Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccc(C(=O)NCCc2ccccc2)cc1N
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NCCc2ccccc2)cc1Nc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Cyanuric chloride (0.74 g, 4.02 mL) was added to an acetone solution (15 mL) of 3-amino-4-methyl-N-phenethyl-benzamide (1.02 g, 4.02 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. Ice was added to the mixture and stirred for 15 min. The solvent was removed to afford 3-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-4-methyl N-phenethyl-benzamide (1.52 g, 94%) as white solid MS (m/z) calced for C19H17Cl2N5O (MH+), 402; found, 402.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][S:12](=[O:15])(=[O:14])[C:11]([CH3:17])([CH3:16])[C:10]([NH2:18])=[N:9]2)[CH:7]=1.N>CO.[Pd]>[F:20][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C@:8]1([CH3:19])[CH2:13][S:12](=[O:14])(=[O:15])[C:11]([CH3:16])([CH3:17])[C:10]([NH2:18])=[N:9]1
Reactant: CC1(C)C(N)=N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC1(C)C(N)=N[C@](C)(c2ccccc2F)CS1(=O)=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (1 g, 2.75 mmol, Eq: 1.00) in methanol (80 ml) and ammonia (7 M in MeOH) (1.18 ml, 8.26 mmol, Eq: 3.0) was added at 23° C. under inert atmosphere Pd/C 10% (293 mg, 275 μmol, Eq: 0.1) and the suspension was set under hydrogen (balloon) and stirred at 23° C. for 2 hours. The catalyst was filtered off, washed three times with methanol and evaporated. The residue was extracted with dichloromethane/sat. NaHCO3-sol. and the organic layer was dried over Na2SO4, filtered and evaporated to give the pure (R)-5-(2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (760 mg, 2.67 mmol, 97.1% yield) as a white solid. MS (ISP): m/z=285.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH:12]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:44])[N:41]([CH3:43])[CH3:42])=[CH:35][C:34]=1C=C)[CH2:13][CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]>ClCCl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[C:29]([Si:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:15][CH2:14][CH2:13][CH:12]1[C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40](=[O:44])[N:41]([CH3:42])[CH3:43])=[CH:37][C:38]=2[CH:3]=[CH:2][CH2:1][N:4]1[C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])([CH3:31])([CH3:30])[CH3:32]
Reactant: C=CCN(C(=O)OC(C)(C)C)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(OC(=O)N(C)C)cc1C=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc2c(c1)C=CCN(C(=O)OC(C)(C)C)C2CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of t-butyl allyl-[3-(t-butyl-diphenyl-silanyloxy)-1-(4-dimethylcarbamoyloxy-2-vinyl-phenyl) -propyl]-carbamate (360 mg, 0.56 mmol) synthesized in step (j) of Example 192 in dichloromethane (40 ml) was added tricyclohexylphosphine [1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (47.5 mg, 0.0560 mmol), and the resulting mixture was stirred for 3 hours at 45° C. under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-2:1) as the eluent to afford the title compound (330 mg, yield: 96%) as a colorless oil
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:20][N:21]=3)[N:18]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[N:29]1[C:30]2[C:25](=[CH:24][C:23]([CH2:22][C:19]3[N:17]4[N:18]=[C:13]([C:10]5[CH:9]=[CH:8][C:7]([OH:6])=[N:12][CH:11]=5)[CH:14]=[CH:15][C:16]4=[N:21][CH:20]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Boron tribromide (1364 mg, 5.44 mmol) was added to a suspension of 6-[6-(6-Methoxypyridin-3-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 62, 200 mg, 0.544 mmol) in DCM (5 mL) at −78° C. The RM was stirred at −78° C. for 15 min and then allowed to reach rt. It was then stirred at rt for 68 h. The RM was filtered and the obtained solid was purified by reverse phase chromatography (water 0.1% TFA/acetonitrile +0.1% TFA). The resulting oil precipitated in TBME/MeOH to afford the title compound as a white powder (tR 4.21 min (conditions 4), MH+=354.3, 1H-NMR in DMSO-d6: 9.00 (m, 1H); 8.58 (m, 1H); 8.31 (m, 2H); 8.19 (dd, 1H); 8.05 (m, 4H); 7.92 (dd, 1H); 7.70 (dd, 1H); 6.54 (d, 1H); 4.65 (s, 2H)).
