Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=O>O1CCCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 25 °C
Yield: 624.4 %

Procedure:
10.3 g of sodium hydride with 20% paraffin oil (0.343 mol) were suspended in 350 ml of tetrahydrofuran while stirring, and 75 g of diethylphosphonoacetic acid morpholide (0.0283 mol) were added dropwise to the suspension over a period of 20 minutes while cooling with ice (internal temperature 25° C.). The mixture was allowed to react for an hour during which a clear solution was formed. 70 g (0.244 mol) of 3,4-dimethoxy-4'-nitrobenzophenone were added to this solution all at once, and the mixture was refluxed for 2 hour while stirring. The solution was then evaporated in vacuo in a rotary evaporator at 60° C., and the residue was dissolved in methylene chloride/water. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo at 60° C. The residue was triturated with 300 ml of hot methanol. 70.4 g of the title compound were obtained in the form of a faintly beige powder (73% of theory), m.p. 149°-163° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.[Au](Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[O:17][C:15]([CH3:16])=[CH:14][N:13]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc(C2CN(C(=O)OC(C)(C)C)C2)o1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
To 0.22 g (0.92 mmol) 3-prop-2-ynylcarbamoyl-azetidine-1-carboxylic acid tert-butyl ester in 4 mL anhydrous acetonitrile, under nitrogen, was added 14 mg (0.046 mmol) gold (III) chloride and the reaction mixture was stirred at 45° C. for 6 hours. After evaporation of the solvent, 20 mL DCM was added, the organic layer was washed with H2O (2×10 mL) then dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 6:4 to 5:5), and used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate (0.60 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.07 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (0.55 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with tetrahydrofuran-hexane (1:1, v/v) to obtain {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazol-4-yl}methanol as a colorless oil (0.35 g, yield 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[C:17]([Cl:18])=[CH:16][N:15]=[CH:14][C:13]=2[Cl:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C>O1CCCC1>[Cl:19][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1onc(-c2c(Cl)cncc2Cl)c1C(=O)O

Procedure:
Combine 3-(3,5-dichloro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (2.75 g, 0.009 mol) with aqueous sodium hydroxide (2N, 30.0 mL, 0.06 mol), ethanol (5 mL), and tetrahydrofuran (5 mL) and stir overnight at ambient temperature. Remove the organic solvents in vacuo and adjust the aqueous mixture to approx. pH 2.0 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as a light solid (2.42 g, 97%). MS(ES): (M+1)+ 273.0, 275.0 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
5-(1-t-butoxyformamido)valeric acid was coupled with β-alanine benzyl ester to give N-[5-(1-t-butoxyformamido)valeryl] -β-alanine benzyl ester, m.p. 69°-70° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:7][CH:6]=1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 2.8 g of 4-(4-acetamidophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid and 28 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5, the precipitate formed filtered off, washed with water and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid of the formula ##SPC11##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8]>C(OC(=O)C)C.[Ni].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8]
Reactant: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(N(C(=O)c2cc(Cl)ccc2F)c2ccccc2N)CC1

