Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:29][C:11]3[C:12](=[O:28])[N:13]([C:16]4[CH:17]=[N:18][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]5)=[CH:20][CH:21]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:29][C:11]3[C:12](=[O:28])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@H:24]([O:27][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23]5)=[N:18][CH:17]=4)[CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2sc(-c3ccc(Cl)cc3)cc2CCN1c1ccc(N2CC[C@H](O)C2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-[6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (1.246 g, 2.93 mmol) in CH2Cl2 (25 mL). Cool to 0° C. and treat with Et3N (0.61 mL, 4.39 mmol), followed by MsCl (0.25 mL, 3.22 mmol). Stir at 0° C. for 15 min and at RT for 2 h. Dilute the mixture with CH2Cl2 (50 mL). Wash with H2O (2×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% CH3OH/CH2Cl2 to give 1.21 g (82%) of the title compound. MS/ES m/z (35Cl) 504.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:38].O>CN(C)C=O>[CH3:38][O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1
Reactant: CI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodomethane (0.187 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained (382 mg, yield: 80%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[Cl:17][C:18]1[C:31]([N:32]=[C:33]=S)=[C:30]([Cl:35])[CH:29]=[CH:28][C:19]=1[CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CC(O)=O.CC#N>[Cl:17][C:18]1[C:19]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:28][CH:29]=[C:30]([Cl:35])[C:31]=1[NH:32][C:33]1[NH:14][C:12]2[CH:13]=[C:5]([O:4][CH2:3][CH:2]([F:16])[F:1])[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11]=2[N:15]=1
Reactant: Nc1cc(OCC(F)F)c(C(=O)O)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(2,2-difluoro-ethoxy)-4,5-diamino-benzoic acid (732 mg, 3.15 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.00 g, 3.15 mmol) and MeCN (15 mL) is stirred for 48 h, then BSTFA (1.03 mL, 3.15 mmol) is added and it is stirred at reflux for 10 min. Then DIC (0.494 mL, 3.15 mmol) is added and it is stirred for another 4 h. The mixture is cooled to rt, diluted with HOAc and concentrated. The residue is stirred with 1N NaOH, filtered and the filtrate is acidified with 4N HCl, extracted with EtOAc and purified via chromatography [DCM→DCM+10% EtOH/HOAc (95:5)] to give the subtitle compound.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].O.[NH2:32][NH2:33]>C(O)C>[N:25]1([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:9]4[NH:10][C:11]5[CH:12]=[N:13][C:5]([C:3]([NH:32][NH2:33])=[O:4])=[CH:6][C:7]=5[C:8]=4[CH:17]=3)=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (425 mg, 1.06 mmol) and hydrazine hydrate (1.29 mL, 26.5 mmol) in ethanol (4.6 mL) was heated under reflux for 1 h under a nitrogen atmosphere. The solution was allowed to cool to ambient temperature and the resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford a yellow solid (337 mg, 79%). The solid was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO[C:14](OC)([CH3:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:9][C:10]#[N:11])=[CH:3][C:2]=2[O:1]1
Reactant: COC(C)(C)OC
Reactant: N#CCc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(CC#N)cc2O1
Yield: 16.3 %

Procedure:
To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.20 g, 1.3 mmol) in toluene (4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g, 0.065 mmol). The mixture was heated at reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO3 solution, H2O, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 1H NMR (CDCl3, 400 MHz) δ 6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].Br[C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:30]3[N:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]4=[N:33][C:29]=3[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:38])=[CH:17][CH:16]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][Si:9]([C:12]#[C:13][C:15]1[N:20]=[CH:19][C:18]([N:21]2[C:30]3[N:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]4=[N:33][C:29]=3[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:38])=[CH:17][CH:16]=1)([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(-n2c(=O)c3ccccc3c3nc4ccccn4c32)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.6 %

