Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:28])[C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.CCN(C(C)C)C(C)C.Cl>C(#N)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=3)[C:31]([C@H:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]3[C:29]([OH:39])=[O:30])=[N:28][C:15]=2[CH:14]=1
Reactant: Nc1cc(OCc2nc3ccccc3s2)ccc1NCc1ccc(Br)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 4 mL microwave vial were added 4-(benzo[d]thiazol-2-ylmethoxy)-N1-(4-bromobenzyl)benzene-1,2-diamine hydrochloride (100 mg, 0.21 mmol), cis-hexahydroisobenzofuran-1,3-dione (34 mg, 0.21 mmol), DIPEA (27 mg, 0.21 mmol), and acetonitrile (2 mL). The mixture was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT, HCl (1 mL, 6 N) was added and the reaction was irradiated for 1 h at 82° C. in a microwave reactor. The reaction was cooled to RT and the solid byproducts were removed by filtration and filtrate was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C29H26BrN3O3S, 575.10; m/z found, 576.1 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ 8.03 (d, J=8.0, 1H), 7.89 (d, J=8.0, 1H), 7.56-7.48 (m, 4H), 7.45-7.38 (m, 2H), 7.19-7.16 (m, 1H), 7.16-7.11 (m, 1H), 6.97 (d, J=8.4, 2H), 5.59-5.49 (m, 1H), 5.46 (s, 2H), 3.40-3.24 (m, 1H), 2.93 (d, J=4.5, 1H), 2.39-2.19 (m, 2H), 1.96-1.83 (m, 2H), 1.82-1.69 (m, 1H), 1.65-1.50 (m, 2H), 1.35 (d, J=13.0, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: COc1ccccc1CC(=O)N=C=O
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyl)-acetyl isocyanate (240 mg, 1.25 mmoL) [A. J. Hill, et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc, to afford the title compound 309c in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 10.98(s, 1H), 10.69(s, 1H), 8.41(d, 1H, J=5.3 Hz), 7.94(d, 1H, J=1.2 Hz), 7.81(dd, 1H, J1=13.1 Hz, J2=2.4 Hz), 7.77(d, 1H, J=0.9 Hz), 7.65(s, 1H), 7.45-7.40(m, 2H), 7.26-7.19(m, 2H), 6.97(d, 1H, J=8.0 Hz), 6.89(dt, 1H, J1=0.8 Hz, J2=8.2 Hz), 6.54(d, 1H, J=5.5 Hz), 4.04(q, 2H), 3.75(s, 3H), 3.70(s, 2H), 1.38(t, 3H). MS (m/z): 546.1(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[NH:35][CH:32]1[CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C24H23N5O3, 429.2.
Reaction SMILES: N.C([S:5][CH2:6][CH2:7][C:8]([N:10]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][C:12]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:11]1)=[O:9])(=O)C>>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:12]1[CH2:13][CH:14]([C:15]([OH:17])=[O:16])[N:10]([C:8](=[O:9])[CH2:7][CH2:6][SH:5])[N:11]=1
Reactant: CC(=O)SCCC(=O)N1N=C(c2ccco2)CC1C(=O)O
Agent: N
Product: O=C(O)C1CC(c2ccco2)=NN1C(=O)CCS
Reaction time: 2.5 h
Yield: 61.9 %

Procedure:
Aqueous ammonia (12 cc) is stirred under nitrogen at 10° C. for 30 minutes, at which point 4.3 g of (±)-1-[3-(acetylthio)-1-oxopropyl]-3-(2-furanyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid is added. The resulting solution is stirred for about 2.5 hours under nitrogen. The solution is extracted with ethyl acetate (discarded) and then made strongly acid with 20% HCl. An oil results which is extracted with 150 cc ethyl acetate. The aqueous layer is extracted with an additional two 150 cc portions of ethyl acetate. The combined organic layers are extracted with 200 cc saturated NaCl and then dried over MgSO4. The solvent is removed to yield 3.7 g of semicrystalline residue which is triturated with ether to yield 2.3 g of product melting at 121°-123° C. The product does not crystallize readily from any solvent tried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][C@@H:16]([CH3:26])[C@H:17]([OH:25])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].CS(O)(=O)=O>C(O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][C@@H:16]([CH3:26])[C@H:17]([OH:25])[C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]([O:9][CH2:13][C:12]1[CH:11]=[CH:10][CH:4]=[CH:3][CH:2]=1)=[O:8]
Reactant: C[C@H](NCCc1ccc(OCC(=O)O)cc1Cl)[C@H](O)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: OCc1ccccc1
Product: C[C@H](NCCc1ccc(OCC(=O)OCc2ccccc2)cc1Cl)[C@H](O)c1ccc(O)cc1
Yield: 109.9 %