Reaction SMILES: [CH2:1](O)[C:2]#[N:3].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([NH:12][CH2:1][C:2]#[N:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: N#CCO
Solvent: CO
Product: N#CCNCc1ccccc1
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a stirred solution of glycollonitrile (25 g) in methanol was added dropwise over 45 minutes benzylamine (46.9 g) keeping the temperature of the reaction between 15°-20°. Following the addition the reaction mixture was kept overnight at room temperature, and then distilled to give benzylaminoacetonitrile (42.0 g) as a colourless oil, b.p. 120°/15 mm. Reaction of this (3.0 g) with 3,5-dimethylbenzoyl chloride (3.46 g) was described above gave crude N-benzyl-3,5-dimethylbenzoylaminoacetonitrile (5.81 g) as a colourless viscous oil which was used in the next stage without further purification. To this crude amide (2.0 g) in anhydrous methylene chloride (8 ml) was added sulphuryl chloride (0.97 g). Following the cessation of gas evolution (ca. 15 min.), anhydrous methanol (20 ml) and finely powdered anhydrous potassium carbonate (1.95 g) was added to the mixture which was then stirred for 30 minutes. Solids were removed from the solution which was then evaporated and the residual oil chromatographed on a column of silica using methylene chloride as an eluent. Following elution from the column and evaporation of the solvent, the product (1.2 g) was obtained as a very pale-yellow viscous oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]#[CH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2].[Br:34][C:35](Br)=[N:36][OH:37].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:37][N:36]=[C:35]([Br:34])[CH:15]=2)[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[F:33])(=[O:3])[CH3:2]
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Yield: 75.6 %

Procedure:
(2R,3 R,4R,5R)4-(acetyloxy)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate (20 mg) was stirred at 22° C. with dibromoformaldoxime (12.5 mg), sodium bicarbonate (39 mg), water (0.075 ml) and ethyl acetate (1.5 ml) for 88 h. The mixture was partitioned between water (20 ml) and ethyl acetate (3×10 ml), the organic layers were washed with brine and evaporated in vacuo to give a brown gum (19 mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate:cyclohexane 20:80-80:20) gave the title compound as a colourless gum (16.8 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30](O)=[O:31])[CH:4]=[N:3]1.[NH2:34][CH:35]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].Cl.CN(C)CCCN=C=NCC.O>O1CCCC1.C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30]([NH:34][CH:35]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)CC(=O)NC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoic acid (600 mg), di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (434 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (522 mg) in tetrahydrofuran (12 ml) and methylene chloride (6 ml) was stirred overnight at room temperature. Water was added and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with diisopropyl ether-ethyl acetate (2:1) to give di-tert-butyl {2-[(3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoyl)amino]-1,3-propanediyl}biscarbamate (699 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].I[C:16]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[C:20]1([S:19][C:16]2([O:1][C:2]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=3[CH:4]=[O:5])[CH2:18][CH2:17]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: IC1(Sc2ccccc2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
Silver carbonate (1.2 g, 4.34 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.5 g, 2.43 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (1.2 g, 4.34 mmol) in toluene (30 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled, diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (95:5), to give the title compound as a yellow oil (191 mg, 27%). 1H NMR (360 MHz, CDCl3) δ1.51-1.56 (2 H, m), 1.44-1.48 (2 H, m), 7.25-7.35 (7 H, m), 7.69 (1 H, d, J 2.0 Hz), and 10.26 (1 H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[O:29]C(=O)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].C(=O)(O)[O-].[Na+]>C(O)C.O>[ClH:34].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[OH:29])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]

Procedure:
