Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15]([O-:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])(=O)=O.[C:26](O)(=O)[CH3:27]>>[C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:18](=[O:20])[CH2:19][Cl:24])[C:15]([O:17][CH2:26][CH3:27])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl

Procedure:
A solution of 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.), sulfuryl chloride (13.5 g.) and acetic acid (30 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hrs. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1.[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC)(=[O:27])C(C)=C.C1(=O)OC(=O)C=C1.C=CC1C=CC=CC=1>>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8]([OH:13])(=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:27])=[O:12].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1C=CC(=O)O1
Agent: C=C(C)C(=O)OC
Solvent: C=Cc1ccccc1
Product: O=C(O)/C=C\C(=O)O

Procedure:
The resulting methyl methacrylate/maleic anhydride/styrene copolymer (b-3) had a methyl methacrylate content of 74% by mass, a maleic anhydride content of 10% by mass and a styrene content of 16% by mass, a weight average molecular weight of 121000, and a melt flow rate (ASTM-D1238; 230° C., 3.8 kg load) of 1.6 g/10 minutes. In addition, it had a photoelastic coefficient (undrawn) at 23° C. of −2.9×10−12 Pa−1 and a negative inherent birefringence.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[C:42]1([C@H:48]([NH2:51])[CH2:49][CH3:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][C@@H:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:49][CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC[C@@H](NC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 147.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-phenylpropylamine (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (75 mg, yield 69%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][CH2:12][CH2:13][CH2:14][S:15]([NH:18][CH2:19][CH:20]([CH2:44][CH:45]([OH:47])[CH3:46])[CH2:21][O:22][C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:12][CH2:13][CH2:14][S:15]([NH:18][CH2:19][CH:20]([CH2:44][C:45](=[O:47])[CH3:46])[CH2:21][O:22][C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:17])=[O:16]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)CC(C)=O
Reaction time: 0.08 h

Procedure:
To a cooled solution of 0.0645 ml (0.75 mM) of oxalyl chloride in 50 ml of dichloromethane at -78° C., is added 0.106 ml (1.5 mM) of dimethylsulfoxide dropwise and the mixture is stirred for another 5 minutes. To this mixture is added a solution of 285 mg (0.5 mM) of 1-(3-chloropropylsulfonylamino)-2-(2-hydroxypropan-1-yl)-3-octadecylcarbamoyloxypropane m10 in 2 ml of dichloromethane at -70° C. with vigorous stirring. The mixture is allowed to react at -70° C. for 15 minutes and 0.836 ml (6 mM) of triethylamine is added. After allowing the temperature of the reaction mixture to rise to room temperature, the product is isolated with dichloromethane extraction. The dichloromethane layer is washed with 2N aqueous hydrochloric acid, water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated to obtain crude product of the titled compound IIIm1.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH:25]=O)[C:18]=2[O:17]1.CO.[BH4-].[Na+]>C(O)=O>[CH3:15][C:16]1([CH3:27])[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:18]=2[O:17]1
Reactant: CC1(C)Cc2cccc(C=O)c2O1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Temperature: 90 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
A mixture of 2-phenoxy-phenylamine (350 mg, 1.89 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbaldehyde (500 mg, 2.83 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (216 mg, 5.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5-10% B, 80 g, 3 CV, 60 mL/min) to afford 560 mg (86%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine as a colourless oil.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Cl[C:59]1[N:66]=[CH:65][CH:64]=[CH:63][C:60]=1[C:61]#[N:62]>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:59]1[N:66]=[CH:65][CH:64]=[CH:63][C:60]=1[C:61]#[N:62]
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C#N)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloronicotinonitrile. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:6]([F:16])[C:5]([C@H:17]([NH:20][CH2:21][C:22]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=[N:25][CH:26]=2)[CH2:18][CH3:19])=[CH:4][CH:3]=1.Cl.CCOC(C)=O.C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:17]([NH:20][CH2:21][C:22]2[NH:23][CH:24]=[N:25][CH:26]=2)[CH2:18][CH3:19])=[C:6]([F:16])[C:7]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC[C@@H](NCc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC[C@@H](NCc1cnc[nH]1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 56.9 %

