Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>O.CO.[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCC(=O)O
Agent: [Ni]
Solvent: O
Solvent: CO
Product: O=C(O)CNCC(O)C(O)C(O)C(O)CO
Yield: 73.2 %

Procedure:
A solution of 39.6 gm of D-glucose in 200 ml of water and 150 ml of methanol was added to a solution of 15 gm (0.2 mol) of glycine in 200 ml of water and 100 ml of methanol in an autoclave. Then, after the addition of 18.0 gm of Raney nickel, a hydrogenation was carried out in the autoclave with stirring at a pressure of 180 to 200 kg/cm2. The autoclave was heated in a progressive manner first for 2 hours to 50° C., subsequently for 2 hours to 70° C. and finally for 2 hours to 90° C. After separation of the catalyst by filtration and evaporation of the reaction solution in vacuum, the highly viscous residue obtained was allowed to stand for a few days. After crystallization had commenced the same was completed by crystallization from 100 ml of boiling methanol. 35 gm (73% of theory) of N-(2,3,4,5,6-pentahydroxy-hexyl)-glycine having a melting point of 172° to 177° C. (decomposition) were obtained. An analytically pure sample recrystallized from water/ 2-propanol melted at 175° to 180° C. with decomposition.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[O-:10].[Na+]>O.O1CCOCC1>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: [O-]Cl
Reactant: CSc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)c1ccccc1

Procedure:
To a solution of methyl-phenyl-sulphide (6.2 g) in water (2 ml) and dioxane (98 ml), stirred at 20° C. (external bath), sodium hypochlorite (88.69 g, titre 4.19%, pH 12.5) is added in 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:27][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CN(C=O)C>O>[Cl:1][C:2]1[C:11]([C:12]([OH:27])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=Cc1cc2ccc(Cl)cc2nc1Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
A dry reaction flask equipped with a magnetic stirring bar and a rubber septum was charged with 2,7-dichloro-3-formylquinoline 3 (1.1 g, 5 mmol), PDC (3.76 g, 10 mmol) and dry DMF (5 mL) and stirred at room temperature for 24 h. The reaction mixture was diluted with water (500 mL), filtered, the filtrate was saturated with NaCl and the resulting aqueous solution was extracted with EtOAc (3×200 mL). The EtOAc extract was dried over anhydrous Na2SO4 and solvent was removed to give 1.02 g (85%) of the desired 2,7-dichloroquinoline-3-carboxylic acid 4. TLC Rf: 0.12 (20% MeOH/EtOAc); 1H NMR (acetone d6): 8.96 (s, 1H); 8.22 (d, 1H, J=9.0 Hz), 8.04 (d, 1H, J=1.8 Hz), 7.97 (bs, 1H), 7.74 (dd, 1H, J=1.8 and 8.7 Hz); LCMS (ret. time): 25.15 min.; MS (m/z): 241 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][C:13](=[O:15])[O-:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][C:13](=[O:15])[O:14][CH2:7][C:6]3[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])NCC1Cc2cccc(Br)c2O1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Product: O=C(NCC1Cc2cccc(-c3cc(Cl)ccc3Cl)c2O1)OCc1ccccc1
Yield: 15.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-benzofuran-2-ylmethyl)carbamate (3.2 g, 8.83 mmol) with 2,5-dichlorophenylboronic acid (2.54 g, 13.24 mmol) generally according to the procedure described for Intermediate 37 provided 0.299 g (27%) of (±)-benzyl {[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([O:26]C)=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C([NH2:30])=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([NH2:30])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([Cl:23])=[CH:17][C:18]([Cl:22])=[CH:19][C:20]=3[Cl:21])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: NC=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of methyl 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (500 mg, 1.12 mmol), formamide (0.446 mL, 1.20 mmol) and sodium methoxide (28% solution in methanol, 1.1 mL) in N,N-dimethylformamide (5 mL) was stirred at 60° C. for 5 min. The mixture was diluted with aqueous saturated ammonium chloride. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound as a colorless solid (432 mg, 1.00 mmol, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: CC(C)(C)c1ccc(OCCOc2ccccc2[N+](=O)[O-])c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)(C)c1ccc(OCCOc2ccccc2N)c(N)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
