% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[N:15]=[N:14][N:13]=2)=[CH:10][C:9]([Br:34])=[CH:8][N:7]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Product: CCc1ccc(-n2nnnc2-c2cc(Br)cnc2NC(C)(C)C)c(F)c1F

Procedure:
Compound 1082 can be further reacted with NBS according to procedures analogous to those provided herein to provide N-tert-butyl-5-bromo-3-(1-(4-ethyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1083).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].Cl.[CH3:19][N:20](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:19]([C:15]1[CH:14]=[CH:13][C:3]([C:4]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])=[C:2]([OH:1])[CH:16]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: O=C(Oc1ccccc1)c1ccc(I)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Product: N#Cc1ccc(C(=O)Oc2ccccc2)c(O)c1
Temperature: 80 °C

Procedure:
A solution of phenyl 2-hydroxy-4-iodobenzoate, as described in Example 1, Step A, (2.38 g, 7.0 mmol) and Zn(CN)2 (575 mg, 4.9 mmol) in DMF was degassed with argon for 25 minutes. Pd(Ph3P)4 (404 mg, 0.35 mmol) was added and the mixture heated to 80° C. for 16 hr. The mixture was poured into 1N HCl and extracted with EtOAc (2×), washed with water then brine, dried (MgSO4) and the solvent removed. Chromatography of the residue (silica gel; hexane:EtOAc 9:1) afforded the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:27]([C:29]1[N:36]2[C:32]([S:33][C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1)=[O:28]>>[CH:27]([C:29]1[N:36]2[C:32]([S:33][C:34]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[CH:35]2)=[C:31]([C:50]([C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:51])[N:30]=1)=[O:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(C=O)nc(C(=O)c3cccnc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(C=O)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 65.2 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-formyl-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (1.12 g) was prepared in the same manner as in step a) of Example 1, except that 1.04 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.56 g of 5-formyl-7(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[Cl-].[Li+].[C:17]([N:20]1[CH2:28][CH2:27][CH:23]([C:24](Cl)=[O:25])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:24]([CH:23]1[CH2:22][CH2:21][N:20]([C:17](=[O:19])[CH3:18])[CH2:28][CH2:27]1)=[O:25]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Product: CC(=O)N1CCC(C(=O)c2cc(Cl)ccc2Cl)CC1

Procedure:
The title compound was prepared according as described on example 65A18 from 2,5 Dichloro 1-iodobenzol, isopropyl magnesium chloride-lithium chloride (2M in THF) and 1-acetyl-isonipecotoyl chloride. (m/e): 301.1 (M+H+).
Reaction SMILES: [CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10]C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([C@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC(=O)O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of (3R)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoate ((R)-22, 2.47 g, 5.26 mmol) in THF (30 mL) at room temperature was added a solution of lithium hydroxide monohydrate (LiOH—H2O, 265 mg, 6.31 mmol, 1.2 equiv) in water (15 mL). The reaction mixture was stirred at room temperature for 3 h. When LCMS showed the reaction was complete, the reaction mixture was then acidified with 1 N aqueous HCl solution to pH 5 before it was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to afford (3R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanoic acid ((R)-23, 2.40 g, 2.40 g theoretical, 100% yield) as a colorless oil, which solidified upon standing at room temperature in vacuo. For (R)-23: 1H NMR (CDCl3, 300 MHz) δ ppm 8.95 (s, 1H), 8.95 (bs, 1H), 8.36 (s, 1H), 7.57 (d, 1H, J=3.7 Hz), 6.99 (d, 1H, J=3.7 Hz), 5.74 (s, 2H), 4.65 (dt, 1H, J=3.1, 10.3 Hz), 3.58 (t, 2H, J=8.2 Hz), 3.24 (dd, 1H, J=16.5, 10.3 Hz), 3.04 (dd, 1H, J=16.2, 3.1 Hz), 2.59 (m, 1H), 2.00 (m, 1H), 1.77-1.24 (m, 7H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H33N5O3Si (MW, 455.63), LCMS (EI) m/e 456.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[NH4+].[Cl-].CC[N:43](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C)C=O>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][C:21]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([NH2:43])=[O:29])=[CH:23][CH:22]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)COc1ccc(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)COc1ccc(Nc2cc(O)nc3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)phenoxy]acetic acid (30 g, 53.90 mmol, 1.00 equip, 98%), NH4Cl (14.72 mg, 0.27 mmol, 5.00 equip, 98%), DIPEA (71 mg, 0.54 mmol, 10.00 equip, 98%), HATU (31.37 mg, 0.08 mmol, 1.50 equip, 98%), and N,N-dimethylformamide (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (1×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was recrystallized from ethyl acetate:n-hexane in a ratio of 1:20 to yield 2-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)phenoxy]acetamide as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:23])(=[O:3])[CH3:2].C(O[CH:29](OC(C)(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>CN(C)C=O>[CH3:29][N:30]([CH3:32])[CH:31]=[CH:2][C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:23])=[O:3]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(C(C)=O)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(C(=O)C=CN(C)C)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
To 5.00 g (15.5 mmol) of the ethyl 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 65 ml of dimethylformamide was added 4.27 ml (1.3 eq) of bis t-butoxydimethylaminomethane. The mixture was taken to 55° C. overnight. The mixture was concentrated and the solids suspended in ethyl ether. Filtration gave 4.88 g of the ethyl 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 175°-177° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[N:7]O)[CH2:5][N:4]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3]1=[O:17]>CO.[Ni]>[NH2:7][CH:6]1[CH2:5][N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3](=[O:17])[C:2]1([CH3:1])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC(=NO)C(C)(C)C1=O
Agent: [Ni]
Solvent: CO
Product: CC(c1ccccc1)N1CC(N)C(C)(C)C1=O
Reaction time: 16 h
Yield: 123.6 %

