Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[O:28][N:27]=[C:26]([C:29]([O:31]CC)=[O:30])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[O:28][N:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: CCOC(=O)c1cc(-c2ccc3nnc(CNc4ccnc5cc(OC)cnc45)n3n2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C(=O)O)no5)nn34)ccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(3-((7-methoxy-1,5-naphthyridin-4-ylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)isoxazole-3-carboxylate (0.045 g, 0.10 mmol) in methanol (1 mL) and water (0.5 mL) was added sodium hydroxide (6M, 0.050 ml, 0.30 mmol). The mixture was stirred at 50° C. for two hours, then was concentrated and diluted with water (2 mL). 2M HCL was added dropwise until precipitation was observed, the tan solid was collected by filtration. The solid was taken up in isopropanol and heated to 100° C. The resulting suspension was cooled to room temperature and filtered to yield the product as a tan solid. MS m/z=418.6 [M+1]+. Calc'd for C19H14N8O4: 418.1.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:25][O:26][C:27]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:31](=[O:32])[CH2:30][CH2:29][C:28]1[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:27]=1[O:26][CH3:25])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: COc1cccc(CCC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)c1OC
Yield: 18 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with 2,3-dimethoxycinnamic acid under the conditions described in example 86. The crude material was purified by flash chromatography (CH2Cl2:MeOH, 49:1 to 9:1) to yield 18% of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])(O)[CH3:13])=[N:9][CH:10]=1.CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:22][C:12]([CH3:15])([CH3:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COCOc1ccc(CC(C)(C)O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)F)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol (7.600 g, 36.0 mmol) was dissolved in 200 ml CH2Cl2 and cooled to −78° C. DAST (9.51 ml, 72.0 mmol) was added drop wise to the solution and stirring was continued for 30 min The mixture was allowed to warm up to 0° C. and was hydrolyzed with NaHCO3 (200 ml). Stirring was continued in the cold until gas evolution had ceased and the phases were separated. The aqueous was extracted 2× with EtOAc and the combined organic layers were dried over MgSO4 and evaporated. Glass col. Chromatography of the crude material provided 2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.80 g, 75.6% yield) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[K+].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)C>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])c1ccc(Br)c2ccccc12
Reactant: O=[N+]([O-])O
Agent: [K+]
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c(Br)ccc(S(=O)(=O)O)c12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Potassium 1-bromo-4-naphthalenesulfonate (1.38 g, 4.24 mmol) was added portionwise over 20 minutes to 90% nitric acid (2 mL), which was cooled in a methanol/ice bath to approximately -15° C. After 1.5 hours, the mixture was placed in a refrigerator for 20 hours. Diethyl ether (20 mL) was added and the precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:5]=[N:6][C:7]=1Cl.[CH3:23][B-](F)(F)F.[K+].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:5]=[N:6][C:7]=1[CH3:23]
Reactant: C[B-](F)(F)F
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(Cl)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A suspension of tert-butyl 4-(5,6-dichloropyridin-3-yl)-3-methylbenzoate (Step A, 650 mg, 1.92 mmol), potassium methyltrifluoroborate (234 mg, 1.92 mmol), Cs2CO3 (1.88 g, 5.77 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (157 mg, 0.192 mmol), dioxane (4 mL) and water (0.25 mL) was flushed with nitrogen and stirred at 110° C. for 2 hours. After cooling down, the mixture was filtered over celite. The filter cake was washed with ethyl acetate and further diluted with ethyl acetate and water. After separating the layers, the organic was washed with brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The crude isolate was purified by silica gel chromatography (0 to 80% ethyl acetate/hexane) to give the titled compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J=1.9 Hz, 1H), 7.94 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 2.7 (s, 3H), 2.35 (s, 3H), 1.64 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1ccccn1
Temperature: 120 °C

Procedure:
To a mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (185 mg, 1 mmol) and 2-(tributylstannyl)pyridine (202 mg, 1.1 mmol) in DMF (4 mL) was added tetrakis(triphenylphosphine) palladium (0) (58 mg, 0.05 mmol). The reaction tube was sealed, the mixture was purged with N2 for 3 min and then heated at 120° C. under N2 for overnight. The reaction was cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with brine and concentrated. The crude product was purified with silica chromatography (60% ethyl acetate in hexanes) to afford 2-(2,5-dimethyl-4-nitrophenyl)pyridine as a white solid. The obtained solid was dissolved in acetic acid/TFA (15 mL/200 uL). To this solution was added PtO2 (10% w/w). The reaction mixture was degassed and purged with H2 for several times and then vigorously stirred under 1 atm. H2 overnight. The mixture was filtered and the filtrate concentrated to afford 2,5-Dimethyl-4-(piperidin-2-yl)aniline as a yellow oil; ESMS m/z 205 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:58][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:12]([O:11][C:9]([N:8]1[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4][C@H:3]1[C:2]([OH:58])=[O:1])=[O:10])([CH3:14])([CH3:15])[CH3:13]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq) in DMF (0.1M) at rt were added PDC (10 eq) and 4A molecular sieve (1 g/mmol of substrate). