Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([O:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-hydroxy-1H-pyrazol-1-yl)methyl]benzoate (2.00 g, 6.94 mmol), benzyl bromide (0.91 mL, 7.7 mmol), potassium carbonate (0.96 g, 6.9 mmol) and N,N-dimethylformamide (25 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (2.14 g, yield 81%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][Br:22]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Yield: 92.4 %

Procedure:
To a solution of 2-Methyl-4-nitro-benzoic acid methyl ester (3.08 g, 15.79 mmole) in 125 ml carbontetrachloride was added NBS (3.1 g, 17.38 mmole) and AIBN (390 mg, 2.38 mmole). The reaction mixture was heated at reflux under light for 22 hours. The reaction mixture was cooled down, concentrated to half, filtered off, solid was washed with 25 ml carbontetrachloride. The filtrate was concentrated to give 4 g crude product, containing about 20% unreacted starting material. This was used for next step without purification.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38]
Reactant: CCCCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Yield: 19 %

Procedure:
Heat a mixture of 2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.83 g, 1.53 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.713 g, 1.51 mmol, example 47.2), diisopropylethylamine (1 mL, 5.74 mmol) and acetonitrile (15 mL) at 90° C. for 72 hours. Concentrate to dryness and dissolve the residue in dichloromethane. Wash the dichloromethane phase with NaHCO3 (10%, 10 mL) and brine (four 10 mL portions), dry (Na2SO4) the organic phase, filter and evaporate. Purify the residue by silica gel chromatography (3.5×35 cm) eluting with 95:5:0.05 dichloromethane:methanol:30% ammonium hydroxide solution. Concentrate the desired fractions to afford 0.19 g of the title compound, Rf=0.80 (silica gel, 90:10:0.1 dichloromethane:methanol:30% ammonium hydroxide solution). The product may be converted to the dihydrochloride by methods as are well known in the art.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>C1COCC1>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 4-aminobenzoic acid (10 g, 73 mmol) in 100 mL of anhydrous THF was added pyridine (1.15 g, 146 mmol), and quinoline-8-sulfonyl chloride (20 g, 88 mmol) at 0° C. The resulting mixture was stirred at 70° C. overnight. After filtration, the residue was washed with EtOH and 14 g of title compound was obtained as pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[O-:13]C1C=CC=CC=1.[K+].O>C(O)COCCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 160 °C

Procedure:
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160° C. for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide. and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)c1
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCc1cccc(CNc2c(N)c(Cl)nc3ccccc23)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
tert-Butyl 3-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate (19.64 g, 44.34 mmol), 5% platinum on carbon (2.0 g), and acetonitrile (325 mL) were added to a Parr vessel and shaken under hydrogen pressure (30 psi, 2.1×105 Pa) overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure and further dried under high vacuum for 1.5 hours to provide 17.03 g of tert-butyl 3-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}benzylcarbamate as a thick, brown oil.
Reaction SMILES: O[C@H:2]([C:37]1[C:65]([F:66])=[CH:64][C:40]2[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N:43][C:39]=2[CH:38]=1)[CH2:3][CH2:4][C@@H:5]([C:7]1[C:35]([F:36])=[CH:34][C:10]2[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:13][C:9]=2[CH:8]=1)O.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:79]([C:83]1[CH:89]=[CH:88][C:86]([NH2:87])=[CH:85][CH:84]=1)([CH3:82])([CH3:81])[CH3:80]>C(Cl)Cl.CCOC(C)=O>[C:79]([C:83]1[CH:84]=[CH:85][C:86]([N:87]2[C@@H:2]([C:37]3[C:65]([F:66])=[CH:64][C:40]4[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:62])([CH3:61])[CH3:63])[C:42]([C@@H:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[N:43][C:39]=4[CH:38]=3)[CH2:3][CH2:4][C@@H:5]2[C:7]2[C:35]([F:36])=[CH:34][C:10]3[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[C:12]([C@@H:14]4[CH2:18][CH2:17][CH2:16][N:15]4[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[N:13][C:9]=3[CH:8]=2)=[CH:88][CH:89]=1)([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc([C@@H](O)CC[C@H](O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc([C@H]3CC[C@H](c4cc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c5cc4F)N3c3ccc(C(C)(C)C)cc3)c(F)cc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of di-tert-butyl (2S,2′S)-2,2′-{[(1S,4S)-1,4-dihydroxybutane-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate (100 mg, 0.10 mmol) in CH2Cl2 (1 mL) at −20° C. was added triethylamine (0.044 mL, 0.31 mmol) followed by mesyl chloride (0.018 mL, 0.23 mmol) and the solution stirred at −20° C. for 1 hour. 4-tert-Butyl aniline (0.083 mL, 0.52 mmol) was added in one portion, and the solution was allowed to warm to room temperature overnight, with stirring. The solution was diluted with EtOAc, washed with 1N HCl, H2O, and brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (0-50% EtOAc/hexane) gave the title compound (46 mg, 0.04 mmol, 41%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[N:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[N:14]=[CH:13][C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ncc(Br)cn1
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ncc(-c2ccccc2F)cn1

