Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: C[C@@H]1CNCCN1c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: C[C@@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(R)-methyl-piperazine (0.2 g, 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 mL, 0.94 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)C=C(c2cccnc2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccnc2)c2cc(C#N)ccc2O1
Yield: 43 %

Procedure:
2.1 g of 2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were dissolved in 50 ml of ethyl acetate and shaken at room temperature under a hydrogen atmosphere with 50 mg of 10% palladium-on-charcoal for a total of 30 hours with several changes of catalyst The mixture was filtered and the filtrate was evaporated The residue was chromatographed on silica gel using ethyl acetate for the elution. 910 mg of 3,4-dihydro-2,2-dimethyl-4-(3-pyridyl)-2H-1-benzopyran-6-carbonitrile were obtained in the form of an oil.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13](NC(=O)NCC(N2C(C3C=CC=CC=3)CCC2(C)C(OC(C)(C)C)=O)=O)[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:9]([OH:10])(=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1(C)CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1

Procedure:
A The reaction is carried out in a way similar to that described in Example 1A but starting from 0.54 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-2-methyl-5-phenyl-pyrrolidine-2-carboxylate and 0.15 g of 10% palladium-on-charcoal in 30 cm3 of ethyl acetate. After treatment, there is obtained 0.25 g of (2RS,5SR)-3-3-2-(2-tert-butoxycarbonyl-2-methyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid melting at 150° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[NH:32][N:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[N:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[NH:32][N:33]=[C:34]([C:36]([F:38])([F:39])[F:37])[N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1nc(C(F)(F)F)n[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C(F)(F)F)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 15 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (5-trifluoromethyl-2H-[1,2,4]triazol-3-yl)-acetic acid methyl ester with heating for 5 days to afford the title compound as tan solid (24 mg, 15%). LC/MS (Method B) 3.94 min, [M+1]+ 530.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[NH:5][C:4](=[O:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)[N:5]([CH3:26])[C:4](=[O:25])[CH:3]=1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1,2-dihydroquinolin-2-one (370 mg, 0.86 mmol, 1.00 equip), potassium carbonate (355 mg, 2.57 mmol, 3.00 equip), and N,N-dimethylformamide (10 mL). To the resulting mixture was then added CH3I (182 mg, 1.28 mmol, 1.50 equip) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 447 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][OH:17])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CO>N1C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 3 h
Yield: 77.1 %

Procedure:
A solution of 2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (6.34 g, 27.1 mmol) dissolved in 25 mL of pyridine was treated with tert-butyldimethylsilyl chloride (4.50 g, 29.8 mmol) and N,N-dimethylaminopyridine (331 mg, 2.71 mmol) and the mixture was stirred under N2. After 3 hours, the reaction mixture was treated with 10 mL of methanol and then concentrated to give a yellow solid. The resulting solid was dissolved in 100 mL of ethyl acetate and washed with H2O (3×50 mL) and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow powder. Crystallization from 50 mL of 1:1 hexane/ethyl acetate gave 7.28 g of N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1OC

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3,4-Dimethoxybenzene boronic acid. MS (M+H) 413.2
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=1>>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([C:22]([F:23])([F:24])[F:25])[CH:14]=1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(Cl)cc1C(F)(F)F

