Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:30][Cl:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[ClH:31].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:30][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CCO
Product: Cl
Product: c1ccc(COc2ccc(CSC3=N[C@@H](c4ccccc4)[C@@H](c4ccccc4)N3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4-dibenzyloxybenzyl chloride (532 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 149 mg of the product 225. MS: m/z 557 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:4]2[O:14][C:15]([C:19](O)=[O:20])=[CH:16][C:17](=[O:18])[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>CN(C=O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:4]2[O:14][C:15]([C:19]([NH:35][C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[O:20])=[CH:16][C:17](=[O:18])[C:3]1=2
Reactant: Nc1nnn[nH]1
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2oc(C(=O)O)cc(=O)c21
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2ccc([N+](=O)[O-])cc2c2oc(C(=O)Nc3nnn[nH]3)cc(=O)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4.7 g (16.4 mmole) 4,5-dihydro-5-methyl-8-nitro-4-oxopyrano[3,2-b]indole-2-carboxylic acid and 3.8 g (23.4 mmole) 1,1'carbonyl-diimidazole in 100 ml DMF was heated at 60° C. for one hour and then cooled to room temperature. In a separate flask, a mixture of 1.8 g (17.5 mmole) 5-aminotetrazole monohydrate and 5.4 g (53.1 mmole) triethylamine were combined in 50 ml DMF. This mixture was cooled in an ice bath while 5.8 g (52.8 mmole) chlorotrimethylsilane was added in one portion. Stirring in ice was continued for one hour, followed by an additional two hours with the ice bath removed. The triethylamine mixture was then added to the original carboxylic acid mixture, and the new mixture was heated on a steam bath for one hour. The mixture was cooled, and the precipitated triethylamine hydrochloride was filtered and discarded. The filtrate was added to 500 g ice/water, the mixture was filtered by gravity, and the filtrate was acidified with 4 N hydrochloric acid. The precipitated crude product was filtered, washed with water and recrystallized twice from DMF-water to yield yellow solid of mp 295° C. dec.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:19]([N:8]([CH2:7][C:6]([OH:27])=[O:5])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
An ice-cooled solution of [octyl-(toluene-4-sulfonyl)amino]-acetic acid tert-butyl ester (5.2 g, 0.013 mol) in dichloromethane (50 ml) was further diluted by the addition of 25% TFA in dichloromethane (200 ml). The reaction mixture was stored at 4° C. overnight. Solvents were removed under reduced pressure and the residue was azeotroped with toluene. The resulting crude oil was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title compound as a white solid (4.4 g, 99%). 1H NMR: δ (CDCl3), 9.77 (1H, br s), 7.71 2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.2 Hz), 4.00 (2H, brs), 3.19 (2H, dd, J=7.4, 7.7 Hz), 2.38 (3H, s),1.50-1.30 (2H, m), 1.30-1.05 (10H, m) and 0.85 (3H, t, J=6.6 Hz).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Li].O>C1COCC1.C(OCC)C>[C:1]1([S:7]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH3:21])=[CH:13][C:12]=2[O:19][CH3:20])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C=O)ccc1NS(=O)(=O)c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)O)ccc1NS(=O)(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 4-phenylsulfonylamino-3-methoxybenzaldehyde (400 mg; prepared in Reference Example 44.) in THF (10 ml) was cooled to at −78° C. mg; prepared in Reference Example 44.) in THF (10 ml) was cooled to at −78° C. in a stream of argon. A solution of methyl lithium (1.0M) in diethyl ether (3.4 ml) was added dropwise thereto. The mixture was stirred for 20 minutes. After the termination of reaction, a mixture of H2O+1N HCl was added thereto to stop the reaction. The mixture was extracted with ethyl acetate three times. The organic layer was washed, dried over and purified on silica gel column chromatography (AcOEt:hexane=1:1) to give the title compound (421 mg) having the following physical data.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])O[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CN([CH:23]=[O:24])C>>[C:23]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:24]
Reactant: CN(C)C=O
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OOC(=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The pH value of a solution containing 4 g (30 mmoles) of anthranilic acid in 20 ml of DMF is adjusted to 8 by adding TEA. After adding 9 g of tertiary-butyloxy carbonate, the reaction mixture is stirred at room temperature overnight. The solvent is evaporated and the thick oily residue is dissolved in 50 ml of ethyl acetate. The organic phase is washed 3 times with 20 ml of ice-cold 0.01N sulfuric acid each, then 3 times with 20 ml of water each. The ethyl acetate solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The thick oily residue becomes crystalline when kept in a refrigerator. The aimed product is obtained in a yield of 5.7 g (80%), m.p.: 91°-93° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:33])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C:7]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10].C1CCCCC=1>C(O)C.[Pd]>[CH3:1][NH:2][C:3](=[O:33])[C@H:4]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[NH:5][C:6](=[O:23])[C:7]([CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:8][C:9]([OH:11])=[O:10]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)OCc1ccccc1)CC(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)O)CC(C)C

