Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:25]1([C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][NH:33][C:31](=[O:32])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)CNC(=O)c1ccccc1
Product: Cl
Product: O=C(CNC(=O)c1ccccc1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and N-(phenylcarbonyl)glycine, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=1)#[CH:2].C(N(CC)CC)C.[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:30]=1[C:31](Cl)=[N:32][OH:33]>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:30]=1[C:31]1[CH:2]=[C:1]([C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:6]=[CH:7][CH:8]=2)[O:33][N:32]=1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate (1.6 g, 5.83 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and treated with triethylamine (0.82 g, 8.1 mmol) and then 2,6-dichloro-N-hydroxybenzimidoyl chloride (1.4 g, 6.3 mmol). After stirring 15 min at room temperature the mixture was heated at reflux for 4 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.51 (br s, 1H), 8.01 (s, 1H), 7.51-7.45 (m, 2H), 7.40-7.28 (m, 4H), 6.63 (m, 1H), 5.28 (br s, 2H), 3.95 (d, 2H), 1.45 ppm (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2].[ClH:15].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:24](O)[CH3:25]>>[ClH:15].[CH2:16]([NH:23][C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:8][C:7]=2[CH:14]=1)=[NH:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CCO
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Agent: Cl
Product: CCOC(=O)c1cc2cc(C(=N)NCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
Ethanol (30 ml) was added to 5-cyano-2-benzofurancarboxylic acid (689 mg, 3.68 mmol) and a hydrogen chloride gas was blown in under ice-cooling for 15 minutes and the mixture was stirred at room temperature for 16 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was dissolved in ethanol (25 ml). Benzylamine (1.58 g, 14.7 mmol) was added under ice-cooling and the mixture was stirred for one hour and at room temperature for 2 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/3-4/1) to give 361 mg of ethyl 5-benzylamidino-2-benzofurancarboxylate hydrochloride as a colorless solid (30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br)([O-:27])=[O:26]>CN(C)C=O>[OH:9][CH2:8][CH:7]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N+:25]([O-:27])=[O:26])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: COc1ccc(S(=O)(=O)NC(CO)C(=O)OC(C)(C)C)cc1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2[N+](=O)[O-])C(CO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.1 %

Procedure:
To 6.16 g (18.6 mmol) of 3-hydroxy-2-(4-methoxybenzenesulfonylamino)-propionic acid tert-butyl ester in 50 ml of N,N-dimethylformamide, cooled in an ice bath, was added 0.781 g (19.5 mmol) of sodium hydride. After gas evolution ceased, a solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of N,N-dimethylformamide was added dropwise. The mixture was stirred under nitrogen at room temperature for 4 hours and 1.0 g of 2-nitrobenzyl bromide was added. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was diluted with water and extracted with CH2Cl2. The organic extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 11.2 g of solid which was chromatographed on silica gel with hexane-ethyl acetate (1:1) as eluent followed by hexane-ethyl acetate (35:65) as eluent. The fractions containing product were combined and the solvent was then removed to gave 7.7 g (89%) of solid. A sample from a 3 mmol run gave a gum. Anal. for C21H26N2O8S: Calc'd: C,54.1; H,5.6; N,6.0; Found: C,54.0; H,5.7; N,6.0.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCO
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (20.4 mmol), piperazine-1-carboxylic acid tert-butyl ester (20.4 mmol), potassium carbonate (40.8 mmol), and N′N-dimethylformamide (80 mL) is heated at 60° C. for 3 hrs. The mixture is cooled to room temperature, treated with water (100 mL), extracted with ethyl acetate (3×80 mL). The extracts are washed with water (3×60 mL) and brine (1×75 ml), dried over magnesium sulfate, and concentrated in vacuo to give 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (11) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[NH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([NH:31][C:8]([C:7]2[C:2](=[O:1])[NH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][CH:6]=2)=[O:10])[CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)[nH]c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NC1CCC1)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C

