Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][CH3:16])=[CH:13][CH:14]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.O>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([C:38]([N:15]([CH3:16])[C:12]2[N:11]=[CH:10][C:9]([CH2:8][N:6]3[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]3)=[CH:14][CH:13]=2)=[O:39])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)nc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 64.4 %

Procedure:
To 1,1-dimethylethyl (2S)-2-methyl-4-{[6-(methylamino)-3-pyridinyl]methyl}-1-piperazinecarboxylate (D96) (0.150 g, 0.469 mmol) and triethylamine (0.098 mL, 0.703 mmol) in DCM (7 mL) under argon was added 6-chloro-3-pyridinecarbonyl chloride (0.099 g, 0.562 mmol). The mixture was stirred at room temperature for ˜0.3 h then diluted with DCM and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with EtOAc/DCM gave the title compound as a white colourless gum (0.139 g). δH (CDCl3, 400 MHz) 8.33 (1H, d), 8.19 (1H, d), 7.70 (1H, dd), 7.57 (1H, dd), 7.23 (1H, d), 6.86 (1H, d), 4.20 (1H, br.s), 3.82 (1H, d), 3.58 (3H, s), 3.49 (1H, d), 3.37 (1H, d), 3.08 (1H, td), 2.70 (1H, d), 2.49 (1H, d), 2.16 (1H, dd), 2.04 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 460/462
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[CH3:24][C:25]1[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][C:28]([CH3:31])=[CH:29][N:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[C:25]([CH3:24])=[N:30][CH:29]=[C:28]([CH3:31])[N:27]=3)[CH2:33][CH2:34]2)=[O:16])[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23]
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccc(F)cc3F)CC2)n1

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 82, step 3) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 523.2 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Temperature: 65 °C
Yield: 99.4 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodomethane (4.9 mL, 11.2 g, 78.6 mmol, 3 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-methoxyphenyl)-cyclohexanone (5.34 g, 100%). 1H NMR(CDCl3) 7.16 (dt, 2H), 6.87 (dt, 2H), 3.78 (s, 3H), 2.99 (tt, 1H), 2.47-2.53 (m, 4H), 2.20 (m, 2H) and 1.83-1.98 (m, 2H); MS (electrospray) m/e, 205 (M+1)+, Calcd for C13H16O2, 204. Step 2:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][N:7]([C:9](OC(C)(C)C)=[O:10])[CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:31][CH:30]=3)[CH2:5]1.Cl.[CH3:47][O:48][C@H:49]([CH3:59])[C@H:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][N:7]([C:9](=[O:10])[CH:50]([NH:54][C:55](=[O:56])[O:57][CH3:58])[CH:49]([O:48][CH3:47])[CH3:59])[CH:6]([C:16]2[NH:20][C:19]3[C:21]4[C:26]([CH:27]=[CH:28][C:18]=3[N:17]=2)=[CH:25][C:24]2[C:29]3[C:34]([CH2:35][O:36][C:23]=2[CH:22]=4)=[CH:33][C:32]([B:37]2[O:38][C:39]([CH3:45])([CH3:44])[C:40]([CH3:42])([CH3:43])[O:41]2)=[CH:31][CH:30]=3)[CH2:5]1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CC(c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)C(NC(=O)OC)C(C)OC)C1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl 4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (0.25 g, 0.41 mmol) in a mixture of CH2Cl2 (4.0 mL) and MeOH (1.0 mL) was added HCl (in dioxanes, 4M, 3.0 mL, 12.0 mmol). The resulting solution was stirred at 40° C. for 45 min. The solution was cooled to room temperature and concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (4.0 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.08 g, 0.42 mmol), HATU (0.17 g, 0.45 mmol), and DIPEA (0.4 mL, 2.3 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with brine. The aqueous layer was backextracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl (1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate (0.24 g, 92%).
Reaction SMILES: [CH3:1][Zn]Cl.Br[C:5]1[C:13]([F:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[CH:11]=[C:10]2[C:6]=1[C:7]([C:39]#[N:40])=[C:8]([C:23]1[N:28]=[CH:27][C:26]([S:29]([NH:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[N:9]2[CH:19]1[CH2:22][CH2:21][CH2:20]1.Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:39]([C:7]1[C:6]2[C:10](=[CH:11][C:12]([O:15][CH:16]([F:18])[F:17])=[C:13]([F:14])[C:5]=2[CH3:1])[N:9]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:8]=1[C:23]1[N:28]=[CH:27][C:26]([S:29]([NH:32][C@@H:33]([CH3:38])[C:34]([F:36])([F:35])[F:37])(=[O:30])=[O:31])=[CH:25][CH:24]=1)#[N:40]
Reactant: C[Zn]Cl
Reactant: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3c(Br)c(F)c(OC(F)F)cc3n2C2CCC2)nc1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(F)c(OC(F)F)cc2c1c(C#N)c(-c1ccc(S(=O)(=O)N[C@@H](C)C(F)(F)F)cn1)n2C1CCC1
Temperature: 40 °C
Yield: 64.9 %

