Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[N:25]([CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](=[O:40])[C:23]2=[O:41].ClCCl>O1CCCC1>[C:34]1([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]2[C:26]3[C:22](=[CH:21][CH:20]=[CH:19][C:18]=3[F:17])[C:23]([OH:41])([C:8]3[C:9]([OH:11])=[CH:10][C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]=4[CH:7]=3)[C:24]2=[O:40])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2c(F)cccc2C1(O)c1cc2c(cc1O)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a cooled (0° C.) suspension of 2,3-dihydro-1,4-benzodioxin-6-ol (0.47 g, 3.0 mmol) in anhydrous tetrahydrofuran (12 mL) was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 1.7 mL, 3.3 mmol). The reaction mixture was stirred at 0° C. for 1 h, and 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione (1.0 g, 3.0 mmol) and anhydrous dichloromethane (10 mL) were added. The reaction mixture was allowed to stir for 19 h at ambient temperature. The reaction mixture was concentrated in vacuo and was diluted with saturated aqueous ammonium chloride (30 mL) and ethyl acetate (30 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 8% to 66% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (1.22 g, 84%) as an off-white solid: MS (ES+) m/z 475.0 (M−17).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][C:5]=1[NH2:21])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:30](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[N:15]1([C:7]2[C:8]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:9][C:4]3[NH:1][CH:30]=[N:21][C:5]=3[CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(OC)OC
Reactant: Nc1cc(N2CCCCC2)c(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cc2[nH]cnc2cc1N1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A mixture of 2-nitro-5-piperidin-1-yl-4-trifluoromethoxy-phenylamine (0.900 g, 2.94 mmol), sodium dithionite (2.67 g, 15.3 mmol), trimethyl orthoformate (8.72 mL, 79.6 mmol), DMF (8.56 mL), and acetic acid (1.45 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc (80 mL) and saturated aqueous NaHCO3 (80 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound (0.589 g, 71%). MS (ESI/CI): mass calcd. for C13H14F3N3O, 285.1; m/z found, 286.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+]>CCO>[CH2:1]([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[C:9](=[O:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN(CCc1ccccc1OC)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccccc1OC)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 12 %

Procedure:
Methyl 2-{[4-(2-{heptyl[2-(2-methoxyphenyl)ethyl]amino}-2-oxoethyl)phenoxy]methyl}benzoate (0.094 g, 0.177 mmol) was dissolved in EtOH (5 ml, 95%), potassium hydroxide (0.015 g, 0.265 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150 deg). Workup by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The waterphase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.011 g of 2-{[4-(2-{heptyl[2-(2-methoxyphenyl)ethyl]amino}-2-oxoethyl)phenoxy]methyl}benzoic acid (yield 12%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22](CC=C)[C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:17]([C:26]#[N:27])[CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN1C(=O)CC(=O)N(C)C1=O.[OH-].[Na+]>ClCCl.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>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:17]([C:26]#[N:27])[CH2:18]3)[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)[C@@H](C#N)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#C[C@H]1C[C@@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@]1(c1ccccc1)N2
Temperature: 32.5 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) was added to a stirred mixture of (1R*,2R*,5S*,7S*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-7-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 57; 68 mg, 0.14 mmol), 1,3-dimethylbarbituric acid (70 mg, 0.5 mmol) in dichloromethane (3 ml) at room temperature. The reaction mixture was stirred at 30-35° C. for 1 hour and treated with 2M aqueous NaOH (5 ml). The mixture was stirred for 5 minutes, then diluted with water (30 ml) and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (37 mg, 60%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([O:40][CH3:41])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[C:37]([C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:42])=[O:2])(=[O:10])=[O:11])=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[O:40][CH3:41])(=[O:39])[CH3:38]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To (S)-2-{4′-[(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester (89 mg) was added 1 mL of THF and 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 2 days. The solvents were removed under vacuum and the residue was triturated with 4 mL of 2N HCl and filtered. The solid product was dried under vacuum to give 54 mg of (S)-2-{4′-[(5-acetyl-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.9, 6.8 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 2.9 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 4.0 (s, 3 H) 7.0 (d, J=8.8 Hz, 1 H) 7.8 (m, 4 H) 7.9 (m, 4 H) 8.0 (d, J=8.6 Hz, 1 H) 8.1 (d, J=9.3 Hz, 1 H) 10.3 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.N#N.[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34]([C:40]#[N:41])=[C:33]2[NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45]([Cl:50])[CH:44]=1>N1C=CC=CC=1>[Cl:50][C:45]1[CH:44]=[C:43]([NH:42][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:31]=3)[N:36]=[CH:35][C:34]=2[C:40]#[N:41])[CH:48]=[CH:47][C:46]=1[F:49]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.061 g, 0.448 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.104 g, 0.672 mmol) and N-methylmorpholine (0.068 g, 0.672 mmol) in 10 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 0.1 g (0.32 mmol) of 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 1.5 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 1.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.046 g (32%) of light brown solid; ESMS m/z 450.2, (M+H+); mp 117-120° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40]>O1CCOCC1.C(OCC)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:39](=[O:40])[O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:31][CH:32]=2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)Oc4ccccc4)cc3)n2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]propan-2-yl]pyrimidin-2-yl]aniline (340 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added sodium bicarbonate (90 mg, 1.08 mmol). Phenyl chloroformate (0.104 mL, 0.83 mmol) was then added dropwise and the resulting mixture was stirred at RT for 6 hours. Reaction mixture was then evaporated and the residue was partitioned between DCM (5 mL) and water (5 mL). The organic layer was separated and aqueous re-extracted with more DCM (5 mL). The combined organic layers were combined and evaporated to dryness to afford an amber gum, which was taken up in diethyl ether (5 mL) and triturated with sonication. The resultant solid was collected by suction filtration and dried to afford the desired material (334 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>>[F:29][C:30]([F:36])([F:35])[S:31]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: COc1ccc2cc(-c3nc(C(C)(C)CNS(=O)(=O)C(F)(F)F)[nH]c3-c3ccncc3)ccc2c1
Yield: 33 %

