Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1.C(O)C>C1S(=O)(=O)CCC1.[Pd]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Pd]
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Product: CNCCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
2-Methyl-5-phenylisoxazolidine (38.1 g, 234 mmol) dissolved in tetramethylene sulfone (38.1 g) is mixed with 5% Pd/C (1.9 g) in a glass pressure reactor. The reactor is warmed to 50° C. and the pressure is maintained at 40 psig with H2 for 24 hours. Ethanol (38.1 g) is added and heating is continued for 48 hours. After cooling, the mixture is filtered and the EtOH is removed to give a solution of N-methyl-3-phenyl-3-hydroxypropylamine in tetramethylene sulfone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2-aminoethyl)pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(pyrrolidin-1-yl)ethyl)terephthalamide. MS (Q1) 483 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Br)cc2)cc1
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of 0.54 g (2 mmol) of 6-methoxy-2-(4-methoxyphenyl)benzo-[b]thiophene and 0.52 g (2.3 mmol) of 4-bromobenzoyl chloride in 20 mL of methylene chloride at 0° C. was added dropwise a solution of 0.3 ml (2.5 mmol) of tin (IV) chloride in 5 mL of methylene chloride. After stirring for 16 hours the solution was concentrated and the residue was washed with aqueous sodium bicarbonate and extracted 2 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude solid was passed through a short plug of silica gel to remove residual tin salts. Elution with 30% EtOAc:hexane and concentration yielded 0.65 g (73%) of yellow crystals, m.p. 127°-129° C.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH2:28]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:28][C:20]4[C:19](=[CH:24][CH:23]=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=4)[CH2:18]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo [2,3-d]pyrimidin-6-one from Step B (50.0 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91.0 mg, 0.295 mmol, described in Intermediate 4) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O (2 mL) and the mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][N:38]=1>ClCCl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[N:38][CH:39]=2)(=[O:45])=[O:44])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)c2ccc(Cl)nc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (409 mg) and triethylamine (202 mg) in dry dichloromethane (20 ml) was stirred under nitrogen and cooled in an ice-bath while a solution of 2-chloro-5-pyridinesulphonyl chloride (212 mg) in dry dichloromethane (10 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring continued for a further 3 hours. The solvent was evaporated and the residue chromatographed on silica, eluting with dichloromethane. Appropriate fractions were combined and evaporated and the residue recrystallised from ethyl acetate to give the title compound (320 mg), m.p. 140°-140.5° C. Found: C, 51,27; H, 4.63; N, 7.25. C25H27Cl2N3O7 requires C, 51.37; H, 4.66; N, 7.19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH2:20][C:21]([OH:23])=O)(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.[N:25]1([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH2:20][C:21]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:37][CH2:36]2)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: C1CCN(CCC2CCNCC2)C1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)N2CCC(CCN3CCCC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (76 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol/ammonia solution (25% aq.) (400:100:5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1([C:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:35]=[CH:34][C:33]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(-c4ccccc4)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-phenylphenol: ESMS m/e: 611.2 (M+H)+.
Reaction SMILES: O.[Br-].[N+:3]([C:6]1[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH:56]([C@H:58]1[N:63]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:62][C@@H:61]([CH2:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][C:74]=2[NH:79][C:80](=[O:100])[C@@H:81]([NH:95][C:96]([O:98][CH3:99])=[O:97])[CH:82]([C:89]2[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[O:60][CH2:59]1)=O>COCCOC>[CH3:99][O:98][C:96]([NH:95][C@@H:81]([CH:82]([C:83]1[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=1)[C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:80]([NH:79][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][C:73]=1[CH2:72][CH2:71][C@H:61]1[O:60][CH2:59][C@@H:58]([CH:56]=[CH:8][C:7]2[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=2[N+:3]([O-:5])=[O:4])[N:63]([C:64]([O:66][C:67]([CH3:68])([CH3:70])[CH3:69])=[O:65])[CH2:62]1)=[O:100])=[O:97]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=O)CO1)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=Cc2ccccc2[N+](=O)[O-])CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2-Nitrobenzyl)triphenylphosphonium bromide monohydrate (1.4 equiv), potassium carbonate (2.0 equiv) and 18-crown-6 (0.1 equiv) were combined in DME (0.16 M vs aldehyde). The mixture was stirred at room temperature for 5 min. tert-Butyl(2R,5S)-5-formyl-2-{2-[2-({(2S)-2-[(methoxycarbonyl)amino]-3,3-diphenylpropanoyl}amino)phenyl]ethyl}morpholine-4-carboxylate (1.0 equiv) was dissolved in DME (0.16 M) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 h, filtered over solka floc and concentrated. The crude product was purified using automated silica-gel flash chromatography using a solvent gradient of 0% to 100% of ethyl acetate and hexanes.
