Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 59.4 %

Procedure:
A solution of above intermediate (S)-ethyl 2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg, 0.021 mmol, 1 eq.) in ethanol (1.5 mL) and 1 N sodium hydroxide (0.42 mL, 20 eq.) was heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). Product lyophilized to give 8 as a white powder (4.4 mg). Analytical HPLC (Gemini, 2-98% ACN/H2O+0.05% TFA, 10 minutes run): tR (min)=6.10. 1H-NMR: 400 MHz, (CD3OD) δ: 7.83 (m, 1H), 7.70 (m, 1H), 7.54 (m, 1H), 7.40 (m, 2H), 5.82, 5.62 (s, s, 1H), 2.58 (m, 3H), 2.62-2.16 (m, 4H), 1.92-1.80 (m, 4H), 1.03 (m, 9H). LCMS-ESI31 (m/z): [M−H]− calcd for C23H27O3: 351.46. Found: 351.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32](O)[CH3:33]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(CC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The title compound was prepared following the procedure described in Example 23 step b) using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (prepared in Example 23, step a) and ethanol. The title compound was obtained as a pale yellow oil (215 mg). HPLC, Rt: 5.8 min (purity: 98.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:8]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)cc2c1OCCO2
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-methoxy-4,5-ethylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:25]2[N:30]=[C:29]3[NH:31][N:32]=[CH:33][C:28]3=[CH:27][N:26]=2)[CH:21]=[N:20]1>>[F:17][C:4]1[C:3]([CH2:2][N:31]2[C:29]3=[N:30][C:25]([NH:24][C:22]4[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=4)=[N:26][CH:27]=[C:28]3[CH:33]=[N:32]2)=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][C:11]1=[O:16]
Reactant: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Reactant: O=C1COCCN1c1cc(F)cc(CBr)c1F
Product: Cn1cc(Nc2ncc3cnn(Cc4cc(F)cc(N5CCOCC5=O)c4F)c3n2)cn1

Procedure:
The title compound was prepared as in Procedure D (Step ii) using 4-(3-(bromomethyl)-2,5-difluorophenyl)morpholin-3-one and N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine. 1H NMR (d6-DMSO) δ 9.90 (s, 1H), 8.93 (s, 1H), 8.13-8.05 (m, 2H), 7.56 (s, 1H), 7.48-7.42 (m, 1H), 7.14 (s, 1H), 5.63 (s, 2H), 4.23 (s, 2H), 3.99-3.93 (m, 2H), 3.83 (s, 3H), 3.70-3.63 (m, 2H); LC-MS method B, (ES+) 441, RT=6.82 min.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[N:24]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:34][C:33]4[CH:32]=[CH:31][C:30]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:36][CH:35]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCOCC4)cc3)(CC1)CC2
Yield: 44.1 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-morpholinylaniline (61.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-morpholinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (33.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:18][C@@H:13]3[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(C#N)cc2)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C#N)cc1)=N[C@H]1CCCC[C@@H]21
Yield: 88.5 %