Procedure:
The title compound (9 mg, 33%) was prepared starting from the product of Example 2 and 1,1,1-trifluoromethanesulfonyl chloride using the method described in Example 4; MS(ES) m/e 505 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1O
Yield: 102.6 %

Procedure:
2-Nitro-4-trifluoromethylphenol (340 μL, 2.41 mmol) was dissolved in methanol (50 mL) and processed through the H-Cube with a 10% Pd/C Catalyst cartridge at ambient temperature and pressure. The eluent was concentrated under reduced pressure to provide 2-amino-4-trifluoromethylphenol as a light brown solid (438 mg, 100%). (CI, m/z): [M+H]+ 178, [M−H]− 176; 1H NMR (CDCl3): δ 6.96 (d, J=2.0 Hz, 1H), 6.89-6.94 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 4.10 (br s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]([C:22]1[C:23](=[O:37])[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21].[C:38]1([S:44]([N:47]2[C:51]3=[N:52][CH:53]=[CH:54][CH:55]=[C:50]3[C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48]2)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:38]1([S:44]([N:47]2[C:51]3=[N:52][CH:53]=[CH:54][CH:55]=[C:50]3[C:49]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[N:6]=[C:5]4[NH:19][C:20]([C:22]3[C:23](=[O:37])[N:24]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:48]2)(=[O:46])=[O:45])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)c2cc(Br)ccc21
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(NC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)c2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)ccc21
Temperature: 100 °C
Yield: 41.2 %

Procedure:
Into a Vial was dissolved 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-amide (0.123 g, 0.209 mmol;) and 1-Benzenesulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (88 mg, 0.23 mmol;) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (21 mg, 0.025 mmol; Strem;) in 1,4-Dioxane (2.69 mL, 34.4 mmol; Acros;). To this was added 2.0 M of Sodium carbonate in water (0.67 mL). The reaction was purged with Ar and sealed. The reaction was heated at 100° C. under an atmosphere of Argon for 2 hours. LC-MS showed the formation of product at 2.41 with the correct mass 767.28. The reaction was worked up by dissolving in methylene chloride then washing 1× with citric acid, 1× with saturated bicarbonate and 1× with brine before drying with magnesium sulfate and concentrating to give the crude product. The crude was then purified by combiflash using a 0-100 percent hex/ea gradient to give 66 mg of pure product. ES (+) MS m/e=767.28
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:13]([O:15][C:16]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([S:29][CH2:30]O)[C:21]2=[N:20][CH:19]=1)=[O:17])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1[C:23](=[O:24])[N:22]2[CH:25]=[CH:26][CH:27]=[C:28]([S:29][CH2:30][N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[C:21]2=[N:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cnc2c(SCO)cccn2c1=O
Reactant: C1CSCCN1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(SCN3CCSCC3)cccn2c1=O
Yield: 54.9 %

Procedure:
To a mixture of 163 mg of thiomorpholine, 920 mg of magnesium sulfate and 5 ml of tetrahydrofuran is added dropwise a solution of 429 mg of 3-ethoxycarbonyl-9-(hydroxymethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (III) in 25 ml of tetrahydrofuran with stirring under ice-cooling. The reaction mixture is stirred for 1 hour as it is, filtered, and the filtrate is concentrated in vacuo. The residue is recrystallized from ethyl acetatehexane to give 307 mg (Yield: 54.9%) of 3-ethoxycarbonyl-9-(thiomorpholinomethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (I c-1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[O:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:31]1[O:32][CH2:33][CH2:34][O:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C[C@@H](COCc2ccccc2)O1
Reactant: C1COCO1
Agent: O=C(c1ccccc1)c1ccccc1
Product: O=C1C[C@H](C2OCCO2)[C@@H](COCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 9 h
Yield: 330.3 %

