Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[C:18]4[C:23](=[CH:24][C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19]4>CCOC(C)=O.CCCCCC>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:24]=[C:23]4[C:18](=[CH:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22]4
Reactant: CCOC(=O)c1cc2c(ccc3cc4ccccc4cc32)[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc2c3cc4ccccc4cc3ccc2n1C
Yield: 97 %

Procedure:
Using the procedure described in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-naphth[2,3-e]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 97% yield of ethyl 3-methyl-3H-naphth[2,3-e]indole-2-carboxylate, mp 141°-144°, (EtOAc/hexane), (C,H,N).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Ba+2].[OH-].Cl>C(O)C>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:2](=[O:3])[CH:1]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1cccc(O)c1
Yield: 93.6 %

Procedure:
To a 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser, was charged 2.7 g (0.02 moles) of 3-hydroxyacetophenone, 2.1 g (0.02 moles) of benzaldehyde, 2.0 g (0.011 moles) of barium hydroxide, monohydrate, and 20 ml of absolute ethanol. The reaction mixture was refluxed for a total of 2.5 hours, after which it became thick and difficult to stir. Upon cooling, the resulting solid was dissolved in 100 ml. of 1 N aqueous hydrochloric acid, and another solid was observed to precipitate from this solution. The solid was collected by vacuum filtration, and washed with 100 ml. of water, then 100 ml. of hexane and dried in vacuuo at 40° C. for 24 hours. As a result, 4.2 g (93% yield) of 3'-hydroxychalcone was isolated as a tan solid, MP=143-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH2:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([NH:25][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2ccc(Cl)nc12
Yield: 80 %

Procedure:
In a similar fashion using route 14 general procedure 27, 2-nitrobenzene-1-sulfonyl chloride (800 mg, 3.65 mmol), 2-chloro-quinolin-8-ylamine (Intermediate 26), pyridine (0.67 ml, 0.8 mmol) and DMAP (cat.) in DCM (30 ml) gave the title compound (800 mg, 80%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)C.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]O)=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][O:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:16])=[O:15])=[CH:13][CH:12]=2)=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)CNC(=O)c1ccc(O)cc1
Reactant: CC(C)Oc1ccc(CCO)cc1
Product: CC(C)Oc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 82 %

Procedure:
The same reaction as in Example 78 (78a) was conducted using N-(4-hydroxybenzoyl)glycine ethyl ester (which is the compound disclosed in J. Med. Chem., (1999), 42, 1041-1052, 397 mg, 2.20 mmol) and 2-(4-isopropoxyphenyl)ethanol (which is the compound disclosed in J. Chem. Soc. Perkin Trans. 1, (1983), 619-624, 447 mg, 2.00 mmol) to give 636 mg of the title compound (white powder, yield: 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[C:14]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:15]=3[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:14]2[C:13]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]#[C:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:10][CH:9]=3)=[O:12])=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:16][C:15]=2[CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Step 2 (195 mg, 0.46 mmol) was dissolved in 3 mL of methylene chloride and treated with 127 mL of triethylamine and methanesulfonyl chloride (53 mL, 0.68 mmol) and stirred 30 minutes at room temperature. The reaction was concentrated and extracted into ethyl acetate. The combined organic layers was washed with brine and dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (205 mg) was obtained.
Reaction SMILES: NC(N)=S.[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6].[C:28]([N:32]=[C:33]=[S:34])([CH3:31])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:5]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:33]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[S:34])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:10][C:9]1([CH3:27])[CH3:26])(=[O:7])[CH3:6]
Reactant: CC(C)(C)N=C=S
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: NC(N)=S
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=S)NC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Thiourea formation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butyl isothiocyanate (7.5 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 18.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([F:24])[C:15]=1[CH2:25][CH2:26][C:27]1[N:28]=[C:29]2[CH:35]=[CH:34][N:33]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=1.[Br:45]C(Cl)(Cl)C(Br)(Cl)Cl>O1CCCC1>[Br:45][C:34]1[N:33]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:30]2=[N:31][CH:32]=[C:27]([CH2:26][CH2:25][C:15]3[C:16]([F:24])=[C:17]([O:22][CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=3[F:13])[N:28]=[C:29]2[CH:35]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: COc1cc(OC)c(F)c(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70456.4 %

