Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:31][CH2:30][C:11]3([CH2:15][N:14](C(OC/C(/C=C)=C/C=C\C)=O)[C@H:13]([C:27]([OH:29])=[O:28])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:32][C@H:33]([C:38]2[CH:43]=[CH:42][C:41](/[CH:44]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:40][C:39]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:34]([F:37])([F:36])[F:35])[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:31][CH2:30][C:11]3([CH2:15][NH:14][C@H:13]([C:27]([OH:29])=[O:28])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:32][C@H:33]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:40][C:39]=2[N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[C:34]([F:37])([F:36])[F:35])[N:3]=1
Reactant: C=C/C(=C\C=C/C)COC(=O)N1CC2(CCN(c3cc(O[C@H](c4ccc(/C=C/C(=O)OCC)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)C[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1

Procedure:
To a solution of ((S)-8-(2-amino-6-((R)-1-(4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and the product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2Cl2 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9]O>>[CH3:9][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Oc1ccc(O)cc1
Product: COc1ccc(O)cc1
Reaction time: 4 h

Procedure:
2.0 g of the catalyst prepared as in the preceding test are fed into the autoclave with 5.0 g of hydroquinone and 40 cm3 of methanol. The autoclave is kept at 105° C. for 4 hours under nitrogen. 0.25 g of hydroquinone monomethyl ether are obtained.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].C1COCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:27]5[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=5)[CH:19]=[CH:18][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2ccc3nc(N4CCN(C5CC5)CC4)sc3c2)cc1
Temperature: 60 °C
Yield: 7.2 %

Procedure:
To a solution of 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (500 mg, 1.48 mmol) and 4-acetamidophenylboronic acid (319 mg, 1.78 mmol) in a 5:1 mixture of THF and H2O (20 mL) was added Pd2(dba)3 (240 mg, 0.148 mmol), followed by P(t-Bu)3BF4 (86 mg, 0.296 mmol) and K3PO4.H2O (1.97 g, 7.4 mmol). The mixture was heated at 60° C. for 3 h, filtered and the volatiles were evaporated. Water (5 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 42 mg (7%) of N-{4-[2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-yl]phenyl}-acetamide as a trifluoroacetate salt.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[N:13]=[C:14](Cl)[C:15]([NH2:21])=[N:16]2>CN(C=O)C>[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[N:13]=[C:14]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:15]([NH2:21])=[N:16]2
Reactant: Nc1nc2cccc(Br)c2nc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc2cccc(Br)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a slurry of NaH (60% dispersion in mineral oil; 0.193 g, 4.84 mmol) in 5 mL DMF at 0° C. under N2 was added phenol (0.455 g, 4.84 mmol). Gas evolution was observed. The reaction was warmed to RT. After 5 min, 5-bromo-3-chloroquinoxalin-2-amine (0.250 g, 0.967 mmol) was added, and the reaction was sealed and stirred overnight. The reaction was partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was sequentially washed with water (1×), and saturated aq. NaCl (1×), and then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and adsorbed onto 2 g silica gel and dried. The material was purified by silica gel chromatography using 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford 5-bromo-3-phenoxyquinoxalin-2-amine (0.209 g, 0.661 mmol, 68% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.55 (1H, dt, J=7.6, 0.7 Hz), 7.37-7.51 (7H, m), 7.26-7.35 (2H, m). m/z (ESI, +ve) 316.0 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]#[N:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])([OH:35])=[O:34]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cc(C#N)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 125.7 %

Procedure:
A solution of 280 mg (0.5 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2 -oxo-ethoxy]-5-cyano-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 280 mg (72%) of the title compound as a white powder. MS m/e (%): 444 (M-H-, 100).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C)C=O>[F:18][C:17]1[C:12]([S:4][CH:1]([CH3:3])[CH3:2])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cccnc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ncccc1F
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
220.93 g of isopropyl mercaptan are added dropwise at a temperature of from 0° to -5° C. to a mixture of 388.6 g of potassium carbonate and 301 g of 2,3-difluoropyridine in 4300 ml of dimethylformamide. After stirring for 20 minutes, the temperature of the reaction mixture is allowed to rise slowly to room temperature and is stirred for a further 30 minutes. The reaction mixture is then added to an ice-water/ethyl acetate mixture, the phases are washed four times with ethyl acetate and ice-water and then dried over sodium sulfate. After filtering and concentrating by evaporation, the resulting crude product (510 g) is purified by column chromatography (ethyl acetated hexane 1:9) to give 327.3 g of 3-fluoro-2-isopropylthiopyridine in the form of an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23]([OH:25])=O)[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH3:35])[C:23](=[O:25])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: c1cn[nH]c1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2cccn2)cc1