Procedure:
A solution of furanone (13) (1.2 g, 5.88 mmols) and benzophenone (108 mg, 0.588 mmols) in [1,3]-dioxolane (108 mg) was degassed for 40 min in a stream of argon. The mixture then was irradiated using one 450 watt ACE glass medium pressure mercury lamp, from a distance of 15 cm, for 9 hours. Progress of this reaction was observed via 1H-NMR. As the reaction mixture was degassed, and throughout all of the irradiation time, the reaction flask was held in a water cooled cooling mantel. The temperature of the cooling water was constantly maintained near 0° C. Upon completion of the reaction, solvent was removed under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent), yielding the title compound (1.34 g, 82%) as a clear oil, Rf=0.14 (30% EtOAc in hexanes), [α]25D 16.5° (c 1.2, CHCl3); 1H-NMR (500 MHz, CDCl3) δ: 2.50 (dd, 1H, J=3.9, 12.9 Hz), 2.70-2.79 (m, 2H), 3.58 (dd, 1H, J=3.5, 7.2 Hz), 3.75 (dd, 1H, J=2.8, 7.9 Hz), 3.87-3.92 (m, 2H), 3.97-4.00 (m, 2H), 4.51 (d, 1H, J=11.9 Hz), 4.57-4.61 (m, 2H), 4.88 (d, 1H, J=3.6 Hz), 7.26-7.36 (m, 5H); 13C-NMR (125.8 MHz, CDCl3) δ: 30.39, 40.53, 65.77, 71.74, 73.99, 79.52, 104.14, 128.00, 128.89, 138.07, 176.79.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:7]2[CH2:8][N:9]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:16]=[C:7]2[CH2:8][N:9]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1
Reactant: CCC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N1CCn2nc(N)cc2C1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 265a (260 mg, 1.16 mmol) in methanol (10 mL) was added 10% Pd/C (26 mg). The system was evacuated and then refilled with H2. After stirring for 2 h, analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 265b as a yellow solid (225 mg, 99%). MS-ESI: [M+H]+ 195.1
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11]([O:14]CC=C)(=[O:13])[CH3:12].C1(C=CC(O)=CC=1)O>>[C:11]([O:14][CH2:1][CH:5]1[CH2:4][CH:8]2[CH2:7][CH:6]1[CH:10]=[CH:9]2)(=[O:13])[CH3:12]
Reactant: C=CCOC(C)=O
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: Oc1ccc(O)cc1
Product: CC(=O)OCC1CC2C=CC1C2
Temperature: 180 °C
Reaction time: 9 h

Procedure:
Dicyclopentadiene 1094 g (manufactured by Wako Pure Chemical Industries, Ltd.), 1772 g of allyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.), 1 g of hydroquinone (manufactured by Wako Pure Chemical Industries, Ltd.) were placed into an autoclave, and a space was replaced by nitrogen. The mixture was stirred at an internal temperature of 180° C. in a sealed system for 9 hours (rotating speed=300 rpm). The reaction mixture was filtered, and volatile components were evaporated. The residue was subjected to precision distillation (length of column=120 cm, filler=Propak, reflux ratio=10/1, pressure=10 mmHg, trap temperature=89° C.), thereby obtaining colorless and transparent NBCH2OCOCH3. The peak purity thereof was measured by gas chromatography, and the NBCH2OCOCH3 has the purity of 99.9% and endo/exo ratio of 83/17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([NH2:16])[N:13]([CH3:17])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24])C>C(O)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:15]3[C:23]([CH3:24])=[CH:22][C:21](=[O:20])[NH:16][C:14]=3[N:13]([CH3:17])[N:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(OC)cc(-c2cc(N)n(C)n2)c1
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-c2nn(C)c3[nH]c(=O)cc(C)c23)c1
Yield: 60 %

Procedure:
A solution of 3-(3,5-dimethoxyphenyl)-1-methyl-1H-pyrazol-5-amine (1.3 g, 5.57 mmol) and 3-oxo-butyric acid ethyl ester (1.09 g, 8.36 mmol) in acetic acid (5 ml) was stirred at 150° C. for 18 h. The solution was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (eluent 10% MeOH in CH2Cl2) to yield 1.0 g (60%) of the title compound. [1H-NMR (DMSO-d6, 360 MHz): δ 6.68 (d, 2H), 6.56 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.78 (s, 6H), 2.24 (s, 3H); UPLC-MS RtJ=0.79 min; [M+H]+=300.1]
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][N:6]=1.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22][CH2:21]1.C[N+](C[C@H](O)CC([O-])=O)(C)C>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]([CH3:19])[CH2:21][CH2:22]2)=[O:13])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Reactant: CN1CCNc2ccccc21
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Product: CN1CCN(C(=O)c2cncnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Yield: 8 %

Procedure:
The title compound was prepared in analogy to Example 77, from 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid and 1-methyl-1,2,3,4-tetrahydroquinoxaline (commercially available, Metina, catalog number M-636). The compound was purified by preparative HPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90 to 98:2) to give 6.5 mg (8%) of the desired compound. MS (ESI): m/z=415.1 [M+H]+.