Procedure:
A solution of 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (200 mg) and methanesulfonic acid (38 μl) in benzyl alcohol (1.0 ml) was stirred for 2 days at room temperature. Purification of the reaction mixture by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1) gave benzyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-phenoxy]acetate (136 mg).
Reaction SMILES: [CH3:1][C:2]1([C:17]([OH:19])=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.CC[N:22](CC)CC.C(Cl)(=O)OCC(C)C.[OH-].[NH4+]>C1COCC1>[CH3:1][C:2]1([C:17]([NH2:22])=[O:19])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CCN(CC)CC
Reactant: CC1(C(=O)O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C(N)=O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: -3 °C
Reaction time: 1.25 h
Yield: 29.4 %

Procedure:
To a solution of 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylic acid (2.65 g, 10.03 mmol) in THF (45 ml) cooled at −5° C. (ice/NaCl bath) was added Et3N (1.537 mL, 11.03 mmol), followed by dropwise addition of isobutyl carbonochloridate (1.443 mL, 11.03 mmol). After addition, the resulting yellow suspension was stirred at −3° C. for 75 min and then 6.25 mL of a 28% aqueous ammonium hydroxide solution (50 mmol, 5.0 equiv.) was added. The reaction mixture was stirred at ˜0° C. for 1.5 hrs. The reaction was quenched with water, the resulting mixture (pH>10) was extracted with EtOAc (3×). The combined organic phase was washed with water (2×), saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from EtOAc to give the title compound, 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxamide (777 mg, 2.95 mmol, 29.4% yield), as a brown solid. Anal. Calcd. for C13H17N3O3 m/z 263.2, found: 264.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.20-8.02 (m, 2H), 7.06-6.85 (m, 2H), 3.91 (d, J=13.19 Hz, 1H), 3.64-3.49 (m, 1H), 3.16 (ddd, J=12.64, 8.25, 4.40 Hz, 1H), 3.09 (s, 2H), 3.06 (d, J=13.19 Hz, 1H), 2.09 (d, J=13.74 Hz, 1H), 1.91-1.72 (m, 2H), 1.62-1.48 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])=[O:2]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formyl-5-methylbenzoic acid (75.0 g, 0.457 moles), thionyl chloride (65 g, 0.0547 moles), and dimethylformamide (1 ml), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 h. The toluene was eliminated in a rotavap to yield 3-formyl-5-methylbenzoic chloride used in the next step as such.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]=[CH:13][N:14](C)C)#[N:2].N[C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CC(O)=O>[C:24]([C:20]1[CH:19]=[C:18]([NH:2][C:1]2[C:3]3[C:4](=[CH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=3)[N:12]=[CH:13][N:14]=2)[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: C#Cc1cccc(N)c1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A mixture of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (1.00 g, 4.58 mmol) and 3-aminophenylacetylene (0.64 g, 5.49 mmol) in HOAc (15 mL) was stirred at 100° C. for 3 h and cooled to room temperature. The precipitate was filtered, washed with ether, and was dried in vacuo to give 1.23 g (93%) of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12](=[O:16])[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:15][C:14]1[CH:13]=[C:12]([OH:16])[C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[N:1]=1
Reactant: Cn1c(N)c(C(=O)CC#N)c(=O)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2c(O)cc(N)nc2n(C)c1=O
Yield: 90.1 %

Procedure:
1.21 g of 6-amino-5-(2-cyanoacetyl)-1,3-dimethyluracil and 2.90 g of sodium carbonate were added to 20 ml of water, and the solution was heated under reflux for 1 hr. After cooling, the precipitate was separated from the solution by filtration to give 1.09 g of 7-amino-5-hydroxy-1,3dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:11](=[O:31])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:11](=[O:31])[CH2:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][O:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(COc2ccccc2C(=O)O)cc1
Yield: 70.6 %