Procedure:
A solution of MeZnCl (2 M in THF, 370 μL, 0.74 mmol) was added to a mixture of (S)-6-(4-bromo-3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (200 mg, 0.33 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol), and THF (1.2 mL). This was heated at 40° C. for 25 hours. The reaction mixture was then poured onto aq. HCl. This was extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (20% ethyl acetate in hexanes), followed by washing with hexanes/ether (1:1) yielded (S)-6-(3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-4-methyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (117 mg, 65%) as a white solid. Melting point: 182-186° C.; MS m/z 547.0 M+H+; 1H NMR (CDCl3, 500 MHz): δ 9.22 (d, 1H, J=2 Hz), 8.35 (dd, 2H, J=8.5 Hz, 2 Hz), 8.02 (d, 1H, 8.5 Hz), 7.40 (d, 1H, J=6.5 Hz), 6.62 (t, 1H, J=75 Hz), 5.26 (pentet, 1H, J=8.5 Hz), 4.95 (d, 1H, J=9.5 Hz), 4.16 (m, 1H), 2.75 (d, 3H, J=2.0 Hz), 2.47 (m, 2H), 2.38 (m, 2H), 1.87 (m, 2H), 1.47 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccccc2)CCNCC1
Yield: 85 %

Procedure:
A mixture of 32.5 parts of methyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies on scratching in 2,2'-oxybispropane. the product is filtered off and dried in vacuo, yielding 20 parts (85%) of methyl 4-(phenylamino)-4-piperidinecarboxylate; mp. 139.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:38]([O:37][C:35](=[O:36])[C:27]1[CH:28]=[C:29]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])[CH:4]=2)[CH:30]=[CH:31][C:26]=1[F:25])[CH3:39]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c2)ccc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 189, step 5) was reacted with 4-fluoro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=528.2 [M+H+].
Reaction SMILES: Cl[C:2]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([NH2:6])=O.CO.[ClH:15]>C1COCC1.C1COCC1.CO>[Cl:15][C:8]1[CH:9]=[CH:10][C:2]([O:11][CH3:12])=[C:3]([CH:7]=1)[CH2:4][NH2:6]
Reactant: COC1(Cl)C=CC=CC1C(N)=O
Reactant: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1CN
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
To a solution of the above 2-chloro-2-methoxy-benzamide (1.0 g, 5.4 mmol) in anhydrous THF (10 mL) was added dropwise 1M BH3-THF complex (12.8 mL, 12.8 mmol) at 0° C. After 10 min. of stirring at 0° C., the reaction mixture was heated at 65° C. for 4 h. MeOH (approximately 10 mL) was then added to the cooled reaction mixture at 0° C. The reaction was warmed to room temperature and stirred for 10 min. The reaction solution was concentrated in vacuo to yield an oily product. The product was dissolved in 50% THF/MeOH (10 mL) and 4M HCl (10 mL) was added slowly to the solution. After 10 min. the mixture was partitioned between water (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted with CH2Cl2 (10 mL) and the organic layers were discarded. The aqueous layer was basified to pH 9 with 5M NaOH solution. The solution was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to afford 0.36 g (39%) of 5-chloro-2-methoxy-benzylamine as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][C@@H:21]([OH:24])[CH2:22][NH2:23])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][C@@H:21]([OH:24])[CH2:22][NH:23][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CN
Product: COc1ccc([N+](=O)[O-])c(NC[C@H](O)CNC(=O)OC(C)(C)C)n1
Yield: 86 %