Procedure:
To a stirred solution of N,N-diisopropylamine (0.150 mL, 1.07 mmol) in tetrahydrofuran (0.48 mL) at 78° C., n-butyllithium (2.5 M in hexanes, 0.428 mL, 1.07 mmol) was added dropwise. After a white precipitate formed, the mixture was warmed up to 0° C. for 10 minutes. The resulting solution was added to a stirred solution of 2-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (400 mg, 0.871 mmol) in tetrahydrofuran (3 mL) at 78° C. After 10 minutes, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (0.283 g, 0.870 mmol) in tetrahydrofuran (2 mL) was added dropwise. After another 1 hour, the reaction mixture was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% EtOAc in hexanes) to give the desired product (330 g, 70%). LCMS calculated for C22H19BrF2N3O4S (M+H)+: m/z=538.0. Found: 538.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](O)=[O:23])([O-:18])=[O:17]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:22](=[O:23])[C:21]1[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-nitro-5-trifluoromethyl-benzoic acid (CAS RN 328-80-3) after a reaction time of 48 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:80). The product-containing fractions were pooled and concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed twice with 30 mL 1M aqueous HCl and with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (66%). MS (ESI): m/z=416.121 [M+H]+.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].CN(C=O)C.[F:19][C:20]1[N:21]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[C:23]([CH:25]=O)[N:24]=1>C(COC)OC>[C:1]([CH:3]=[CH:25][C:23]1[N:24]=[C:20]([F:19])[N:21]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: N#CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Examples 15 and 16: Diethyl cyanomethylphosphonate was converted to its anion with sodium hydride in dimethoxyethane solution. An equal volume of DMF was added, followed by 2-fluoro-4-formyl-1-triphenylmethylimidazole. Reaction at room temperature gave 4-(2-cyanovinyl)-2-fluoro-1-triphenylmethyl imidazole. A suspension of this in MeOH was reduced by magnesium turnings to give 4-(2-cyanoethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 2.71 (t, 4H); 6.42 (s, 1H); 7.1-7.4 (m, 15H).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:31][CH:30]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH:34]=[CH:33][C:32]1[CH:38]=[CH:39][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=CC(=O)O)cc1
Product: COc1ccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 65 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 4-methoxycinnamic acid under the conditions described in example 86 to yield 65% of the desired product.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]C(=O)C=2C=1O)[C:9]3=[O:44].[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:52](=[N:51]\[CH2:4][CH2:3][CH2:2][OH:1])/[C:53]=2[C:54]=1[OH:55])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: NCCCO
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)/C(=N/CCCO)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 3-aminopropan-1-ol (107 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (25 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(3-hydroxypropylimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (61.3 mg, 56.6%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.94 (s, 1H), 7.89 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.48 (s, 1H), 6.12 (s, 1H), 5.27 (s, 1H), 5.02-4.99 (m, 1H), 4.74 (d, J=9.5 Hz, 2H), 4.12 (dd, J=14.2, 7.1 Hz, 2H), 3.83 (s, 3H), 3.81-3.72 (m, 9H), 3.68 (br s, 1H), 3.60 (s, 3H), 3.40 (s, 4H), 3.13 (t, J=9.1 Hz, 1H), 2.53 (s, 1H), 2.36 (s, 3H), 2.02-2.00 (m, 2H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC 97.5% (AUC), tR=10.36 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:57]=[CH:56][C:45]([C:46]([NH:48][CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)=[O:47])=[CH:44][C:43]=1[CH3:58]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:57]=[CH:56][C:45]([C:46]([NH:48][CH2:49][C:50]6[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=6)=[O:47])=[CH:44][C:43]=5[CH3:58])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)NCc2cccnc2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCc4cccnc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 4-bromo-3-methyl-N-pyridin-3-ylmethyl-benzamide (60 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-N-pyridin-3-ylmethyl-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-301) as a grayish white powder (32 mg, 47%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:6]1.[OH-].[Li+].O>CO>[Cl:24][C:21]1[S:20][C:19]([C:7]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:25])=[O:2])[N:6]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (7.60 mmol) of the ester from Example 153A are dissolved in 77 ml methanol and treated with a 1 N solution of lithium hydroxide in water (30.3 ml, 30.4 mmol). The mixture is stirred overnight at RT, then freed of methanol on the rotary evaporator and diluted with 200 ml water. After addition of 1 N hydrochloric acid to a pH value of 2, the product precipitates out as a white solid, which is isolated by filtration and drying in high vacuum. 2.45 g (88% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]=[CH:11][CH3:12]>>[N:1]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C=CC
Reactant: O=[N+]([O-])c1ccccc1
Product: c1ccc2ncccc2c1
Temperature: 220 °C

