Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([C:16](=[O:28])[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[NH:27])[NH2:26])[CH2:21][CH2:20]1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>>[ClH:1].[NH2:8][C@@H:9]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:16]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[NH:26])[NH2:27])[CH2:21][CH2:20]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)N1CCC(CNC(=O)[C@@H](N)C2CCCCC2)CC1
Yield: 96.2 %

Procedure:
{[(1-Carbamimidoyl-piperidine-4-ylmethyl)-carbamoyl]-(S)-cyclohexyl-methyl}-carbamic acid tert butyl ester hydrochloric acid salt (3.64 g crude material) was stirred with aqueous trifluoroacetic acid (90%) at room temperature for 20 hours, evaporated, dissolved in aqueous hydrochloric acid and lyophilized to yield 2.69 g (89%) of the desired product, MS m/z: 296 (M+H)+, 148 (M+2H)2+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:25])[C:14]2[C:19]([O:20]C)=[CH:18][C:17]([O:22]C)=[CH:16][C:15]=2[Cl:24])=[O:10])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:25])[C:14]2[C:19]([OH:20])=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2[Cl:24])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cl)c(C(=O)NNC(=O)Cc2cccc(O)c2)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cc1cccc(O)c1)NNC(=O)c1c(O)cc(O)cc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
5.2 9 g of “69a” are suspended in 30 ml of dichloromethane. 40 ml of BBr3 are added dropwise with ice-cooling. After 48 hours at room temperature, 200 ml of ice-water are stirred in. The mixture is subjected to conventional work-up, separated over silica gel by means of a CombiFlash COMPANION instrument and crystallised from diethyl ether, giving 3.3 g of N′-[2-(3-hydroxyphenyl)acetyl]-2-chloro-4,6-dihydroxybenzohydrazide (“70”), m.p. 217°
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C>[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: [H][H]
Solvent: CCO
Product: NC1CCCC(C(=O)O)C1
Reaction time: 192 h
Yield: 57.2 %

Procedure:
A mixture of 3-aminobenzoic acid (66.12 g, 0.48 mol) and 10% palladiumon-carbon (13.2 g) in 30% aqueous ethanol (1200 mL) was placed in a 4 L stainless steel high-pressure reactor and reduced at 50° C. and 500 psi of hydrogen for 30 h. The mixture was filtered through Celite and the filter cake was washed with ethanol. The solvent was evaporated, boiling ethanol (1 L) was added and the mixture was allowed to stand for 8 days at room temperature. The mixture was filtered and the product was washed with ethanol and then dried in a vacuum oven at 50° C., to give 3-aminocyclohexanecarboxylic acid (39.30 g, 57%) as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (200 mg), benzyl bromide (144 mg) and potassium carbonate (155 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hour. Then the mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-benzyl-4-(3-benzyloxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (206 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:3][CH2:2][CH2:1][OH:4])=[CH:10][CH:9]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 1-Bromo-4-(bromomethyl)benzene (370 mg, 1.5 mmol) was added to the reaction, and the residual 1-bromo-4-(bromomethyl)benzene was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (139 mg, 40%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [Br:1]C1CC(=O)NC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:14]=[N:15][CH:16]=1>C(#N)C>[Br:1][C:16]1[N:15]=[CH:14][C:13]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:10][CH3:9]
Reactant: COc1cncc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C1CC(Br)C(=O)N1
Solvent: CC#N
Product: COc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cnc1Br
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Bromosuccinimide (3.56 g, 20.0 mmol) was added to a mixture of 1-(5-methoxy-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (6.14 g, 20.0 mmol) and acetonitrile (200 ml) at room-temperature and stirred for 20 minutes. The mixture was evaporated and purified by chromatography on silica gel with ethyl acetate and petroleum (1:1) as solvent and gave 4.4 g, 57% of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:20]
Reactant: CCI
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a suspension of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine (7.0 g, 13.84 mmol) and powdered sodium bicarbonate (5.88 g, 70 mmol) in DMF (100 mL) was added excess of iodoethane (10.91 g, 70 mmol) at room temperature. The resulting suspension was stirred for 20 h at which time TLC analysis of the mixture indicated the absence of staring material and the excess iodoethane and some DMF was removed on a rotary evaporator under vacuum. The remaining residue was diluted with 150 mL of ethyl acetate and washed successively with water (2×100 mL), brine solution (100 mL) and dried over MgSO4. Filtration of the drying agent and removal of the solvent afforded a white solid which was crystallized from acetonitrile. The resulting crystalline solid was collected by filtration and dried under high vacuum to afford 5.58 g (77%) of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine ethyl ester as a white solid. mp 230-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.[NH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22](Cl)[N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[N:21]=1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Product: COC(=O)c1cc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)nc(N)n1