Procedure:
E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide (3.0 g.) was heated under reflux for 2 hours in ethanol (60 mls.) and cyclohexene (30 mls.) in the presence of 10% palladium on charcoal (0.75 g.). The resultant reaction mixture was filtered through Celite and the solvent removed by evaporation in vacuo to yield a gum. This gum was crystallized from methanol/water to yield E and Z N-[3-carboxy-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide.
Reaction SMILES: [CH3:1][N:2]([C:4](=[Se:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[C:12]([OH:18])(=O)[CH2:13][C:14](O)=[O:15].[CH2:19](Cl)[CH2:20]Cl>C(Cl)Cl>[CH3:1][N:2]([C:4]([C:20]1[CH:19]=[CH:7][CH:6]=[CH:5][CH:10]=1)=[Se:11])[NH:3][C:12](=[O:18])[CH2:13][C:14]([NH:3][N:2]([CH3:1])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[Se:11])=[O:15]
Reactant: ClCCCl
Reactant: O=C(O)CC(=O)O
Reactant: CN(N)C(=[Se])c1ccccc1
Solvent: ClCCl
Product: CN(NC(=O)CC(=O)NN(C)C(=[Se])c1ccccc1)C(=[Se])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methylbenzoselenohydrazide (215 mg, 1.0 mmol) and malonic acid (53 mg, 0.5 mmol) in CH2Cl2(5 mL), was added EDC (240 mg, 1.25 mmol). The mixture was stirred for 1 h at RT. The reaction mixture was diluted with CH2Cl2 (15 mL) and washed with water and brine. The organic layer was dried over MgSO4 and filtered. After removal of the solvent, the product was purified by chromatography column on silica gel (1:1 Hexane:EtOAc and EtOAc) and to give (N′1,N′3-dimethyl-N′1,N′3-di(phenylcarbonoselenoyl)malonohydrazide (Compound 1), 188 mg in 76% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][CH2:33][Cl:34].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:21][CH2:31][CH2:32][CH2:33][Cl:34])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[CH:2]
Reactant: ClCCCBr
Reactant: C#Cc1cc(Nc2ncnc3cc(OC)c(O)cc23)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)ccc1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a suspension of 4-((3-ethynyl-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (3.90 g), K2CO3 (4.36 g) in DMF (30 mL) was added 1-bromo-3-chloropropane (3.80 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (3.30 g, 68.00%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[NH3+:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1.O.C(OC)(C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:22])[NH:23][C:29]2=[O:30])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [NH3+]c1cccc(Cl)c1CNC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(Cl)c2CN1C1CCN(Cc2ccccc2)CC1
Yield: 36.6 %

Procedure:
16 g 2-((1-benzyl-piperidin-4-ylamino)-methyl)-3-chloro-phenyl-ammonium and 8.2 g CDI in 150 mL DMF were stirred for 3 h at 60° C. Water and tert.-butyl-methyl-ether were added. The precipitate was filtered to give 6.3 g of the desired product. (M+H)+: 356
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8](Br)[CH:7]=1)([CH3:3])[CH3:2].C(N([CH2:20][CH3:21])CC)C.C[Si:23]([C:26]#C)([CH3:25])[CH3:24].C(OCC)(=O)C>CCCCCC.[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>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=[C:8]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:7]=1[C:20]#[CH:21])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC(=O)c1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#Cc1c(C(=O)OC(C)C)cc([Si](C)(C)C)cc1[Si](C)(C)C