Procedure:
To a solution of 8.75 g of 3,3-dimethyl-4-hydroxyimino-1-[1-(R)-phenylethyl]-pyrrolidin-2-one in 300 ml of methanol there was added 20 ml of Raney-nickel, and reduction was carried out under a hydrogen atmosphere at room temperature for 16 hr (H2 pressure: 1 atm). The catalyst was removed by filtration and the solvent of the filtrate was removed under reduced pressure. The residue was purified through column chromatography using a column filled with 300 g of silica gel. From a fraction eluted with a mixture of methanol and chloroform(1:30, v/v), 3.75 g of the less polar isomer of the titled compound was obtained along with 10.2 g of a mixture of the less polar and more polar titled compound.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C([Li])CCC.B(OC)(OC)OC.[Cl:30][C:31]1[C:32](Br)=[C:33]([CH:39]=[CH:40][C:41]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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.CCO.C1(C)C=CC=CC=1.O>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:39]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][CH:2]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)=[CH:40][C:41]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc3ccc4cccc5ccc2c3c45)c(C(=O)OCC)cc1Cl
Temperature: -75 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
28.9 g (103 mmol) of bromopyrene are dissolved in 275 ml of dry THF, the solution is cooled to −75° C., and 52 ml (104 mmol) of a 2 M solution of n-butyllithium are added dropwise at this temperature. The yellow suspension is stirred at −75° C. for 1 h, and 17.5 ml (155 mmol) of trimethyl borate are then added dropwise. After warming to RT, 34.5 g (103 mmol) of diethyl chlorobromoterephthalate, 22 g (206 mmol) of Na2CO3, 1.2 g (1.03 mmol) of tetrakis(triphenylphosphine)palladium(0), 140 ml of H2O, 280 ml of toluene and 140 ml of EtOH are added, and the mixture is heated at the boil for 2 h. After the organic phase has been separated off, washed twice with water and dried over Na2SO4, the solvent is removed in vacuo, and the oil remaining is brought to crystallisation in heptane. Double recrystallisation gives the product in the form of a colourless solid (33 g, 70%) having a purity of >98%, which is employed in this form in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH:7]2[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[H][H]>C(O)C.[Pd]>[CH3:17][O:16][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]([CH2:12][C:13](=[O:15])[CH3:14])[NH:8][C:9]2=[O:11]
Reactant: [H][H]
Reactant: COc1ccc(Br)c2c1C(CC(C)=O)NC2=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc2c1C(CC(C)=O)NC2=O
Yield: 73.4 %

Procedure:
A mixture of 7-bromo-1,3-dihydro-4-methoxy-3-(2-oxopropyl)-2H-isoindol-1-one (5.0 g, described in Example 20) and potassium carbonate (2.5 g) in ethanol (100 ml) is hydrogenated in the presence of 5% palladium on carbon (2.5 g) at atmospheric pressure and room temperature until 1.1 equivalent of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated. A solution of the residue in chloroform is washed with water, dried and evaporated. The residue is crystallized from dichloromethane-diethyl ether to give the title compound (2.7g): mp 176.5°-177.5° C.; nmr (CDCl3) δ 2.20 (s, 3H), 2.30 (2d, 2H), 3.57 (2d, 2H), 3.87 (s, 3H), 4.85 (2d, 1H), 6.70(s, 1H), 6.97 (t, 1H) and 7.37(d, 2H); and Anal. Calcd for C12H13NO3 : C, 65.74 % H, 5.98% N, 6.39% and Found: C, 65.64% H, 6.09% N, 6.70%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19]>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Yield: 40.8 %

Procedure:
Tert-butyl 3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionate (3.86 g, 8.116 mmol) was dissolved in trifluoroacetic acid-water (9:1, 25 ml) and the solution allowed to stand for 3 about hours (hereinafter “h), then evaporated in vacuo. The residue was purified by column chromatography over silica (70 g) eluting with cyclohexane-ethyl acetate (5:1)-(3:1) to give the product as an gum (1.39 g).