Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14].[Cl-].[OH:23][NH3+:24].Cl>CO>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:24]\[OH:23])/[C:13]([O:15][CH3:16])=[O:14]
Reactant: [NH3+]O
Reactant: COC(=O)C(=O)c1ccccc1COc1ccccc1C
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)/C(=N/O)c1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
56.8 g (0.2 mol) of methyl 2-(2-methylphenoxymethyl)phenylglyoxylate and 15.2 g (0.22 mol) of hydroxylammonium chloride in 67.5 ml of methanol are refluxed for 6.5 hours. The resulting mixture (of E- and Z-oximes) is cooled to 0° C. and 14.2 g (0.39 mol) of hydrogen chloride are passed in, and the mixture is then stirred at 25° C. for 5 hours. The solvent is removed by distillation under reduced pressure, the residue is taken up in diethyl ether, and the solution is washed with water, dried over sodium sulfate and evaporated to dryness. 55.3 g of solid E isomer (melting point 115° C.) are obtained.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[C:12]([O:13][Si](C)(C)C)=[C:11]([C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH:10]=[CH:9][C:8]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.[H-].[Na+].[O:36]=[C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=2)[CH:45]=[O:46])[NH:38]1>O1CCCC1>[C:18]([C:11]1[CH:10]=[CH:9][C:8]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:45]([OH:46])[C:44]3[CH:43]=[C:42]([C:39]4[NH:38][C:37](=[O:36])[O:41][N:40]=4)[CH:49]=[CH:48][CH:47]=3)=[CH:29][CH:28]=2)=[C:7]([Cl:6])[C:12]=1[OH:13])(=[O:20])[CH3:19]
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(Cl)c1O[Si](C)(C)C
Reactant: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4noc(=O)[nH]4)c3)cc2)c(Cl)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 1.01 ml, 2.02 mmol) to a solution of 2-chloro-1-(4-iodo-benzyloxy)-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (1.00 g, 1.83 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15 minutes, warm to room temperature. After 1 hour, cool to −78° C. Add sodium hydride (60% dispersion, 80 mg, 2.01 mmol) to a solution of 3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (348 mg, 1.83 mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes, then add it via syringe to the gringard reagent. After 30 minutes, warm the reaction to room temperature. Quench with 10% aq hydrochloric acid. Pour the reaction into brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine the organic layers, dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with 5% methanol:methylene chloride to yield the title product as a off white solid (389 mg, 46%): 1H NMR (DMSO-d6) δ 2.61 (s, 3H), 5.31 (s, 2H), 5.80 (d, 1H), 6.12 (d, 1H), 6.87 (d, 1H), 7.43 (m, 4H), 7.51 (t, 1H), 7.64 (tt, 2H), 7.90 (t, 1H), 7.91 (d, 1H), 12.96 (bs, 1H), 13.12 (s, 1H); MS (esi negative) m/z (rel intensity) 465 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C

Procedure:
To 31 g of 2,6-dichlorophenol in 120 ml acetic acid cooled in an ice bath is added over 5 minutes 50 ml of 70% nitric acid. After stirring an hour at room temperature, the mixture is purged with nitrogen, then poured into water, filtered; the product is washed with water and dried in vacuo to give 2,6-dichloro-4-nitrophenol. NMR (CD3OD): δ8.2(s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=O)[CH2:32]Br)=[CH:29][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:32]=[C:31]([C:30]3[CH:35]=[CH:36][C:27]([Cl:26])=[CH:28][CH:29]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2)cc1
Yield: 54.9 %

Procedure:
To a mixture of 4-chloro-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 4-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80–85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2,4-bis-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (545 mg, 55%) as a pale yellow solid: mp 169–171° C. Anal. Calc'd. for C22H16N2SO2Cl2: C, 59.60; H, 3.64; N, 6.32; S, 7.23. Found: C, 59.86; H, 3.80; N, 6.10; S, 7.27.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8]=1[O:25][CH3:26])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8]=1[O:25][CH3:26]
Reactant: [H][H]
Reactant: CCCCCCCCC(=O)NCc1ccc(Oc2ccccc2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(=O)NCc1ccc(Oc2ccccc2N)c(OC)c1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
N-(4-(2-nitrophenoxy)-3-methoxyphenylmethyl)nonanamide (1.23 g) is dissolved in methanol (50 mL). To this is added 10% palladium on charcoal (100.1 mg). The mixture is placed on a Paar shaker for 60 minutes at room temperature and 42 psi hydrogen. The mixture is filtered through celite, evaporated to dryness on a rotary evaporator, then dried overnight at room temperature and reduced pressure (0.5 mm Hg) to yield N-(4-(2-aminophenoxy)-3-methoxyphenylmethyl)nonanamide (1.11 g, 97%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(O)(C(F)(F)F)=O.[CH2:20]([N:27]([CH2:33]O)[CH2:28][Si](C)(C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([N:27]1[CH2:33][C@@H:4]([CH2:3][C:2]([F:11])([F:12])[F:1])[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[Si](C)(C)CN(CO)Cc1ccccc1
Reactant: CCOC(=O)/C=C/CC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1CC(F)(F)F
Yield: 98 %