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was then filtered on a celite and the celite pad was washed with EtOAc and water. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, 1N aqueous HCl and brine, dried over Na2SO4, filtered and concentrated. The crude product was used as such for next step.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(OCC)(=O)C>[CH:14]1([N:13]([CH3:12])[C:2]2[C:3]3[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: CNC1CCCCC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(N(C)C3CCCCC3)ncnc2[nH]1
Yield: 57.7 %

Procedure:
The product from Method G (50 mg/0.298 mmol) was reacted with 100 mg (0.883 mmol) of N-methylcyclohexylamine as described in Method A. The reaction mixture was worked up as in Method A with the exception that ethyl acetate was used in place of ether. The title compound (42 mg, 58% yield) was obtained as a white solid. Mp 221° C. dec. 1H NMR (400 MHz, CDCl3) δ: 1.15-1.25 (m, 1H), 1.43-1.62 (m, 4H), 1.73 (br s, 1H, J=13.7 Hz), 1.82-1.90 (m, 4H), 2.41 (d, 3H, J=0.8 Hz), 3.21 (s, 3H) 4.63 (br s, 1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (br s, 1H). LRMS: 245 (M+1).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][NH:8][CH2:9]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][CH:19](Br)[CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][N:8]1[CH2:9][CH:10]2[CH:5]([CH2:4][CH2:3][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:1]2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2CCNCC2C1
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CCN(CCCCl)CC2C1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of tert-butyl octahydro-2,7-naphthyridine-2(1H)-carboxylate (320 mg, 1.33 mmol, 1 eq), chloro bromopropane (530 mg, 3.33 mmol, 2.5 eq) and K2CO3 (736 mg, 5.33 mmol, 4 eq) in acetone (25 mL) was heated to reflux overnight, then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as pale yellow oil (190 mg, 47%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 317.2 (M+1).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[O:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(O)(C(F)(F)F)=O>[CH3:20][C:18](=[CH2:19])[CH2:17][O:16][CH:4]1[C:3](=[O:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1
Reactant: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=C(C)COC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 68.1 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 4,4-dimethoxy-3-[(2-methyl-2-propen-1-yl) oxy]piperidine-1-carboxylate obtained in Example (117a) (4.8 g, 18.7 mmol), a water/TFA mixed solution (1/1, 20 mL) and di-tert-butyl dicarbonate (4.8 g, 22 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 3.43 g of the title compound as a light brown oily substance (84%).
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](N)=[CH:18][C:17]=1[CH:31]([CH3:33])[CH3:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC#N>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:5]=[N+:6]=[N-:7])=[CH:18][C:17]=1[CH:31]([CH3:33])[CH3:32])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)c1cc(N)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
tBuONO (2.25 ml, 19 mmol) and TMSN3 (2 ml, 15.2 mmol) were added to a solution of 1,5-bis-benzyloxy-2-isopropyl-4-amino-benzene (1.10 g, 3.18 mmol) in CH3CN (40 ml). The reaction mixture was stirred for 1 hour at 0° C. and for 12 hours at RT. The solvent was evaporated under reduced pressure and the crude reaction mixture was purified by flash chromatography (PE/AcOEt:95/5 to 90/10). The title compound was obtained as a brown solid (890 mg, 75%).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[N:6]=[C:7](OC)[N:8]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24]>C(O)C>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][C:5]2[CH:4]=[C:3]([NH:25][CH2:22][CH2:23][CH3:24])[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH3:3])[N:6]=2)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCCN
Reactant: COc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(OC)n1
Solvent: CCO
Product: CCCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NCCC)n1
Temperature: 140 °C
Reaction time: 65 h
Yield: 85.2 %

Procedure:
1.50 g (0.00483 mol) of sulfadimethoxine were suspended in 20 ml of ethanol, treated with 16 ml (0.193 mol) of propylamine and stirred in an autoclave at 140° C. for 65 hours. The mixture was cooled and, after 24 hours., the crystals which separated were filtered off under suction. There was obtained 0.75 g (50%) of 4-amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamide as pale beige crystals; m.p. 211-215° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]2[O:9][C:8]([F:11])([F:10])[O:7][C:6]=2[CH:12]=1.[C:20](=[O:22])=[O:21].[NH4+].[Cl-]>C(OCC)C>[F:10][C:8]1([F:11])[O:9][C:5]2[C:4]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:3][C:2]([C:20]([OH:22])=[O:21])=[CH:12][C:6]=2[O:7]1
Reactant: CC[Si](CC)(CC)c1cc(Br)cc2c1OC(F)(F)O2
Reactant: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