Procedure:
5.1 g of (+/−)-cis-N-[2-(3-ethoxy-4-methoxyphenyl)-cyclohexyl]-4-cyanobenzamide (compound A5) are dissolved in 100 ml of acetonitrile and 3 ml of phosphorus oxychloride and the solution is stirred at 50° C. for 8 h. The reaction mixture is added to 100 ml of saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with sodium hydrogencarbonate solution and water, dried using sodium sulfate and concentrated. 4.3 g of the title compound are obtained as solidified oil.
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:9][CH2:10][CH2:11][CH:4]2[CH2:3]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[O:23]([C:21]([N:2]1[CH2:8][CH2:7][CH2:6][C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:9][CH2:10][CH2:11][CH:4]2[CH2:3]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(C23CCCC2CN(C)CCC3)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: COc1cccc(C23CCCC2CN(C(=O)Oc2ccccc2)CCC3)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.4 g. of 2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine in 200 ml. of dichloromethane was added dropwise over thirty minutes to a stirred solution of 11.2 g. of phenyl chloroformate. The reaction mixture was then heated to reflux and stirred for four hours. The reaction mixture was then cooled to 25° C., and the solvent was removed therefrom by evaporation under reduced pressure to provide 2-phenoxycarbonyl-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine as a solid. The solid thus formed was dissolved in 600 ml. of ethyl alcohol containing 140 ml. of 50 percent aqueous sodium hydroxide solution. The reaction mixture was heated at reflux and stirred for sixty hours. After cooling to 25° C., the reaction mixture was added to 500 ml. of water, and the aqueous solution was acidified to pH 2 by the addition of 12 N hydrochloric acid. The aqueous acidic solution was washed with diethyl ether to remove any unreacted carbamate, and the aqueous acidic solution was then made alkaline by the addition of 50 percent aqueous sodium hydroxide solution. The aqueous alkaline solution was extracted with fresh diethyl ether. The ethereal extracts were combined, washed with water, and dried. Removal of the solvent by evaporation under reduced pressure provided 7 g. of 5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine. B.P. 136°-140° C. at 0.05 torr.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:20]2[C:16](=[N:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[C:15]([C:25]#[N:26])=[C:14]([CH3:27])[CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[N:20]3[C:16](=[N:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)[C:15]([C:25]#[N:26])=[C:14]([CH3:27])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)n2c(nc3ccccc32)c1C#N
Product: Cc1cc(-c2ccc(N)cc2)n2c(nc3ccccc32)c1C#N

Procedure:
General experimental procedure (A) for Suzuki coupling reaction with 4-aminophenyl boronic acid was followed. Reaction was performed on a 241 mg scale of 1-chloro-3-methylpyrido[1,2-a]benzimidazole-4-carbonitrile. Isolated 100 mg (34%) of T672 as a yellow solid. NMR (CD3OD): δ 7.85 (1H, d, J=8.4 Hz), 7.66 (1H, m), 7.43 (2H, m), 7.26-7.30 (2H, m, overlapped), 7.07 (1H, d, J=8.4 Hz), 7.38 (1H, dd, J=9.0, 2.6 Hz), 6.97 (2H, m), 2.80 (3H, s); MS: 299 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.53 g of N-(3,6-dichloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected and recrystallized from ethyl acetate to yield 0.711 g of the title compound.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=[O:14]>C(O)C>[N+:30]([C:27]1[CH:28]=[CH:29][C:16]2[NH:15][C:13](=[O:14])[CH2:12][N:2]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[CH:26]=1)([O-:32])=[O:31]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2-liter, 4-necked flask equipped with a stirrer, a reflux condenser and an ammonia tube, there was added 600 ml. of ethanol and 37.9 g. of hexamethylenetetramine with stirring. Ammonia was bubbled through the resultant reaction medium with stirring until reflux temperature was reached. Then there was carefully added to the refluxing solution 40.0 g. of 2-chloroacetamido-5-nitro benzophenone. Ammonia is steadily bubbled into the reaction mixture while continuing to reflux for three hours. The resultant solution was cooled, evaporated to dryness at 50° C. The residue was dissolved in 300 ml. of toluene. 0.3 G. of paratoluene sulfonic acid was added to the resultant solution. The solution was heated to reflux. The refluxing was continued for 1 hour. The reaction medium was then permitted to cool to room temperature. The product which separated was filtered off, washed with water and dried. This material was taken up in 435 ml. of methylene chloride. It was then filtered through Hyflo. Upon the addition of 90 ml. of 3N nitric acid to the filtrate, crystals appeared. They were filtered off, washed with methylenechloride and dried for 15 minutes. The crystals were added to 1 liter of water with stirring. Ammonium hydroxide was then carefully added to the resultant medium until a pH of about 8 was reached. After stirring the resultant medium for 1/2 hours, the crystalline precipitate which formed were filtered off, washed with cold water and dried at 80° for 8 hours yielding 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one of melting point 217°-219° .
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:40]([CH3:39])(=[O:42])=[O:41])[C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 4.0 g of 1-[(4-butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)urea and 2.6 ml of triethylamine in 90 ml of dichloromethane was added dropwise a solution of 0.8 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was allowed to come to room temperature and was stirred for 16 hours. The procedure of Example 515 was continued and gave 4.5 g of the desired product as a light yellow oil in 97% yield.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:25]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:25])[C:3](=[O:2])[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCCCC2)c1C
Temperature: 25 °C
Yield: 67.6 %