Procedure:
To a stirred solution of ethyl (2E)-5,5,5-trifluoropent-2-enoate (3.0 g, 16.5 mmol) and TFA (0.38 g, 3.3 mmol) in DCM (40 mL) was added dropwise {benzyl[(trimethylsilyl)methyl]amino}methanol (7.8 g, 33 mmol) at 0° C. over a period of 30 min. After the addition, the mixture was refluxed overnight. TLC (petroleum ether:EtOAc 10:1) indicated ethyl (2E)-5,5,5-trifluoropent-2-enoate was consumed. The reaction mixture was washed with sat. NaHCO3 (40 mL), brine (40 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether:EtOAc=100:1 to 10:1) to give the title compound (5.1 g, 98% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1cncc(-c2ccc(C#N)c(Cl)c2)c1
Yield: 46.6 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1.1 eq) in anhydrous pyridine (500 μl) was added propane-1-sulfonyl chloride (10.8 μl, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)propane-1-sulfonamide (13.6 mg, >95% purity, yield: 46.5%).
Reaction SMILES: [N:1]1([CH2:6][C:7](=[O:18])[CH2:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[Na]>CO>[N:1]1([CH2:6][CH:7]([OH:18])[CH2:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cn1ccnc1)CS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Product: O=S(=O)(CC(O)Cn1ccnc1)c1ccccc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred mixture of 10 g (0.0377 mole) 1-(1-imidazolyl)-3-phenylsulfonylpropan-2-one (the product of Example 11) in 50 ml methanol cooled in an ice-water bath, 0.9 g (0.0237 mole) sodium borhydride, was added in 5 portions. The reaction mixture became viscous, and methanol (100 ml) was added. The reaction mixture was allowed to come to room temperature and to stir for about 11/2 hours. The reaction mixture was cooled in an ice-water bath and the product removed by filtration. The precipiate was dried under vacuum to give 8.9 g of the above-identified product as an off-white solid, melting point 153°-156° C.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO.O>[OH:2][CH2:1][C:3]12[CH2:17][CH:10]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=31)[C:11]1[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9-formyl-9,10-dihydro-9,10-methanoanthracene (200 mg) and sodium borohydride (60 mg) in methanol (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]([O:23][CH2:24][CH3:25])=[CH2:22])CCC.[F-].[K+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[CH2:22])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Yield: 50.3 %

Procedure:
A degased solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (7 g, 26.82 mmol), tributyl(1-ethoxyvinyl)stannane (9.51 mL, 28.16 mmol) and bis(triphenylphosphine)-palladium chloride (0.376 g, 0.54 mmol) in dimethylformamide (200 mL) was heated under argon at 100° C. for 1.5 h. The mixture was poured into a solution of potassium fluoride (20 g) in water 250 mL, and the mixture was extracted with MTBE (300 mL). The organic phase was washed with water, dried over sodium sulfate, and filtered through a pad of silica gel. The residue was crystallised from heptane (50 mL) to yield the title compound (4.0 g). The mother liquor was concentrated in vacuum and purified by column chromatography on silica gel, using a gradient of 0-15% ethyl acetate in heptane as eluent to yield additional amount of the title compound (2.9 g), total yield being 6.45 g (81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1>C(NCC)C.CC(=O)OCC>[Cl:9][C:4]1[N:3]=[C:2]([N:3]([CH2:4][CH3:5])[CH2:2][CH3:7])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(C)cc(Cl)n1
Yield: 104.3 %

