Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:26])/[CH:23]=[CH:24]/[CH3:25]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:22](=[O:26])[CH:23]([CH2:24][CH3:25])[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: C/C=C/C=O
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: CCC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Yield: 80 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and trans-crotonaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 18 as an off-white solid (85 mg, 80%). Analytical data for 18: 1H NMR (500 MHz, CDCl3) δ 9.43 (br s, 1H), 7.91 (ddd, J=9.3, 6.1, 3.2 Hz, 1H), 7.37-7.28 (m, 3H), 7.15-7.03 (m, 3H), 7.02-6.93 (m, 1H), 4.31 (d, J=6.9 Hz, 1H), 3.06 (q, J=6.8 Hz, 1H), 1.89-1.78 (m, 1H), 1.31-1.20 (m, 1H), 1.04 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 159.1 (d, JCF=243.5 Hz), 155.4 (d, JCF=240.5 Hz), 149.3, 137.1, 136.4, 129.2, 128.2, 127.7, 118.5 (dd, JCF=13.1, 9.2 Hz), 117.1 (dd, JCF=25.7, 8.8 Hz), 116.5 (dd, JCF=24.9, 9.5 Hz), 114.5 (dd, JCF=27.0, 4.0 Hz), 110.5 (d, JCF=3.9 Hz), 47.8, 39.1, 20.4, 11.9; IR (film) cm−1 2968, 2933, 2877, 1773, 1763, 1618, 1528, 1482, 1464, 1388, 1174, 1138, 1115, 1089, 1067, 766, 736, 699; LRMS (ESI): Mass calcd for [M+H]+ C20H17F2N2O2: 355.1. found 355.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 15% IPA/hexanes 1.0 mL/min, 280 nm), Rt1=20.2 min (major), Rt2=36.1 min (minor)); er=>99:1.
Reaction SMILES: OS([C:5]([F:8])(F)F)(=O)=O.[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24]C([Sn](C)(C)C)=[C:22]2[C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1)=[O:12].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.[Al]>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24][C:5]([F:8])=[C:22]2[C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:35]=2)=[CH:16][CH:17]=1)=[O:12]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C([Sn](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: [Al]
Solvent: ClCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(F)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 0.5 h
Yield: 5 %

Procedure:
An analogous procedure to that described in Marcus A. Tius and Joel K. Kawakami Tetrahedron 1995, 51, 3997 was Used. A Solution of Triflic Acid (37 μL, 0.42 Mmol) in 0.37 mL CH2Cl2 was added to a mixture of Ag2CO3 (83 mg, 0.30 mmol) in 2.8 mL CH2Cl2 and the flask was covered in aluminum foil. After 30 min., a solution of 57 (ca. 0.38 mmol, directly from above) and 2,6-di-tert-butyl-4-methylpyridine (49 mg, 0.24 mmol) in 2.8 mL CH2Cl2 was added dropwise by cannula, rinsing with 1 mL CH2Cl2. At this time, a solution of XeF2 (82 mg, 0.48 mmol) in 5.5 mL CH2Cl2 was added by cannula. The reaction was stirred for 1 h and then was quenched by addition of 10 mL saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (3×30 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on a Teledyne Isco Combiflash unit (40 g silica gel column, 0%→100% ethyl acetate/hexanes) followed by HPLC (Phenomenex 50 mm×250 mm silica gel column, 5% ethyl acetate/hexanes) to give the title compound (12 mg, 5%).
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CCOC(C)=O>[C:21]([O:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[C:5]([CH3:13])([CH3:14])[CH2:4][CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CC1(OC(C)=O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (+/−) ethyl 2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate (Compound E47, 200.0 mg, 0.586 mmol) and 4-NN-dimethylaminopyridine (86.0 mg, 0.703 mmol) in 4.0 mL CH2Cl2 at 0° C. was added acetic anhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed to room temperature and stirred overnight. The reaction was warmed to 50° C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL). The solution was washed with H2O, saturated aqueous NaHCO3, 10% aqueous HCl, and saturated aqueous NaCl, before being dried over MgSO4. Removal of the solvents under reduced pressure followed by column chromatography afforded the title compound as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O-:24])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O:24][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COCc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.6 ml of DMF was added 4.2 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (34 mg) was added, and the mixture was stirred for 1 hour, diluted with 30 ml of ethyl acetate, and washed with 20 ml of saturated aqueous saline and 20 ml of semi-saturated squeous saline. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The concentrate was purified by column chromatography on silica gel (chloroform:methanol=95:5) to give the title compound was obtained in a yield of 18.4 mg.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)CCCN
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethyl-1,3-propanediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[NH:8][C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(O)(=O)C>[CH3:14][C:5]1([CH3:15])[C:4]2[CH:3]=[C:2]3[NH:1][C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:12][C:11]3=[CH:10][C:9]=2[NH:8][C:7](=[O:13])[CH2:6]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccccc4)[nH]c3cc21