Procedure:
A solution of 32.4 g 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-N-(2-nitrophenyl)-benzamide in 700 ml acetic acid ethyl ester and 2 to 3 g Raney nickel is hydrogenated at room temperature and normal pressure. The precipitated product is dissolved in methanol under warming and the catalyst is filtered off. The filtrate is evaporated and the crystalline residue suspended in ether and filtered, to give the heading compound, m.p. 179°-182°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.O1CCCC1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44](=[O:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([OH:47])([C:11]2[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)[N:10]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(-c3cccc(C(F)(F)F)c3)cn2COCC[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a 100 mL round bottom flask (fitted with cooling bath, stir bar and nitrogen blanket) add 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.995 g; 1.00 equiv; 2.91 mmoles; 995.00 mg), n-Butyl Lithium (2.8 mL; 1.54 equiv; 4.48 mmoles; 2.80 mL; 1.90 g), and Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g) and cool the mixture to −78° C. with stirring on and hold for 30 min. Add N-T-Butoxycarbonyl-4-piperidone (0.706 g; 1.22 equiv; 3.54 mmoles; 706.00 mg) and allow the reaction to warm to room temperature. Dilute the reaction with CH2Cl2, wash with water, dry over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica eluting with ethyl acetate/hexane from 10-50% EtOAc. Combine the appropriate fractions and concentrate to give 4-Hydroxy-4-[4-(3-trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (1.248 g; 0.79 equiv; 2.30 mmoles; 1.25 g; 79.29% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH3:24])[CH:14]=2)[C:5]([N+]([O-])=O)=[N:4]1)[CH3:2].[O-:28][CH2:29][CH3:30].[Na+]>C(O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH3:24])[CH:14]=2)[C:5]([O:28][CH2:29][CH3:30])=[N:4]1)[CH3:2]
Reactant: CC[O-]
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])nn(CC)c(=O)c2Cl)ccc1OC
Agent: [Na+]
Solvent: CCO
Product: CCCOc1cc(CNc2c(OCC)nn(CC)c(=O)c2Cl)ccc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
300 mg of 2-ethyl-4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 24) prepared in Example 4, was dissolved in 6 ml of dried ethanol, and 160 mg of sodium ethoxide was added thereto. The mixture was gently refluxed under stirring for 10 minutes. After cooling, ice water was poured into the reaction solution, and then most ethanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and a saturated sodium chloride aqueous solution in this order and dried over sodium sulfate. The solvent was distilled off and the residual oily substance thereby obtained was purified by silica gel thin layer chromatography by using benzene:ethyl acetate (7:3 v/v) as the developer, to obtain 300 mg of the above identified compound. The physical properties and the spectrum data of NMR, IR and MS of the compound completely agreed to those of the compound prepared by the above method (1).
Reaction SMILES: [Cl-].[Li+].BrC(Br)C.Cl[Si](C)(C)C.I[CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[C:19]([C:21]1[CH:22]=[C:23]([S:39]([N:42](CC2C=CC(OC)=CC=2OC)[C:43]2[S:47][N:46]=[CH:45][N:44]=2)(=[O:41])=[O:40])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1I)#[N:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Cl-].[NH4+]>O1CCCC1.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:21]1[CH:22]=[C:23]([S:39]([NH:42][C:43]2[S:47][N:46]=[CH:45][N:44]=2)(=[O:41])=[O:40])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][C:29]=1[CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)#[N:20]
Reactant: IC1CCOCC1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(Br)Br
Solvent: C1CCOC1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(C(F)(F)F)cc1C1CCOCC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of zinc dust (458 mg, 7.00 mmol) and lithium chloride (212 mg, 5.00 mmol) in tetrahydrofuran was added dibromoethane (0.043 mL, 0.50 mmol) under nitrogen. The mixture was heated at 70° C. for 10 minutes before cooling and adding chlorotrimethlsilane (0.013 mL, 0.10 mmol). The reaction mixture was stirred for 1 hour then 4-iodotetrahydro-2H-pyran (1060 mg, 5.00 mmol) was added and stirring continued for 18 hours. This mixture was added to a pre-stirred (10 minutes) suspension of 3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 429, 11 mg, 0.3 mmol), palladium(II) acetate (6.7 mg, 0.03 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (24.6 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours before pouring into saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to obtain a residue that was purified using an ISCO™ system eluting with heptane:ethyl acetate (1:0 to 4:6, by volume). The residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was added. After stirring for 1 hour at room temperature, methanol (20 mL) was added and the resulting precipitate was filtered and the filtrate concentrated in vacuo. The crude material was purified using preparative HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(C(=O)O)c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 92 %