Procedure:
Analogously to example 53, the title compound is synthesized from 1.01 g (4.05 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) and 0.84 g (4.06 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])[C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(c2cnc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
3-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-azetidine-1-carboxylic acid tert-butyl ester (56 mg, 0.2 mmol) was dissolved in DMA (2 ml) and cooled to 0° C. Sodium hydride (16 mg, 0.37 mmol, 55%) was added, and the reaction mixture was stirred for 30 minutes at 0° C. Benzenesulfonyl chloride (40 μl, 0.29 mmol) was added slowly to the reaction mixture. Stirring was continued for 3 hours. Water and ethyl acetate was added to the reaction mixture. The organic phase was extract three times with water. The organic phase was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate:cylcohexane) to afford the title compound (10 mg, 12% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1cccc(C)c1N
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-n1cccc1

Procedure:
A solution of 2,6-dimethylaniline (60.5 g), glacial acetic acid (600 ml) and 2,5-dimethoxytetrahydrofuran (572 g) is refluxed for 5 hours. The solvent is evaporated at 60° and reduced pressure to give 1-(2,6-dimethylphenyl)-1H-pyrrole as an oil.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:39]=[O:40])[CH2:26][CH2:27][C:28](=NNC(N)=O)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:41])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[O:43].Cl>CO>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:39]=[O:40])[CH2:26][CH2:27][C:28]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:43])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:41])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)=NNC(N)=O
Reactant: C=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CCC(C=O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of semicarbazone 233e (390 mg, 0.68 mmol) in methanol (10 ml) was cooled at 0° C. and then treated with a 38% aq. solution of formaldehyde (2 ml) and 1M HCl (2 ml). The reaction mixture was then stirred overnight at room temperature. The solution was concentrated to remove the methanol. The aq. solution was extracted with EtOAc (30 ml). The organic solution was successively washed with 10% NaHCO3 (30 ml) and sat. aq. NaCl (30 ml), dried (MgSO4) and concentrated. Purification by flash chromatography or silica gel (2-5% methanol in CH2Cl2) afforded 234e (179 mg, 51% as a white foam: [α]D20 −101° (c 0.064, MeOH; IR (KBr)3346, 2976, 2934, 1730, 1657, 1535, 1456, 1425, 1278, 1255, 1156, 708; 1H NMR (CDCl3) δ9.56 (1H, s), 7.88-7.38 (5H, m), 7.01 and 6.92 (2H, 2d) 5.27-5.08 (2H, m), 4.69-4.46 (1H, m), 3.50-3.27 (2H, m), 3.15-2.73 (2H, m), 2.46-1.83 (10H, m), 1.43 (9H, s).
Reaction SMILES: CN(C(ON1N=NC2C=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:36]=[C:37]([O:47][C:48]3[N:49]=[CH:50][C:51]([C:54]([OH:56])=O)=[N:52][CH:53]=3)[CH:38]=[C:39]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:40]=2)=[O:34])=[N:28]1)[CH3:26].Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:15]1([C:54]([C:51]2[N:52]=[CH:53][C:48]([O:47][C:37]3[CH:36]=[C:35]([CH:40]=[C:39]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:38]=3)[C:33]([NH:32][C:29]3[CH:30]=[CH:31][N:27]([CH2:25][CH3:26])[N:28]=3)=[O:34])=[N:49][CH:50]=2)=[O:56])[CH2:14][CH2:13][CH2:10]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)cn3)cc(O[C@@H](C)COC)c2)n1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@@H](C)COC)c2)n1
Reaction time: 16 h
Yield: 51 %

Procedure:
HATU (304 mg, 0.80 mmol) was added to 5-[(3-{[(1-ethyl-1H-pyrazol-3-yl)amino]carbonyl}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)oxy]pyrazine-2-carboxylic acid (0.4 mmol) and azetidine hydrochloride (75 mg, 0.89 mmol) in DMF (5 mL) followed by addition of DIPEA (0.278 mL, 1.6 mmol) and the reaction was stirred for 16 hours. The reaction mixture was added to ethyl acetate (20 mL), the organic solution washed with water (10 mL), 2N citric acid (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL), then dried (MgSO4), filtered and evaporated under reduced pressure to a gum. The residue was purified by chromatography on silica, eluting with 70-100% ethyl acetate in hexane, to give the desired compound as a white foam (98 mg). 1H NMR δ (CDCl3): 1.27 (d, 3H), 1.40 (t, 3H), 2.31 (quin, 2H), 3.34 (s, 3H), 3.43-3.54 (m, 2H), 4.01 (q, 2H), 4.19 (t, 2H), 4.54 (q, 1H), 4.62 (t, 2H), 6.73 (d, 1H), 6.87 (t, 1H), 7.18 (t, 1H), 7.27 (d, 1H), 7.30 (t, 1H), 8.26 (d, 1H), 8.49 (s, 1H), 8.78 (d, 1H); m/z 481 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)([O-:21])=[O:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and 3-nitrobenzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a red solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].Br[CH:16]=[C:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[CH2:21][CH2:20][C:19]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:18]1=2>>[F:28][C:27]1[C:22]2[CH2:21][CH2:20][C:19]3[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:18]=3[C:17](=[CH:16][C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: Fc1cccc2c1CCc1c(F)cccc1C2=CBr
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3cccc(F)c3CCc3c(F)cccc32)c1
Yield: 134.3 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-methanesulfonamidophenyl boronic acid (592 mg, 2.75 mmol) and 5-bromomethylene-1,9-difluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (803 mg, 2.75 mmol), provides 1.52 g of the title compound crude product. The crude product is purified using column chromatography (15% EtOAc/hexane to 30% EtOAc/hexane) to give 690 mg (67%) white solid. MS (ES) 410 (M−1). HPLC (ISO90-10M) shows 92% purity at t=2.64 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc2ccc(Cl)cc2c1Cl
Product: ClCc1cnc2ccc(Cl)cc2c1Cl
Reaction time: 24 h

