Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCNCC
Reactant: COC(=O)c1cc(CBr)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1

Procedure:
A solution of 518.4 mg (1.0 mmole) of the product of Example 279, 0.5 ml (4.8 mmol) of diethylamine and 0.172 ml (2.0 mmol) of pyridine in 10 ml of dichloromethane was stired at room temperature for 18 hr. The resulting mixture washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 2% MeOH/CH2Cl2 as eluant to provide 425 mg (83%). Electrospray Mass Spec 511 (M+H).
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@H:4]1[C:15]([OH:17])=O)#[N:2].C[N:19]1CCOCC1.ClC(OCC(C)C)=O>C1COCC1>[C:1]([C@@H:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][C@@H:4]1[C:15]([NH2:19])=[O:17])#[N:2]
Reactant: N#C[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: N#C[C@@H]1CN(Cc2ccccc2)C[C@@H]1C(N)=O
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Crude (3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid (3.24 g) was dissolved in THF (50 mL). N-methyl morpholine (0.93 mL, 8.49 mmol) was added and the solution allowed to stir overnight. A bit of solid remains undissolved. The solution was cooled to −15 degrees C. in an ethylene glycol/dry ice bath. Isobutyl chloroformate (1.1 mL, 8.49 mL) was added and the reaction stirred at −15 degrees C. for 1 hour. Ammonia was then bubbled through the solution for 20 minutes. The solution was allowed to warm to ambient temperature and the solvent removed under reduced pressure. The crude material was chromatographed on silica gel to yield a solid (1.56 g, 88% over 2 steps). LCMS: m/z 230.4 (MH+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9]([O:11]C)=O)[N:5]=1)=[O:2].[CH3:13][S:14][CH2:15][S:16]([CH3:18])=[O:17].[H-].[Na+].C(Cl)Cl>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:11])[CH:15]([S:14][CH3:13])[S:16]([CH3:18])=[O:17])[N:5]=1)=[O:2]
Reactant: COC(=O)c1nsc(NC=O)n1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSC(C(=O)c1nsc(NC=O)n1)S(C)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a mixture of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2 g) and methyl methylthiomethyl sulfoxide (6.1 g) in N,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) with cooling in an ice-bath. The mixture was stirred for an hour at ambient temperature and for an additional one hour at 40° C. After cooling to ambient temperature, methylene chloride (300 ml) was added to the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to a stirred mixture of hydrochloric acid (14.7 ml), ice-water (200 ml) and methylene chloride (200 ml). An insoluble material was filtered off and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, evaporated and the residue was triturated with diethyl ether to give the title compound (4.5 g), mp. 130° to 132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:17].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[I:17])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1I
Solvent: c1ccccc1
Product: O=C(CCl)Nc1ccc(-c2nc3ccccc3s2)cc1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of 2-(4'-amino-3'-iodophenyl) benzothiazole (DF129) (0.15 g, 0.426 mmol) in benzene (15 ml) was added dropwise chloroacetyl chloride (0.18 g) at room temperature. A yellow precipitate was formed and the resulting mixture was stirred at 50° C. for 30 minutes, and then cooled in an ice-bath. The solid was filtered off, washed with cold benzene and petroleum ether, and dried to give a yellow powder (0.13 g, 71.2%), m.p. 192.1-193.8° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:8]1[C:9]2[NH:1][C:2]3[C:3](=[CH:18][CH:19]=[CH:20][CH:16]=3)[C:4]=2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2[nH]c3ccccc3c12
Yield: 13.5 %

Procedure:
A mixture of 52.56 g of methyl indole-4-carboxylate, 51.55 g of 2,5-dimethoxytetrahydrofuran and 28.53 g of p-toluenesulfonic acid monohydrate in 300 ml of methanol was refluxed for 10 hours. Then, following a treatment similar to that of Example 1(1), there was obtained 9.14 g of methyl carbazole-4-carboxylate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[Br:15]Br>Cl>[Br:15][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][C:5]2=[O:14])=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2ccc(Br)cc21
Temperature: 80 °C
Yield: 19 %

Procedure:
To a 3-neck 250 mL round bottom flask equipped with a mechanical stirrer and charged with anhydrous aluminum chloride (16.6 gm, 0.125 mole) was added indanone (6.6 gm, 0.05 mole) in-two portions over 3 minutes. The reaction mixture was stirred for 10 minutes before bromine (9.7 g, 0.06 mole) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 5 minutes. The resulting mixture was poured into a mixture of ice (100 g) and concentrated HCl (20 mL). The resulting mixture was extracted with ether. The ether layer was separated, washed with water, dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography over silica gel eluting with 15% ether/hexanes to afford 6-Bromo-indan-1-one(2.0g, 19%). 1HNMR(CDCl3) δ 7.81 (d, 1H, J=1.76 Hz),7.62 (dd, 1H, J=8.36, 2.20 Hz), 7.30 (d, 1H, J=8.30 Hz), 3.03 (t, 2H, J=6.16 Hz), 2.65 (t, 2H, J=6.20 Hz). HPLC Rt=3.09 min.