Procedure:
To (6-Chloro-2-fluoro-3-{(R)-1-[(3-trityl-3H-imidazol-4-ylmethyl)-amino]-propyl}-phenyl)-pyridin-3-yl-methanone (0.208 g, 0.33 mmol) suspended in acetone (2 ml) treated with saturated HCl/EtOAc, ethanol added till all in solution stirred at ambient for 18 hours, concentrated then purified by Prep HPLC to give [(1R)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propyl](1H-imidazol-5-ylmethyl)amine (0.07 g), MS: [M+H] 373
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[O:10])[CH:5]=[C:4]([CH3:22])[N:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:22][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH3:21])[S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH2:16][CH2:15]2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CNC1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)S(=O)(=O)c3ccccc3)CC2)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) mixture of 1-(2,6-dimethyl-pyridin-4-yl)-3-[2-(4-methylamino-piperidin-1-yl)-ethyl]-urea (Example E1., 0.3 mmol) and TEA (0.5 mL, 0.35 mmol) in CH2Cl2 (2 mL) is added a solution of benzenesulfonyl chloride (53.0 mg, 0.3 mmol) in CH2Cl2 (1 mL). The mixture is stirred at r.t. for 15 h and evaporated. the residue is purified by HPLC to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[CH2:25]1[CH2:30][CH2:29][C:28]([CH2:35][NH2:36])([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]1.C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:36][CH2:35][C:28]2([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27]2)=[O:22])[N:4]=1)#[N:2]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCC2(CC(=O)O)CCCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), gabapentin (96 mg, 0.56 mmol, TCI) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes with 0.5% formic acid) to give the title compound in 11 mg. MS: (−) m/z 458.00 (M-1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[N:29]([C@H:30]2[C@H:35]([OH:36])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[C:28](=[O:44])[CH2:27][S:26]1>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:27]4/[C:28](=[O:44])[N:29]([C@H:30]5[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32][CH2:31]5)[C:25](=[O:24])[S:26]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[4-Fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [4-fluoro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 5) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxy-piperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[CH3:21]>C(OCC)(=O)C>[CH2:35]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:28][CH2:27]1)[CH3:36]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CCCC1CCN(CCN)CC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCCC1CCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[4-[3-(diethylamino)propyl]-piperidin-1-yl]ethanamine in yield of 92% of theory. Colourless crystals, m.p. 165°-166° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C.C1COCC1>[C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:7](=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 53.1 %

Procedure:
To a 200 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 3.16 g (21.2 mmom) of 1-ethyl-3-tert-butyl-cyclopentadiene and 100 ml of THF were charged under a nitrogen atmosphere. In the ice/methanol bath, 14 ml (22 mmol) of 1.58M n-butyllithium hexane solution was added dropwise over 45 minutes and stirred for 4 hours. Thereto, 8 ml of hexamethylphosphoric triamide, subsequently 5.85 g (32.1 mmol) of benzophenone were charged, and the solution was stirred for 27 hours at room temperature. The reaction solution was poured into 400 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 150 ml of ether. The obtained organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate and the solvent was distilled off, and purified by column chromatography to obtain 3.51 g of an orange solid. The yield was 53%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[NH:56](CC)CC.[C:61]([NH:78][C@@H:79]([C:81](O)=[O:82])[CH3:80])([O:63][CH2:64][CH:65]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]2[C:66]1=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:62].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC#N.CCCCCCC>[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13]([NH:56][C:81](=[O:82])[C@H:79]([NH:78][C:61]([O:63][CH2:64][CH:65]1[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2[C:76]2[C:77]1=[CH:72][CH:73]=[CH:74][CH:75]=2)=[O:62])[CH3:80])[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCNCC
Reactant: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H](NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a stirred solution of 3 (400 mg, 0.53 mmol) in CH3CN (30 mL) at rt was added Et2NH (1.5 mL). After stirring for 3 h at rt the reaction mixture was diluted with heptane (60 mL) and concentrated to give the crude amine as a colourless oil. To a stirred solution of Fmoc-D-alanine (198 mg, 0.636 mmol) in CH3CN (25 mL) was added EDAC.HCl (122.0 mg, 0.634 mmol), HOBt (86 mg, 0.636 mmol) and DIEA (502 μl, 1.91 mmol). After stirring at rt for 15 minutes the crude amine was then added and the reaction mixture stirred for 18 h, solvent removed and the residue dissolved up in CH2Cl2 (50 mL), washed with water (15 mL) 10% HCl (15 mL), 5% NaHCO3 (15 mL) and sat NaCl (15 mL) solutions, dried (Na2SO4), filtered, and solvent removed to give a off white solid which was recrystallised from CH3CN to give 4 as a white solid (670 mg, 81%): mp=195-197° C.; [α]22D +5.1 (c 0.50, CHCl3); IR νmax 3267, 3054, 1744, 1706, 1635, 1531.1 cm−1; 1H NMR 400 MHz 7.75 (d, J=7.5 Hz, 2H), 7.52 (d, J=7.0 Hz, 2H), 7.39 (m, 7H), 7.26-7.15 (m, 13H), 6.79 (s, 1H), 6.62 (s, 1H), 5.47 (s, 1H), 4.43-4.28 (m, 4H), 4.13 (m, 1H), 4.01 (m, 1H), 3.88 (s, 2H), 3.63 (s, 3H), 2.81 (m, 1H), 2.52 (m, 1H), 2.26, (m, 1H), 1.30 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H); 13C NMR 100 MHz 172.7, 171.1, 170.2, 156.1, 144.4, 143.9, 143.8, 141.4, 129.6, 128.3, 127.9, 127.2, 127.1, 125.1, 120.1, 58.5, 52.7, 52.3, 50.8, 47.2, 41.0, 33.5, 30.4, 19.3, 19.0, 17.7; MS m/z 849.2 (M+Na)+, 865.1 (M+K)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].[H-].[Na+].O>O1CCCC1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:34])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CS(N)(=O)=O
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide and 0.73 g (4.7 mmol) of carbonylduimidazole were dissolved in 80 mL of tetrahydrofuran and 5 mL of dimethylformamide and stirred for 30 minutes at ambient temperature and for 2 hours at 90° C. In parallel, 0.55 g (5.8 mmol) of methanesulfonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 mL of dimethylformamide and stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature, 50 mL of water were added and the pH value was adjusted to 6.8. The solution was extracted 4× with methylene chloride, the combined organic phases were dried over sodium sulfate and evaporated down. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44% of theory), C26H25N7O4S (531.6); Rf value: 0.72 (silica gel; dichloromethane/methanol=9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:10]([OH:11])=[O:9])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CCc2ccccc2C(=O)O)cc1

