Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[C:15]1(C)C=CC=C[C:16]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[CH2:16]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Temperature: 85 °C
Yield: 738.1 %

Procedure:
A solution of N-(5-bromopyridin-2-yl)-2,2-dimethylpropionamide (5.60 g, 21.8 mmol) in acetonitrile (20 ml) and triethylamine (5.49 ml) was treated with palladium acetate (177 mg, 0.8 mmol) and tri-o-tolylphosphine (795 mg, 2.6 mmol). The mixture was placed in a pressure reactor under 130 psig of ethylene pressure and heated at 85° C. for 18 hours. The reaction mixture was cooled, vented, diluted with ethyl acetate and filtered. The ethyl acetate solution was washed sequentially with dilute citric acid, water and brine and then dried over sodium sulfate. The dried solution was filtered and evaporated. Chromatography of the residue on silica gel, eluting with dichloromethane/ethyl acetate (24:1) afforded 3.92 g (88%) of the title product as an oil. 1H NMR (CDCl3): δ=8.21 (m, 2 H); 8.03 (br, 1 H); 7.76 (d of d, 1 H); 6.63 (d of d, 1 H); 5.71 (d, 1 H); 5.25 (d, 1 H); 1.29 (s, 9H). MS (Cl): m/z=205 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C(OCC)(=[O:30])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:30])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CCOC(C)=O
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc(I)cc3)ccc2O1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc(I)cc3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6-(4-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(4-iodobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 171°-173° C. (from ethyl acetate).
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].O.NC1N=C2C(N=CN2[CH:29]2[C:31]([C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:30]2([Cl:45])[Cl:44])=C(Cl)N=1>CS(C)=O>[Cl:11][C:30]([Cl:44])([Cl:45])[CH:29]=[C:31]([C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OC(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
In a 0.3-liter four-necked flask, 15.0 g (88.5 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 26.9 g (194.6 mmol) of potassium carbonate were added to 195 ml of dimethylsulfoxide, and 8.0 g (442.5 mmol) of water was then added to the resulting mixture. The resulting mixture was stirred at room temperature. Next, 42.2 g (132.9 mmol) of diisopropyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for two hours and a half at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were washed with 100 ml of water, collected by filtration, and then recrystallized from isopropyl alcohol, to give 27.1 g (60.1 mmol) of pale yellow crystals of 2-amino-6-chloro-9-(3,3-dicarboisopropoxy-2,2-dichlorocyclopropyl)purine. The yield was 67.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:23]([C:22]4[CH:26]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC[C@H]3CN(c4nc(C)cc(C)n4)[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.7 %

Procedure:
A mixture of (1R,6S)-8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (60 mg, 0.28 mmol), 5-methyl-2-pyrimidin-2-yl-benzoic acid (61.82 mg, 0.29 mmol), HOAT (56.12 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (79.1 mg, 0.41 mmol), TEA (83.5 mg, 0.83 mmol) was taken into DMF (5 mL) and stirred at 50° C. for 4 h. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). It was washed with sat. aqueous NaHCO3 solution (2×25 mL) and with water (2×60 mL). The ethyl acetate layer was dried over Na2SO4, filtered and concentrated. The crude product was purified three times on Agilent Basic HPLC system to yield the title compound (24 mg, 21%). MS (ESI) mass calcd. for C24H26N6O, 414.51; m/z found 415.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17-5.47 (m, 7H), 4.89-1.08 (m, 19H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(O[C:35]([N:37](C)[C:38]1([C:42](O)=[O:43])[CH2:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:42]([C:38]4([NH:37][CH3:35])[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC1(C(=O)N2CCC(c3cc(F)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (50.0 mg, 0.12 mmol), 1-(tert-butoxycarbonyl(methyl)amino)cyclobutanecarboxylic acid (27.5 0.12 mmol), HATU (45.8 mg, 0.12 mmol) and di-isopropylethylamine (20 μL, 0.12 mmol) in 1 mL of DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The resulting crude mixture was dissolved in 5 mL of DCM and 4 mL of TFA, and was stirred for 2 h followed by concentration in vacuo. The crude product was purified by RP-HPLC to afford (4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)(1-(methylamino)cyclobutyl)methanone; ESMS m/z 527.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([C:22]1[N:23]=[CH:24][N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:26]=1)=[O:21])[CH:14]=[CH:13]2>>[NH:25]1[CH:26]=[C:22]([C:20]([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH:16]=2)([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[OH:21])[N:23]=[CH:24]1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: Brc1ccncc1
Product: COc1ccc2cc(C(O)(c3ccncc3)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 6-(i), the reaction of 4-bromopyridine (0.92 ml) with (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was carried out to give the titled compound (0.88 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15]>>[Cl:12][C:9]1[C:10]([Cl:11])=[C:2]2[C:3]([C:4](=[O:5])[NH:13][C:14](=[O:15])[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC(N)=O
Reactant: Nc1c(C(=O)O)ccc(Cl)c1Cl
Product: O=c1[nH]c(=O)c2ccc(Cl)c(Cl)c2[nH]1

