Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-])=O)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1N
Reaction time: 8 h

Procedure:
A mixture of (±)-2-Methyl-3-((2-nitro)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (80 mg), ammonium chloride (53 mg), and zinc powder (106 mg) in 6 ml of EtOH—H2O (9-10) was stirred overnight, and then filtered through a layer of zeolite. The filtercake was rinsed with methanol (5 ml×3), and the combined filtrate was concentrated under reduced pressure. The residue was then partitioned between of dichloromethane and saturated aq. sodium bicarbonate (6 ml each). The aqueous layer was then extracted with dichloromethane (6 ml). The organic layer was washed with brine and then concentrated to yield (±)-2-Methyl-3-((2-amino)benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide as a resin: MS (m+1)=460.3; 1H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 1.15 (dd, 3H), 2.00 (m, 1H), 2.25 (m, 2H0, 2.60 (q, 1H), 2.70 (q, 1H), 2.90 (m, 1H), 3.05 (m, 1H), 3.10 (m, 1H), 3.20 (q, 1H), 3.35 (q, 1H), 3.45 (q, 1H), 3.70 (m, 2H), 4.25 (m, 2H), 4.35 (m, 2H), 4.55 (m, 2H), 6.6-7.2 (m, 4H), 6.8-7.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[N:10]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:9][CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Cl)c2CC1)NCCC3
Reactant: CC(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)C(=O)N1CCCc2cc3c(c(Cl)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 60 °C

Procedure:
To a solution of 193 mg of t-butyl 11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 2 ml of toluene was added 0.121 ml of isobutyric chloride, followed by stirring at 60° C. The reaction mixture was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 80 mg of t-butyl 11-chloro-1-isobutyryl-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless solid.
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH:37]1([CH:42]2[CH2:53][CH:52]=[CH:51][CH2:50][CH2:49][CH:48]=[CH:47][CH2:46][CH:45]([CH:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)[N:44]=[N:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:43][CH:42]([CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH:45]([NH2:44])[CH:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: C1=CCC(C2CCCC2)N=NC(C2CCCC2)CC=CCC1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: NC(CCCCCCCCC(N)C1CCCC1)C1CCCC1