200 ml of anhydrous diethyl ether were poured to 1.9 g of Mg turnings and 2.0 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J. Org. Chem. 2004, 1, 64) added. The mixture was then stirred at 35° C. for 30 minutes. Then, the heating was shut down and 23.4 g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was added dropwise to the stirred mixture at a rate that ensured gentle boiling. Stirring was continued at 35° C. for 2 h. Then, the mixture was intensly stirred at room temperature under an excess of anhydrous CO2 for 2 h. The reaction mixture was then poured into 300 ml of a saturated aqueous NH4Cl-solution, acidified to pH=3 using aqueous HClI-solution and the organic layer separated. The aqueous layer was then extracted using 200 ml of diethyl ether. The combined organic layer was dried using MgSO4 and evaporated to yield 22.0 g of the title compound that was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH3:11].C[O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)=O>O>[CH2:7]([NH:12][C:15]([C:17]1[N:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[CH2:27][CH2:28]2)=[N:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCN
Reactant: COC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCCCCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Potassium tert-butoxide (0.112 g, 1.00 mmol) was added to a premixed mixture of amylamine (2.5 mL) and 4-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (0.258 g, 0.65 mmol) in a 5 mL reactor for microwave oven. The reaction mixture was irradiated under stirring for 10 minutes at 120° C. On completion of the reaction, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed sequentially with 10% HCl solution, water and sodium hydroxide solution, then separated and dried with Na2SO4. Removal of the solvent afforded the title compound in 68% yield (0.200 g). 1H NMR (300 MHz, CDCl3) δ 8.85, 7.97, 7.74, 7.63, 7.56, 7.49, 7.36, 4.05-4.00, 3.89-3.82, 3.78-3.73, 3.70-3.61, 3.44-3.40, 3.33-3.31, 2.16, 1.63-1.58, 1.37-0.134.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([N:11]3[C:19](=O)[C:18]4[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=4[NH:12]3)=[C:9]([F:21])[CH:8]=[C:7]([Cl:22])[C:5]=2[N:6]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:19]1[N:11]([C:10]2[C:4]3[S:3][C:2]([Cl:1])=[N:6][C:5]=3[C:7]([Cl:22])=[CH:8][C:9]=2[F:21])[N:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=c1c2c([nH]n1-c1c(F)cc(Cl)c3nc(Cl)sc13)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(Cl)c2nc(Cl)sc2c1-n1nc2c(c1Cl)CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.2 g 2-(2,4-Dichloro-6-fluorobenzothiazol-7-yl)1,3,4,5,6,7-hexahydro-2H-indazol-3-one was treated with 2 ml phosphorus oxychloride and the mixture stirred for one hour under reflux. After cooling, it was poured into ice-water, extracted with ethyl acetate and the organic phase washed with sodium hydrogen carbonate and water. It was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography. Yield: 0.07 g=32% of theory m.p.: 161°-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2].[CH2:14]=O.[OH-].[Na+]>[OH-].[Na+].C(O)(=O)C>[C:9]([O:8][C:6](=[O:7])[C:5](=[CH2:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=O
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=C(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
This compound employed as the starting material in example 7 is prepared as follows: 10% NaOH (2 drops) is added to malonic acid tert-butyl ethyl ester (20 g). Aqueous 40% formaldehyde (15 ml) is then added very slowly thereto while keeping the temperature of the reaction mixture ≤5° C. and the pH at about 8.5 by means of 10% NaOH. The reaction mixture is then stirred at room temperature for 24 hours. The resulting reaction mixture is acidified by the addition of few drops of glacial acetic acid and charged, together with Cu(CH3COO)2, into a suitable distilling apparatus.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:22])=[C:4]([C:8]([I:21])=[C:9]([C:12](=[O:20])[N:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH:15]=[CH2:16])[C:10]=1[I:11])[C:5]([Cl:7])=[O:6].[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl>[Cl:7][C:5]([C:4]1[C:3]([I:22])=[C:2]([NH:1][C:28]([CH2:27][O:26][C:23](=[O:25])[CH3:24])=[O:29])[C:10]([I:11])=[C:9]([C:12](=[O:20])[N:13]([CH2:14][CH:15]=[CH2:16])[CH2:17][CH:18]=[CH2:19])[C:8]=1[I:21])=[O:6]
Reactant: CC(=O)OCC(=O)Cl
Reactant: C=CCN(CC=C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 40 °C

Procedure:
The mono-diallylamide (9) (6.56 g, 10 mmol) was dissolved in anhydrous DCM (10 ml), and stirred. The acetoxy acetyl chloride (2.1 ml, 20 mmol) was added to the solution, and heated to 40° C. for 3 days. The solvent was removed at reduced pressure and the reaction mixture was absorbed onto silica gel. The crude mixture was separated by silica gel chromatography 10% EtOAc/Petrol=>100% EtOAc over 11 CVs. The main peak was collected, concentrated at reduced pressure and analysed by both LCMS (m/z 756.83 (+ve) and NMR. This indicated the desired material had been made in good purity. The yield was 6.5 g (86%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].O.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CO)cc1
Yield: 51.1 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51%). The purity of the product was 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])Nc1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,6-Dichloro-4-amino pyridine (1.58 g) was taken up in sulfuric acid (20 mL) at 0° C. under a nitrogen atmosphere and nitric acid (2.5 mL) added dropwise. After 30 mins, the reaction turned to an orange colour and was poured slowly into ice water. The precipitate was filtered, washed with water and then dissolved in ethyl acetate. The organic solution was then dried over MgSO4, filtered and evaporated in vacuo to give the title compound (1.7 g) as a yellow solid.