Procedure:
CuI (0.2 equiv., 0.256 mmol, 0.049 g), dichlorobis(triphenylphosphine)-palladium(II) (0.1 equiv., 0.13 mmol, 0.090 g), triethylamine (1.0 equiv., 1.28 mmol, 0.129 g), (trimethylsilyl)acetylene (10.0 equiv., 12.8 mmol, 1.26 g) and KI (10.0 equiv., 12.8 mmol, 2.12 g) were added to a mixture of 6-(6-bromo-pyridin-3-yl)-pyrido-[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (21) (1.0 equiv., 1.28 mmol, 0.50 g) in dry DMF (10 ml). The reaction mixture was stirred at room temperature under N2 atmosphere for 24 h. After addition of a second portion of CuI (0.20 equiv., 0.256 mmol, 0.049 g) and dichlorobis(triphenylphosphine)-palladium(II) (0.1 equiv., 0.13 mmol, 0.090 g), the reaction mixture was further stirred at 60° C. for 17 h. The solvent was evaporated under reduced pressure and the pasty residue was mixed with dichloromethane and washed with water. The organic layer was evaporated under reduced pressure and the residue purified by column chromatography (ethyl acetate/heptane 60:40) to afford 6-[6-[(trimethylsilanyl)ethynyl]-pyridin-3-yl]-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-5(6H)-one (I9) (0.50 g, yield=96%, purity (LC)=95%).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[S:6]([Cl:10])(=[O:8])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccccc2)sc2ccccc12

Procedure:
2-Benzylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.41 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-benzylbenzo[b]thiophene. Flash chromatography (5% ethyl acetate/hexanes) provided 0.55 g (64%) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (3R,4S)-pyrrolidine-3,4-diol (313 mg, 3.03 mmol) in a mixture of DIPEA (0.883 mL, 5.06 mmol) and iPrOH (2.53 mL) was subjected to MW irradiation at 140° C. for 30 min. The RM was treated with 0.5 M aq. HCl (30 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3, brine and dried over Na2SO4. The crude product was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 50% to 100% EtOAc) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=462.1-464.0 [M+H]+, m/z=460.1-462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.61 (dd, J=11.13, 4.28 Hz, 2H) 3.84 (dd, J=10.76, 4.89 Hz, 2H) 4.10 (d, J=3.42 Hz, 2H) 4.96 (d, J=3.91 Hz, 2H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=8.80 Hz, 2H) 8.34 (s, 1H) 8.67 (s, 1H) 10.21 (s, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[N+:33]([C:36]([CH3:41])([CH2:39]O)[CH2:37][OH:38])([O-:35])=[O:34]>C(Cl)Cl.C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:39][C:36]([CH3:41])([N+:33]([O-:35])=[O:34])[CH2:37][OH:38])=[O:30])[CH:22]=[CH:21]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)[N+](=O)[O-])ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9 mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) in CH2Cl2 (50 mL) and THF (50 mL) was stirred at ambient temperature overnight. The solvent was evaporated and EtOAc (100 mL) was added to the resulting crude material, cooled in a dry-ice bath and the byproduct, dicyclohexyl urea was removed by filtration. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture of diasteromers) as an oil (2.77 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 7.69-7.60 (m, 3H), 7.34-7.3 (m, 1H), 7.14-7.08 (m, 2H), 4.44 (d, J=4.2 Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d, J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.14, 174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87, 125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04, 18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>O1CCCC1.O1CCOCC1>[NH2:10][C:8](=[O:9])[C@@H:7]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)C(N)c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=O)[C@@H](NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of D-Phenylglycine amide (850 mg, 7.5 mmol) in tetrahydrofuran (10 mL) and 1,4-dioxane (4 mL) was added 1,3-propanesultone (818 mg, 6.8 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (720 mg, 34%). 1H NMR (D2O, 500 MHz) δ ppm 7.38 (m, 5H), 4.92, (s, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.78 (m, 2H), 1.97 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.14, 130.95, 130.24, 129.94, 128.74, 63.40, 47.99, 44.92, 21.27. [α]D=+106° (c=0.0016 in water), ES-MS 273 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1.ClCCl.CO.N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([NH:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]2)=[C:20]([O:36][CH3:37])[CH:19]=1)=[O:16]
Reactant: COc1cc(N)ccc1OCCN1CCC(C(N)=O)CC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 194 mg (0.66 mmol) of 1-[2-(4-amino-2-methoxyphenoxy)ethyl]piperidine-4-carboxylic acid amide. Yield: 310 mg (98% of theory); melting point: 150° C.; C25H25ClF3N3O4 (M=523.93); calc.: molecular ion peak (M+H)+: 524/526 (Cl); found: molecular ion peak (M+H)+: 524/526 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[N+:12](=[CH2:14])=[N-:13].N(NC(N)=O)=O>CCOCC>[N+:12](=[CH:14][C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4]1)=[O:9])=[N-:13]
Reactant: CC1(C)CCC(C(=O)Cl)CC1
Reactant: C=[N+]=[N-]
Agent: NC(=O)NN=O
Solvent: CCOCC
Product: CC1(C)CCC(C(=O)C=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next at room temperature, 2.0 g of the 4,4-dimethylcyclohexylcarbonyl chloride obtained as above was added dropwise to 100 ml of an ether solution of diazomethane prepared from 10 g of nitrosourea, and the mixture was thereafter stirred at room temperature for about 1 hour. The solvent was distilled off from the reaction mixture in a vacuum, quantitatively giving pale yellow oily 1-diazo-2-(4,4-dimethyl-cyclohexyl)-2-ethanone (Compound I).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:8][C:9]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=1[NH2:11])=[O:5])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](O)=[O:48])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23>C(O)(=O)C.C(OCC)(=O)C>[Br:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](=[O:48])[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:15][C:9]=3[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)C(=O)OCC
Yield: 59.8 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(3,3-diethoxycarbonylpropyl)-4-tert-butoxycarbonylaminomethylaniline (1.5 g, 3.67 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.37 g, 4.04 mmol) to give 1.60 g of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (60%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:20])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])[CH:7]=2)[CH3:5])(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(NC(=O)Oc2ccccc2)no1
Temperature: 35 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
To a stirred solution of phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 131A steps 1 through 4) (250 mg, 0.91 mmol) and pyridine (0.15 mL, 1.81 mmol) in dichloromethane (5 mL) at 0° C., was added dropwise, 4-nitrophenylsulfonyl chloride (245 mg, 1.08 mmol) in dichloromethane (3 mL). The reaction mixture was warmed to 35° C. and stirred for a further 15 h. Concentration under reduced pressure gave the crude product which was purified via silica gel column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 2-methyl-2-(3-(phenoxycarbonylamino)isoxazol-5-yl)propyl 4-nitrobenzenesulfonate (250 mg, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3) 88.36-8.39 (m, 2H), 8.01-8.03 (m, 2H), 7.88 (m, 1H), 7.43-7.45 (m, 2H), 7.21-7.31 (m, 3H), 6.54 (s, 1H), 4.19 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:15]2[C:14]3[C:9](=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1