Procedure:
500 mg (1.73 mmol) of (5-bromo-pyrimidin-2-yloxy)-acetic acid tert -butyl ester from step (a), 190.4 mg (2.07 mmol) of 2-fluorophenylboronic acid, 19.4 mg (0.086 mmol) of palladium acetate, 45.4 mg (0.17 mmol) of triphenylphosphine and 1.07 ml of an aqueous 1 M sodium carbonate solution in 40 ml of toluene were heated under reflux for 8 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. Yield: 335 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[CH3:17].BrC1C(C)=C2C(=CC=1)NC(C([O-])=O)=C2C.[OH-].[K+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[CH3:17]
Reactant: CCOC(=O)c1[nH]c2cc(C)c(Br)cc2c1C
Agent: Cc1c(Br)ccc2[nH]c(C(=O)[O-])c(C)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2[nH]c(C(=O)O)c(C)c2cc1Br
Yield: 90.6 %

Procedure:
A 1:1 isomeric mixture of ethyl 5-bromo-3,6-dimethyl-1H-indole-2-carboxylate and 5-bromo-3,4-dimethyl-1H-indole-2-carboxylate (5.36 g, 18.1 mmol) was dissolved in EtOH (20 mL) and KOH (3.6 g, 54 mmol). The mixture was refluxed for 3 h and gave 4.67 g (99%) of a 1:1 isomeric mixture of the corresponding acids. The mixture was acidified and the precipitate that formed was filtered and dried at 120° C. to afford the title compound (4.39 g, 90.6%). 1H NMR (300 MHz, DMSO-d6) δ, mix 12.96 (s, 1H), 11.50 and 11.40 (2s, 2×0.5H), 7.85 and 7.33 (2s, 2×0.5H), 7.34 and 7.16 (2d, J=8.7 Hz, 2×0.5H), 2.76, 2.73, 2.49 and 2.47 (4s, 4×1.5H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[N:9][C:8]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:7]=2[CH:6]=1)=O.O1CCCC1CO.[BH4-].[Na+]>O>[N:9]1[C:8]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][C:7]=2[CH:6]=[C:5]([CH2:3][OH:2])[N:10]=1
Reactant: COC(=O)c1cc2c(nn1)Oc1ccccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: OCC1CCCO1
Product: OCc1cc2c(nn1)Oc1ccccc1O2
Yield: 66.6 %

Procedure:
To methyl[1,4]benzodioxino[2,3-c]pyridazine-3-carboxylate (950 mg) was added a mixed solvent of tetrahydrofuran-methanol (1:1) (20 ml), and the mixture was stirred under ice-cooling. To the mixture was added sodium borohydride (450 mg), and the mixture was stirred at 0° C. for 2 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with water to give [1,4]benzodioxino[2,3-c]pyridazin-3-ylmethanol (560 mg).
Reaction SMILES: [I-].[K+].CC1C=CC(S(O[CH2:14][CH2:15][F:16])(=O)=O)=CC=1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([C@@H:29]([NH2:31])[CH3:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([C@@H:29]([NH:31][CH2:14][CH2:15][F:16])[CH3:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: C[C@H](N)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NCCF)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
Potassium iodide (0.71 g, 4.27 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (0.93 g, 4.27 mmol) (Kopka, et al., 2006) are added to a solution of (S)-1-((R)-1-benzylpyrrolidin-3-yl)ethanamine (0.83 g, 4.06 mmol) (Shroeder, et al., 1992) in DMF (10 mL). The reaction mixture is heated for 2 h at 100° C. and evaporated under reduced pressure. The residue is purified by column chromatography (chloroform-ethanol-triethylamine=30:1:1) to afford the desired product (0.51 g, 50%) as a brown oil. 1H NMR (CDCl3): δ 1.09 (d, J=6.3 Hz, 3H, methyl), 1.55 (m, 1H), 1.96 (m, 1H), 3.15-2.15 (m, 9H), 3.65 (s, 2H, —CH2Ph), 4.46 (m, 1H, —CHF), 4.61 (m, 1H, —CHF), 7.31 (m, 5H, ArH). 13C NMR (CDCl3): δ 18.1, 27.5, 43.8, 53.9, 56.7, 57.5, 60.4, 82.4, 84.6, 126.6, 128.1, 128.5, 139.0. LCMS: m/z calcd for C15H23FN2 ([M]+) 250. found 251 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:19]=[N:18][C:5]2[NH:6][CH2:7][CH2:8][N:9]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:4]=2[CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:19]=[N:18][C:5]3[NH:6][CH2:7][CH2:8][N:9]([C:10](=[O:11])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:4]=3[CH:3]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: O=C(c1ccccc1)N1CCNc2ncc(I)cc21
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(C(=O)c2ccccc2)CCN3)cc1
Yield: 32 %

