Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)Cl.[CH3:5][O:6][C:7]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:8]=1[CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]1.[CH3:25]O>>[CH3:5][O:6][C:7]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:8]=1[CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH:12]([C:16]([O:18][CH3:25])=[O:17])[CH2:11]1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
SOCl2 (6.4 g, 54 mmol) was added dropwise to methanol (40 mL) followed by addition of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.0 g, 18 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h and then heated under reflux for 7 h. The mixture was cooled to ambient temperature and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=6:1 to 2:1) to afford methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (a mixture of two enantiomers, 4.3 g, 81% yield) as a colorless oil. The two enantiomers were separated by chiral prep-HPLC.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1.C(OCC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Oc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A 0.5 M solution of 4-phenoxy-phenylmagnesium bromide in tetrahydrofuran (30 mL, 15 mmol) was introduced into a flame-dried flask placed under an argon atmosphere. A solution of 1-benzyl-4-piperidone (2.84 g, 15 mmol) in dry tetrahydrofuran (12 mL) was then added dropwise, while the temperature was maintained at less than 20° C. with an ice bath. After completion of the addition, the mixture was allowed to reach room temperature and further stirred for 2 hr. Ice was then added to the mixture, and 1 N HCl was added until the resulting precipitate was completely dissolved. The reaction was then diluted with diethyl ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with diethyl ether (2×50 mL), and the combined organic layers were sequentially washed with saturated aqueous sodium hydrogencarbonate (2×50 mL) and water (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (dichloromethane and then diethyl ether). The desired product was then isolated as a colorless solid (1.74 g, 33% yield).
Reaction SMILES: [CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[CH2:1]([N:8]([CH:33]([CH3:35])[CH3:34])[C:9](=[O:32])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[NH:36][CH:37]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[CH:29][CH:30]=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 104.7 %

Procedure:
Following the procedure described for Example 1 (A), Step A, N-benzyl-N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 10) (13.9 g, 29.8 mmol) was condensed with 1H-indole-3-carbaldehyde (5.2 g, 35.8 mmol) for 48 hours. The volatiles were concentrated in vacuo to provide 18.5 g of N-benzyl-2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.01 (d, 1H), 7.67-7.50 (m, 4H), 7.43-7.11 (m, 12H), 6.99 (m, 1H), 6.99 (m, 1H), 6.80 (m, 1H), 4.96 (m, 1H), 4.71-4.49 (m, 4H), 4.23 (m, 1H), 1.20 (m, 6H); MS 593.3 (M+1).
Reaction SMILES: C(OC([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:16][C:10]=2[C:9]=1[O:24]C(=O)C(C)(C)C)=O)CCC.[OH-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[C:19]([CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:11]2[S:12][CH:8]=[C:9]([OH:24])[C:10]=2[CH:16]=1)([OH:21])=[O:20]
Reactant: CCCCOC(=O)c1sc2ccc(OCC(=O)OCC)cc2c1OC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc2scc(O)c2c1
Yield: 80 %

Procedure:
1.96 g (4.5 mmol) VIII and 2.70 g (67.5 mmol) NaOH were heated under reflux for 15 h in 300 ml degassed water. The pH was then adjusted to pH 1 with concentrated HCl and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. Flash chromatography (200 g SiO2, ethyl acetate:acetic acid=100:1, pre-adsorption: 10 g SiO2/ethanol) yielded 801 mg (3.6 mmol, 79%) IX.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH2:19][CH2:18][NH:17][C:16]3=[C:12]2[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13]2=[N:14][N:15]3[CH:19]=[CH:18][NH:17][C:16]3=[C:12]2[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2c3n(nc2n(Cc2ccccc2)c1=O)CCN3
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2c(nn3cc[nH]c23)n(Cc2ccccc2)c1=O