Procedure:
To a solution of methyl 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (0.46 g, 1 mmol) in methanol (30 mL) was added an aqueous solution (3 mL) of lithium hydroxide monohydrate (0.42 g, 10 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (0.41 g, 93.2%) as crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:24]([NH:40][NH2:41])=[N:25][C:26]([CH3:39])=[N:27][C:28]=1[N:29]1[CH2:32][C:31]([CH3:38])([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:41][NH:40][C:24]2[C:23]([F:22])=[C:28]([N:29]3[CH2:30][C:31]([CH3:38])([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:32]3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:10])[CH2:11][N:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: Cc1nc(NN)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (107 mg, 0.357 mmol), 5-fluoro-4-hydrazino-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]pyrimidine (100 mg, 0.357 mmol), EDC (82 mg, 0.428 mmol), HOAt (53 mg, 0.393 mmol), and NMM (0.20 mL, 1.79 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was then purified via RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (118 mg, 58%). LCMS: (M+H)+: 562.2.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:26](O)[CH3:27].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>O>[CH2:26]([O:2][C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:27]
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Reaction time: 3 h
Yield: 46 %

Procedure:
0.8 g (2.4 mmol) of 3-(5-carboxy-2-furyl)-1-(2-phenylethyl)indazole were admixed with 25 ml of ethanol, 150 ml of toluene and 2 ml of conc. sulfuric acid and heated on a water separator for 3 h. Silica gel chromatography using dichloromethanelhexane (2:1) of the residue that was obtained after concentration using a rotary evaporator gave 400 mg (46%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[OH:23])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(=O)C1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution (60 ml) of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (9.18 g) in acetonitrile was added Dess-Martin reagent (15.1 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (7.47 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27]C)=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[OH-].Cl>CN(C)C=O.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>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:25]([OH:27])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[C:10]([CH3:37])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2c(Br)cn(Cc3ccccc3)c2c(=O)n1C
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccccc2)c2c(=O)n(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
A mixture of the methyl 2-(1-benzyl-3-bromo-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (15 mg, 0.026 mmol), trimethylboroxine (3.65 μL, 0.026 mmol) and Na2CO3 (5.56 mg, 0.052 mmol) in N,N-Dimethylformamide (DMF) (1 mL), was degassed with N2 for 5 minutes. Palladium tetrakis (3.03 mg, 2.62 μmol) was added and the mixture was degassed again with N2 for 5 minutes. The mixture was irradiated in the microwave at 140° C. for 30 minutes. The mixture was diluted with Methanol (1.000 mL), and Tetrahydrofuran (THF) (1.000 mL), treated with 2M LiOH (1 mL, 2.000 mmol) and then stirred at room temperature overnight. The mixture was treated with HCl (1M) until pH<2 and extracted with ethyl acetate. The combined extracts were concentrated and purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford 2-(1-benzyl-4-(4-chlorophenyl)-3,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetic acid (4.0 mg, 0.007 mmol, 30% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.63-7.57 (m, 1H), 7.49-7.41 (m, 2H), 7.38-7.29 (m, 6H), 6.81 (s, 1H), 5.81 (s, 2H), 5.18 (s, 1H), 3.67 (s, 3H), 1.44 (s, 3H), 1.07 (s, 9H); LCMS (m/z) ES+=493 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#N)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)(Cl)=[O:15]>CN(C)C=O>[Cl:1][C:2]1[C:11]([CH:12]=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc2ccccc2nc1Cl
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2nc1Cl

Procedure:
Where the starting material above is a 2-chloro-3-cyanoquinoline, this can be prepared by starting from an appropriate substituted acetanilide. This is heated with phosphoryl chloride and dimethylformamide to give the corresponding 2-chloro-3-quinolinecarboxaldehyde. The process involved is discussed in detail by meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, 1981, 1520. The chloroquinolinecarboxaldehyde is then reacted with hydroxylamine hydrochloride, formic acid and sodium formate with heating to give the corresponding 3-cyano-2(1H)-quinolinone. This is then heated with an excess of phosphoryl chloride to give the desired 2-chloro-3-cyanoquinoline.