Procedure:
The title compound, yellow oil, MS: m/e=361.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-chloro-2-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18](F)[N:17]=1>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([O:8][C:18]1[N:17]=[C:16]([Br:15])[C:21]([Cl:22])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cl)c(Br)n1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(OCc2ccccc2)nc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl alcohol (55.5 mg, 0.513 mmol) in tetrahydrofuran (5 mL) at 0° C. was added potassium tert-butoxide (57.6 mg, 0.513 mmol) and the mixture was stirred at 0° C. for 2 hours. The mixture was cooled to −78° C. and a solution of 2-bromo-3-chloro-6-fluoropyridine (120 mg, 0.570 mmol) in 2 mL tetrahydrofuran was added. After stirring at −78° C. for 1 hour the mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound. LCMS: 299.9 (M+3)+.
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[CH:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12]2)=[CH:8][CH:7]=1.BrB(Br)Br>ClCCl>[OH:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[C:34](=[O:35])[C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=[CH:26]5)[C:20]=4[CH3:36])=[CH:17][N:16]=[C:15]([C:37]([NH2:39])=[O:38])[C:11]=3[NH:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCO)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
To a solution of 7-(2-methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (101 mg, 0.194 mmol) in dichloromethane (5 mL) at 0° C. was added tribromoborane in dichloromethane (0.622 mL, 0.622 mmol) over 5 min. The resulting heterogeneous mixture was stirred at room temperature for 1.5 hr. The reaction was quenched with ice water (15 mL). The mixture was basified with 1 N NaOH solution to pH 10 and extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (44.0 mg, 0.084 mmol, 43.3% yield) as a yellow solid. The product is mixture of two atropisomers at rt. LCMS (M+H)+=506.23. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.67 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.37 (s, 1H), 4.07 (m, 2H), 3.78 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])O.[Na+].C([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](C(O)=O)[CH2:27][CH2:26]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O.C1C=NC2N(O)N=NC=2C=1>[ClH:1].[ClH:1].[CH:3]1([N:7]2[CH2:12][CH2:11][N:10]([C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N1CCCCC1)N1CCN(C2CCC2)CC1
Yield: 127.1 %

Procedure:
1-Cyclobutyl-piperazine di-hydrochloride (D6)(1.8 g) in DMF (15 ml) was stirred with sodium hydrogen carbonate (1.53 g) for 5 min before being added to a DMF (15 ml) solution of 1-tert-butoxycarbonyl-piperidine-4-carboxylic acid (1.94 g), EDCl (3.2 g) and HOAT (0.05 g). After 4 h the reaction was diluted with EtOAc and washed with saturated sodium hydrogen carbonate solution and brine (3×), before being evaporated. The residue was dissolved in a small volume of EtOAc and treated with TFA (90% TFA/water). After 2 h toluene was added and the reaction evaporated and re-evaporated from toluene. The residue was taken up into EtOAc and treated with 2N HCl in diethyl ether. The precipitate was filtered, washed with diethyl ether and dried under vacuum. Crystallisation from ethanol/diethyl ether afforded the title compound (D7)(1.74 g). LCMS electrospray (+ve) 252(MH+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C.O>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][N:3]1[C@@H:2]([CH3:1])[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4]1=[O:17]
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1ccc(F)cc1Cl
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of Example 77 (40 mg, 0.17 mmol) in DMF (1.7 mL) was added cesium carbonate (226 mg, 0.70 mmol) and 2-chloro-4-fluorobenzyl bromide (58 mg, 0.26 mmol) and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-20% iPrOH in EtOAc) to provide the desired compound (41 mg, 65%). MS (ESI): mass calcd. for C17H14ClFN6O, 372.8; m/z found, 373.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.47 (d, J=1.3 Hz, 1H), 8.84-8.80 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7.26-7.19 (m, 1H), 5.10 (d, J=15.9 Hz, 1H), 5.01-4.89 (m, 1H), 4.70 (dd, J=13.9, 4.6 Hz, 1H), 4.48 (d, J=16.0 Hz, 1H), 4.13-4.03 (m, 1H), 1.18 (d, J=6.7 Hz, 3H).
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]([C:21]2[N:22]=[C:23](N)[C:24]3[N:29]=[N:28][NH:27][C:25]=3[N:26]=2)=[N:13]1.O>CN(C)C=O>[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]([C:21]2[N:22]=[CH:23][C:24]3[N:29]=[N:28][NH:27][C:25]=3[N:26]=2)=[N:13]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Cn1nc(-c2ncc3nn[nH]c3n2)c2cccnc21
Temperature: 65 °C
Yield: 1 %

Procedure:
570 mg (5.535 mmol) of tert-butyl nitrite were dissolved in 20 ml of dry dimethylformamide, and 1000 mg (2.767 mmol) of the compound from example 53 suspended in 15 ml of dimethylformamide were added at 65° C. by means of a syringe pump within 1 h. After stirring at 65° C. for a further hour, 100 ml of water were added, forming a precipitate. The precipitate was filtered off and purified by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 64:20:16→0:100:0). 10 mg of the title compound were obtained (1% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:8]([C:7]4[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[CH:5][CH:6]=4)=[O:10])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(Cl)nc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,6-dichloropyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (19% yield). 1H NMR (300 MHz, CDCl3) δ 8.06, 7.97, 7.65, 7.37, 7.01, 3.70-4.10, 3.29-3.61, 1.52, 0.68-0.80, 0.42-0.49, 0.06-0.13. MS (ES+) m/z 449 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][CH:5]([CH2:4][N:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:10][C:9]=2[CH:11]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: CCNCC1COc2ccc(O)cc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccc(O)cc2O1
Temperature: 94 °C
Yield: 13.5 %

