Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([N+:14]([O-])=O)=[CH:6][N:5]=1)[CH3:2].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>CC(=O)OCC>[CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:14])=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12])[CH3:2]
Reactant: CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ncc(N)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a mixture of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.508 mmol) in EA (10 mL) was added tin(II) chloride dihydrate (459 mg, 2.033 mmol). The mixture was stirred at 50° C. for 16 h. Then the solution was distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=4:1, Rf=0.6) to yield a light yellow oil of 6-ethoxy-5-(trifluoromethyl)pyridin-3-amine (80 mg, 0.310 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) δ 6.27 (d, J=2.5 Hz, 1H), 5.86 (d, J=3.0 Hz, 1H), 2.81 (m, 2H), 0.17 (t, J=7.0 Hz, 3H); ES-LCMS m/z 207.1 (M+H).
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.[Na+].[I-]>[CH2:20]([N:19]([CH3:18])[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCc1ccccc1
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nn2ccccc2c1C(=O)C(C)N(C)Cc1ccccc1
Yield: 33.4 %

Procedure:
A mixture of 2.37 g (13.4 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, 1.74 ml (13.4 mmol) of N-methyl benzylamine and 50 mg of NaI in 15 ml of MeOH was refluxed overnight. The mixture obtained after evaporation of the solvent was purified on an Al2O3 column, and recrystallized from ether/hexane to obtain 1.5 g of 2-(benzyl(methyl)amino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1041.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14](COC(=O)C(C)(C)C)[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[N:10]=[CH:9]1.[H-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1ncn2-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2,2-Dimethyl-propionic acid 7-(2-chlorophenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydropurin-1-ylmethyl ester (144 mg) was dissolved in methanol (2 ml) and tetrahydrofuran (1 ml), and sodium hydride (20 mg) was added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate-diethyl ether to give 72 mg of 7-(2-chlorophenyl)-3-methyl-3,7-dihydropurine-2,6-dione. This was dissolved in N,N-dimethylformamide (1 ml), and N-chlorosuccinimide (35 mg) was added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 58 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[C:21](/[CH:23]=[C:24](\[O-:26])/[CH3:25])#[N:22].[Na+].C(O)(=O)C.N1CCCCC1.C(=O)(O)[O-].[Na+]>ClCCl>[C:21]([C:23]([C:24](=[O:26])[CH3:25])=[CH:1][C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]=2[CH:4]=1)#[N:22]
Reactant: C/C([O-])=C/C#N
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Yield: 80.4 %

Procedure:
A mixture of 1.50 g (5.63 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A), 0.65 g (6.2 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 0.4 ml (7.04 mmol) acetic acid and 56 μl (0.56 mmol) piperidine in dry dichloromethane (35 ml) containing 4 Å molecular sieve was stirred under reflux for 1 h. After cooling, 50 ml aq. sodium bicarbonate solution were added, and the mixture was stirred for 1 h at rt. The molecular sieve was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with ethyl acetate and saturated aq. sodium carbonate solution. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to afford the title compound (1.5 g, 80% of th.) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:24]([NH:32][NH:33][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:3]=[C:2]2[I:1])=[O:12])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirring suspension of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (515 mg, 1.17 mmol) and benzohydrazide (159 mg, 1.167 mmol) in THF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.92 mmol) followed by HATU (488 mg, 1.28 mmol) in one portion and the solution was stirred at RT for 2 h. The reaction was quenched with 20 mL of ice cold H2O and extracted with EtOAc (2×50 mL). The organic layer was washed with 10 mL of sat. NaHCO3 followed by brine, and dried over Na2SO4. It was concentrated to about 5 mL and the precipitated solid was filtered, rinsed with EtOAc (2×2 mL). The white solid was collected and dried in a vacuum oven for 5 h at 40° C. affording N′-benzoyl-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (305 mg, 47%) as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 560.0 (M+1). 1H NMR (400 MHz, DMSO-D6) δ ppm 10.67 (1H, s), 10.52 (1H, s), 8.19 (1H, s), 8.08 (1H, d, J=8.4 Hz), 78.03-7.88 (6H, m), 7.67-7.49 (3H, m), 7.42 (2H, d, J=8.2 Hz), 2.33 (3H, s).
Reaction SMILES: [C:1]([C:4]1[C:12](=[O:13])[N:11]2[C:7]([S:8][C:9]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=32)=[N:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:1]([C:4]2[C:12](=[O:13])[N:11]3[C:7]([S:8][C:9]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=43)=[N:6][CH:5]=2)=[O:3])=[N:36][N:35]=[N:34]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnc2sc3ccc(Cl)cc3n2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc(Cl)cc3n2c1=O