A suspension of N-(1-benzylpiperid-4-yl)-2-acetoxy-4-acetamido-5-nitrobenzamide (4.5 g; 0.01 mol) [prepared by the procedure described in Example 1] in ethanol (25 ml), concentrated hydrochloric acid (4.5 ml) and water (50 ml) was boiled under reflux for 2 hours. The mixture was diluted with water, made alkaline with sodium bicarbonate and extracted with chloroform. The organic solution was dried (Na2SO4), the solvent removed in vacuo and the residue triturated with diethyl ether to give a solid which was treated with a saturated solution of hydrogen chloride in ethanol. After crystallization from ethanol, 3 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide hydrochloride were obtained, m.p. 248°-250° C. (dec).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C@@H:9]([N:11]1[C:15](=O)[CH2:14][C@@H:13]([CH3:17])[C:12]1=O)[CH3:10].[OH-].[Na+].O>CCOCC.CO>[CH3:17][C@@H:13]1[CH2:14][CH2:15][N:11]([C@@H:9]([CH3:10])[CH2:8][OH:7])[CH2:12]1
Reactant: C[C@@H]1CC(=O)N([C@@H](C)CO)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Lithium aluminum hydride (96 mL of 1.0 M solution in ether, 0.096 moles) was added to a cold (ice bath) solution of (3R)-1-[(1S)-2-hydroxy-1-methylethyl]-3-methylpyrrolidine-2,5-dione (8.26 g, 0.048 moles) in anhydrous ether (565 mL). The cold bath was removed and the resulting mixture was stirred at room temperature for 17 hours. The resulting mixture was cooled in an ice bath as water (3.7 mL) was added slowly dropwise (CALIMON: vigorous reaction, gas evolution) followed by 15% NaOH (3.7 mL) and additional water (11.0 mL). The resulting mixture was stirred vigorously for 15 minutes then sonicated for 15 minutes and filtered. The collected solid was washed with ether (2×125 mL; stirred vigorously for 15 minutes then sonicated 15 minutes and filtered) and the combined filtrates were dried (MgSO4), filtered, and evaporated to a light yellow oil (5.76 g). The crude product was purified by flash chromatography on silica gel (65×222 mm column) eluted with 10:7:2:1 ethyl acetate:hexane:methanol:triethylamine collecting 50 mL fractions after a forerun of 750 mL to afford the pure product (in fractions 6–50) as a light yellow liquid. 1H NMR: (CDCl3, 600 M) δ 3.54 & 3.32 (2H, 2 dd, J=5, 10 Hz, H1), 3.30 (1H, br s, OH), 2.83 & 2.11 (2H, 2 dd, J=8, 8 Hz, H2′), 2.62–2.67 & 2.54–2.59 (2H, 2m, H5′), 2.65–2.68 (2H, m, H2), 2.15–2.24 (1H, m, H3′), 1.92–1.98 & 1.28–1.34 (2H, 2m, H4′), 1.00 (6H, d, J=7 Hz, 2CH3s); 13C NMR: (CDCl3, 150 MHz) δ 64.54, 58.02, 57.46, 48.87, 32.45, 31.67, 20.24, 12.49; MS (electrospray): m/e 144 (M+H). [α]D−0.5° (c=1.0 in MeOH).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:8][CH:7]=1.O>C(O)(C(F)(F)F)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16](=[O:19])[NH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(Cc2ccc(F)cc2)c[nH]1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 90% HNO3 (57 mL, 1.22 mol) was added slowly to a stirred solution of 5-[(4-fluorophenyl)methyl]-2(1H)-pyridinone (249 g, 1.22 mol) in TFA (750 mL). The solution was heated at 75° C. for 2 h during which time additional 90% HNO3 (25 mL, 0.5 mol) was added. Water (1L) was added slowly and most of the TFA was removed by distillation. The mixture was allowed to cool to rt and the product was isolated by filtration as a yellow solid: 1H NMR (d6-DMSO) δ 12.76 (1H, br), 8.31 (1H, d, J=2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 7.30 (2H, dd, J=8.6, 5.7 Hz), 7.11 (2H, t, J=8.6 Hz), 3.76 (2H, s); ES+ MS: 249 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N+:17]([O-])=O)=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:12]1[C:11]([NH2:17])=[CH:10][C:3]([C:4]([NH:6][CH:7]2[CH2:9][CH2:8]2)=[O:5])=[C:2]([Cl:1])[CH:13]=1
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(C(=O)NC2CC2)cc1N
Temperature: 60 °C
Yield: 67.4 %

Procedure:
2-Chloro-N-cyclopropyl-4,5-dinitrobenzamide (7.5 g, 26.3 mmol) was initially charged in ethanol (200 ml) and water (40 ml). At room temperature, ammonium chloride (2.53 g, 47.4 mmol) was added and the reaction mixture was heated to 60° C. At this temperature, iron powder (14.7 g, 263 mmol) was added in portions and the reaction mixture was then heated under reflux for 4 h. The ethanol was removed under reduced pressure and the remaining aqueous suspension was filtered through Celite. The filtrate was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After removing the solvent under reduced pressure, 4 g (68% of theory) of 4,5-diamino-2-chloro-N-cyclopropylbenzamide were obtained. 1H NMR (D6-DMSO): δ 0.44-0.48 (m, 2H), 0.61-0.64 (m, 2H), 2.71-2.75 (m, 1H), 4.68 (bs, 2H), 4.98 (bs, 2H), 6.47 (s, 1H), 6.55 (s, 1H), 7.95-7.97 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[CH2:27][NH:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCNCc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N

Procedure:
A mixture of N-[3-(4-nitro-3-propylaminomethyl-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.0016 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.1 g) as a catalyst. After uptake of H2 gas (3 equiv.), the catalyst was filtered off and the filtrate was evaporated to yield the title compound as a residue. (The product was used in subsequent steps without further purification.)