Reaction SMILES: C([O:4][C:5]1[C:6](Br)=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)(=O)C.[CH2:24]([O:26]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:25]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:4][C:5]1[C:6]([C:24](=[O:26])[CH3:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH:9]=[CH:8]2
Reactant: CC(=O)Oc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
4-Bromo-1-(phenylsulfonyl)-1H-indol-5-yl acetate (Intermediate 22, 0.57 g, 1.5 mmol) was dissolved in toluene (10 mL) under an atmosphere of N2 gas and 1-ethoxyvinyl-tributylstannane (0.78 g, 2.2 mmol) and bis-(triphenylphosphin)-palladium(II)-chloride (50.8 mg, 0.072 mmol) were added and the mixture was heated at 110° C. After 30 minutes additional catalyst (25 mg, 0.036 mmol) was added and the mixture was heated at 110° C. for an additional 3 hours, cooled and filtered through a plug of silica gel using EtOAc as the eluent. The filtrate was washed with 1 M HCl and saturated aqueous brine, dried over (MgSO4) and evaporated. The crude product was dissolved in THF/1 M HCl 2:1 (40 mL) and stirred for 30 minutes at room temperature. The mixture was evaporated and partitioned between water and DCM. The organic phase was dried (MgSO4) and evaporated. The crude material was purified by flash chromatography on silica gel using 10% petroleum ether in DCM as the eluent to give the title compound (100 mg) as a light yellow solid. MS m/z 316 [M+H]+.
Reaction SMILES: O.[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([OH:17])=[O:16])=[N+:3]=[N-:4].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>CN(C=O)C>[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([O:17][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:16])=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=Nc1c(C(=O)O)cnc2ccccc12
Reactant: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(C(=O)ON2C(=O)CCC2=O)cnc2ccccc12
Reaction time: 0.5 h

Procedure:
4-Azido-3-quinolinic acid monohydrate (2.3 g; 0.01 M) was suspended at ambient temperatures in dry DMF (25 ml). N-hydroxysuccinimide (1.2 g; 0.01 M) was added and the resulting mixture cooled to 0°-5° C. N,N-dicyclohexylcarbodi-imide (2.3 g; 0.11 M) was added and the mixture stirred at 0°-5° C. for 1/2 hr. then at ambient temperatures for 4 days. The insoluble material was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual solid was recrystallized from iso-propyl alcohol as a light-brown, crystalline solid, 2.5 g. (80%), m.p. 173°-5° C. (dec.)(Found: C, 53.71; H, 2.80; N, 22.47%. C14H9N5O4 requires: C, 54.02; H, 2.89; N, 22.47%), νmax (KBr), 2120, 1790, 1760, 1730, 1490, 1390, 1370, 1202, 890, 780, 640cm-1, δ[(CD3)2SO] 2.9(s)(CH2CH2), 7.57-8.4(m), 9.18(s) (aromatic protons), m/e 311(M+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3([OH:23])[CH2:21][CH2:22][O:18][CH2:19]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOC1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOC1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tetrahydrofuran-3-one. Brown oil. MS (m/e): 296.4 ([M+H]+, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:19])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([O:20][CH3:21])[C:5]([O:22][CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=1.II>CS(C)=O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:1][C:2]3[C:7]([C:8](=[O:19])[CH:9]=2)=[C:6]([O:20][CH3:21])[C:5]([O:22][CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=3)=[CH:16][CH:15]=1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)c(OC)c2OC)cc1
Agent: II
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(=O)c3c(OC)c(OC)c(OC)cc3o2)cc1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