Reaction SMILES: Br[CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4].[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>C(O)(=O)C>[C:23]([O:26][CH:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH2:3][CH3:4])(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(OC(C)=O)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Temperature: 6 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (323 mg) in acetic acid (3 ml) was added potassium acetate (345 mg) and the mixture was stirred at 6° C. for 2 hours. The resulting mixture was evaporated in vacuo, then he residue was diluted with ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-acetoxypropyl)-3-isobutyrylindole-6-carboxylate (207 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5](C(Cl)=O)[C:6]([CH3:9])=[CH:7][CH:8]=1.[H-].C([O:18][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:18])=[CH:5][CH:4]=1
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Reactant: Cc1ccc(CBr)cc1C(=O)Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the 4-bromomethyltoluoyl chloride (3.48 g. 15 mmol) in dry tetrahydrofuran (15 ml) was added dropwise to a solution of lithium tri-t-butoxyaluminium hydride (3.81 g, 15 mmol) in dry tetrahydrofuran (50 ml) at -70° C., stirred for 2 h, allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured into water, filtered, extracted with ethyl acetate, dried (magnesium sulphate), and evaporated in vacuo to yield 4-bromomethylbenzaldehyde (1.31 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29]O.[Cl-:31].O>CN(C)C=O>[CH3:1][C:2]1[C:7]([N:8]([C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)[CH3:27])=[CH:6][CH:5]=[C:4]([CH3:28])[C:3]=1[CH2:29][Cl:31]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cc1
Reactant: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2,6-dimethyl-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (2.00 g) in N,N-dimethylformamide (100 ml) was added mezhanesulfonyl chloride (784 mg) under ice-cooling, and the mixture was stirred for 2 hours at the same temperature and overnight at ambient temperature. To the mixture was added water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was pulverized with diethyl ether to give 2,6-dimethyl-3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]benzyl chloride (2.00 g) as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([NH2:10])=O)[NH:6][CH:7]=1)#[N:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:20]2)=CC=1>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:8](=[S:20])[NH2:10])[NH:6][CH:7]=1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1c[nH]c(C(N)=O)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1c[nH]c(C(N)=S)c1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 4-cyanopyrrole-2-carboxamide (1.35 g, 10.0 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.0 g, 9.9 mmol) in toluene is heated at 100° C. for 41/2 hours, diluted with tetrahydrofuran and heated at reflux for 20 minutes. The reaction mixture is then cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate mixture gives the title product as a yellow solid (0.9 g, mp 253° C. dec.).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][N:19]=[C:20]=[O:21].C(N(CC)CC)C>CCOCC>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:21])[NH:19][CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: CN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (12 parts) in ether (46 parts) was added methyl isocyanate (4.5 parts) and triethylamine (0.3 parts). The solution was left at room temperature for two hours and the solvent evaporated off. The crude product was recrystallised from a mixture of benzene and light petroleum to give 2-methylcarbamoyloxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 126°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH3:33].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH3:33])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC[Mg]Cl
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (10 ml) was added dropwise a solution of ethyl magnesium chloride in THF (2M, 0.61 ml) and the mixture was stirred at room temperature for 10 min. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=1:2), followed by crystallization from ethyl acetate-hexane to give the title compound (250 mg).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:21]=[C:22]1[O:26][C:25]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[O:24][CH:23]1P(=O)(OCC)OCC.CN(C)C(=N)N(C)C>O1CCCC1.C(OC)(C)(C)C>[CH3:20][C:12]1[CH:13]=[C:14](/[CH:15]=[C:23]2\[C:22](=[O:21])[O:26][C:25]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[O:24]\2)[CH:17]=[C:18]([CH3:19])[C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: CCOP(=O)(OCC)C1OC2(CCCCC2)OC1=O
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(/C=C2/OC3(CCCCC3)OC2=O)cc(C)c1OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