Procedure:
600 mg (2.9 mmol) of 2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid were dissolved in 5 ml of tetrahydrofuran, 658 mg (4.1 mmol) of N,N-carbonyldiimidazole were added and the mixture was heated initially at room temperature for 30 min and then under reflux for 30 min. A solution of 247 mg (3.5 mmol) of cyclobutylamine in 5 ml tetrahydrofuran was then added dropwise, and the mixture was heated under reflux for a further 2 h. The solution was evaporated to dryness and then taken up in ethyl acetate, washed with 1 N hydrochloric acid and water, dried and concentrated. Purification by column chromatography gave 160 mg (19% of theory) of a light-brown powder.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH:3]=[CH2:4].CCN(CC)CC.[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:26]1([CH2:25][O:32][C:33](=[O:34])[NH:17][CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:2]([CH3:1])([CH3:5])[CH:3]=[CH2:4])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C=CC(C)(C)c1[nH]c2ccccc2c1CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,1-dimethyl-2-propenyl)-1H-indole-3-ethanamine (0.707 g, 3.07 mmol) in dry CH2Cl2 (30 mL) at 0° C. under argon was added NEt3 (0.98 mL, 6.93 mmol) and BnOC(O)Cl (1.10 mL, 7.32 mmol). The reaction was permitted to warm to rt while stirring overnight. It was diluted with CH2Cl2, and extracted with cold H2O. The CH2Cl2 layer was separated. The H2O layer was re-extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with satd aq NaHCO3 and brine, dried, filtered and concentrated to give an oil. This oil was purified by silica chromatography to provide the title compound: TLC Rf=0.34 (CH2Cl2); MS (EI) m/z 362.3, 254, 211, 198, 182. 168, 167, 108, 91, 77, 65, 51; 1H NMR (300 MHz, CDCl3) δ 7.89 (1H), 7.56 (1H), 7.33-7.26 (6H), 7.10 (2H), 6.12 (1H), 5.18-5.12 (2H), 5.12 (2H), 4.87 (1H), 3.47 (2H), 3.07 (2H), 1.53 (6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15])[CH3:2]
Reactant: O=CCCl
Reactant: CCc1cccc(OC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cccc(OC)c1NCC=O
Temperature: 150 °C

Procedure:
2-Ethyl-6-methoxyaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27]([NH:29][C:30](=[N:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:44]=1)OC1C=CC=CC=1)#[N:28]>>[C:27]([NH:29][C:30]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:24])=[N:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]2)[CH:44]=1)#[N:28]
Reactant: CN(CCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.33 g (0.9 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,6-hexanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-(3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Chromatographic working-up analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=657 ([M+H]+, 11), 229 (100); IR (KBr): 2164 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 58° C. (ethanol/ether).
Reaction SMILES: CO[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.OS([O-])(=O)=O.[Na+].[C:34]([O:37][CH2:38][CH3:39])(=[O:36])[CH3:35].[CH3:40]CCCCC>C(Cl)Cl>[CH:25]([O:24][C:22](=[O:23])/[CH:21]=[CH:20]\[N:17]1[CH:18]=[N:19][C:15]([C:7]2[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[O:4]/[CH:3]=[CH:35]/[C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[N:16]1)([CH3:26])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: COCOc1cc(-c2ncn(/C=C\C(=O)OC(C)C)n2)cc(C(F)(F)F)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)/C=C\n1cnc(-c2cc(O/C=C/C(=O)OC(C)C)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 3-neck 50 mL RBF, (Z)-isopropyl 3-(3-(3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (0.05 g, 1 eq.) was dissolved in DCM (5 mL) and activated NaHSO4.SiO2 (0.050 g) was added and reaction mixture was stirred at RT for 30 min. Reaction completion was monitored on TLC using ethyl acetate:hexane (3:7) mobile phase. Reaction mixture was filtered and concentrates under reduced pressure to afford 0.02 g of pure compound, Yield (45%). 1H NMR (400 MHz, CDCl3): δ 10.5 (s, 1H, D2O Exchangeable), 9.14 (s, 1H), 7.703-7.707 (d, 2H), 7.45-7.48 (d, J=10 Hz, 1H), 7.14 (s, 1H), 5.973-5.998 (d, J=10 Hz, 1H), 5.02-5.08 (m, 1H), δ 1.22-1.24 (s, 6H): LCMS for C15H14F3N3O3 MW 341.3 found 341.8 at 3.812 min (LCMS 98.66%).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18])[C@@H:9]2[CH3:14].Br>>[ClH:1].[OH:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18])[C@@H:9]2[CH3:14]
Reactant: CCCCCN(CCC)[C@H]1CCc2c(OC)cccc2[C@H]1C
Agent: Br
Agent: Cl
Product: CCCCCN(CCC)[C@H]1CCc2c(O)cccc2[C@H]1C