Procedure:
A solution of 1-benzyl-3-propyl-1,2,3,4,6,7-hexahydro-5H-imidazo [2',1': 5,1]- pyrazolo[3,4-d]pyrimidine-2,4-dione (4.5 g) and benzoyl peroxide (5.0 g) in chloroform (100 ml) was refluxed for 18 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in chloroform. The solution was washed with an aqueous solution of sodium carbonate and water, followed by drying and concentration to dryness. The residue was purified by flash chromatography. Recrystallization of thus obtained crystals from methylene chloride/hexane afforded colorless crystals (2.3 g, 52%), m.p. 290°-292° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Nc1cccc2cc(-c3ccccn3)[nH]c12
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cc(-c3ccccn3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a mixture of 2-(pyridin-2-yl)-1H-indole-7-amine (0.35 g) and pyridine (6 mL) was added thiophene-2-sulfonyl chloride (0.38 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.50 g, yield 82%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].IC.[C:26](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:26])[CH:17]=1)=[O:11]
Reactant: O=C(CC(c1ccccc1Cl)C1CCCC1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccccc2Cl)C2CCCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(2-chloro-phenyl)-3-cyclopentyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=344.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc2ccccc2c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: O[Li].O.OO.C([C@H]1COC(=O)N1[C:19](=[O:40])[C@@H:20]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:21]N(C(C)C)C(=O)OC(C)(C)C)C1C=CC=CC=1.[O-:41]S([O-])=O.[Na+].[Na+]>O.C1COCC1>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:20]([CH3:21])[C:19]([OH:40])=[O:41])=[CH:38][CH:37]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
LiOH—H2O (168 mg, 4.00 mmol) was added to a stirring solution of THF (30 mL) and water (15 mL) at room temperature until it was dissolved. The mixture was treated with hydrogen peroxide (658 uL of a 35% wt. solution in water, 8.00 mmol) and allowed to stir at room temperature for 10 minutes. The reaction was cooled to 0° C. in an ice bath, and the tert-butyl (S)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (1.00 g, 2.00 mmol) was added dropwise via addition funnel as a solution in THF (15 mL) over a 10 minutes. The mixture was allowed to stir overnight at room temperature to completion by LCMS analysis of the crude. The reaction was cooled to 0° C., and then treated with 1M Na2SO3 (9.00 mL) solution via addition funnel over a ten minute period. After the addition was complete, the mixture was allowed to warm to room temperature for 10 minutes. The mixture was concentrated to remove the THF, and then diluted with water. The aqueous layer was washed twice with ethyl acetate (discarded). The aqueous layer was partitioned with ethyl acetate, then treated dropwise while stirring with 1M HCl until pH 2-3 was attained. The aqueous layer was extracted twice with ethyl acetate, and the organics were combined. The organic was washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The colorless oil product was dried under high vacuum for one hour to afford (S)-3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a viscous oil/foam (685 mg, 100%). LC/MS (APCI+) m/z 242.1 [M−Boc]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1B(O)O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]=[O:9])=[CH:7][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccc(Cl)cc2)c(F)c1
Yield: 89.5 %

Procedure:
2-Fluoro-4-formylphenyl boronic acid (263 mg, 1.57 mmol) was added to the mixture of 1-chloro-4-iodobenzene (250 mg, 1.05 mmol), PdCl2(PPh3)2 (36 mg, 0.5 mmol), and disodium carbonate (332 mg, 3.13 mmol) in a solution of water (1 mL) and dioxane (2 mL). The mixture was reacted at 130° C. for 22 min in a microwave reactor. After cooling, water was added, and the mixture was extracted with ethylacetate. The organic solvent was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in heptane to give the title compound (220 mg, 0.94 mmol, 90%) as a white solid. 1H NMR (D2O) δ 10.02 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.67 (d, J=10.4 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzyloxycyclopropyl)-phenylethynyl]-benzoate (Compound 75, 78.0 mg, 0.20 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 65.0 mg (89%) of the title compound as a solid.
Reaction SMILES: C(OC([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O)(C)(C)C.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH3:27])=[N:23][NH:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C>[C:12]([O:11][C:9]([O:8][N:24]1[C:25]2[C:21](=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:26]=2)[C:22]([CH3:27])=[N:23]1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: COc1ccc2c(C)n[nH]c2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(C)nn(OC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di-tert-butyl-dicarbonate in acetonitrile was mixed at 0° C. with 6-methoxy-3-methyl-1H-indazole (prepared following the procedure described by F. Dennler, Tetrahedron, 22, 1966, 3131-3139) (26.27 g, 0.162 mol), acetonitrile (200 ml), triethylamine (25 ml, 0.178 mol), DMAP (3.96 g, 0.0324 mol). The mixture was stirred at room temperature overnight. Acetonitrile was concentrated under vacuum. The mixture was extracted with ethylacetate and acidified at pH=2 with a solution of concentrated HCl, dried over Na2SO4, filtered and put in diisopropylether. 23.9 g of the expected product were obtained (as solid, 59%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][CH:11]=2)=[CH:6][N:5]=1.[CH3:27][Si:28]([CH2:31][CH2:32][O:33][CH2:34]Cl)([CH3:30])[CH3:29]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:34][O:33][CH2:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][CH:11]=2)=[CH:6][N:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)n1COCC[Si](C)(C)C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) was added in one portion to a stirred solution of (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152d-1, 2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperature under N2. The mixture was stirred for 5 min. before SEM chloride (1.01 mL, 5.72 mmol) was added in approx. 0.1 mL increments. The mixture was stirred for 3 h before being quenched with sat'd NH4Cl soln and diluted with ethyl acetate. The organic phase was washed with sat'd NaHCO3 soln and brine, dried over (Na2SO4), filtered, and concentrated. The original aqueous phase was extracted twice more and the combined residue was purified by Biotage™ flash chromatography (40M column, 50 mL/min, preequilibration with 5% B for 750 mL, followed by step gradient elution with 5% B to 5% B for 150 mL, 5% B to 75% B for 1500 mL, then 75% B to 100% B for 750 mL where solvent B is ethyl acetate and solvent A is hexanes). Concentration of the eluant furnished the title compound as a pale yellow foam (2.35 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1(C)C(C)=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(=O)Nc1ccccn1
Temperature: 35 °C