Procedure:
(7-Iodo-3,4-dihydro-2H-pyrido[2,3-b]pyrazin-1-yl)phenylmethanone (215 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as an off-white solid (32% yield). M.p. 177-178° C., LCMS: m/z=388.23 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.38 t, (J=7.1 Hz, 3H), 3.67-3.72 (m, 2H), 4.01-4.08 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 5.21 (bs, 1H), 7.12-7.16 (m, 2H), 7.40-7.53 (m, 5H), 7.95 (d, J=8.3 Hz, 2H), 8.08 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[C:12]([N:9]1[C:10]([Cl:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)n1ncc(C(=O)O)c1Cl
Yield: 91 %

Procedure:
To a solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 21.7 mmol) in methanol (50 mL) and water (50 mL) was added LiOH (0.63 g, 26.3 mmol). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (4 mL), and extracted with ethyl acetate. The organic extracts were evaporated in vacuo to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (4 g, 91%) which was used without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])[C:10](=[O:22])[NH:11]2)[C:6]([OH:32])=[C:5]1[C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cc(F)ccc3OC)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1C1C=C2C(=CN(Cc3ccccc3)C(C(=O)NCCC(=O)O)=C2O)NC1=O
Temperature: 25 °C
Yield: 150.3 %

Procedure:
A mixture of 1-benzyl-3-(5-fluoro-2-methoxy-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.062 mmol), β-alanine (737 mg, 8.3 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a white solid. MS: (+) m/z 492.25 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]#[N:13])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2>>[C:12]([C:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=3)[C:23]([CH3:24])=[C:15]2[CH3:14])[CH2:11][CH2:10]1)#[N:13]
Reactant: N#CC1(c2cccc(CBr)c2)CC1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cccc(C2(C#N)CC2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using 1-(3-(bromomethyl)phenyl)cyclopropanecarbonitrile and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)CCC1C=CC(O)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Agent: O=C(CCc1ccc(O)cc1)OCc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1

Procedure:
This compound was prepared analogously to 3-(4-tert-butoxycarbonylmethoxy-3-chloro-phenyl)-propionic acid benzyl ester (Int. B step 2) by replacing 3-(3-chloro-4-hydroxy-phenyl)-propionic acid benzyl ester with 3-(4-hydroxy-phenyl)-propionic acid benzyl ester (commercially available).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:6][C:5]=1[F:19].C([Li])CCC.[CH2:25]=[C:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31].C(=O)(O)[O-].[Na+]>O1CCCC1>[F:19][C:5]1[CH:6]=[C:7]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])[CH:8]=[CH:9][C:4]=1[C:27](=[O:31])[C:26]([CH2:30][CH2:29][OH:28])=[CH2:25]
Reactant: C=C1CCOC1=O
Reactant: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(CCO)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
136 mg of 60% sodium hydride was added to a tetrahydrofuran (20 ml) solution of 1.0 g of N-(4-bromo-3-fluorophenyl)pyridine-2-carboxamide with cooling with ice, and the reaction liquid was stirred at the same temperature for 15 minutes. The reaction liquid was cooled to −78° C., and 1.53 ml of n-butyllithium (2.66 M hexane solution) was dropwise added to it, and the reaction liquid was stirred at the same temperature for 30 minutes. 0.36 ml of 3-methylenedihydrofuran-2 (3H)-one was added to the reaction liquid at the same temperature, and the reaction liquid was stirred at the same temperature for 2 hours, and then heated up to 0° C., and stirred for 30 minutes. Aqueous saturated sodium bicarbonate was added to the reaction temperature at the same temperature, extracted with ethyl acetate, and the organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:23])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH2:21][CH3:22])[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:4]([Cl:23])[CH:3]=1
Reactant: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(SC)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(S(C)=O)nc21
Reaction time: 5 h
Yield: 88.6 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenyl)-8-ethyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one (10, 1.30 g, 3.16 mmol) in dichloromethane (20 mL) was added dropwise a solution of 3-chloroperbenzoic acid (77%, 0.57 g, 2.54 mmol) in dichloromethane (5 mL) at 0-5° C. and the mixture was stirred for 5 h. The reaction mixture was washed with saturated sodium bicarbonate solution (2×20 mL) and water (10 mL), and the organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography using dichloromethane:ethyl acetate (5:1→5:2→2:1→1:1) to give the title compound as an off-white solid (0.96 g, 2.25 mmol, 71%). ESMS m/z 426 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([OH:13])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]([N:27]([O:28][CH3:29])[CH3:26])=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1coc2c(Br)cccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)c1coc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-bromo-1-benzofuran-3-carboxylic acid (8.9 g, 37 mmol), CDI (9.1 g, 56 mmol) and DCM (200 mL) was stirred for 4 hours at room temperature, and then MeNHOMe (5.5 g, 56 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (300 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4. The solvent was concentrated in vacua. The residue was purified with silica gel chromatography to give 7-bromo-N-methoxy-N-methyl-1-benzofuran-3-carboxamide. 1H-NMR (400 MHz, CDCL3) δ ppm 8.33 (s, 1H), 8.21 (d, J=8.0, 1 H), 7.51 (d, J=7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 3.72 (s, 3H), 3.39 (s, 1H).