Reaction SMILES: [OH-].[Na+].O.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11][CH2:10]1)=O)C>C(O)C>[CH2:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:15]=1[CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Yield: 50.4 %

Procedure:
In a 500 ml three-necked flask, 9 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid ethyl ester are dissolved in 180 ml of ethanol, and then 40 ml of a 5M solution of sodium hydroxide are added. The reaction mixture is brought to reflux for 48 hours. The reaction mixture is poured into 400 ml of water. The solid is filtered off and then chromatographed on silica gel (98/2 dichloromethane/methanol). 3.8 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.[CH3:45][C@@H:46]1[CH2:51][NH:50][CH2:49][CH2:48][N:47]1[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].O1CCCC1.C([BH3-])#N.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH2:21][N:50]4[CH2:49][CH2:48][N:47]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[C@H:46]([CH3:45])[CH2:51]4)[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)[N:10]=2)=[CH:40][CH:39]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)[C@H](C)C4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a 15 mL round-bottomed flask was added 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (0.438 g, 0.735 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.368 g, 1.838 mmol), tetrahydrofuran (0.053 g, 0.735 mmol), titanium (iv) ethoxide (0.761 mL, 3.68 mmol) (Aldrich). The flask was sealed and the solution was stirred at 70° C. overnight. The solution was stirred at 0° C. and treated in one portion with sodium cyanotrihydridoborate (0.462 g, 7.35 mmol) (Aldrich). The suspension was stirred at 0° C. for two hours. The suspension was quenched with drops of MeOH and water, then DCM. The suspension was stirred for 10 minutes vigorously and was filtered through Celite® (diatomaceous earth) and the filtrated cake was washed with DCM. The organic phase was concentrated to afford (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-2-methylpiperazine-1-carboxylate (0.425 g, 0.545 mmol, 74.1% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH2:17]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:26]([C:31]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[CH:31]=[CH:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH3:30]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Reactant: OCC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C=CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
to a cooled solution of oxalyl chloride (11.1 μL, 105 mmol) in dichloromethane (250 mL) was added at −78° C. a solution of dimethylsulfoxide (14.6 mL, 206 mmol) in dichloromethane (250 mL). After 5 min at the same temperature cyclohexylmethanol (10.8 mL, 87.5 mmol) and after additional 5 min triethylamine (60.7 mL, 438 mmol) were added. The reaction remained at −78° C. for two hours and then let warm to room temperature. The solvent was removed in vacuo. The resulting aldehyde was used for the next step without further purification. The crude cyclohexanecarbaldehyde was dissolved in toluene (200 mL) and ethanol (150 mL). After 15 min of stirring at 70° C. carbethoxy-methylene triphenylphosphorane (33.6 g, 96.5 mmol) was added in one portion. Stirring was continued for additional 24 hours. The solvent was removed in vacuo. The product was obtained by flash chromatography in 78% yield (12.5 g). 1H NMR (300 MHz, [D6-DMSO]: δ=1.07-1.34 (m, 8H, CH3 and cyclohexyl-CH2), 1.60-1.80 (m, 5H, cyclohexyl-CH2), 2.04-2.18 (m, 1H, cyclohexyl-CH); 4.16 (q, J=7.1 Hz, 2H, EtCH2), 5.74 (dd, J=15.8 Hz and J=1.5 Hz, 1H, C═C—H), 6.89 (dd, J=15.8 Hz and J=6.8 Hz, 1H, C═C—H).