4.2 g lithium chloride (0.1 Mol), 20.0 g (83.2 mmol) of 4-benzyloxy-3,5-dimethylbenzaldehyde (D) and 31.62 g (108.2 mmol) of diethyl (3-oxo-1,4-dioxaspiro[4.5]dec-2-yl)-phosphonate (C) are suspended in 130 mL tetrahydrofuran and cooled to −20° C. At this temperature 12.5 mL (0.1 Mol) tetramethylguanidine are added dropwise. After the addition has ended the suspension formed is heated to ambient temperature and stirred for 1 hour. After the addition of 190 mL tert.butyl-methylether the organic phase is washed with 150 mL water and 30 mL saturated saline solution, dried and evaporated down. The resulting yellow oil is taken up in 145 mL methanol and stirred intensively for 1 hour at −10° C., during which time a white solid is formed. The solid formed is suction filtered, washed twice with 20 mL methanol/water (1:1) and dried at 45° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4=[N:25][CH:26]=[N:27][C:28]([NH2:29])=[C:23]4[C:22]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:32][CH:31]=4)=[N:21]3)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(C2CCNCC2)CC1
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
1-[1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (254 mg, 0.446 mmol) was stirred in 25 ml of 10% trifluoroacetic acid in dichloromethane overnight. The solvent was evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromathane. The combined organic layer was washed, dried and evaporated to give 108 mg of 1-[1-(4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate GG) which was used without further purification.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[NH:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37]>C(OC(=O)C)C>[NH:23]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:24]([C:32]([N:35]([CH3:54])[C@H:36]([C:38]([NH:40][C@H:41]([C:50]([O:52][CH3:53])=[O:51])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:39])[CH3:37])=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
The procedure of Example 1 is followed using 1 liter of ethylacetate, 30.68 ml of isobutyl chloroformate, 26.00 ml of N-methylmorpholine, 62.72 grams of BOC-phenylalanine and 68 grams of N-Me-Ala-Tyr-OMe affording 3 crops of product as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]4[N:50]=[CH:49][C:48]([NH:51]S(C)(=O)=O)=[CH:47][CH:46]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:29]=[C:30]([CH:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[C:39]([O:44][C:45]5[N:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=5)[CH:40]=4)[O:35]3)[CH:31]=[CH:32][CH:33]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1

Procedure:
5-Nitropyridin-2-yl)(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-yl)amine was prepared using the same procedure as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from N-{6-[2-(3-hydroxyphenyl)chroman-6-yloxy]pyridine-3-yl}methanesulfonamide. 1H NMR (300 MHz, d6-DMSO) δ: 10.14 (s, 1H), 9.02 (m, 1H), 8.63 (dd, 1H, J 2.8, 8.8 Hz), 8.40 (d, 1H, J 2.8 Hz), 8.30 (dd, 1H, J 2.8, 9.2 Hz), 8.13 (dd, 1H, J 2.6, 8.6 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.8 Hz), 7.31 (s, 1H), 7.28 (d, 1H, J 9.2 Hz), 7.21 (dd, 1H, J 2.1, 7.9 Hz), 6.70 (d, 1H, J 8.8 Hz), 6.85-6.90 (m, 5H), 5.18 (d, 1H, J 8.1 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.23 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:2]=C.[OH:18]OS([O-])=O.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CO>[OH:18][CH:2]1[CH2:1][C:4]2=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[C:13]2[O:14]1
Reactant: O=S([O-])OO
Reactant: C=CCc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c2c1CC(O)O2
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
Methyl 2-allyl-3-hydroxy-4-nitro-benzoate 1d (5.39 g, 22.70 mmol) was dissolved in 110 mL of the mixture solvent of dichloromethane and methanol (V/V=10:1), the reaction solution was cooled down to −78° C. and filled with oxone. After stirring for 50 minutes, oxone was removed from filling with. The reaction mixture was stirred for another 20 minutes, then filled with argon and stirred for 10 minutes. Triphenyl phosphine (17.80 g, 68.10 mmol) was added. After removing the dry ice bath, the resulting mixture was allowed to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, added with 200 mL of ethyl acetate, washed with water (100 mL×3) and saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 2-hydroxy-7-nitro-2,3-dihydrobenzofuran-4-carboxylate 1e (5.20 g, yield: 96.0%) as a brown solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:32])[NH:16][C:17]2[S:18][C:19]3[CH2:25][C@@H:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:20]=3[N:21]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([NH:16][C:17]1[S:18][C:19]2[CH2:25][C@@H:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][CH2:22][C:20]=2[N:21]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)Nc2nc3c(s2)C[C@@H](N2CCOCC2)CC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(C(=O)Nc2nc3c(s2)C[C@@H](N2CCOCC2)CC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Dissolve [3-((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester (4.82 g, 10.2 mmol) in DCM (5 mL) and add TFA (trifluoroacetic acid) (20 mL). Stir the mixture at rt for 1 h. LCMS analysis indicates the desired deprotected material. Concentrate to give the desired product 3-aminomethyl-N—((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide as a foam (4.80 g, 9.87 mmol).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72 g, 73%).