Procedure:
Following General Procedure D and using 3,5-dibromo-benzoic acid isopropyl ester (Intermediate 205, 2.7 g, 8.6 mmol), triethyl amine (30 mL), copper(I)iodide (0.45 g, 2.4 mmol), trimethylsilyl acetylene (6.8 mL, 48 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.75 g, 2.4 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 3% ethyl acetate in hexane as the eluent, the intermediate 3,5-bis-trimethylsilanylethynyl-benzoic acid isopropyl ester was obtained. The intermediate (2.8 g, 7.85 mmol) was treated with a 1M solution of tetra-n-butyl ammonium fluoride in tetrahydrofuran (25 mL, 25 mmol) and the resulting reaction mixture was stirred in an ice bath for 1 h. Water was added and the reaction mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was redissolved in diethyl ether (10 mL) and treated with hexane (150 mL). The solid that precipitated out was filtered and dried to afford the title compound (1.3 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: OC1CCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2 g (0.012 mol) of 2-amino-6-chloro-3-nitropyridine, 30 ml of dioxane and 10 ml of water, and 1.8 g of 3-pyrrolidinol are charged to a fully equipped round-bottomed flask. The mixture is brought to 70° C. for one hour with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2.36 g of yellow powder are obtained, Yd=87.4%.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)(O[NH2:24])=O)C=CC=CC=1.[Cl:31]CCl>>[Cl-:31].[NH2:1][N+:2]1[CH:6]=[CH:5][N:4]([NH2:24])[C:3]=1[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nccn2N)cc1
Reactant: ClCCl
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Product: COc1ccc(-c2n(N)cc[n+]2N)cc1
Product: [Cl-]

Procedure:
0.1 g of 1-amino-2-(4-methoxyphenyl)imidazole is dissolved in 10 ml of dichloromethane. The solution is treated portionwise during 8 days with 0.29 g of O-diphenylphosphinylhydroxylamine, evaporated and the residue is suspended in 10 ml of water. The difficulty soluble diphenylphosphinic acid is removed by filtration and the filtrate is placed on a column loaded with Amberlite IRA 400 (chloride), whereupon the column is eluted with water. There is obtained 1,3-diamino-2-(4-methoxyphenyl)imidazolium chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([CH2:37][CH2:38][C:39]([N:22]2[CH2:23][CH2:24][N:19]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[OH:18])[N:7]=3)[CH2:20][CH2:21]2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)CCC4CCCC4)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.62 mmol) in CH2Cl2 (6.0 mL) was stirred under an N2 atmosphere. Then triethylamine (170 μL, 1.24 mmol) was added, and the reaction was cooled to −10 to −20° C. After adding 3-cyclopentylpropanoyl chloride (96 μL in 600 μL THF, 0.62 mmol), the reaction mixture was stirred for 30 minutes. CH2Cl2 was added, and the organic phase was washed 2× with H2O, dried over Na2SO4, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2: hexanes gave 3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one (240 mg, 86%). LC/MS: m/z 445.50 (M+H)+ at 3.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.45 (dd, J=8.2, 1.8 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 3.95 (dd, J=19.9, 5.6 Hz, 4H), 3.74 (m, 4H), 2.52 (s, 3H), 2.38 (t, J=7.8 Hz, 2H), 1.76 (m, 3H), 1.55 (m, 6H), 1.16 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]=[C:14]([C:16](O)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:31])[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][CH:25]=1.B(F)(F)F.O(CC)CC>>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH:13]=[C:14]([C:16]([C:26]3[CH:27]=[CH:28][C:29]([OH:30])=[C:24]([CH3:31])[CH:25]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)(CC)c1cc2ccc(OCc3ccccc3)cc2o1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Yield: 78.9 %

Procedure:
3-(6-Benzyloxy-benzofuran-2-yl)-pentan-3-ol (5.40 g, 17.4 mmol) and o-cresol (3.76 g, 34.8 mmol) and BF3—OEt2 (2.47 g, 17.4 mmol) are reacted analogous to Example 1D to give the title compound as a pale yellow oil (5.50 g, 79%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C@@H:47]([C@@H:56]([NH:61][CH3:62])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:61]([CH3:62])[C@@H:56]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:47]([O:46][CH3:45])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC)[C@@H](CC(=O)OC(C)(C)C)OC
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 3 h
Yield: 113.1 %