Procedure:
To 70.5 g. of 2-aminopyridine, partially dissolved in 180 g. of xylene, was slowly added, with stirring, 79.6 g. acetic anhydride. The addition was carried out over a 20-minute period. The reaction vessel was water-cooled so as to maintain the reaction mixture at 30-40° C during the addition. The reaction solution was then heated for 1 hour at a temperature of 74°-78° C to give 2-acetamidopyridine, which was used without isolation.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O.B.C1COCC1.C1COCC1>CO>[CH3:1][CH:2]([CH3:27])[CH2:3][NH:4][CH2:5][C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: CC(C)CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CNC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-((2-methylpropyl)carbamoyl)-1,4-piperazinedicarboxylate (1.77 g, 4.60 mmol), BH3.THF (1.0 M in THF, 13.8 mL, 13.8 mmol, Sigma-Aldrich, St. Louis, Mo.) and THF (60 mL). The reaction mixture was heated at 50° C. for 12 h. The mixture was allowed to cool to room temperature and then MeOH was added until the bubbling ceased. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (100 g of silica gel, 0 to 10% iPrOH (with 10% NH4OH) in CHCl3) to obtain di-tert-butyl (2S)-2-(((2-methylpropyl)amino)methyl)-1,4-piperazinedicarboxylate (0.939 g) as a clear oil which solidified upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[N+:21]([O-])=O)[S:7]1(=[O:25])=[O:24]>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[NH2:21])[S:7]1(=[O:25])=[O:24]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])S2(=O)=O)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CN2C(=O)CN(c3ccc(N)cc3N)S2(=O)=O)c(OC)c1
Reaction time: 1 h

Procedure:
A mixture of the title C compound, 2-(2,4-dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (200 mg, 4.42 mmol) in 20 mL of MeOH/EtOAc (3:1) and 10% palladium on carbon (100 mg) is shaken under hydrogen atmosphere at 40 psi for 1 h. The catalyst is removed by filtration and the solvents are evaporated to afford 2-(2,4-dimethoxy-benzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a brown solid: [M+1]+=393.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: OCCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32 mmol), 4-(3-hydroxypropyl)morpholine (70 mg, 0.48 mmol), (prepared as described for the starting material in Example 60), triphenylphosphine (168 mg, 0.64 mmol) in methylene chloride (1 ml) and DMF (0.5 ml) cooled at 4° C. was added a solution of diethyl azodicarboxylate (101 μl, 0.64 mmol) in methylene chloride (0.4 ml). The mixture was stirred for 12 hours at 4° C. and overnight at ambient temperature. The mixture was poured onto a column of silica (IST Isolute®10 g of silica) and was eluted with methylene chloride (15 ml) followed by 5% methanol in methylene chloride (45 ml) followed by 5% methanol (saturated with ammonia) in methylene chloride (30 ml) followed by 10% methanol (saturated with ammonia) in methylene chloride (45 ml) followed by 15% methanol (saturated with ammonia) in methylene chloride (30 ml). The fractions containing the expected product were evaporated to give 6-methoxy-4-(2-methylindol-5-ylamino)-7-(3-morpholinopropoxy)quinazoline (63 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Br[CH2:24][CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][Cl:27])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCCl
Temperature: 45 °C
Yield: 33.8 %

Procedure:
A mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.2 g, 3.3 mmol), (prepared as described for the starting material in Example 48), 1-bromo-3-chloropropane (1.6 ml, 16 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (25 ml) was heated at 45° C. for 3 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×70 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexantlethyl acetate, collected by filtration and dried under vacuum to give 4-(4-bromo-2-fluoroanihno)-7-(3-chloropropoxy)-6-methoxyquinazoline (492 mg, 34%).