Procedure:
70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 36 mg of 1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=[C:29]4[C:33]=3[NH:32][C:31](=[O:34])[CH2:30]4)[CH3:24])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:37])([F:36])[F:38])[CH:28]=[C:29]4[C:33]=3[NH:32][C:31](=[O:34])[CH2:30]4)[CH3:24])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl 4-(4-fluorophenyl)-4-((1-(2-oxo-5-(trifluoromethyl)indolin-7-yl)ethoxy)methyl)piperidine-1-carboxylate (13 mg, 0.024 mmol) in dichloromethane (1.5 mL) at ice bath temperature was added TFA (200 μL, 2.60 mmol). The mixture was stirred at this temperature for 1 hour. TLC (30% ethyl acetate/hexanes) indicated complete conversion of starting material. The mixture was concentrated and the crude residue was loaded onto an SCX cartridge (Phenomenex Strata X-C 200mg) with methanol then the resin was washed with methanol and the compound eluted with 2N NH3 in methanol to give the product (10.2 mg, 0.023 mmol, 96%) as a clear pale yellow film. 1H-NMR (CDCl3, 400 MHz) δ 7.57-7.88 (m, 1H), 7.32 (s, 1H), 7.21-7.29 (m, 2H), 7.11 (s, 1H), 7.03 (t, J=8.69 Hz, 2H), 4.28 (q, J=6.55 Hz, 1H), 3.42 (s, 2H), 3.31-3.36 (m, 1H), 3.24-3.30 (m, 1H), 2.83-2.96 (m, 2H), 2.63-2.80 (m, 2H), 2.17 (ddd, J=13.72, 2.27 Hz, 1H), 2.06 (dt, J=13.60, 2.27 Hz, 1H), 1.74-1.91 (m, 2H), 1.29 (d, J=6.55 Hz, 3H). Mass spec. (M-H)−: 435.5, (MH)+: 437.3.
Reaction SMILES: [CH:1]1([CH2:7][C:8](=[O:14])[CH2:9][C:10](OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15](Cl)[C:16](=C)[CH3:17].C[O-].[Na+].[OH-].[Na+].S(=O)(=O)(O)O>CO.O.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:16]([CH3:17])=[CH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)CC1CCCCC1
Reactant: C=C(C)CCl
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CCC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
A 250 ml flask was charged with 15.0 g of methyl 4-cyclohexyl-3-oxobutanoate (96% GC, 1 molar equivalent) and 9.8 g of methallyl chloride (1.5 molar equivalent). The mixture was heated to 70° C. and over the course of 90 minutes 13 g of a 30% solution of sodium methylate in methanol (1 molar equivalent) was added. Stirring was continued for 30 minutes and then 50 g of toluene was added. Within 1 hour 19.3 g of a 30% aqueous sodium hydroxide solution was added and stirring continued for 1 hour. After cooling to 25° C., 28.4 g of a 50% aqueous sulfuric acid solution was added over the course of 1 hour. To the slurry 70 g toluene and 40 g water were added and after decantation, the aqueous phase was drained. After concentration the crude product was fractionated leading to 8.9 g of 1-cyclohexyl-5-methylhex-5-en-2-one (95% GC, 60% yield).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][C:26]4=[O:35])[CH2:21][CH2:20]3)=[O:18])=[C:15]([O:38][CH3:39])[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>CO>[CH2:40]([N:42]([CH2:43][CH3:44])[CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([N:19]3[CH2:20][CH2:21][CH:22]([N:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][C:26]4=[O:35])[CH2:23][CH2:24]3)=[O:18])=[C:15]([O:38][CH3:39])[CH:14]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:41]
Reactant: C=CS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)N1CCC(Oc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(1-(4-(N-vinylsulfonyl-4-piperidinyloxy)-2-methoxybenzoyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (80 mg, 0.14 mmol) from Example 192 in 5 mL of dry MeOH was added diethylamine (0.14 mL, 1.4 mmol) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 98:2 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1cc(Cl)cnc1Br
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloro-3-fluoropyridine. MS (ESI) 454 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1[N:43]=[C:42]2[O:44][C:45]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:46](I)[C:47](=[O:48])[C:41]2=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:46]3[C:47](=[O:48])[C:41]4[C:42]([O:44][C:45]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:43][C:38]([Cl:37])=[CH:39][CH:40]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4nc(Cl)ccc4c3=O)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-chloro-3-iodo-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (8.4 mg, 64%) as a colourless gum. LCMS (Method B): RT=4.42 min, [M+Na]+=525/527.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][C@H:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][C@@H:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Slowly add trichloromethyl chloroformate (5.80 mL; 2.0 equiv; 48.35 mmoles) over 15 minutes to a 0° C. solution of (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (9.2 g; 1.0 equiv; 24.17 mmoles) and pyridine (15.64 mL; 8 equiv; 193.40 mmoles) in acetonitrile (450 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (30 mL) and concentrate the reaction mixture. Add dichloromethane (50 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired (6R)-6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (5.50 g; 56%). MS (m/z): 407(M+1).