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 200 g (0.666 mol) of crude 3,12-dicyclopentyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with the procedure otherwise being the same, there is obtained, after chromatographic purification and distillation, 39.2 g (19% of theory) of 1,10-diamino-1,10-dicyclopentyldecane as colourless oil [b.p. 174°-178° C./0.002 Torr; nD20 =1.4885; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH2:58][O:59][Si](C(C)(C)C)(C)C)=[CH:54][CH:53]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([O:71][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:79])[CH3:2].C1(C)C=CC(S(O)(=O)=[O:87])=CC=1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:27])[CH2:30][CH:20]([CH3:37])[CH2:21][CH:22]([O:35][CH3:36])[CH:23]2[O:34][C:19]([OH:38])([CH:26]([CH3:31])[CH2:25][CH:24]2[O:32][CH3:33])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([C:58]([OH:59])=[O:87])=[CH:56][CH:57]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([OH:71])[CH2:5][C:4]1=[O:79])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(CO[Si](C)(C)C(C)(C)C)cc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccc(C(=O)O)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(p-(tert-butyldimethylsiloxymethyl)-benzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (420 mg) in methylene chloride (10 mL) was added a methanolic solution of p-toluenesulfonic acid (10 mL of a 10% solution w/v) and the mixture stirred at room temperature. After 5 minutes, the reaction was cooled to 0° C. and quenched by the careful addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the organic portion washed with brine, dried over magnesium sulfate, and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1+1% methanol) to give the title compound (316 mg).
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:22].C(N(CC)CC)C>CO>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:21]([CH2:20][N:15]1[CH2:14][CH2:13][CH:12]([N:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2][C:3]2=[O:18])[CH2:17][CH2:16]1)=[O:22]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In this example, 2.67 g of 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 2.33 g of α-bromo-m-chloroacetophenone, 2.8 ml of triethylamine and 30 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.89 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 1.93 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Br.CC(O)=O>[C:1]1([C:7]2[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)[CH:10]=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(-c3ccccc3)c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: c1ccc(-c2cncc(OC[C@@H]3CCCN3)c2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
The 5-phenyl-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine from the previous step was dissolved in HBr/HOAc, and the reaction was stirred at room temperature for 16 hours and at 40° C. for 4 hours. The volatiles were removed under vacuum, and the residue was chromatographed on a silica gel column, eluting with chloroform/methanol 10/1.5 to afford the title compound (57 mg). MS (DCI/NH3) m/z 255 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.54-2.12 (m, 5H), 2.95-3.13 (m, 2H), 3.54-3.66 (m, 1H), 3.94-4.08 (m, 2H), 7.36-7.52 (m, 4H), 7.54-7.62 (m, 2H), 8.29 (d, J=3, 1H), 8.46 (d, J=2, 1H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: NCCCCCCNc1ccc(Cl)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCCCCCCNc2ccc(Cl)cc2)c(Nc2cccnc2)c1=O
Yield: 86 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and N-(4-chlorophenyl)-hexane-1,6-diamine.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:9]1[S:10][CH:11]=[CH:12][C:8]=1[O:7][CH3:6]
Reactant: COc1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1[Si](C)(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A solution of n-BuLi (19.7 mL of 1.6 M in hexanes, 31.5 mmol) is added dropwise to a solution of 3-methoxythiophene (3.0 g, 26.3 mmol) in anhydrous Et2O (20 mL) under nitrogen at −70° C. The mixture is stirred at −70° C. for 2 hr. Chlorotrimethylsilane (4.5 mL, 35.4 mmol) is added slowly to the solution. The mixture is warmed to room temperature and stirred for 3 hr. The reaction is quenched with water (50 mL) and hexanes (100 mL). The aqueous layer is extracted with hexanes (50 mL). The combined organic extracts are dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with hexanes to afford the title compound (4.0 g, 82%) as a colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9](C)CC=C.[S:14]([C:18]1[CH:19]=[C:20]([N:32]=[C:33]=[S:34])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([OH:17])(=[O:16])=[O:15].[Na:35]>ClCCl.O>[S:14]([C:18]1[CH:19]=[C:20]([NH:32][C:33]([NH2:9])=[S:34])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:23][CH:22]=2)([OH:17])(=[O:16])=[O:15].[Na:35]
Reactant: O=S(=O)(O)c1ccc2c(N=C=S)cc(S(=O)(=O)O)cc2c1
Reactant: C=CCN(C)C
Agent: [Na]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a suspension of BHAlyslys2lys4lys8DBL16 (73 mg; 0.01 mmol) in dry dichloromethane (2 ml) under nitrogen A vigorous evolution of gas was observed for a short time and the resulting solution was stirred at room temperature for two hours and then concentrated. The residual syrup was dissolved in water (5 ml), the solution passed through a column of Amberlite IRA-401 (OH) and the filtrate concentrated to give BHAlyslys2lys4lys8lys16 as a viscous oil. The oil was redissolved in water (5 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 3 ml) added. Solid sodium 3,6-disulfonapthylisothiocyanate (234 mg; 0.60 mmol) was then added and the resulting solution heated under nitrogen at 53° for two hours and then cooled. The solution was concentrated and the brownish solid residue purified by gel filtration (Sephadex LH20; water). The pure fractions were combined, passed through a column of Amberlite IR 120(Na) and freeze dried to give BHAlyslys2lys4lys8lys16 terminated with 32 sodium 3,6-disulfonapthylthiourea groups as a fluffy off-white solid (119 mg). 1H nmr (D2O): δ 1.0-2.0; 3.18; 3.43; 4.31; 7.22; 7.80; 7.89; 8.25. 13C nmr (D2O): δ 27.2; 32.4; 35.3; 43.7; 49.0; 58.5; 63.6; 128.4; 129.1; 131.4; 136.1; 136.6; 138.6; 139.0; 145.1; 145.6; 178.4; 184.8; 186.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:19])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:25]=[O:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([F:19])([C:14]2[S:15][C:16]([CH2:25][OH:26])=[CH:17][N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2nccs2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CO)s2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) and stirred solution of 4-fluoro-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 12.7 mmol) in THF (20 mL) was added n-BuLi (1.33 mL, 1.05 eq., 10.0 M in hexanes). The mixture was stirred at this temperature for 30 minutes. Then a suspension of paraformaldehyde (383 mg, 1 eq.) in THF (10 mL) was added in. The resulting mixture was continued to stir at −78° C. for another 30 minutes and gradually warmed to room temperature overnight. The reaction was quenched by addition of water (10 mL). The mixture was extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (60% EtOAc in hexanes) to afford the desired product as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:15][CH2:16][O:17][C:18](/[C:20](/Cl)=[N:21]\[OH:22])=[O:19]>C1(C)C=CC=CC=1>[O:14]=[C:11]1[N:10]2[CH:4]([CH2:1][CH:2]3[O:22][N:21]=[C:20]([C:18]([O:17][CH2:16][CH3:15])=[O:19])[CH2:3]3)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]2=[N:13][O:12]1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=CCC1CCCCc2noc(=O)n21
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=NOC(CC2CCCCc3noc(=O)n32)C1
Reaction time: 18 h
Yield: 74.6 %

