Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:19])[N:13]2[CH2:16][CH:17]=O)=[CH:8][CH:7]=1.[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][N:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(Cl)(Cl)Cl.C(O)(=O)C>[C:38]([O:37][C:36]([N:35]([CH2:34][C:32]1[CH:31]=[CH:30][C:29]2[O:24][CH2:25][CH2:26][O:27][C:28]=2[CH:33]=1)[CH:43]1[CH2:48][CH2:47][N:46]([CH2:17][CH2:16][N:13]2[C:14]3[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH3:4])[CH:15]=3)[CH:10]=[C:11]([C:20]([O:22][CH3:23])=[O:21])[C:12]2=[O:19])[CH2:45][CH2:44]1)=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cc2ccc(OC)cc2n(CC=O)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2ccc(OC)cc2n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To 0.37 g of methyl 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 4 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.44 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-3-carboxylate. (2) To 5 mL of a dichloromethane solution containing 0.44 g of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-3-carboxylate, 0.46 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 60 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 0.37 g of sodium triacetoxyborohydride was added and stirred for 2 hours. Chloroform and water were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.31 g of methyl 1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.[I-].[Na+].[OH-].[Na+].Cl>C(O)(=O)C.Br.O>[NH2:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Br
Agent: Cl
Agent: [I-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(O)cc2s1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
6-Methoxy-1,3-benzothiazole-2-amine (10.4 g, 57.8 mmol) was dissolved in 25% hydrogen bromide acetic acid solution (80 mL), water (40 mL) was added and the mixture was heated under reflux for 16 hr. To the reaction mixture was added sodium iodide (10.4 g, 69.4 mmol) and the mixture was heated under reflux for 12 hr. Sodium iodide (15.2 g, 101 mmol) was added and the mixture was heated under reflux for 16 hr. The reaction mixture was cooled to room temperature, and added to 8N aqueous sodium hydroxide solution (350 mL) stirred vigorously. The reaction mixture was neutralized with 6N hydrochloric acid and stood at 0° C. The resulting dark-gray crystals were collected by filtration and the mother liquid was preserved. The obtained crystals were dissolved in methanol (35 mL) and ethyl acetate (350 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated to give the title compound (6.90 g, 72%) as a gray solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[ClH:21].CCOC(C)=O>CCOC(C)=O>[ClH:21].[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cc1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(CN)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 3-(3-bromophenyl)-2,2-dimethylpropylcarbamate (72) (3.2 g, 9.35 mmol) was dissolved in EtOAc (55 mL), and a solution of HCl-EtOAc (−4.2 M, 20 mL, 84 mmol) was added. The reaction was vented with a needle and stirred at room temperature for 2.5 h. The reaction was then diluted with hexanes and the white solid was collected on a flitted glass funnel The mother liquor was concentrated under reduced pressure, suspended in ˜5-10% EtOAc-hexanes, and the white solid was collected and combined with the first batch. The solid was dried in a vacuum oven at room temperature overnight to give pure 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride as a white solid. Yield (1.52 g): 1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 2H), 7.37 (dq, J=1.2 and 8.0 Hz, 1H), 7.31 (t, J=1.6 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.08 (dt, J=8.0, 1.6 Hz, 1H), 2.83-2.84 (m, 2H), 2.67 (s, 2H), 1.09 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH3:20])[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1N
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-ylamine (130 mg, 0.46 mmol) in THF (6 ml) was added a solution of K2CO3 (126 mg, 0.91 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.05 ml, 0.48 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 ml) and a solution of borane in THF (1M) was added (1.9 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (2 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (30 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 77 mg (56%) of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 299.3 (M+H+).
Reaction SMILES: CI.[Br:3][C:4]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:14]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:4]=1[Br:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(I)ccc1Br

Procedure:
Methyl iodide (13 g, 91.5 mmol) is added to slurry of 2-bromo-5-iodobenzoic acid (23 g, 70.4 mmol) and K2CO3 (14.6 g, 106 mmol) in DMF (50 mL) at room temperature. After TLC shows complete consumption of the starting material, the reaction is diluted with Et2O and washed three times with a saturated aqueous solution of NaCl. The combined aqueous layers are extracted once with fresh Et2O and once with EtOAc. The organic layers are combined, dried with Na2SO4, filtered and concentrated to an oil. The oil is diluted with a minimal amount of Et2O and filtered through a plug of silica. The silica is rinsed with a 20% ether/hexanes mixture. The eluents are concentrated in vacuo to give 2-bromo-5-iodobenzoic acid methyl ester as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:7]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 83.4 %

Procedure:
To a stirred solution of 5-bromo-pentanoyl chloride (0.167 ml, 1.25 mmol) in THF (10 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.50 g, 1.19 mmol) and triethyl amine (0.18 ml, 1.30 mmol) in THF (5 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.58 g (83%) of the title compound as a white solid. ES-MS m/e: 584.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C(=O)([O-])[O-:11].[Na+].[Na+]>C(O)(=O)C.OO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccnc1C
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc[n+]([O-])c1C
Temperature: 95 °C