Procedure:
3.0 g. 6,7-diamino-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one and 1.5 ml. benzaldehyde were stirred for 20 hours in 50 ml. ethanol and 5 ml. glacial acetic acid. Half of the solvent was removed in a vacuum and the remainder was mixed with 50 ml. water and filtered off with suction. After recrystallisation from ethyl acetate, there were obtained 2.4 g. of the title compound; m.p. 296 -298° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]1[C:33]2([CH2:37][CH2:36][NH:35][CH2:34]2)[CH2:32]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)=[N:13][C:14]([N:35]2[CH2:36][CH2:37][C:33]3([CH2:31][CH2:32]3)[CH2:34]2)=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2(CC2)CN1
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ccccc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCC4(CC4)C3)ncc2C(=O)NCc2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 17.9 %

Procedure:
In absolute anhydrous THF (15 mL) were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-formamide (180 mg, 0.41 mmol) and 5-azaspiro[2.4]heptane (59 mg, 0.61 mmol). The solution was cooled in an ice bath, and triethylamine (82 mg, 0.82 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h then was quenched with water. The reaction mixture was extracted with DCM. The organic phase was dried over sodium sulfate and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=50/1) to give the product as a solid (35 mg, 18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13].CC1CCCCN1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1Br
Agent: CC1CCCCN1
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br

Procedure:
2-Bromo-5-chlorosulfonylbenzoic acid is prepared by reacting o-bromobenzoicacid with chlorosulfonic acid by the method of Example 1. This is reacted with 2-methylpiperidine by the procedure of Example 6. Recrystallization from acetone-hexane yields the product, m.p. 148°- 150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (CAS Reg. No. 170850-75-6) (1 g, 3.48 mmol) in 20 ml of CH2Cl2 was added pyridine (3.9 ml) and p-toluene sulphonyl chloride (0.7 g, 3.67 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 72 hours. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (100 ml) and washed with saturated citric acid solution (50 ml) then water (50 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate:heptane (3:10) to give the title compound (1.5 g, 98%) as a colourless gum.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[N:28]=[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.O>O1CCCC1>[CH3:17][C:18]1[N:28]=[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1nc2c(C=O)cccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccn2nc(C)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.42 g, 35.5 mmol) in tetrahydrofuran (35 mL) was added a solution of ethyl diethylphosphonoacetate (7.10 mL, 35.5 mmol) in tetrahydrofuran (5.0 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde (5.20 g, 32.3 mmol) in tetrahydrofuran (60 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.30 g, yield 84%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[C:10]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]3[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:17]([O:16][CH2:14][CH3:15])[CH:18]=3)[CH2:22][CH2:23]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)nc4cc(Cl)ccc34)CC2)ccc1OC
Yield: 2.6 %

Procedure:
A solution of 2,4,7-trichloro-quinazoline (35.0 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP): 461.3 [M+H]+.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[CH:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[Br:22])[CH2:7][CH2:8]1)=[O:2]
Reactant: COc1ccc(N2CCN(C=O)CC2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N2CCN(C=O)CC2)c(Br)c1