Procedure:
To 280 ml of an ethanol solution containing 20.0 g (79.3 mmol) of 3-(4-methoxybenzylidene)phthalide were added 16.6 ml (119 mmol) of triethylamine and Raney nickel (available from Kawaken Finechemical, developed nickel catalyst NTD-65, 24 ml), and the resulting mixture was stirred at 80° C. for 2.5 hours under pressure with hydrogen (10 atm).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[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].[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:19][CH:20]([CH3:22])[CH3:21])[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]
Reactant: CC(C)C=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1N=CC(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (0.940 g, 3.88 mmol) in 20 mL of toluene and 5 mL of isopropanol was treated with isobutyraldehyde (0.800 mL, 8.81 mmol) and pyridinium p-toluenesulfonate (0.098 g, 0.39 mmol) and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 48 h, the reaction mixture was concentrated under reduced pressure and dissolved in CHCl3. The organic portion was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown oil which solidified under vacuum to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isobutylideneamine (1.15 g) as a tan solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[OH:17].[Na+].[I-].[Na+]>CS(C)=O>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH:2]=[O:17]
Reactant: COc1ccc(CCCCBr)c(OC)c1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCCC=O)c(OC)c1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromobutyl)-2,4-dimethoxybenzene (11.0 g, 40.2 mmol), sodium hydrogen carbonate (6.75 g, 80.3 mmol) and sodium iodide (9.03 g, 60.2 mmol) in DMSO (80 mL) was stirred at 105° C. for 1.5 h. The reaction mixture was allowed to cool to some extent after which ice water (240 mL) was added. The mixture was extracted with diethyl ether (2×200 mL), washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane-EtOAc, 80:20) yielding the title compound as a colorless liquid (3.56 g): 1H NMR (CDCl3 -d) 9.74 (t, J=1.8 Hz, 1 H), 7.00 (d, J=7.9 Hz, 1 H), 6.45-6.40 (m, 2 H), 3.79 (s, 3 H), 3.79 (s, 3 H), 2.59 (t, J=7.4 Hz, 2 H), 2.44-2.39 (m, 2 H), 1.90 (quintet, J=7.4 Hz, 2 H); 13C NMR (CDCl3 -d) 202.91, 159.32, 158.28, 130.14, 121.90, 103.78, 98.44, 55.28, 55.16, 43.25, 28.80, 22.50; MS (EI, 70 eV): m/z (rel.int.) 208 (M+, 31), 164 (44), 151 (100), 121 (76), 91 (16).