Procedure:
71.79 g of 2,3-dimethylpyridine (II) was dissolved in 240 ml of acetic acid, to which 40 ml of 30% hydrogen peroxide solution was added and the resulting mixture was heated at 95° C. for 3 hours. Furthermore, 18 ml of a 30% hydrogen peroxide solution was added to the mixture and heated at 95° C. for 13 hours, and thereafter, 700 ml of water was added thereto and the resulting mixture was neutralized with sodium carbonate and extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting precipitation was recrystallized from diisopropylether to obtain 71.34 g of 2,3-dimethylpyridine N-oxide (III).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:38][O:39][CH2:40]Cl.[OH-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO>[CH3:38][O:39][CH2:40][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: COCCl
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Yield: 22.3 %

Procedure:
To a solution of methyl 3-{4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.50 g, 1.28 mmol), potassium carbonate (0.35 g, 2.56 mmol) and sodium iodide (0.19 g, 1.28 mmol) in N,N-dimethylformamide (5.0 mL) was added chloromethyl methyl ether (0.13 mL, 1.66 mmol) at room temperature with stirring and the mixture was stirred at 50° C. for 24 hrs. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give a colorless oil. Then, to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL) was added 1 N aqueous sodium hydroxide solution (2.6 mL) at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was adjusted to pH3 with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) to give the title compound (0.12 g, yield 22%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:16]([O:19][CH2:20][CH3:21])([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])[N:4]=1.C[O-].[Na+:24]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:16]([O:19][CH2:20][CH3:21])([CH3:17])[CH3:18])[C:13]([O-:15])=[O:14])[N:6]=1.[Na+:24]
Reactant: CCOC(C)(C)C(Oc1nc(OC)cc(OC)n1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(C)(C)C(Oc1nc(OC)cc(OC)n1)C(=O)[O-]
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To Compound 52 (30.0 g, 0.1 mol) prepared in the above (2) dissolved in methanol (100 ml) was added sodium methoxide (19.3 g, 28% methanol solution), and the mixture was stirred for 10 minutes. Subsequently, methanol was removed under reduced pressure to obtain 32 g of the title compound as white crystals.
Reaction SMILES: C(OC([C:8](=[C:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C(C(=O)OC(C)(C)C)=C2CCCN2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2CCCN2)cc1

Procedure:
Add 80 ml of trifluoroacetic acid to 15 g of the title compound of Example 17 with ice cooling, and stir the produced reaction mixture for 2 hours at room temperature. Distil off the acid under a vacuum. Dissolve the resulting residue in 250 ml of diethyl ether and wash the thus-prepared solution with almost saturated cold sodium carbonate solution (150 ml) and saturated sodium chloride solution. Dry the washed solution over sodium sulfate and distil off the ether before dissolving the residue in 300 ml of ethanol and reducing it with Raney nickel/hydrogen. Concentrate the reduced solution to an oil and distil the oil under a vacuum to obtain 7.5 g (76% of theory) of the title compound (b.p. 88° to 90° at 0.008 mm of Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[C:10](=[S:29])[NH:9][C:8]=2[C:7]1=[O:30].[OH-].[Na+].I[CH2:40][CH3:41].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=3)[C:10]([S:29][CH2:40][CH3:41])=[N:9][C:8]=2[C:7]1=[O:30]
Reactant: COc1ccc(CN2CCc3c([nH]c(=S)n(-c4ccc(OCC(F)(F)F)cc4)c3=O)C2=O)c(OC)c1
Reactant: CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(2,4-dimethoxybenzyl)-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,5,6,7-hexahydropyrido[3,4-d]pyrimidine-4,8-dione (68 mg) in N,N-dimethylformamide (2 ml) were added 1M aqueous sodium hydroxide solution (140 μl) and iodoethane (11 μl), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into 0.5M hydrochloric acid (4 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the colorless title compound (72 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C@H:28]([CH3:58])[C@@H:29]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[C:47]([C:53]([F:56])([F:55])[F:54])[C:46]=1[CH3:57])[C:30]([NH:32][NH:33][C:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=1)=[O:31])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:27][C@H:28]([CH3:58])[C@@H:29]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[C:47]([C:53]([F:56])([F:54])[F:55])[C:46]=1[CH3:57])[C:30]1[O:31][C:34]([C:35]2[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=2)=[N:33][N:32]=1)([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Yield: 83.3 %