Reaction SMILES: Cl.[N:2]1([C:8]([O:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>C(#N)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:5]2[CH2:6][CH2:7][N:2]([C:8]([O:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[O:9])[CH2:3][CH2:4]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COC(=O)N1CCN(CCOc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of 0.073 g (0.3 mmol) of 2-(methylamino)-2-oxoethyl piperazine-1-carboxylate hydrochloride, prepared in step 3.3., 0.13 g (0.9 mmol) of potassium carbonate and 0.069 g (0.29 mmol) of 1-(2-bromoethoxy)-4-chlorobenzene in 3 ml of acetonitrile is heated at 85° C. for 16 hours. After cooling to ambient temperature, the inorganic components are filtered off through a cartridge fitted with a frit and containing celite. The cartridge is rinsed with acetone and the filtrate is concentrated under reduced pressure. Chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether give 0.089 g of product in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:20][C:10]1[C:9]([C:21]#[N:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=1)[CH:26]=[CH2:25]
Reactant: C=CCI
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1nc2ccc(OC)cc2c(-c2cccc(F)c2)c1C#N
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.00 g, 3.40 mmol) in 20 mL of N,N-dimethylformamide at 0° C. was added sodium hydride (163 mg of 60% dispersion in mineral oil, 4.08 mmol). After 30 minutes, allyl iodide was added (0.342 mL, 3.74 mmol), and the reaction was stirred for 2 hours. The reaction was quenched with water and partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was subjected to flash chomatography through SiO2 (5-60% EtOAc/hexane) to provide the second eluting product as the titled compound. 1H NMR, difference nOe, and HMQC NMR spectral data for the product were consistent with the titled compound. ESI+ MS: 335.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N+:4]([O-:18])=[C:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6](=[O:13])[NH:7][C:8]=1[C:9]([O:11]C)=[O:10])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[N+:4]([O-:18])=[C:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6](=[O:13])[NH:7][C:8]=1[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: CCc1c(C(=O)OC)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)O)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of 7.99 g of 5-ethyl-3-isobutyl-6-methoxycarbonyl-1,2-dihydropyrazin-2-one 4-oxide in ml of methanol was added 63 ml of 2N-sodium hydroxide aqueous solution, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in water, then under ice-cooling condition with stirring, the solution was acidified by adding 11 ml of concentrated hydrochloric acid. The crystals thus precipitated were collected by filtration, and were washed with water, then recrystallized from dichloromethanemethanol to obtain 6.24 g of 5-ethyl-3-isobutyl-1,2-dihydropyrazin-2-one-6-carboxylic acid 4-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:27][CH:28]=O)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]([CH2:40][OH:41])[NH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:27][CH2:28][N:31]1[C@H:32]([CH2:40][OH:41])[CH2:33][C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30]1)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[O:22]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@](CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reactant: OC[C@@H]1Cc2ccccc2CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1Cc2ccccc2C[C@H]1CO)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.148 g, 0.358 mmol, 1.0 equiv.) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (0.088 g, 0.54 mmol, 1.5 equiv.) in 1,2-dichloroethane (0.34 mL, 0.5 M) was treated with sodium triacetoxyborohydride (0.19 g, 0.90 mmol, 2.5 equiv) in one portion. After stirring for 1.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and stirred for an additional 5 min. The resulting mixture was added to a separatory funnel, diluted with saturated aqueous NaCl (5 mL) and extracted with dichloromethane (2×10 mL). The organic layer was dried over MgSO4, filtered and concentration under reduced pressure. Purification by flash column chromatography eluting with 5% methanol in chloroform gave (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-((S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a pale yellow oil (0.187 g, 93%). Rf 0.52 (10% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 7.15-7.08 (m, 2H), 7.07-6.98 (m, 2H), 5.90 (s, 1H), 3.78 (d, J=16.2 Hz, 1H), 3.70 (s, 3H), 3.60-3.47 (m, 2H), 3.04-2.93 (m, 1H), 2.92-2.82 (m, 1H), 2.71-2.60 (m, 1H), 2.56-2.38 (m, 2H), 2.37-2.23 (m, 1H), 2.21-2.10 (m, 1H), 1.77-1.63 (m, 1H), 1.42 (s, 9H), 1.43-1.26 (m, 3H), 1.23 (s, 12H), 1.22-1.16 (m, 1H), 0.99-0.82 (m, 2H), 0.74 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C30H49BN2O7: expected 560.4. found 561.4 (M+H)+.