Procedure:
In a manner similar to Example 4, 1.4 g. of 3-carboxy-7-chloro-4-oxo-4H-pyrimido[2,1-b]benzothiazole is reacted with 892 mg. of 1,1'-carbonyldiimidazole in 60 ml. of dimethylformamide at steam bath temperatures for 15 min. 5-Aminotetrazole (468 mg.) is added and the reaction mixture is heated for 30 min. The resulting suspension is cooled and filtered, 1.5 g., m.p. > 300° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:16])[CH2:14][CH3:15])[N:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:16])[CH2:14][CH3:15])[N:12]=1
Reactant: CCC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)c1csc(N)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
(4-Propionyl-thiazol-2-yl)-carbamic acid tert-butyl ester (5.0 g, 19.5 mmol) was suspended in dichloromethane (100 mL) at 0° C. Trifluoroacetic acid (100 mL) was added and the mixture was stirred at 0° C. for 1.5 hours. The cooling bath was removed and stirring was continued for 1 hour prior to concentration of the reaction mixture in vacuo. The residue was triturated with ether and filtered. The solid was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 1-(2-amino-thiazol-4-yl)-propan-1-one (2.3 g, 75%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[NH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[C:19]([O-])([O-])=O.[Na+].[Na+].CI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][CH:15]=[CH2:16])[C:9]=2[C:8](=[O:17])[N:7]([CH3:19])[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCC
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCC
Temperature: 35 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
A stirred solution of 3-butyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.0 g, 4.03 mmol) in anhydrous DMF (10 ml) was treated with Na2CO3 (470 mg, 4.43 mmol) followed by Methyliodide (275 ul, 4.43 mmol). The mixture was heated at 35° C. for 17 hours. K2CO3 (500 mg, 3.6 mmol) and Methyliodide (275 ul, 4.43 mmol) were added and then stirred at 50° C. for a further 18 hours. The reaction mixture was allowed to cool then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated giving a yellow/brown oil (1.24 g). The product was purified by silica SPE (10 g), eluting with EtOAc/cyclohexane mixtures. The product fractions were combined and concentrated to afford the title compound as a pale yellow solid (1.11 g, quant.); m/z 263.3[MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](N)=[C:4]([O:9][CH3:10])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:27].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([I:27])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1N
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)ccc1I
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
4-Bromo-2-methoxy-phenylamine (2.02 g, 10 mmol) was added to a solution of p-toluensulphonic acid monohydrate (3.80 g, 20 mmol) in acetonitrile (30 mL). The mixture was cooled in an ice bath and treated with an solution of sodium nitrite (0.69 g, 10 mmol) and potassium iodide (4.15 g, 25 mmol) in water (7 mL) over 15 min maintaining the internal temperature below 10° C. After stirring at that temperature for 15 min and then for 0.5 h at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (5×50 mL). The combined organic extracts were washed with 2M sodium thiosulfate (10 mL), brine (4×20 mL), water (20 mL), anhydrified over sodium sulphate, and evaporated to dryness affording a black oil that was purified by flash chromatography (petroleum ether/tert-butylmethyl ether 5/1) to yield the title compound (1.63 g, 52.2%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([CH:17]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18]2)=[O:16])=[C:10]([OH:23])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].[C:27]1([O-:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].C(Cl)(=O)C=CCC=C>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([CH:17]2[CH2:20][C:19]([CH3:21])([CH3:22])[CH2:18]2)=[O:16])=[C:10]([O:23][C:27](=[O:33])[CH:28]=[CH:29][CH2:30][CH:31]=[CH2:32])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1
Reactant: [O-]c1ccccc1
Agent: C=CCC=CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Product: C=CCC=CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)C1CC(C)(C)C1

Procedure:
Following a procedure similar to that described in Example 2A above when 3-hydroxy- 4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 2,5-hexadienoyl chloride there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][CH3:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)N1CCC(O)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(OC)CC1
Temperature: 3 °C

Procedure:
1-ethoxycarbonyl-4-hydroxypiperidine (30.3 g) and triethylamine (23 g) were dissolved in ethyl acetate (182 mL) and the obtained mixture was cooled to 3° C. Methanesulfonyl chloride (22.05 g) was added thereto under stirring while taking caution such that the temperature did not exceed 20° C., and the mixture was continuously stirred under ice cooling for 1 hour. The obtained reaction mixture was washed with water (90 mL×3). The organic layer was isolated and concentrated to obtain a target compound as a light yellow oily substance. The yield amount was 43.09 g (98%).
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:12](=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:23][NH2:24]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:12](=[O:22])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]2[CH:2]([NH:24][CH3:23])[CH3:3])=[CH:15][CH:16]=1
Reactant: COc1ccc(-n2c(C(C)Cl)nc3ccccc3c2=O)cc1
Reactant: CN
Product: CNC(C)c1nc2ccccc2c(=O)n1-c1ccc(OC)cc1
Temperature: 110 °C
Yield: 98 %