The compound prepared in Step A (6.1 g, 17 mmole) was suspended in 100 ml of absolute ethanol with 0.20 g of 10% Pd/C and the mixture was heated to reflux. Hydrazine (5 ml) was added and the resulting solution was refluxed for 30 minutes. The solution was filtered while hot through celite, then cooled to 0° C. The resulting white precipitate was collected and dried to give 4.7 g of the desired product (92%), m.p. 147.5°-150.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.[CH3:18][N:19]1[C:23]([OH:24])=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1>C(C(C)=O)C.C(Cl)Cl>[CH3:18][N:19]1[C:23]([O:24][CH2:13][C:12](=[O:15])[C:11]2[CH:16]=[CH:17][C:8]([CH3:7])=[CH:9][CH:10]=2)=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)COc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)cc1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
In a four necked flask, 2 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy pyrazole was dissolved in 35 ml of methyl ethyl ketone, and 2 g of anhydrous potassium carbonate was added to the solution and 1.4 g of 4-methylphenacyl bromide was added dropwise to the mixture under stirring. The reaction was carried out for 2 hours under refluxing. The reaction mixture in the flask was cooled and filtered and methyl ethyl ketone was distilled off to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride and the solution was sequentially washed with water, an aqueous solution of sodium bicarbonate and water, and after drying over anhydrous sodium sulfate, methylene chloride was distilled off from the solution to obtain a crude product. The product was separated by a silica gel column with developing solvent (CH2Cl2 : 99.5% C2H5OH=100: 3) to obtain 1.87 g of brown oily product of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-(4-methyl benzoylmethoxy) pyrazole.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:12][CH2:13][CH3:14])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O.[BH4-].[Na+].O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH2:12][CH2:13][CH3:14])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: CCCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1n[nH]c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A solution of 4-nitro-3-n-propylpyrazole-5-carboxamide (198 mg, 1.0 mmol ) in methanol (5 ml) was added dropwise to a mixture of sodium borohydride (113 mg, 2.97 mmol), 10% palladium on carbon (5 mg) and water (3 ml). The mixture was stirred at room temperature for 3 hours, filtered and the solvent removed by evaporation under vacuum. Crystallisation of the residue from ethyl acetate-methanol gave the title compound as an off-white solid (61 mg, 36%), m.p. 196°-201° C. Rf 0.4 (silica; dichloromethane, methanol, ammonium hydroxide; 90:10:1). Found: C,48.96; H, 6.98; N,32.08. C7H12N4O requires C,49.98; H, 7.19; N, 33.31%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11]O.[ClH:13]>O1CCOCC1>[Cl:13][CH2:11]/[CH:10]=[CH:9]/[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: OC/C=C/c1cc(F)ccc1F
Reactant: Cl
Solvent: C1COCCO1
Product: Fc1ccc(F)c(/C=C/CCl)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
A mixture of (2E)-3-(2,5-difluorophenyl)prop-2-en-1-ol (Intermediate 70, 700 mg, 4.12 mmol), 1,4-dioxane (5 mL), and hydrochloric acid (12.1 M, 1 mL) was heated in the microwave at 100° C. for 3 hours. It was concentrated to dryness under reduced pressure, the residue taken up in ethyl acetate (10 mL), washed with water (1×10 mL), saturated sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 688 mg (89% yield) of product as a yellow oil.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH:17]=[CH2:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH2:18][CH:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: C=CC(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1)c1ccc(Cl)cc1
Yield: 28.6 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (218 mg, 1 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (2 mmol) was added a solution of triethylamine (111 mg, 1.1 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes:EtOAc, 4:1) to afford the title compound as a white solid (107.3 mg). 1H NMR δ 3.54 (s, 1H), 3.60 (dd, 1H), 3.76 (dd, 1H), 5.12 (t, 1H), 7.45 (d, 2H), 8.14 (d, 2 H); ESIMS: m/z 374 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Clc1ccc(C2OC3(CCN(Cc4ccccc4)CC3)N3CCCCC23)cc1

Procedure:
A mixture of 17 g alpha-(4-chlorophenyl)-2-piperidinemethanol, 15 g of N-benzyl-4-piperidone, and 0.3 g of p-toluenesulfonic acid in 150 ml of xylene is stirred under reflux for 48 hours in a vessel provided with a Dean-Stark water separator. The cooled mixture is filtered and evaporated in vacuo. The residue is crystallized from methanol to provide the product, hexahydro-1'-benzyl-1-(4-chlorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 134°-136° C.