Procedure:
To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (18.53 g, 54.60 mmol, 1.3 eq.) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.58 g, 54.6 mmol, 1.3 eq.) in 2-methyltetrahydrofuran (118.00 mL, 0.34 M) was added N-methylmorpholine (6.52 mL, 59.1 mmol, 1.5 eq.) followed by #4 (11.80 g, 39.9 mmol, 1 eq.). After 3 hours, the reaction was quenched with water (50 mL) and stirred for 15 minutes. The aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a colorless oil, which was purified by silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to give #5 (26.2 g, 91%) as a colorless foam. LC-MS (Protocol I) m/z 581.3 [M+H+]1604.3 [M+Na+], retention time=4.993 minutes; 1H NMR (400 MHz, DMSO-d6), possibly a mixture of rotamers, characteristic major signals: δ 7.88 (d, J=7.4 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.62 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4, 7.4 Hz, 2H), 7.27-7.34 (m, 2H), 4.13-4.32 (m, 4H), 3.70-3.82 (br m, 1H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.54 (dd, J=15.7, 2.4 Hz, 1H), 2.17 (dd, J=15.4, 9.4 Hz, 1H), 1.95-2.07 (m, 1H), 1.70-1.83 (br m, 1H), 1.40 (s, 9H), 0.83-0.94 (m, 9H), 0.69 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:6][CH2:7][C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:20])=O>>[C:1]([O:4][CH:5]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:6][CH2:7][C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(CCC(=O)O)OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Product: C=CCOC(=O)C(CCC(=O)Cl)OC(C)=O

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-acetoxy-5-allyloxy-5-oxopentanoic acid (345.3 mg, 1.50 mmol) obtained from Example 2-(4) and oxalyl chloride (209.4 mg, 1.65 mmol) were reacted, and the reaction mixture was worked up to afford 4-acetoxy-5-allyloxy-5-oxopentanoyl chloride as a crude product.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Yield: 84.7 %

Procedure:
A mixture of 5-(4-bromo-5-chloropyrimidin-2-yl)thiophene-2-sulfonyl chloride (164 mg, 0.45 mmol, 1.0 equiv.), tert-butyl hydrazinecarboxylate (119 mg, 0.9 mmol, 2.0 equiv.) and DIPEA (5 mL) was stirred in DCM at r.t. for 2 h, The reaction was extracted with EA and the combined layers were dried (Na2SO4), filtered. The filtrate was concentrated to afford tert-butyl 2-(5-(4-bromo-5-chloropyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (179 mg, 85%). LC-MS (m/z)=469 [M+H]+
Reaction SMILES: CNC1C=CC2N=C3C(SC=2C=1)=CC(=[N+](C)C)C=C3.[Cl-].[Cl-].[CH3:22][N:23]([CH3:40])[C:24]1[CH:25]=[C:26]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]1[C:28]([CH:29]=[C:30]([NH:38][CH3:39])[CH:31]=[CH:32]1)=[S+:27]2.[CH:41]([OH:43])=O.N1C=CC=CC=1.[CH:50]([OH:53])(C)C>[Zn].CCCCCC>[CH3:22][N:23]([CH3:40])[C:24]1[CH:25]=[C:26]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH:50]=[O:53])[C:33]1[CH:32]=[CH:31][C:30]([N:38]([CH:41]=[O:43])[CH3:39])=[CH:29][C:28]=1[S:27]2
Reactant: CNc1ccc2nc3ccc(N(C)C)cc3[s+]c2c1
Reactant: CC(C)O
Reactant: O=CO
Agent: CNc1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: [Cl-]
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CN(C)c1ccc2c(c1)Sc1cc(N(C)C=O)ccc1N2C=O
Temperature: 90 °C

Procedure:
A mixture of 10.0 g of Azure B (Aldrich) 7-(dimethylamino)-3-(methylamino)phenothiazin-5-ium chloride, 75.0 ml of 90 percent formic acid, 5.0 g of zinc dust and 5.0 ml of pyridine was maintained at approximately 90° C. for approximately three hours. The reaction mixture was cooled to room temperature and filtered, saving the filtrate. The filter cake was washed twice, each time with 50.0 ml of acetone, and the washes combined with the filtrate. The combined filtrate and washes was poured into ice water with stirring. The resulting solution was extracted with toluene. The toluene solution was separated, treated with decolorizing carbon, filtered and the resulting solution was evaporated under reduced pressure to obtain a gummy residue. The gummy residue was titurated with a 1:1 (V:V) mixture of isopropyl alcohol and hexane. The solid which formed was collected by filtration and dried to obtain 0.14 g of 7-(dimethylamino)-3-(N-formyl-N-methylamino)-10-formylphenothiazine (Formula II: R=R1 =R5 =H; R2 =R3 =R4 =CH3), an off-white-colored powder which melted at 139° to 143° C. A significant infrared maximum appeared at 1685 cm-1 (C=O;s). A paper treated with an ink formulation of the product produced a black-colored image when traced with an applied voltage stylus.