Procedure:
To the neat 2-(1-chloroethyl)-3-(4-methoxyphenyl)-3H-quinazolin-4-one (1.0 g, 3.2 mmol) in a sealed tube was added 40 mL of a methylamine solution (1M in THF, 40 mmol). The tube was sealed and heated to 110° C. 16 h. The resulting solution was cooled to room temperature and concentrated under vacuum to afford the crude product that was purified by flash chromatography (5% MeOH/DCM, silica gel) to afford the title compound (yield 0.97 g, 99%). 1H-NMR (CD3OD): δ 8.28 (m, 1H), 7.93 (m, 1H), 7.86 (m, 1H), 7.65 (m, 1H), 7.43 (m, 1H) 7.33 (m, 1H), 7.19 (m, 2H), 4.09 (q, 1H), 3.92 (s, 3H), 2.75 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]=[O:26])=[CH:24][C:19]=2[O:18][CH2:17]1.C(OCC)=O>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([CH:25]([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[OH:26])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC=O
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyllithium (1.8 mL, 3.1 mmol, 1.7M in pentane) at −78° C. was added dropwise a solution of 5-bromobenzo-1,3-dioxole (1.5 mmol) in THF (3 mL). After 30 min, benzo-1,3-dioxole-5-carbaldehyde (1.5 mmol) or ethyl formate (0.5 mmol) in THF (1 mL) was added. The mixture was stirred at −78° C. for 1 h and subsequently warmed to room temperature and stirred for an additional 4 h. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude oil by flash chromatography (20% EtOAc/hexanes) provided the diphenyl methanol product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:27]=1[C:28](Cl)=[O:29].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Cl:25][C:26]1[C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:29])=[C:31]([O:35][CH3:36])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(Cl)c1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(Cl)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 76 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-chloro-6-methoxybenzoyl chloride, the title compound (yield 76%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][N:18]([CH3:33])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:18]([CH3:33])[CH3:17])[CH:20]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CN(C)c1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:76])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]CC2C=CC=CC=2)[CH:27]=[C:26]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68]CC2C=CC=CC=2)[CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:76])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][OH:68])[CH:27]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])[CH:29]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCO)cc(OCCOCCOCCOCCOCCO)c1
Reaction time: 6 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 90 mg) in methanol (2.7 ml), a solution of Compound 48 (500 mg, 0.462 mmol) in methanol (3.6 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for about 6 hours. After a nitrogen atmosphere was restored, ethyl acetate (about 20 ml) was added, and the mixture was filtered on silica gel and washed with an ethyl acetate solution containing 10% methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 49.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH:24]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:36])[CH:28]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[C:3]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([NH:8][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([CH:24]3[CH2:26][CH2:25]3)=[CH:28][C:29]=2[CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C2CC2)ccc1C(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(N)cccc1Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(C2CC2)ccc1C(=O)Nc1cccc(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of [3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenylamine (21.28 g, 67.3 mmol) and anhydrous pyridine (6.5 mL, 80 mmol) in 50 mL of anhydrous toluene was added a solution of 4-cyclopropyl-2-methylbenzoyl chloride (13.25 g, 68.1 mmol) in 50 mL anhydrous toluene dropwise. A precipitate formed immediately upon addition. Stirred the mixture at ambient temperature under nitrogen overnight. Diluted the reaction mixture with 125 mL hexane and filtered off the precipitate. Washed the filtrate with 2×200 mL 1.0 M KHSO4, 2×200 mL 5% NaHCO3, and 250 mL water. Dried the solution over MgSO4 and concentrated in vacuo to obtain N-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-4-cyclopropyl-2-methyl-benzamide as a waxy light brown solid (31.54 g, 66.4 mmol). MS (ESI) 474, 476.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2>[C].[Pd].O1CCCC1>[NH2:15][C:13]1[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc([N+](=O)[O-])c2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Yield: 99.7 %

Procedure:
A mixture of ethyl 5-(2-methoxyethoxy)-7-nitro-1H-indole-2-carboxylate (2.30 g), 10% palladium carbon (50% containing water, 500 mg) and tetrahydrofuran (100 mL) was subjected to catalytic reduction at room temperature under hydrogen atmosphere at normal pressure. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was washed with hexane to give the title compound (2.07 g, yield 99%) as pale-brown crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-brown prism crystals. melting point 162-163° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:4]([C:15]([O:17]C)=[O:16])[CH2:3]1.O1CCOCC1.CO.[OH-].[Na+]>O>[C:11]([O:10][C:8]([N:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]([C:15]([OH:17])=[O:16])[CH2:5]1)=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)C1CC(C)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1CC(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
136B was dissolved with dioxane (14 mL) and methanol (7 mL). Sodium hydroxide (1.32 g, 33 mmol) in water (2 mL) was added and the mixture was heated to 80° C. for 5 hrs. Solvent was removed under vacuum and the residue was partitioned between 2N HCl (50 mL) and ethyl acetate (50 mL). The mixture was transferred to a separatory funnel and the organics were separated. The aqueous layer was extracted with ethyl acetate (2×25 mL), and the organics were combined and dried over sodium sulfate and filtered. Solvent was removed under vacuum to leave 1-(tert-butoxycarbonyl)-5-methylpiperidine-3-carboxylic acid (136C) as a white solid which was used without further purification. ESI-MS:m/z 266.4 (M+H)+.