Procedure:
In a sealed vial, a solution of 2,6-dichloro-4-picoline (1.80 g, 11.1 mmol) in diethylamine (5 mL) is heated to 135° C. for 40 h in a microwave oven. The pressure in the vial reaches 6.5 bar. The mixture is diluted with EA (200 mL) and washed with 1 N KHSO4, solution. The washings are extracted back with EA (100 mL) and the combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 95:5 to give (6-chloro-4-methyl-pyridin-2-yl)-diethyl-amine (1.15 g) as a colourless solid; LC-MS: tR=1.05 min, [M+1]+=198.97.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:49]([O:53][C:54]([N:56]1[CH2:61][CH2:60][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[C:64]([O:69][CH3:70])[CH:63]=2)[CH2:58][CH2:57]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[CH2:57][CH2:58][CH:59]([C:62]2[CH:67]=[CH:66][C:65]([NH:68][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:10]=5)[N:23]4[N:22]=3)=[C:64]([O:69][CH3:70])[CH:63]=2)[CH2:60][CH2:61]1)=[O:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (120 mg, 0.3464 mmol) and N,N-Diisopropylethylamine (0.242 mL, 1.39 mmol) in 3.0 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (136 mg, 0.381 mmol). After stirring at room temperature for 30 minutes, 4-(4-Amino-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.460 mmol) was added. The reaction mixture was heated at 65° C. for 2.5 days. The reaction mixture was purified via silica gel column chromatography using 100:1 DCM:MeOH as the eluant. The collected fractions afforded impure 4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperidine-1-carboxylic acid tert-butyl ester as a sticky brown solid.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(OC)=[O:2].[Cl-].[Mg+2].[Cl-].[CH3:22][Mg]Br.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:2])[CH3:22]
Reactant: C[Mg]Br
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
In 7 ml of THF, was dissolved 295 mg of 2-carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane. After addition of 138 mg of anhydrous magnesium chloride, the mixture was refluxed for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution of 1.36 equivalents of methylmagnesium bromide. After having been stirred for 15 minutes at -70° C., the reaction mixture was admixed with saturated aqueous ammonium chloride solution and ether and brought to room temperature. The mixture was extracted with ether and the ether layer was dried. The ether layer was freed from the solvent by distillation in vacuo and the residue was purified by alumina column chromatography to obtain 199 mg (72%) of 2-acetyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ (ppm)=1.5-2.2 (4H, multiplet), 1.9 (3H, singlet), 2.4-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.1 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:8])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1Oc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)c(F)cc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,5-difluoro-2-(4-fluorophenoxy)benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate (step 3 of Example 5): MS (ESI) m/z 430 (M+H)+, 428 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([OH:23])=O)[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2.C([O:29][CH2:30][CH2:31][O:32][NH2:33])(C)(C)C.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([NH:33][O:32][CH2:31][CH2:30][OH:29])=[O:23])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OCCON
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c(F)c(=O)n2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
7-Fluoro-8-(2-fluoro-4-iodophenylamino)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7e, 216 mg, 0.48 mmol, 1 eq), O-(2-tert-butoxyethyl)hydroxylamine (129 mg, 0.97 mmol, 2 eq) and N-hydroxybenzotriazole (82 mg, 0.53 mmol, 1.1 eq) were stirred in DCM (12 ml) and DMF (1.5 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (111 mg, 0.58 mmol, 1.2 eq) and triethylamine (101 μl, 0.73 mmol, 1.5 eq) were added and the solution stirred at RT for 16 hours. After washing with 0.1N HCl (30 ml) then brine (30 ml) the organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in TFA and stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by HPLC to give the title compound as a white solid (58 mg, 24%). 1H NMR (400 MHz, MeOD) δ ppm 1.75-1.90 (m, 2H) 1.90-2.01 (m, 2H) 2.76-2.90 (m, 2H) 3.14 (d, J=3.28 Hz, 2H) 3.49 (d, J=3.28 Hz, 1H) 3.68-3.77 (m, 1H) 3.89 (t, J=4.29 Hz, 2H) 3.99-4.10 (m, 2H) 5.50 (s, 1H) 6.83-6.95 (m, 1H) 7.39-7.52 (m, 2H) [M+H] calc'd for C18H18F2IN3O4, 506. found, 506.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[Cl:15][C:16]1[C:17]([F:25])=[CH:18][C:19](I)=[C:20]([O:22][CH3:23])[CH:21]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:19]2[CH:18]=[C:17]([F:25])[C:16]([Cl:15])=[CH:21][C:20]=2[O:22][CH3:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: COc1cc(Cl)c(F)cc1I
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: COc1cc(Cl)c(F)cc1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 5-chloro-4-fluoro-2-iodoanisole (prepared as described in Step A above) using the procedure described in Example 7. HRMS, observed: 312.9943, Calcd for (M−H)+: 312.9947.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 100 ml-three-necked flask, 3.04 g (24.9 mmole) of phenylboronic acid (made by Tokyo Kasei), 4.0 g of (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.20 g (yield=43.0%) of 1-phenylisoquinoline. FIG. 7 shows a 1H-NMR spectrum of a solution of the compound in heavy chloroform.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([O:6][CH2:5][C:4]([CH3:3])=[CH2:7])[N:12]=[CH:11][N:10]=1
Reactant: C=C(C)CO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)COc1cc(Cl)ncn1
Reaction time: 0.17 h
Yield: 310 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 0.322 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.16 g of 2-methyl-2-propenol in tetrahydrofuran was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 1 g of 4,6-dichloropyrimidine in tetrahydrofuran, followed by stirring at the same temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.27 g of 4-chloro-6-(2-methylallyloxy)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[CH2:5]2.[C:16]([O:19][C:20](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/[O:19][CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1Br)CC(=O)NC2=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21

Procedure:
A mixture of 6-Bromo-7-methoxy-4H-isoquinoline-1,3-dione (275 mg, 1.02 mmole), 7 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (0.8 mL, 7.28 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the solid collected with ether. A brown solid, 202 mg, (63%), mp 245-248° C. dec, MS (ESI): m/z 310.1, 312.1 (M−H).