Procedure:
Triphenylphosphine (590 mg, 2.25 mmol) was dissolved in 25 mL of DCM followed by addition of 12 (571 mg, 2.25 mmol) and TEA (456 mg, 4.50 mmol) at 0° C. N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (630 mg, 1.13 mmol) in 25 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extract with EtOAc. The crude mixture was chromatographed to give the product (510 mg, 84%) 1H NMR (400 MHz, acetone-d6, δ in ppm): 8.23 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 2H), 7.67 (d, J=9 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 5.94 (d, J=9 Hz, 1H), 5.19 (m, 1H), 4.74 (m, 1H), 2.39 (m, 3H), 1.48 (d, J=6 Hz, 3H), 0.81 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C(O[C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:21]([O:23][C:24](=[O:36])[CH:25](C(OCC)=O)[C:26](OCC)=[O:27])[CH3:22]>>[CH2:21]([O:23][C:24]([C:25]1[C:6](=[O:20])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:26]=1[OH:27])=[O:36])[CH3:22]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)n1cccc1
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2)c1=O

Procedure:
A mixture of benzyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.28 g, 4.70 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 mL) in a test tube was heated in an oil bath (bath temperature: 220° C. to 230° C.) for 10 min; TLC (EtOAc/hexanes:1/1 by volume) showed good conversion; then cooled, the reaction mixture was directly purified with silica gel column to give the desired product as brown solid (1.00 g). ESI (m/z): 313 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:30]2[CH:35]=[C:34]([C:36]3[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=3)[CH:33]=[CH:32][N:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:38](=[O:39])[CH2:37][C:36]([C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:35]=1)=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as a brown solid (284 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@H:5]([C@H:6]([CH3:30])[C@H:7]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=2)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1>>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:30])[C@@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1[C@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2O[C@@]3(C)CC[C@@H]4[C@@H](C)CC[C@@H]1[C@]24OO3
Agent: On1nnc2ccccc21
Product: C[C@H]1[C@@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Yield: 561 %

Procedure:
4-Arm PEG (MW 20 Kda, 20 g, ˜1 mmol) (Shearwater Corporation) was azeotropically dried in vacuo with CHCl3 (3×200 ml) and was redissolved in CH2Cl2 (250 ml). To this clear solution was added artelinic acid (3.30 g, 7.88 mmol), N,N-dimethylaminopyridine (DMAP) (catalytic amount), and 1-hydroxybenzotriazole (HOBT) (0.680 g, 5.03 mmol). N,N-dicyclohexylcarbodiimide (DCC) (1.74 g, 8.43 mmol in about 10 ml of CH2Cl2) was then added and the mixture was allowed to reflux under of argon for 17 hours. The mixture was then concentrated in vacuo and the residual syrup was dissolved in toluene (˜200 ml) and filtered. The toluene was removed in vacuo at about 45° C. and the residue was treated with 5 ml of CH2Cl2 and triturated with 2-propanol (300 ml). The resulting precipitate was collected by vacuum filtration and dried in vacuo to obtain a pure water-soluble product (18.5 g, 92% yield) with >95% substitution as indicated by 1H NMR. Partial 1H NMR data (CDCl3, 300 MHz): δ 0.94 (s, 12H, C9—CH3), 0.95 (s, 12H, C6—CH3), 1.44 (s, 12H, C3—CH3), 2.68 (m, 4H, H-9), 3.63 (bs, 1818H, PEG backbone), 4.45 (t, 8H, J 4.4 Hz, PEG—OCH2CH2O—COAr), 4.56 (d, 4H, J 13.1 Hz, OCHAHB—Ar), 4.91-4.96 (m, 8H, H-10 overlapped with OCHAHB—Ar), 5.44 (s, 4H, H-12), 7.37 (d, 4H, J 7.8 Hz, Ar), 8.01 (d, 4H, Ar).
Reaction SMILES: Cl.O.[NH2:3]N.Cl.[CH2:6]([O:8][C:9](=[O:22])[C:10](=[CH:18][N:19](C)C)[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:7]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[NH:3][N:19]=[CH:18][C:10]=1[C:9]([O:8][CH2:6][CH3:7])=[O:22])=[O:13])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn[nH]c1C(=O)OCC
Temperature: 60 °C
Yield: 0 %

Procedure:
Under an atmosphere of argon, hydrazine monohydrate hydrochloride (1.91 g, 28 mmol) and HCl (36.5% in water, 2.8 ml) were added to a solution of 2-dimethylaminomethylene-3-oxo-succinic acid diethyl ester (6.8 g, 28 mmol) in ethanol (100 ml). The mixture was heated to 60° C. (3 h). The solvent was evaporated, and the residue was taken up in dichloromethane and washed (water). The organic layer was dried (Na2SO4), the solvent was evaporated and the title compound (1.81 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=383.3 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccccc23)C1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
To a 5 mL microwave vial containing 4-chloro-3-nitroquinoline (Ark Pharm, 312.9 mg, 1.500 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 358.9 mg, 1.792 mmol), 1-butanol (3.00 mL) was added followed by DIPEA (405.1 mg, 3.134 mmol). The reaction mixture was heated at 100° C. under microwave irradiation for 2 h. The reaction was then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow oil (293.5 mg, 53%). LCMS calc. for C19H25N4O4 (M+H)+: m/z=373.2. found 373.2.