Procedure:
11.4 g. of 4,6-dichloroquinoline-3-methanol (0.05 mol.) are added in portions to 150 ml. of thionyl chloride. The reaction mixture is allowed to stand for 24 hours at room temperature. Then the solution is filtered and the excess thionyl chloride removed by a rotary evaporator. The residue is triturated with water, filtered off, washed again with water and dried in a desiccator over P2O5 to obtain 3-chloromethyl-4,6-dichloroquinoline; yield: 11.5 g. (93.5%); m.p. 102°-105°. Recrystallization from cyclohexane does not change the melting point.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:13]([N:20]1[CH2:25][C@H:24]([CH2:26][CH3:27])[NH:23][CH2:22][C@H:21]1[CH3:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:22][C@@H:21]([CH3:28])[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:25][C@@H:24]1[CH2:26][CH3:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Benzyl bromoacetate (2.6 mL, 16 mmol) was added to a solution of (2R,5S)-1-benzyl-5-ethyl-2-methyl-piperazine (3.5 g, 16 mmol) in acetonitrile (20 mL) containing K2CO3 (2.4 g, 17.6 mmol). The reaction mixture was stirred at ambient temperature overnight. The suspension was diluted with CHCl3 and the solid was filtered off. Filtrate was evaporated in vacuo and the residue was purified by SiO2 chromatography (EtOAc:petrol 4:6) to give ((2S,5R)-4-benzyl-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid benzyl ester (3.4 g) as a pale yellow oil. 1H NMR (CDCl3): 7.46-7.14 (10H, m), 5.18 (2H, d), 4.10 (1H, d), 3.49 (1H, d), 3.32 (1H, d), 3.17 (1H, d), 2.91-2.79 (1H, m), 2.73 (1H, dd), 2.60-2.42 (3H, m), 2.01-1.79 (1H, m), 1.60-1.44 (1H, m), 1.41-1.23 (1H, m), 1.14 (3H, d), 0.77 (3H, t).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].[OH-].[K+].Cl.[C:29]([O-])([O-])=O.[K+].[K+].C(I)C>CN(C=O)C.O>[F:25][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH2:24][CH3:29])=[O:22]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OC)c1NC(C)C
Yield: 775.4 %

Procedure:
A mixture of 4.1 g (0.001 mol) of product of Example 76, 0.62 g (0.011 mol) of KOH and 5 ml of H2O overnight. The reaction mixture was poured into 250 ml of H2O containing 50 ml of concentrated HCl, extracted with ether, dried (mgSO4) and concentrated in vacuo to 3.76 g of yellow air. This oil, 152 g (0.011 mol) of K2CO3 and 0.88 ml (0.011 mol) of ethyl iodide in 30 ml of DMF was stirred at room temperature overnight. The reaction mixture was poured into water extracted with ether, drid (MgSO4) and concentrated in vacuo to 3.64 g of yellow oil. Kugelrohr distillation at 53 Pa, pot temperature 103° C., afforded 2.98 g (70.5%) of product sa a light yellow oil which solidified; mp 37°-39° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 62.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (104 mg, 0.22 mmol), 3-tributylstannanyl-pyridine (0.11 mL, 0.34 mmol) and PdCl2(PPh3)2 (31 mg, 0.045 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (20-100% EtOAc/hexanes+2% AcOH) to give 64 mg of the title compound. MS: (+) m/z 464.15 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:23])[NH:18][CH2:19][CH2:20][O:21][CH3:22])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[NH2:23][C:17](=[N:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][NH:3][C:33](=[O:34])[CH2:32][NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[CH:6]=2)[N:12]=1)[NH:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CN)c2)cs1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CNC(=O)OC(C)(C)C)c2)cs1
Reaction time: 7 h
Yield: 34.6 %

Procedure:
A suspension of 4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethylamino)methylene]amino]thiazole dihydrochloride (3.9 g), N-(t-butoxycarbonyl)glycine (1.85 g), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (2.6 g) and triethylamine (2.3 g) in N,N-dimethylformamide (50 ml) was stirred for 7 hours with cooling on an ice bath. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of water (80 ml) and tetrahydrofuran (20 ml), and the mixture was alkalized with 30% aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (200 ml) and the extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1) to afford 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-t-butoxycarbonylaminoacetylaminomethylphenyl)thiazole (1.65 g).