Procedure:
Prepared according to general method C from 2-amino-3,4-dichlorobenzoic acid (2.23 g) and urea (6.49 g). Yield 2.18 g (87%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 11.64 (br s, 1H), 10.87 (br s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Yield: 99 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 14.0 g, 33.7 mmol) in anhydrous DMF (50 mL) was treated with sodium azide (NaN3, 4.4 g, 67.5 mmol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 4 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (100 mL) and EtOAc (100 mL). The two layers were then separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were then washed with water (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 12.08 g, 12.2 g theoretical, 99%) as white powders. For 1023: 1H NMR (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 3H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H5FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH:6]=1)C.C1COCC1.O.O.[OH-].[Li+].Cl>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:22])=[O:3])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: CCOC(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 60 °C
Yield: 97.5 %

Procedure:
The product from Example 181a (3.0 g, 9.8 mmol) was added to a solution of THF/H2O (5:1). Lithium hydroxide monohydrate (0.82 g, 19.5 mmol) was added in one portion. The solution was warmed to 60° C. for 2 h. The reaction was cooled. Distilled water was added. The pH was adjusted to 4.0 with 10% HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaHCO3, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (2.65 g, 97%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][S:10][C:11]2[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([OH:3])=[O:2].Cl[C:23]1[C:32]2[C:27](=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[C:13]1[CH:12]=[C:11]([S:10][CH2:9][C:8]3[CH:20]=[CH:21][C:5]([CH2:4][C:1]([OH:3])=[O:2])=[CH:6][CH:7]=3)[CH:16]=[CH:15][CH:14]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: O=C(O)Cc1ccc(CSc2cccc(B(O)O)c2)cc1
Product: O=C(O)Cc1ccc(CSc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-benzylsulfanyl)phenylboronic acid and [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone according to the procedure of Example 1. MS (ES) m/z 541.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:12]([NH2:14])=O>O>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:11])[NH:14][CH:12]=[N:1][C:2]=2[CH:7]=1
Reactant: NC=O
Reactant: Nc1cc(Br)cnc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cc(Br)cnc12
Temperature: 25 °C

Procedure:
A solution of 3-amino-5-bromopicolinic acid (1.0 g, 4.6 mmol) in formamide (1.1 g, 25 mmol) was stirred at 150° C. for 4 h. After it was cooled to room temperature, the reaction mixture was poured into water (50 mL). A suspension was formed and filtered. The cake was washed with water and dried to give the desired product. MS (ESI): 226, 228 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:22]4[C:23](=[O:26])[O:24][CH2:25][C:21]=4[CH:20]=3)[CH2:13][C:12]1=[O:29])[CH2:5]2.[CH3:30][N:31](CCN(C)C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C=O)C.CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:29]=[C:12]1[CH2:13][N:14]([CH2:17][CH2:18][C:19]2[CH:28]=[CH:27][C:22]3[C:23](=[O:26])[O:24][CH2:25][C:21]=3[CH:20]=2)[CH2:15][CH2:16][N:11]1[CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:30]#[N:31])[CH:3]=2)[CH2:7]1
Reactant: O=C1OCc2cc(CCN3CCN(C4Cc5ccc(Br)cc5C4)C(=O)C3)ccc21
Reactant: CN(C)CCN(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)CC(N1CCN(CCc3ccc4c(c3)COC4=O)CC1=O)C2
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
To a solution of 1-(5-Bromo-2,3-dihydro-1H-inden-2-yl)-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (60 mg, 0.132 mmol) in 2 mL of DMF was added Zn(CN)2 (15 mg, 0.132 mmol), Pd2(dba)3 (20 mg), TMEDA (10 mg), Xantphos (10 mg), and the mixture was stirred under microwave irradiation for 3 min at 100° C. The mixture was diluted with EtOAc and then filtrated. The filtrate was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J=7.8 Hz, 1H), 7.44-7.48 (m, 2H), 7.28˜7.34 (m, 3H), 5.49˜5.57 (m, 1H), 5.26 (s, 2H), 3.19˜3.28 (m, 4H), 2.88˜3.1 (m, 6H), 2.65˜2.7 (m, 4H).
Reaction SMILES: C(B(CC)CC)C.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[C:12]([CH2:20][CH2:21][CH:22]([OH:31])[CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:11]([CH3:32])[CH:10]=1.[BH4-].[Na+].OO>C1COCC1.CO>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[C:12]([CH2:20][CH2:21][CH:22]([OH:31])[CH2:23][CH:24]([OH:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:11]([CH3:32])[CH:10]=1
Reactant: COC(=O)CC(=O)CC(O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Agent: CCB(CC)CC
Agent: OO
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(O)CC(O)CCc1c(C)cc(Cl)c2ccc(Cl)cc12
Temperature: -100 °C
Reaction time: 0.25 h
Yield: 49.4 %