Procedure:
MeOH (200 mL) was added to a flask containing 4-[1-(cyclohexylmethyl-amino)-ethylidene]-pent-2-enedioic acid dimethyl ester (6.3 g, 21.4 mmol). NaOMe solution (4.9 mL, 21.4 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.56 g, 25.6 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (20% EtOAc/hexanes) to give 4.95 g of the title compound. MS: (+) m/z 364.21, 366.16 (M+Na, 79/81Br).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH2:21]([O:1][C:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([CH:12]([CH2:14][CH3:15])[CH3:13])[CH:10]=2)[N:5]=[C:4]([CH3:17])[C:3]=1[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(C)c1cc(Br)c2nc(C)c(C)c(O)c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1cc(Br)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5 Grams of 4-hydroxy-6-s-butyl-8-bromo-2,3-dimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 20 ml of dimethylformamide, to which 700 mg of 60% sodium hydride was added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 3 g of benzyl bromide under cooling with ice and the mixture was allowed to react at room temperature overnight. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane to obtain 2.5 g of 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline. 2.5 Grams of the thus-obtained 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline was dissolved in 25 ml of anhydrous tetrahydrofuran and cooled to −78° C., to which 2.8 ml of a 2.5 M solution of n-butyl lithium in n-hexane was added dropwise and the mixture was stirred for 10 minutes. One ml of methyl formate dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at 0° C. for 30 minutes. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and a saturated brine and then dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 800 mg of 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:27]([NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].O>C1COCC1>[NH2:1][C@H:2]([C:27]([NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:20])[CH3:21])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)NCC(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)C2
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)NCC(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)C2
Yield: 86 %

Procedure:
A solution of 30 g of Z-Arg(Pbf)-Gly-OtBu in 350 ml of THF is mixed with 3 g of water-moist Pd/C (10%) and the Z group is removed by hydrogenation under a gentle stream of H2. The catalyst is then filtered off and the solvent is removed. The residue is taken up in ethyl acetate and treated further as in Example 2.1. H-Arg(Pbf)-Gly-OtBu is obtained in a yield of 86%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH:20]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:19])=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:20]2)[CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2I)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2I)C1=O
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (1.18 g, 2.73 mmol) in methanol (50 ml) at 35° C. is added 50% aqueous hydrogen peroxide solution (0.31 ml, 5.46 mmol), followed immediately by 2M aqueous lithium hydroxide (0.34 ml, 0.68 mmol). This mixture is stirred at 35° C. for 3 hours, then quenched with saturated aqueous sodium metabisulfite and extracted with dichloromethane. The organic phase is separated, and the aqueous phase extracted again with dichloromethane. All organics are combined then evaporated under reduced pressure to afford 2-(5-bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one as an oil which is used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[CH2:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1.[H][H].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]>[Pd].C(O)C>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28].[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([CH3:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1
Reactant: C=C1c2ccccc2CC(CCN(C)C)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC1c2ccccc2CC(CCN(C)C)c2ccccc21

Procedure:
A mixture of 5.54 g. (0.02 mole) 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene and 0.6 g 5% palladium on carbon in 60 ml. ethanol is hydrogenated at atmospheric pressure and room temperature. The hydrogenation is stopped after 1 equivalent of hydrogen is absorbed, the catalyst is removed by filtration and the filtrate concentrated to a small volume in vacuo. The concentrated filtrate is treated with 2.32 g. (0.02 mole) maleic acid in ethanol and the resulting solid is filtered and washed with cold ethanol to give 10,11-dihydro-10-(2-dimethylaminoethyl)-5-methyl-5H-dibenzo[a,d]cycloheptene maleate, m.p. 120°-122° C.