Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=5[CH:29]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:28][N:24]1[C:23]2[CH:29]=[C:19]3[O:18][CH2:17][C:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[NH:8][C:9]4=[O:30])[C:20]3=[CH:21][C:22]=2[O:26][C:25]1=[O:27]
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1H,3H)-dione was obtained (88%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ10.64 (br s, 1H), 7.30-7.22 (m, 1H), 7.09 (d, J=7.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.75 (s, 1H), 4.82 (d, J=9.3 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H), 3.30 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.2, 157.0, 154.5, 141.8, 136.2, 132.8, 132.4, 128.9, 123.8, 122.3, 122.0, 109.9, 104.9, 92.3, 79.8, 57.8, 28.2; MS (ES+) m/z 309.1 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:17])=[O:16]
Reactant: c1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Yield: 106.6 %

Procedure:
To a solution of pyrazole (10.0 g, 147 mmol) in dichloromethane (150 mL), triethylamine (26.6 mL, 192 mmol) and N,N-dimethylsulfamoyl chloride (20.0 mL, 181 mmol) were added and the reaction mixture was heated to reflux for approximately 60 h. The reaction mixture was then cooled to ambient temperature and filtered through a pad of silica gel using dichloromethane as an eluent. The filtrate was then concentrated under reduced pressure and treated with diethyl ether (100 mL) resulting in the formation of a solid. The suspension was filtered, and the precipitate was washed with diethyl ether. The combined filtrates were combined and concentrated in vacuo to give 27.46 g of the title compound. This compound was of sufficient purity to use in subsequent reactions. 1H NMR (CDCl3) δ 2.94 (s, 6H), 6.40 (s, 1H), 7.75 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2([CH3:21])[O:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][O:12]2)[CH:5]=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.C(OC(=O)C)(=[O:32])C>>[CH3:8][C:7]1[C:2]([CH2:1][OH:32])=[N:3][CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1([CH3:21])[O:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][O:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)cc[n+]([O-])c1C
Solvent: CCN(CC)CC
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
The 2,3-dimethyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methoxy)pyridine 1-oxide (1.20 g, 3.84 mmol) obtained in the step (5d) was mixed with acetic anhydride (10 ml). To the mixture, triethylamine (0.8 ml, 5.74 mmol) was added and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated and methanol (10 ml) was added to the residue. Thereafter a 5N aqueous sodium hydroxide solution (7 ml) was added to the mixture, and stirred at room temperature for 30 minutes. To the resultant mixture, a saturated aqueous ammonium chloride solution (7 ml) was added and the pH was adjusted to about 10. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a 2N aqueous sodium hydroxide solution, water, and a saline solution, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and a desired fraction(s) was concentrated to obtain the title compound (312 mg, 26.1% yield) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14](=[NH:17])[NH:15][OH:16].[Cl:21][C:22]1[CH:27]=[C:26]([C:28](Cl)=O)[CH:25]=[C:24]([Cl:31])[N:23]=1>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:18][CH2:19][CH3:20])[N:6]2[CH2:13][C:14]1[N:17]=[C:28]([C:26]2[CH:25]=[C:24]([Cl:31])[N:23]=[C:22]([Cl:21])[CH:27]=2)[O:16][N:15]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2n1CC(=N)NO
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)nc(Cl)c2)n1
Temperature: 120 °C

Procedure:
Synthesized as described for Examples 32A-32B using 2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with 2,6-dichloro-4-pyridinecarbonyl chloride (0.021 g, 0.1 mmol) and TEA (0.012 g, 0.12 mmol) and heated at 120° C. for 1 h in the microwave: 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2H), 7.96 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 5.87 (s, 2H), 2.91 (t, 2H), 1.67-1.54 (m, 2H), 0.92 (t, 3H); MS (ES) m/z 447 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24])([OH:3])=[O:2].[N+](=[CH2:27])=[N-]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH:15]([OH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24])([O:3][CH3:27])=[O:2]
Reactant: CCCCCCCC(O)[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)O
Reactant: C=[N+]=[N-]
Product: CCCCCCCC(O)[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC

Procedure:
To a solution of 0.5 g. (1.47 mmol) of trans-2-(6-carboxyhexyl)-3-(1-hydroxyoctyl)cyclopentanone is added on etheral solution of diazomethane until a permanent yellow color remains. The solvent and excess diazomethane are removed un a stream of nitrogen. After removing traces of solvent at reduced pressure, 0.52 g. of trans-2-(6-carbomethoxyhexyl)-3-(1-hydroxyoctyl)cyclopentanone is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:17])([CH3:19])[CH3:18])[C:13]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[O:15])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CCCN
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](C(=O)NCCC#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 53.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (5 mg, 0.016 mmol). DMF (0.5 mL), 3-aminopropanenitrile (1.089 mg, 0.016 mmol), HOBt (3.57 mg, 0.023 mmol), EDC (4.47 mg, 0.023 mmol) and N,N-dimethylpyridin-4-amine (1.898 mg, 0.016 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.2 mg, 55.1%). 1H NMR (500 MHz, CD3OD) δ 1.19 (s, 9 H) 2.63-2.72 (m, 2 H) 3.38-3.53 (m, 2 H) 4.89 (br. s., 1 H) 5.29 (d, J=19.04 Hz, 1 H) 5.41 (d, J=19.00 Hz, 2 H) 7.85 (s, 1 H) 8.24 (s, 1 H) 8.55 (d, J=4.88 Hz, 1 H). [M+H] calc'd for C18H20ClN5O2, 374; found, 374.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Yield: 71 %