Procedure:
cis-5-Methoxy-1-methyl-2-(N-n-pentyl-N-n-propyl-amino) tetralin hydrochloride (500 mg; 1.5 mmol) was heated in aqueous 48% HBr (3 ml) for 2 hours at 120° C. under N2. The mixture was evaporated and the residue was made alkaline with diluted NaHCO3 and extracted 3 times with ether. After drying (Na2SO4) and evaporation the product was precipitated as hydrochloride salt. Yield: 290 mg (60%) NMR (CDCl3). δ0.86 (t, 6H) δ1.17 (d, 3H), δ3.23-0.60 (m, 27H) δ5.36 (s, 1H phenolic) δ6.90 (m, 3H),MS (70 eV) m/z 289 (33%), 161 (100%), 232 (82%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=O)(C)(C)C.[ClH:15].O1CCOC[CH2:17]1>>[ClH:15].[CH3:17][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:14]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: Cl
Product: CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N HCl-dioxane (20 mL) was added to 3-oxopiperazine-1-carboxylic acid tert-butyl ester (2.06 g) obtained from Referential Example 90, followed by stirring at room temperature for 1 hour. The reaction solvent was removed under reduced pressure, to thereby give the title compound as an oily product (1.44 g, 99%).
Reaction SMILES: [I:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:13]([O:15][C:16]([C:18]1([NH2:29])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[I:1])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[C:24]=2[F:27])[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)c(F)c2C1
Reactant: Cc1cccc(C(=O)O)c1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)c(F)c2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (1.31 g, 5 mmol), 2-amino-4,5-difluoro-indan-2-carboxylic acid ethyl ester HCl salt (D7, 1.38 g, 5 mmol), HATU [O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium PF6, 3.8 g, 10 mmol) in anhydrous DMF (20 mL) is added DIPEA (N,N-diisopropylethylamine, 3.3 mL, 15 mmol). The resulting solution is stirred at room temperature for two days. After the removal of DMF in vacuo, the residue obtained is dissolved in ethyl acetate (200 mL) and washed with saturated NaHCO3 (1×100 mL) and brine (2×100 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The obtained residue is purified by flash column chromatography (24 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (386) as white solid (1.93 g, 79%).
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].[OH:7][C:8]1[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13]>CC(O)=O>[OH:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:15][CH:16]=1)[C:12](=[O:13])[NH:5][C:17]2=[O:19]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Product: O=C1NC(=O)c2cc(O)ccc21
Temperature: 120 °C

Procedure:
To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120° C. for 45 min., then the clear, bright yellow mixture was heated at 160° C. for 2 h. The resulting mixture was maintained at 160° C. and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a 1N NaOH solution. This mixture was cooled to 0° C. and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 1H NMR (DMSO-d6) δ7.00-7.03 (m, 2H), 7.56 (d, J=9.3 Hz, 1H). Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:16]1[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1Cl
Yield: 59.7 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.043 g (60%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=[C:7]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: O=C1Nc2ccccc2Oc2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: Clc1cccc2c1Oc1ccccc1N=C2N1CCCNCC1

Procedure:
In a like manner as Example 1, 4-Chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepine-11-one (2.46 g, 10.0 mmol) was reacted with homopiperazine (7.41 g, 74.0 mmol) in the presence of titanium tetrachloride (2.09 g, 11.0 mmol) in toluene (55.0 mL) and anisole (2.00 mL) to produce 4-Chloro-11-(1-homopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.92 g (28%). This crude product (0.26 g, 0.79 mmol) was reacted with 1-bromohexane (0.13 mL, 0.16 g, 0.95 mmol) in the presence of sodium hydride (0.044 mg, 60% in oil, 1.11 mmol) in DMF (10.0 mL) to produce 4-Chloro-11-(4-hexylhomopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.17 g (52%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (15.4 g, 45.1 mmol) in dichloromethane (150 mL) at 0° C. was added mCPBA (approximately 77% purity, 19.7 g, 87.9 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours, then concentrated ammonium hydroxide (50 mL) was added. p-Toluenesulfonyl chloride was added in portions to the mixture, which was stirred for 1 hour then filtered. The filtrate was transferred to a separatory funnel, saturated aqueous sodium bicarbonate (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with 5% aqueous sodium hydroxide (2×75 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to yield a brown solid that was slurried in ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the solid was recrystallized from ethanol/water four times, then was dissolved in dichloromethane (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), then was concentrated under reduced pressure to yield a solid that was recrystallized from ethanol/water three times. The crystals were dried in a vacuum oven at 70° C. to provide ethyl 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as pale yellow crystals, mp 129-131° C.