Reaction SMILES: Br[C:2]1[C:28]([CH3:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32]>CN1C(=O)CCC1>[CH2:24]([C:21]1[CH:22]=[N:23][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[CH2:10][CH2:11][C@H:7]([O:6][C:5]4[C:4]([F:30])=[CH:3][C:2]([C:31]#[N:32])=[C:28]([CH3:29])[CH:27]=4)[C:8]3=[O:26])[CH2:13][CH2:14]2)=[N:19][CH:20]=1)[CH3:25]
Reactant: N#C[Cu]
Reactant: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(Br)cc4F)C3=O)CC2)nc1
Solvent: CN1CCCC1=O
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4cc(C)c(C#N)cc4F)C3=O)CC2)nc1
Temperature: 160 °C
Yield: 56.1 %

Procedure:
(S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 96, Steps A-F; 200 mg, 0.419 mmol) was dissolved in NMP (1 mL) and cyanocopper (150 mg, 1.68 mmol) was added and heated to 160° C. overnight. The reaction was partitioned between dilute sodium bicarbonate and EtOAc, dried, filtered and concentrated. The residue was purified on 25M biotage (90% EtOAc/hexane) to afford (S)-4-(1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-5-fluoro-2-methylbenzonitrile (99.6 mg, 0.235 mmol, 56.1% yield) as a pale yellow solid. Mass spectrum (apci) m/z=424 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][C:4]=1[CH3:15]>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6]([CH2:9][CH2:10][CH2:11][C:12]2=[O:14])=[CH:5][C:4]=1[CH3:15]
Reactant: COc1ccc(CCCC(=O)O)cc1C
Agent: CS(=O)(=O)O
Product: COc1cc2c(cc1C)CCCC2=O
Yield: 87.5 %

Procedure:
A solution of 4-(4-methoxy-3-methylphenyl)butyric acid (Compound 27, 24.0 g, 115.4 mmol) and 400 mL of methanesulfonic acid was stirred at room temperature under the argon atmosphere for 24 h, then poured into ice, extracted three times with ethyl acetate, washed with NaHCO3 1N, brine, dried over MgSO4, and filtered. The solvent was removed to give 19.2 g (88%) of the title compound as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromonicotinaldehyde (XLVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (LVI) (1.8 g, 9.57 mmol, 90.0% yield) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO m/z 188 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1>ClCCl>[CH3:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2ccccc21
Solvent: ClCCl
Product: C[C@H]1NCCc2ccccc21
Temperature: -35 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a cooled (−35° C.) solution of reducing agent 9 (526 mg, (0.78 mmol) in dichloromethane (3 mL) is added solution of 1-methyl-3,4-dihydroisoquinoline (32 mg, 0.22 mmol) in dichloromethane (3 mL) dropwise over 15 min. The mixture is allowed to warm to −10° C. over 1 h and then kept at 0° C. for 4 h. The solvent is removed in vacuo and the residue is dissolved in methanol (10 mL). After cooling to 0° C., Amberlyst 15 (1 g) is added and the mixture is shaken for 1 h at room temperature. The resin is filtered off and washed with dichloromethane and methanol, then solution of ammonia in methanol (2M, 3 mL) is added and the mixture is shaken overnight, then filtered. The filtrate is evaporated in vacuo to give (R)-1-Methyl-1,2,3,4-tetrahydroisoquinoline (26 mg, 82%, e.e.=74%, determined by chiral HPLC).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:11][CH:10]=2)=[CH:6][C:5]=1[C:28]([F:31])([F:30])[F:29])([O-:3])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:6][C:5]=1[C:28]([F:29])([F:30])[F:31])([O-:3])=[O:2]