Procedure:
Starting from 2-chloro-6-methoxy-3-nitropyridine (5.4 g; commercial) and ((S)-3-amino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (5.3 g, 1 eq.; prepared according to Adv. Synth. Catal. 2004, 346, 1195) and proceeding in analogy to Example 17, step 17.i, the title compound was obtained as a yellow solid (8.20 g; 86% yield).
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([OH:29])=[O:28])(=[O:4])[CH3:3].Cl[CH2:31][N:32]([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[CH2:36]([O:35][C:33]([N:32]([CH2:38][O:28][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:29])[CH3:31])=[O:34])[CH3:37]
Reactant: CCOC(=O)N(C)CCl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)COC(=O)C1=C(COC(C)=O)CSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Temperature: 0 °C

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2.5 mmole) in 50 ml of dimethylformamide (DMF) is treated at room temperature with 2.5 mmole of N-chloromethyl-N-methylurethane for 1 hour. The mixture is carefully poured into ice water and the precipitated solid is removed by filtration and is then washed with water. The filtered solid is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:27]([N:29]2[CH2:34][CH2:33][C:32]3([CH2:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:45]#[N:46])[CH:40]=4)[O:35]3)[CH2:31][CH2:30]2)=[O:28])[CH:16]=1.[OH-].[Na+]>O.CN(C=O)C>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:27]([N:29]2[CH2:34][CH2:33][C:32]3([CH2:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:45]5[NH:46][N:3]=[N:2][N:1]=5)[CH:40]=4)[O:35]3)[CH2:31][CH2:30]2)=[O:28])[CH:16]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Alternatively, 195 mg of sodium azide, 413 mg of triethylamine hydrochloride and 5 mL of DMF were added to the nitrile derivative (458 mg) produced in Example 16, and stirred at 100° C. under a nitrogen atmosphere for 20 hours. After cooled, the mixture was added by 30 mL of water and 0.60 mL of aqueous 5 N sodium hydroxide solution, then the mixture was washed five times with chloroform (10 mL each). 0.60 mL of 5 N hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated. The resulting residue was purified through silica gel chromatography (chloroform/methanol=50/1 to 30/1, chloroform/methanol/acetic acid=300/100/1), the fraction containing it was concentrated, and ethyl ether was added to the residue. The resulting insoluble material was taken out through filtration, washed with ethyl ether, and dried under reduced pressure to obtain the intended compound as a pale yellow powder. 1H-NMR (300 MHz, DMSO-d6) δ: 8.44 (1H, d, J=2.3 Hz), 8.26 (1H, dd, J=8.6, 2.3 Hz), 7.69 (1H, dd, J=8.4, 1.1 Hz), 7.53 (1H, dd, J=8.4, 7.8 Hz), 7.38 (1H, d, J=8.6 Hz), 7.25 (1H, dd, J=7.8, 1.1 Hz), 7.21 (1H, s), 4.38-4.30 (1H, m), 4.08 (3H, s), 3.95 (3H, s), 3.70-3.62 (1H, m), 3.52-3.43 (1H, m), 3.38-3.28 (1H, m), 3.02 (2H, s), 2.15-2.08 (1H, m), 1.99-1.82 (3H, m). MS [M+H]+=501
Reaction SMILES: [CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][CH:2]1[N:11]([CH2:16][CH:15]=[C:14]([CH3:18])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: CC(C)=CCBr
Reactant: CC1Nc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)=CCN1c2ccccc2NC(=O)C1C
Temperature: 25 °C
Yield: 83.9 %

Procedure:
(3RS)-3-Methyl-3,4-dihydroquinoxalin-2(1H)-one (4.86 g, 0.03 mol) dissolved in 50 ml of N,N-dimethylformamide, was alkylated with 4.2 ml (0.033 mol) of 3-methyl-2-buten-1-yl bromide (90%) in the presence of 4.60 g (0.033 mol) of pulverulent potassium carbonate. The reaction mixture was stirred at room temperature until reaction of the educt was complete. The solvent was then stripped off in vacuo, the residue was taken up in ethyl acetate and water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were washed twice with water. Drying over sodium sulfate, concentration in vacuo and crystallization from pentane gave 5.80 g (84%) of white crystalline product of melting point 92-93° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[OH:38]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:27]4[CH:26]=[CH:25][C:24]([OH:38])=[C:23]([O:22][CH3:21])[CH:28]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)ccc1O
Yield: 58 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol according to the procedure described in example 8 gave 9-hydroxy-4-(4-hydroxy-3-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (23) (I, Ar=4-hydroxy-3-methoxyphenyl) in a 58% yield; mp 290–295° C. (dec). 1H NMR δ [(CD3)2SO] 11.67 (br s, 1H), 10.97 (br s, 1H), 9.22 (br s, 1H), 9.15 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.04 (m, 2H), 6.86 (d, J=8.1 Hz, 1H), 3.82 (s, 3H). FABMS found [M+H]+: 375.0973. C21H15N2O5 requires 375.0981.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:12]#[N:13])=[N:8][C:9]=2[CH2:10]O)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:15][CH2:10][C:9]1[N:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(C2CC2)c(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CC2)c(CBr)n1
Yield: 70.3 %