Procedure:
To a solution of 0.5 g (2.6 mmol) of the product of Example 6 in 100 mL of toluene was added 0.8 g (5.2 mmol) of ethyl chlorooximidoacetate (Aldrich). This solution was brought to reflux and stirred for 18 hours. All solvent was removed in vacuo and the residue purified via C-18 chromatography (0-60% acetonitrile/water, 25 min.) with the product eluting at 54% acetonitrile. Concentration of the relevant fractions afforded 0.6 g (75% yield) of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)cc(C#CCOCC2CC2)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOCC4CC4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 72 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-[3-(cyclopropylmethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (182 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (247 mg, 72%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 0.23 (m, 2H), 0.51 (m, 2H), 1.04 (m, 1H), 1.96 (quintet, 2H), 2.38 (m, 4H), 2.46 (t, 2H), 3.37 (d, 2H), 3.59 (m, 4H), 3.93 (s, 3H), 4.20 (t, 2H), 4.42 (s, 2H), 6.16 (s, 2H), 7.15 (s, 1H), 7.19 (s, 1H), 7.84 (s, 1H), 8.34 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 581/583.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:14]([N:17](S(C)(=O)=O)[S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[CH2:26]([C:13]1[C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[N:12]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cc3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
5-(4-Acetoxyphenyl)-3-benzyl-2-bis(methanesulfonyl)aminopyrazine (c-39) (239 mg, 503 μmol) was suspended in methanol (5 mL) and to this was added 10% (w/v) aqueous solution of sodium hydroxide (1.2 mL) while stirring at room temperature and then stirred at 65° C. for 30 min. After cooling to room temperature, to this was added 2 M hydrochloric acid to stop the reaction and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (23 g, n-hexane/ethyl acetate=1/1) to give 3-benzyl-5-(4-hydroxyphenyl)2-(methanesulfonylamino)pyrazine (coelenteramesylamide) (c-34) as a pale yellow solid (166 mg, 92.6%). Rf=0.30 (n-hexane/ethyl acetate=1/1). Mp. 208-209° C. (dec.). UV (MeOH) λmax (log ε) 335 (4.12), 290 (4.25), 276 (4.27). UV (pH 7.4 PB) λmax (log ε) 349 (4.14), 281 (4.38). 1H NMR (400 MHz, DMSO-d6) δ 3.36 (s, 3H), 4.25 (s, 2H), 6.82-6.87 (AA′BB′, 2H), 7.15-7.23 (m, 1H), 7.29 (d, J=5.0 Hz, 4H), 7.83-7.88 (AA′BB′, 2H), 8.73 (s, 1H), 9.80 (s, 1H), 10.41 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 38.2, 42.7, 115.8 (2C), 126.4, 126.6, 127.7 (2C), 128.4 (2C), 129.0 (2C), 135.9, 138.1, 144.3, 146.0, 146.4, 158.8. IR (KBr, cm−1) 521, 538, 588, 606, 700, 750, 827, 841, 889, 916, 939, 970, 1118, 1138, 1153, 1175, 1213, 1273, 1314, 1400, 1456, 1495, 1609, 3206. HRMS (FAB+) m/z 356.1060 (M+H, C18H18N3O3S requires 356.1069).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].CC1C=CC(S(O[CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (161 mg, 0.5 mmol), (prepared as described in Example 49), 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (222 mg, 0.6 mmol), (prepared as described for the starting material in Example 10), and potassium carbonate (188 mg, 1 mol) in DMF (1.6 ml) was heated at 100° C. for 2 hours. After cooling, water was added. The precipitate was collected by filtration, washed with water, and dried under vacuum over phosphorus pentoxide at 60° C. The solid was triturated with petroleum ether, collected by filtration, washed with a mixture of ether/petroleum ether (1/1) and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (200 mg, 77%).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(OCC)(=O)C>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:24])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(NC(=O)CCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(NC(=O)CCC(=O)O)s2)ccc(C(C)=O)c1O

Procedure:
yl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-4-oxobutyrate obtained in Example 23. Further 2 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 20 minutes An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off The residue was recrystallized from isopropyl alcohol to give 0.11 g of 4-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-4-oxobutyric acid.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.[C:12]([NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](Br)=[CH:22][CH:21]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[B:31](OC)([O:34]C)[O:32]C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:12]([NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([B:31]([OH:34])[OH:32])=[CH:22][CH:21]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Agent: CCCC[Mg]Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(B(O)O)c2ccccc12
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
In a dry flask under Argon was added butylmagnesium chloride (2.0 M in THF, 2.0 mL, 4.0 mmol) and anhydrous THF (10 mL). The solution was cooled to −5° C. and butyllithium (1.6 M in hexane, 5.0 mL, 8.0 mmol) was added dropwise while the temperature was kept below 0° C. After the resulting solution was stirred at 0° C. for 0.5 h, the temperature was lowered to −5° C. N-Boc-4-bromo-1-aminonaphthalene (0.64 g, 2.0 mmol) was dissolved in anhydrous THF(10 mL) and added dropwise while the temperature was kept below 0° C. The solution was stirred at 0° C. for 0.5 h. HPLC of a sample taken from the solution and quenched with MeOH indicated that no starting material was left. The temperature was lowered to −5° C. and trimethyl borate(2.5 mL, 22.0 mmol) was added slowly. After the mixture was stirred at 0° C. for 2 h, ammonium chloride solution (saturated, 20 mL) was added and the mixture was stirred at 21° C. for 0.5 h. The pH of the mixture was adjusted to 7 with sodium bicarbonate and the mixture was stirred at 21° C. for 18 h. Ethyl acetate (10 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated and dried with magnesium sulfate. The solvent was removed under vacuum and then hexane (60 mL) was added and the resulting slurry was stirred for 0.5 h. Filtration and hexane (10 mL) wash gave the title compound as a white solid (0.46 g, 80.5% pure, 65% yield).