Procedure:
A 1M solution of triethylborane (3.75 ml, 3.75 mmoles) was added to a solution of methyl 7-(4,7-dichloro-2-methylnaphthalen-1-yl)-5-hydroxy-3-oxo-heptanoate (0.96 g, 2.5 mmoles) in dry THF (9 ml). Air (7.5 ml) was bubbled slowly into the solution at room temperature with stirring. Stirring was continued at room temperature for 15 minutes then cooled in frozen methanol bath (-100° C.). Sodium borohydride (0.142 g, 3.75 mmoles) was added followed by the slow addition by syringe through a septum of methanol (2.7 ml) in about 10 minutes at -100° C. The reaction was stirred at -100° C. for 30 minutes. The frozen methanol bath was replaced by an ice-salt water bath and stirred for 10 minutes. Then added slowly a 30% solution of hydrogen peroxide (6.0 ml) dropwise so that the internal temperature does not exceed 5° C. Removed cooling bath and stirred at ambient temperature for 30 minutes. Made slightly acidic by the addition of 1N HCl then extracted with ethyl acetate three times. Washed the combined ethyl acetate extracts with water two times then brine, dried (MgSO4), filtered and the solvent evaporated in vacuo to leave 0.968 g of crude product which was flash chromatographed on 50×180 mm silica column eluting with 50% ethyl acetate in hexane to give 0.476 g of title compound, exact mass calc. for C18H18Cl2O3 (M-CH3OH): 352.0633; Found: 352.0638.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH3:11][CH:12]1OC(C)OC(C)O1>C(O)C(C)C>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CC1OC(C)OC(C)O1
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Solvent: CC(C)CO
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 12.5 °C
Yield: 176.6 %

Procedure:
Synthesis according to the invention: A mixture of 100.1 g of metformin hydrochloride, 36.5 g of paraldehyde and 4 g of Dowex DR-2030 in 237.8 ml of isobutanol was heated under reflux for 6 hours. The catalyst was subsequently filtered off, and some of the solvent was removed by distillation. The remainder of the solution was cooled to 10-15° C., and the white precipitate was separated off, giving 93.5 g (80.7%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([Cl:14])P(CCC)(CCC)=O)[CH3:2].C([Li])CCC.[I:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4](=[O:15])[C:5]([Cl:14])=[CH:26][C:25]1[CH:28]=[CH:29][C:22]([I:21])=[CH:23][CH:24]=1)[CH3:2]
Reactant: O=Cc1ccc(I)cc1
Reactant: CCCP(=O)(CCC)C(Cl)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)=Cc1ccc(I)cc1
Reaction time: 0.17 h

Procedure:
A stirred, cooled (−78° C.) solution of chloro-(dipropyl-phosphinoyl)-acetic acid ethyl ester (6.1 g, 23.5 mmol) in anhydrous tetrahydrofuran (70 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (14 mL, 22 mmol). After 10 min the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (2.61 g, 11.2 mmol) in tetrahydrofuran (25 mL). After 30 minutes, it was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 4-5% ethyl acetate in hexane as the eluent to afford the title compound as a 1:1 mixture of E and Z isomers (3.6 g, 95%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[N:21]([S:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])[C:20]([CH3:31])=[C:19]([C:32]([O:34]CC)=[O:33])[CH:18]=2)[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[N:21]([S:22]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:24])=[O:23])[C:20]([CH3:31])=[C:19]([C:32]([OH:34])=[O:33])[CH:18]=2)[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(S(=O)(=O)N2CCCCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Yield: 89.4 %

Procedure:
To a solution of NaOH (2.72 g, 67.8 mmol) in H2O was added to compound 4c (800 mg, 1.7 mmol) in MeOH (60 mL) and refluxed for 3 h, evaporated, diluted with H2O, acidified with conc. HCl to pH ˜2, extracted with EA (3×30 mL), washed by brine, dried with Na2SO4 and concentrated to get the compound 4d (700 mg, 90%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(=O)N3CCOCC3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with morpholine (170 mg, 2.0 mmol) and the stirring was continued for 14 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 610 mg (1.9 mmol, 94% in yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C(O)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:34][CH2:33][CH2:31][OH:32])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Reactant: NCCO
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3N=C(NCCO)C2)cc1

Procedure:
A mixture of 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (453 mg, 1.0 mmol), ethanolamine (122 mg, 2.0 mmol) and red mercuric oxide (216 mg, 1.0 mmol) was heated in n-butanol (5 ml) at reflux for 1 hour. The mixture was cooled, diluted with an equal volume of toluene and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography, eluting with ethyl acetate:methanol=4:1. Fractions containing product were evaporated yielding 7,8-dichloro-2-[2-hydroxyethylamino]-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-3H-[1,5]-benzodiazepine as a yellow foam, (345 mg, 72%).