Procedure:
Twenty grams of nitrobenzene, 1.1 grams of iodo (4-iodophenyl) bis(triphenylphosphine)palladium catalyst and 39 grams of liquified propylene was placed in a 300 ml. stainless steel rocking autoclave and cooled to -78° C. The vessel was sealed and heated to 220° C. This temperature was maintained for 24 hours. The autoclave was then cooled and vented. The reaction mixture removed from the autoclave was analyzed by gas chromatography and found to contain 0.32 grams of quinoline (1.9% efficiency) 5.8 grams of aniline (44.0% efficiency) and 2.8 grams of unreacted nitrobenzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.[CH3:18][C:19]([CH:22]=[O:23])([CH3:21])[CH3:20].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([CH:22]1[O:17][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[O:23]1)([CH3:21])([CH3:20])[CH3:18]
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Reactant: CC(C)(C)C=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C1OC(c2cccnc2)C(c2ccccc2Br)O1
Reaction time: 8 h

Procedure:
8 g (0.027 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 4.5 g (0.0525 mol) of pivaldehyde were dissolved in 100 ml of methylene chloride. This was achieved by adding 4.35 ml (0.0525 mol) of boron trifluoride etherate dropwise at room temperature and stirring overnight. Thereafter, the mixture was poured onto ice water and was neutralized with NaHCO3 solution. The organic phase was washed with water, dried over Na2SO4 and filtered, and the filtrate was evaporated down. The crude product was purified by chromatography.
Reaction SMILES: C(Cl)(Cl)Cl.Cl.[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([OH:12])=O)[CH2:8]1.ClC(OCC(C)C)=O.[CH:24]1([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([NH:33][CH2:32][CH:24]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:12])[CH2:8]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: NCC1CCCCCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCCC(C(=O)NCC2CCCCCCC2)C1
Yield: 62 %

Procedure:
To 80 ml of chloroform were added 3.59 g of 1-methylnipecotic acid hydrochloride and 6.26 ml of triethylamine. Thereto was added 3.0 g of isobutyl chloroformate under ice cooling and stirring. The mixture was stirred for 30 minutes. Thereto was added 3.1 g of cyclooctylmethylamine, and the mixture was subjected to a reaction for 2 hours at room temperature. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was purified by a Silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 3.3 g of 1-methyl-3-cyclooctylmethylaminocarbonylpiperidine.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([CH2:12][C:13]1[N:17]([CH:18]2[CH2:20][CH2:19]2)[C:16]2[CH:21]=[C:22]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:23]([F:25])=[CH:24][C:15]=2[N:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.O.[O:51]1CCC[CH2:52]1>>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[CH:12]=[C:13]2[N:17]([CH:18]3[CH2:19][CH2:20]3)[C:16]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[C:23]([F:25])=[CH:24][C:15]=3[N:14]2[C:52]1=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(=O)NOCc2ccccc2)n3C2CC2)CC1
Reactant: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 5 %

Procedure:
tert-Butyl 4-[2-[[(benzyloxy)carbamoyl]methyl]-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (779 mg, 1.18 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N,N'-carbonyldiimidazole (480 mg, 2.96 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (225 mg, 1.48 mmol). The suspension obtained is poured into water (200 ml) and then extracted with ethyl acetate. The organic phase is washed in succession with water and 10 percent sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate/n-hexane 8:2). The product is crystallized from ethyl acetate/n-hexane. There are obtained 42 mg (5%) of tert-butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:16][CH:17]=O.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][N:3]2[C:4]3[C:9](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1 mL of a chloroform solution containing methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-5-carboxylate, 26.5 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 6.9 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 24.2 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 9.3 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.