Procedure:
A solution of 5-cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile (0.1 g, 0.6 mmol), CBr4 (0.8 g, 1.2 mmol), PPh3 (0.3 g, 1.2 mmol) in THF (10 mL) was stirred for 12 h at 40° C. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (0.1 g, 74%) as yellow solid; MS (EI): m/e=236.9 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH3:12])=[CH:9][C:4]=2[N:3]=[CH:2]1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:30]=[C:31]1[NH:40][C:39]2[N:38]=[CH:37][C:36](/[CH:41]=[CH:42]/[C:43]([OH:45])=O)=[CH:35][C:34]=2[CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH3:12])[C:43](=[O:45])/[CH:42]=[CH:41]/[C:36]3[CH:37]=[N:38][C:39]4[NH:40][C:31](=[O:30])[CH2:32][CH2:33][C:34]=4[CH:35]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CNCc1ccc2[nH]cnc2c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2[nH]cnc2c1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 37 %

Procedure:
According to the procedure of Example 1 (a), except substituting ((1H-benzo[d]imidazol-5-yl)-N-methylmethanamine) for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride. Purification by preparative HPLC (water/acetonitrile/0.05% TFA mixture) gave the title compound ((E)-N-((1H-benzo[d]imidazol-5-yl)methyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide) (143 mg, 37%) as a white solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.60 (m, 1H), 8.36 (m, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.59-7.21 (m, 4H), 7.12-7.08 (m, 1H), 4.91-4.72 (m, 2H), 3.10-2.86 (m, 5H), 2.55-2.49 (m, 2H); ESI MS m/z 362 [C20H19N5O2+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.[NH2:24][C@@H:25]1[C:32](=[O:33])[N:31]2[C@@H:26]1[S:27][CH2:28][C:29](/[CH:37]=[C:38]1/[C:39](=[O:47])[N:40]([CH2:43][CH:44]3[CH2:46][CH2:45]3)[CH2:41][CH2:42]/1)=[C:30]2[C:34]([OH:36])=[O:35]>CN(C)C=O>[CH:44]1([CH2:43][N:40]2[CH2:41][CH2:42]/[C:38](=[CH:37]\[C:29]3[CH2:28][S:27][C@H:26]4[N:31]([C:32](=[O:33])[C@H:25]4[NH:24][C:21](=[O:23])[CH2:20][S:19][C:16]4[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=4)[C:30]=3[C:34]([OH:36])=[O:35])/[C:39]2=[O:47])[CH2:46][CH2:45]1
Reactant: O=C(O)CSc1ccncc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1ccncc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 111.0 mg (0.68 mmol) 1,1′-carbonyldiimidazole, 116.0 mg (0.68 mmol) (pyridin-4-ylsulfanyl)-acetic acid and 200.0 mg (0.57 mmol) ) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 4 ml N,N-dimethylformamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[C:7]([N:12]=1)=[N:8][CH:9]=[N:10][CH:11]=2.CCN(C(C)C)C(C)C.[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[O:13]=[C:5]1[C:6]2[C:7](=[N:8][CH:9]=[N:10][CH:11]=2)[N:12]=[C:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:4]1
Reactant: NCc1nc2ncncc2c(=O)[nH]1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)NCc1nc2ncncc2c(=O)[nH]1
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a suspension of 2-aminomethyl-3H-pyrimido[4,5-d]pyrimidin-4-one (12 mg, 0.068 mmol) in THF (0.2 mL) and DIPEA (0.050 mL, 0.29 mmol) was added 3-phenyl-propionyl chloride (14 mg, 0.08 mmol) at ambient temperature. The reaction mixture was stirred one hour, evaporated and purified by column chromatography (silica gel, EtOAc/MeOH, 1/1) to yield N-(4-oxo-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide as a white solid (0.8 mg, 3.8%). MS (m/e): 310.3 [M+H+].