Procedure:
Sodium acetate (VI, 9.702 g, 0.1182 mol) is added to a mixture of 1-formyl-4-(4-methoxyphenyl)piperazine (VI, 5.17 g, 23.5 mmol) and acetic acid (102 ml). When the sodium acetate had completely dissolved, a solution of bromine (7.912 g, 49.5 mmol) in acetic acid (9.5 ml) is added over 14 min. After 35 min the mixture is poured into water and extracted exhaustively with dichloromethane. The combined organic extracts are backwashed with water, followed by saturated sodium bicarbonate, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel eluting first with ethyl acetate/dichloromethane (10/90) and then ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give 1-formyl-4-(2-bromo-4-methoxyphenyl)piperazine (VII), NMR (CDCl3) 2.94, 3.55, 3.74, 3.78, 6.83, 6.97, 7.16 and 8.10 δ.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:1]([C:3]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCNCC2)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(NCC2CCN(C3CCN(C)CC3)CC2)cc1
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A solution of Compound 165 (0.250 g, 0.69 mmol) in 1,2-dichloroethane (3.5 mL) was added with 1-methyl-4-piperidone (0.128 mL, 1.04 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 166 (0.172 g, 0.37 mmol, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([O:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:26]=[CH2:25]
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (5.00 g) in dimethyl formamide (150 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (15.47 g). The reaction mixture was stirred at room temperature for 30 mins then allyl bromide (2.39 ml) was added, and stirring continued for a further 36 h at room temperature. The mixture was poured into water (200 ml) and the emerging precipitate was filtered and triturated with boiling methanol to give the desired compound as a beige solid in 50% yield. 1H NMR (360 MHz, DMSO-d6) 5 4.04 (2H, dd, J=6.45 Hz, J=1.84 Hz, OCH2CHCH2), 5.08 (2H, m, OCH2CHCH2), 5.88 (1H, m, OCH2CHCH2), 7.23 (1H, dd, J=12.45 Hz, J=3.00 Hz, 6-H), 7.36 (6H, m, Ph+8-H), 7.81 (1H, d, J=12.45 Hz, 5-H), 11.94 (1H, bs, NH).
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[CH:5]2.[H-].[Na+].[CH3:20][C@H:21]1[CH2:23][O:22]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[C:3]([C:14]([F:15])([F:16])[F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C@H:21]([OH:22])[CH3:23])[CH:6]=[CH:5]2
Reactant: O=C(O)c1cc2c(C(F)(F)F)c(F)ccc2[nH]1
Reactant: C[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[C@@H](O)Cn1ccc2c(C(F)(F)F)c(F)ccc21
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A suspension of 0.8 g of 5-fluoro-4-trifluoromethylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 16 ml of tetrahydrofuran. 122 mg of sodium hydride dispersion were added and the mixture was stirred for 1 hour. Subsequently, 0.46 ml of (S)-methyloxirane was added and the reaction mixture was stirred at room temperature for 60 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 40 g of silica gel with hexane-toluene (1:1) and subsequently with toluene-ethyl acetate (15:1). There was obtained 0.3 g (35.5%) of (R)-1-(5-fluoro-4-trifluoromethyl-indol-1-yl)-propan-2-ol as light brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19]C(=N)OC>C(O)(=O)C.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:19]([C:18]([Cl:25])([Cl:24])[Cl:17])[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: COC(=N)CC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Yield: 81.2 %

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (16.5 g, 58.90 mmol) in acetic acid (55 mL) was added methyl 2,2,2-trichloroethanecarboximidate (11 g, 62.35 mmol) dropwise with stirring. The reaction mixture was stirred at room temperature for 3 hr and then at 45° C. overnight. The resulting solution was diluted with 100 mL of water and the precipitate was collected by filtration. The solid was dried in a vacuum oven to give 19.5 g (81%) of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a light brown solid: 1H NMR (300 MHz, DMSO) delta 8.58 (d, J=4.8 Hz, 1H), 7.68 (t, J=4.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.21 (s, 2H), 7.01 (d, J=5.1 Hz, 3H); LC-MS: m/z=+408 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:30])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[S:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[Cl:31].[OH-].[Na+].CO>CCCCCC>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:30])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[Cl:31]
Reactant: COC(=O)c1ccc(CCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccc(C(=O)O)s2)cc1Cl
Yield: 86 %

Procedure:
A solution of methyl 5-[2-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethyl]-2-thiophenecarboxylate (0.274 g) in a 2N sodium hydroxide solution (4.5 ml) and methanol (20 ml) was stirred at room temperature under nitrogen for 28 h. Dowex 50 (H+) methanol-washed ion exchange resin was added portionwise to neutralise the mixture to pH7. The mixture was filtered and evaporated in vacuo to give an orange solid. Trituration with hexane gave the title compound as a yellow solid (229 mg), m.p. 178°-185° (decomp).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].O>CN1C(=O)CCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc2cnccc2c2cnccc12
Reactant: Nc1cccc(Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cccc(Nc2nc3cnccc3c3cnccc23)c1
Temperature: 120 °C

Procedure:
5-chloropyrido[4,3-c][1,7]naphthyridine (10 mg) was mixed in NMP (0.3 ml) with 3-chloroaniline (60 ul) and the mixture was heated at 120° C. for 10 min. Water was added and the resulting solid was filtered and dried. N-(3-chlorophenyl)pyrido[4,3-c][1,7]naphthyridin-5-amine was isolated as a solid (5 mg). LCMS (ES)>95% pure, m/z 307 [M+1]+.