Procedure:
N-Ethyl-2,3-dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (2.11 g, 13.1 mmole), 7-(3-chloropropoxy)coumarin (3.44 g, 14.4 mmole), diisopropylethylamine (11 ml, 63.2 mmole) and sodium iodide (1.98 g, 13.2 mmole) were combined in 175 ml of DMF and heated at 94° C. for 2 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1.5% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the dichloromethane gradually being replaced with isopropanol. 4N HCl/isopropanol (4 ml) was added and the title compound was collected by filtration. A second recrystallization from isopropanol yielded 0.73 g of white solid, monohydrochloride, m.p. 208°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[N:6]/[NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:2].[N+]([C:22]([CH2:49][CH2:50][CH2:51][CH3:52])=[CH:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[C:37]([N:39]1[CH2:48][CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40]1)=[O:38])([O-])=O>>[C:31]([O:30][C:28]([C:27]1[CH:35]=[CH:36][C:24]([C:23]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[N:6][N:7]([C:8]3[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=3)[C:22]=2[CH2:49][CH2:50][CH2:51][CH3:52])=[C:25]([C:37]([N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)=[O:38])[CH:26]=1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCOC(=O)/C=N/Nc1cccc(C(=O)OC)c1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1cccc(C(=O)OC)c1
Yield: 28.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-methyl 3-(2-(2-ethoxy-2-oxoethylidene)hydrazinyl)benzoate (65 mg, 0.26 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (120 mg, 0.26 mmol) were converted to the title compound (50 mg, 29%). MS(ESI+) m/z 666.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([OH:21])[CH:11]([S:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:18][CH:19]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(Sc2ccc(O)cc2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)C(Sc2ccc(OCc3ccccc3)cc2)C1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
(3RS,4RS)-3-Hydroxy-4-(4-hydroxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.6 mmol) was dissolved in acetone (5 ml), and treated with K2CO3 (0.1 g, 0.7 mmol). After 1 hour refluxing, the reaction mixture was cooled to room temperature and benzylbromide (0.084 ml, 0.7 mmol) was added. Reaction mixture was refluxed for an additional 3 hours then cooled to room temperature and quenched with H2O. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (hexane-ethyl acetate 2:1) to provide (3RS,4RS)-3-(4-benzyloxy-phenylsulfanyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.208 g, 81%) as a yellow oil, MS: m/e=402.4 (M+H+).
Reaction SMILES: [C:1]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CO>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N+:17]([O-:19])=[O:18])[CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH2:14][CH2:13]2
Reactant: C=CC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Reactant: C1COCCN1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN1CCOCC1)CC2
Temperature: 65 °C

Procedure:
A solution of 2-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (425 mg, 1.62 mmol) in methanol (5 mL) was treated with morpholine (1.00 mL, 11.5 mmol, Aldrich) and heated at 65° C. in a sealed tube for 16 h. The mixture was cooled, concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, dried over magnesium sulfate, filtered, and purified by chromatography on SiO2 (dichloromethane to 25% methanol/dichloromethane) to give 6-(methyloxy)-2-[3-(4-morpholinyl)propanoyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline. This material was taken directly to the next step without a determination of yield. 1H NMR (400 MHz, DMSO-d6) is complicated by amide rotomers δ ppm 2.32-2.41 (m, 4 H), 2.52-2.62 (m, 4 H), 2.79-2.97 (two app triplets at 2.83 and 2.94, 2 H), 3.48-3.58 (m, 4 H), 3.63-3.72 (m, 2 H), 3.89 (s, 3 H), 4.55-4.69 (two singlets at 4.57 and 4.67, 2 H), 7.18-7.21 (m, 1 H), 7.80 (s, 1 H); ESIMS (M+H)+=350.