Procedure:
310 mg of 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-fluoro-benzonitrile (Example I10) 73 mg of 1,2,4-triazole and 166 mg of potassium carbonate were stirred in 5 ml acetonitrile at room temperature for 24 hours. The solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified on silica gel (elutant diethylether) affording 5-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-[1,2,4]triazol-1-yl-benzonitrile as a solid in 71% yield. 1H-NMR (CDCl3, δ in ppm): 8.96 (s, 1H), 8.17-8.28 (m, 3H), 7.99 (d, 1H), 7.37-7.39 (m, 2H), 7.17 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 124.3 %

Procedure:
To a solution of 4-[2-(4-iodo-phenoxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (0.1 g, 0.428 mmol) in a mixture of tetrahydrofuran (21 mL) and water (5 mL) was added 4-fluorophenylboronic acid (40.3 mg, 0.288 mmol) and cesium carbonate (313 mg, 0.96 mmol). The solution was then degassed by bubbling a flux of argon for 20 minutes before adding polymer bound tetrakis(triphenylphosphine)palladium (Aldrich-511579, 12.86 mg, 0.009 mmol). The reaction mixture was then stirred for 90 min at 80° C. under argon atmosphere before allowing to cool down to room temperature and diluting with ethyl acetate. The reaction mixture was then filtered; the filtrate was then washed twice with brine and dried over sodium sulfate before being concentrated in vacuo. The residue was then filtered through a pad of silica (SiO2, EtOAc, 100%) to yield the title compound as a light brown solid (138 mg, 99%).
Reaction SMILES: C[N:2](C)/[C:3](/[CH3:14])=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[NH:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=1)[C:21]#[N:22])N.CC(O)=O>CCO>[CH3:14][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:16]([C:18]2[CH:19]=[C:20]([C:21]#[N:22])[CH:23]=[CH:24][N:25]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: C/C(=C\C(=O)c1ccc(C)cc1)N(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(-c2cc(C)nn2-c2cc(C#N)ccn2)cc1
Yield: 56.3 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-methylphenyl)but-2-en-1-one (227 mg, 1.1 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3 and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 20 mL brine, dried, and concentrated to dryness to give the title compound (170 mg, 55.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (6H, s), 6.30 (1H, s), 7.15 (4H, s), 7.33 (1H, d, J=4.0 Hz), 7.78 (1H, s), 8.44 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4, 275; Found, 275.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][Mg]Cl.Cl.O>C1COCC1.[Pd]>[CH:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[OH:1])([CH3:11])[CH3:13]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: C[Mg]Cl
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone (10.0 g) in 80 mL of THF was gradually added 46.4 g of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours. To the stirred solution was then added 10% palladium on carbon (1.02 g, 50% water wet) suspended in 4 mL of THF. The reaction mixture was placed under a hydrogen atmosphere at 5 psig and cooling was applied to maintain a temperature of approximately 25° C. To the cooled mixture was gradually added concentrated HCl (20 mL) while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 45 mL water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated under reduced pressure to give 10.4 g of 2-isopropyl-4-methoxy-phenol, MS (M+H)=167. This product was dissolved in 2-butanone (20.4 g) and the crude solution was employed directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.[S:17]([OH:21])([OH:20])(=[O:19])=[O:18].[NH2:22][OH:23]>>[S:17](=[O:19])(=[O:18])([OH:21])[OH:20].[CH3:1][C:2]([CH3:16])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[CH:3]=[N:22][OH:23].[CH2:14]([CH:5]([NH2:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]([CH3:16])([CH3:1])[CH2:3][NH2:4])[CH3:15]
Reactant: NO
Reactant: CCC1CC=CCCC=CCC(C)(C)C=N1
Agent: O=S(=O)(O)O
Product: CCC(N)CC=CCCC=CCC(C)(C)C=NO
Product: CCC(N)CCCCCCCCC(C)(C)CN