Reactant: CC(C)[Si](Oc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)aniline (3 g, 6.6 mmol) in tetrahydrofuran (60 ml) was added TBAF (2.59 g, 9.9 mmol) with stirring for 1 hour at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 30% ethyl acetate in petroleum ether to afford 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenol as a orange solid (1.5 g, 76%); (ES, m/z): [M+H]+ 299; 1H NMR (300 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.28 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.01-7.05 (m, 1H), 6.81 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[C:15]([N+:21]([O-])=O)=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[O:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:21][C:15]1[C:13]2[CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10](=[O:24])[NH:11][C:12]=2[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2c(c1[N+](=O)[O-])CN(Cc1ccccc1)CC(=O)N2
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(c1N)CN(Cc1ccccc1)CC(=O)N2
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of 4-benzyl-7-methoxy-6-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (860 mg, 2.6 mmol) in methanol (100 mL) was treated with Ra—Ni (˜200 mg; 2800 grade) and shaken on a Paar apparatus under 40 psi H2. After one hour LCMS showed completion of the reaction. The mixture was filtered and concentrated to constant weight to afford 6-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (764 mg, 98%) as a tan solid; 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.34 (m, 5H), 6.75 (d, J=8 Hz, 1H), 6.27 (d, J=8 Hz, 1H), 4.74 (s, 2H), 3.77 (s, 3H), 3.72 (s, 2H), 3.69 (s, 2H), 2.85 (s, 2H); MS (m/e) 298 (M+1); mp 153° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH:14]C(OC(C)(C)C)=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl.O1CCOCC1>O1CCOCC1.O.C(OCC)(=O)C.CO>[CH3:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([NH:13][NH2:14])=[O:12])[CH2:9][CH2:10]3)=[CH:6][CH:7]=2)=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(c2ccc(Br)cc2)CC1
Reactant: Cc1ncc(B(O)O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncc(-c2ccc(C3(C(=O)NN)CC3)cc2)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
The compound (2.34 g, 6.59 mmol) obtained in Example 16-2), (2-methylpyrimidin-5-yl)boronic acid (1.00 g, 7.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.54 g, 0.66 mmol), and potassium carbonate (2.73 g, 19.76 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (10 mL), and the mixture was stirred at 90° C. for 3 h. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50 to 100:0). The obtained partially purified product was dissolved in methanol (5 mL). 4 N hydrochloric acid-dioxane (2.39 mL) was added to the solution, and the mixture was stirred at room temperature for 2 h. The solvent was distilled off, and the residue was separated into organic and aqueous layers with methylene chloride (150 mL) and saturated aqueous sodium hydrogencarbonate (50 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (591 mg, yield: 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:15][N:14]([CH3:13])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a suspension of 3,4-dichlorobenzoic acid (1.0 g, 5.24 mmol) in CH2Cl2 (25 mL) was added N,O-dimethylhydroxylamine hydrochloride (613 mg, 6.28 mmol) followed by N-methylmorpholine (865 μL, 7.85 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g, 6.28 mmol) at which point the reaction mixture became homogeneous. After 2 h, the reaction mixture was diluted with EtOAc and washed with 1N HCl, H2O, saturated NaHCO3 solution and brine, sequentially. The organic layer was dried over Na2SO4, and the removal of solvent in vacuo gave the title compound (1.16 g) that required no further purification.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.71 mL (5.1 mmol) of triethylamine was added and dissolved in a suspension of 0.82 g (4.63 mmol) of ascorbic acid in acetonitrile (9 mL). The above crude product of (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.