Procedure:
The title compound was prepared from 4-chloro-8-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester and 3-aminophenylboronic acid according to the procedure of Example 1. MS (ES) m/z 361.0;
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.[CH2:16](Br)[CH:17]=C.O>CN(C)C=O>[CH2:10]([NH:11][C:6]1[C:7](=[CH:14][CH:15]=[C:4]([F:3])[CH:5]=1)[C:8]([OH:9])=[O:13])[CH:16]=[CH2:17]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCNc1cc(F)ccc1C(=O)O
Reaction time: 1 h

Procedure:
Sodium hydride (0.41 g of 80% suspension in oil) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (2.5 g) in dimethylformamide (30 ml). The mixture was cooled to keep the temperature below 30° and then stirred for 1 hour until a clear solution was obtained. A solution of allyl bromide (1.2 ml) in dimethylformamide (30 ml) was added dropwise with cooling and the mixture stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The extract was washed with water, dried and evaporated and the residue added to aqueous sodium carbonate (10%; 20 ml) and stirred for 3 hours, acidified with hydrochloric acid to pH 3, filtered and the solid washed with water and dried to give N-allyl-4-fluoroanthranilic acid, mp 136°-139°. (Compound 21).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:13][C:14]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[C:14]([O:17][C:18](=[O:19])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1)([CH3:16])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 3 h

Procedure:
5-Fluoro-3-methyl-2-nitro-phenylamine (0.97 g, 5.7 mmol), 4-N-BOC-aminopiperidine (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) are combined and stirred at 85° C. for 3 hours. The reaction mixture was poured on saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layers were washed with water (3×) and brine, dried over Na2SO4 and concentrated. Flash column chromatography on silica (eluent hexanes-ethyl acetate-triethylamine 50-50-1, then 33-66-1) gave the tiitle compound as a yellow solid. (1.57 g, 79%). LCMS (M+H)+ m/z 351 (t=1.55 min.). 1H NMR (500 MHz, CD3OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J=2.5 Hz)), 6.13 (1H, d, J=2.5 Hz), 3.88 (2H, d, J=13.3 Hz), 3.58 (1H, broad s), 2.98 (2H, t, J=11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J=11.3 Hz), 1.48 (2H, m), 1.45 (9H, s). Procedure for the Preparation of 3-methyl-5-(2-morpholin-4-ethoxy)-2-nitro phenylamine