A solution of the chalcone 6 (1.72 g, 5 mmol) and iodine (catalytic amount) in dimethyl sulfoxide (6 mL) was refluxed for 30 min, and then the reaction mixture was poured onto crushed ice (50 g). The resulting precipitate was collected and washed with 5% sodium thiosulfate solution (30 mL) and water. Recrystallization from ethanol afforded the title flavone (1.38 g, 81%) as bright yellow crystals: 1H NMR (CDCl3, 200 M Hz) δ 7.81 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.79 (s 1H), 6.57 (s, 1H), 3.99 (s 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 177.1 (s), 162.0 (s), 161.0 (s), 157.5 (s), 154.3 (s), 152.4 (s), 140.2 (s), 127.5 (d, 2C), 123.6 (s), 114.2 (d, 2C), 122.7 (s), 106.8 (d), 96.1 (d), 62.0 (q), 61.4 (q), 56.1 (q), 55.3 (q).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:4][CH2:3]1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: CCCCCCCCCCCCOCC1CO1
Product: CCCCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.7 %

Procedure:
Using the method of Example 5, supra, dodecyl glycidyl ether (242 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 121 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 422 (M+1, 1), 406 (4), 300 (100), 222 (11), 163 (23), 121 (34); 1H-NMR (CDCl3) δ 7.09 (2H, d, J=8.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.76 (1H, m), 3.45 (4H, m), 2.81 (1H, dd, J=7.6 and 4.0), 2.65 (4H, m), 1.53 (2H, m), 1.26 (20H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.4); 13C-NMR (CDCl3) δ 1.58.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.0, 55.1, 53.4, 46.4, 44.6, 31.9, 29.6, 29.4, 29.3, 26.7, 26.6, 26.1, 22.7, 14.1; FT-IR (film) cm−1 3415 (broad, s), 1612, 1512, 1246, 1121, 825.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][C:12]=3[O:30][CH3:31])[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][C:12]=4[O:30][CH3:31])[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[CH:49]=[N:48]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 686.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxyphenyl)piperazine-1-carboxylate (intermediate 52) (300 mg, 0.0435 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (145 mg, 0.479 mmol) using sodium carbonate (138 mg, 1.307 mmol) and Pd(dppf)Cl2 (16 mg, 0.0217 mmol) in toluene/ethanol/water (6/6/3 ml) to afford 220 mg (62.0% yield) of titled compound after purification by column (Silica gel 60/120) using 10% ethyl acetate in DCM as eluent. MS: m/z=737.2 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]=[C:22]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:33]=2)[C:23]2[C:29](=[O:30])[NH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)C(=O)[O-])(C)C>ClCCl>[NH2:40][CH2:39][CH2:38][C:34]1[CH:33]=[C:32]([NH:31][C:22]2[C:23]3[C:29](=[O:30])[NH:28][CH:27]=[CH:26][C:24]=3[N:25]=[C:20]([NH:19][CH2:18][CH2:17][CH2:16][NH2:12])[N:21]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)N(CCCNc1nc(Nc2cccc(CCN)c2)c2c(=O)[nH]ccc2n1)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNc1nc(Nc2cccc(CCN)c2)c2c(=O)[nH]ccc2n1
Reaction time: 0.5 h

Procedure:
To a premixed solution of TFA (0.5 mL, 6.49 mmol) and dichloromethane (0.5 mL) was added to 1,1-dimethylethyl{3-[(4-{[3-(2-aminoethyl)phenyl]amino}-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino]propyl}carbamate (11 mg, 0.024 mmol) and the reaction mixture was stirred for 30 min. It was concentrated and the product lypholized (4 mg, white solid).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Reactant: O=C(Cl)C1CC1
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NC(=O)C3CC3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate B-1, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with cyclopropanecarbonyl chloride gave the title compound as a light yellow solid. MS: 376.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: COc1ccccc1C(C)OC(=O)Nc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4ccccc4OC)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-methoxy-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.