Procedure:
Reaction of 3,3-dimethyl-12-ethyl-1-aza-1,5,9-cyclododecatriene with hydroxylamine sulfate, in the presence of sulfuric acid, to 2,2-dimethyl-11-ethyl-11-aminoundeca-4,8-dienal-oxime, and hydrogenation of this to give 1-ethyl-10,10-dimethyl-1,11-diaminoundecane; b.p. 93° C./7 Pa; nD20 =1.4622.
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[C:11]([CH3:17])=[N:12][C:13](N)=[N:14][CH:15]=1.CCCC(C)C.C(Br)(Br)[Br:25]>>[Br:25][C:13]1[N:12]=[C:11]([CH3:17])[C:10]([Br:9])=[CH:15][N:14]=1
Reactant: Cc1nc(N)ncc1Br
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Solvent: CCCC(C)C
Product: Cc1nc(Br)ncc1Br
Temperature: 85 °C

Procedure:
Isoamylnitrite (21 ml) was added to a stirred suspension of 5-bromo-4-methyl-2-pyrimidinamine (1.75 g) in bromoform (30 ml) and the mixture heated at 85° C. for 4 h. After cooling, isohexane (300 ml) was added and the solution passed through a pad of silica-gel. The silica was washed with petrol (1000 ml), dichloromethane (200 ml) then the product eluted with ethylacetate. The ethylacetate layer was evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 5% diethylether/isohexane, yield 0.9 g
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3,4-dichlorophenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.90-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.58-7.70 (m, 6H), 7.38 (dd, J=8.3, 2.1 Hz, 1H), 3.75 (s, 2H); MS (ESI−) M/Z 456 (M−H)−.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.O>C1COCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccc(OCCN2CCCC2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
175 mg (4.01 mmol, 55%) NaH are added to a solution of 0.50 mL (4.04 mmol) N-(2-hydroxyethyl)pyrrolidine in 50 mL THF at 0° C. The reaction solution is stirred for 60 min and heated to RT. 500 mg (3.26 mmol) 3,6-dichloro-pyridazine are added. The solution is stirred for 5 h at RT. 50 mL water are added and the aqueous phase is extracted with 100 mL EtOAc. The organic phase is extracted once with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: EtOAc to EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:5]=[O:7])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]=[C:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]1[C:7]2([CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9][CH2:8]2)[CH2:6]1
Reactant: CC[Zn]CC
Reactant: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
Diethyl zinc (40 mL, 1 M solution in hexane) was slowly added to 300 mL of anhydrous DCM at −78° C. under nitrogen, further dimethyl iodide (15 g, 56 mmol) was added slowly. After 30 minutes, warmed to room temperature and maintained for 30 minutes, cooled with an ice-water bath. Then a solution of Compound 7-2 (2 g, 9.5 mmol) dissolved in 10 mL of methylene chloride was added and reacted overnight. To the reaction mixture was poured 100 mL of saturated aqueous solution of ammonium chloride, and liquid separated, the organic phase was extracted with ethyl acetate (100 mL) twice, the organic phases were combined and dried over anhydrous sodium sulfate. Suction filtered to remove desiccant, and rotary evaporated to remove solvents. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 7-3 as a white solid (0.8 g, 37.4% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](Cl)=[O:45]>ClCCl>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:10][N:11]=1)[C:44](=[O:45])[C:43]1[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=1[CH3:48]
Reactant: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)N(CCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 0.75 g of 10-[[6-[2-(dimethylamino)ethylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane is added (slowly) 0.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solution washed well with water. The organic layer is dried (MgSO4) and the solvent removed under vacuum. The residue is purified by column chromatography on silica gel with 30% methanol in chloroform as eluent to give 0.80 g of yellow solid; mass spectrum (CI), 511 (M+1).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]1([CH3:16])[CH:11]=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.C1OC1CO.[C:30]([O:36]C)([O:34]C)([O:32][CH3:33])[CH3:31]>>[C:1]([O:5][CH2:16][CH:6]1[CH2:11][O:36][C:30]([O:32][CH3:33])([CH3:31])[O:34]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: COC(C)(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC1CO1
Agent: Oc1ccc(O)cc1
Product: C=CC(=O)OCC1COC(C)(OC)O1
Temperature: 104 °C
Reaction time: 0.75 h
Yield: 56 %

Procedure:
47 g of acrylic acid and 3.04 g of p-toluenesulfonic acid were initially charged in a round-bottom flask together with 0.2 g of hydroquinone and heated to 104° C. 40 g of glycidol were added dropwise to this reactant mixture and the resulting solution was stirred at 100° C. for 45 minutes. Subsequently, the reaction mixture was cooled to 25° C. 84 g of trimethyl orthoacetate were added dropwise to this reaction mixture, which was subsequently stirred at 25° C. for one hour. The reaction mixture was then freed of the low boilers present by means of a distillation. Subsequently, a vacuum distillation was carried out at 4 mbar and 95° C. 4-Acryloyloxymethyl-2-methoxy-2-methyl-1,3-dioxolane was obtained in a yield of 56%.