Procedure:
Methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}benzyl)oxy]-benzoate (0.224 g, 0.418 mmol) was dissolved in EtOH (5 ml, 95%) and potassium hydroxide (0.047 g, 0.836 mmol) was added. The reaction was performed in an single node microwave oven (7 min, 150° C.). Work-up was by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml) and the organic phase was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The product was not pure and was therefore purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation to give 0.154 g of 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)amino]-2-oxoethyl}benzyl)oxy]-benzoic acid (yield 76.8%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1.[CH3:37][C:38](=O)[CH2:39][CH3:40]>CO.C(=O)([O-])O.[Na+]>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[C:28]2=[N:29][C:30]3[C:31](=[C:32]([NH:36][CH:38]([CH3:37])[CH2:39][CH3:40])[CH:33]=[CH:34][CH:35]=3)[N:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: CCC(C)=O
Reactant: Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(C)Nc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium triacetoxyborohydride (171 mg, 0.807 mmol) was added to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (183 mg, 0.549 mmol) and butan-2-one (1.0 mL) in methanol (1.0 mL) at 0° C., and the mixture was stirred at room temperature for 8 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (86.4 mg, 0.222 mmol, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24].CCN(CC)CC>C(Cl)CCl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:23]([CH2:22][CH2:21][Si:20]([CH3:28])([CH3:27])[CH3:19])(=[O:25])=[O:24]
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a mixture of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (0.9822 g, 3.18 mmol, 1.0 equiv) and 2-(trimethylsilyl)ethanesulfonamide) (SESNH2) (0.6338 g, 3.50 mmol, 1.1 equiv) in ClCH2CH2Cl (10 mL), cooled to 0° C., were successively added Et3N (0.9 mL, 6.46 mmol, 2.0 equiv) and TiCl4 (1.0 M in CH2Cl2, 3.4 mL, 3.4 mmol, 1.1 equiv). After 10 min, the ice bath was removed. The reaction mixture was stirred at room temperature for 3 h and then heated at 110° C. for 42 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.3685 g (91%) of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (8) as a solid. LC-MS tR=2.31 min in 3 min chromatography, m/z 472, 474 (MH+); 1H NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (s, 3H), 3.29-3.21 (m, 3H), 2.98 (s, 2H), 2.16-2.12 (m, 2H), 1.80-1.76 (m, 2H), 1.62-1.57 (m, 2H), 1.42-1.33 (m, 2H), 1.21-1.17 (m, 2H), 0.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 189.97, 151.30, 137.91, 133.35, 127.50, 121.43, 78.10, 55.80, 51.79, 51.39, 39.55, 33.97, 28.60, 9.98, −1.93.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][OH:14])=[NH:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[C:17]([C:16]([F:21])([F:20])[F:15])[O:14][N:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: N=C(NO)Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2noc(C(F)(F)F)n2)cc1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
In 100 ml of tetrahydrofuran was dissolved 4.0 g of N-(4-carboxyphenyl)-N'-hydroxyguanidine produced in Reference Example 27. To the solution was added, while stirring at 0° C., 6.75 g of anhydrous trifluoroacetic acid. The mixture was stirred for 1.5 hour under the same conditions, followed by concentration under reduced pressure. To the concentrate was added water. The resulting crystalline product was collected by filtration, which was recrystallized from ethyl acetate--hexane to afford 3.5 g of the title compound as a colorless crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[C:26]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC(=O)Nc1ccc2cccc(N3CCN(C)CC3)c2c1
Yield: 37.8 %

Procedure:
The title product was prepared following the procedure of example 16 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.182 g, 0.755 mmol) and triethylamine (0.201 mL, 1.51 mmol) and hexanoyl chloride (0.211 mL, 1.51 mmol)in acetonitrile (10 mL) with an overnight reflux. The product was purified by recrystallization from ethyl acetate/hexane to yield 0.097g (37%) of the title compound: mp 144°-146° C. Analysis calculated for C21H29N3O: C, 74.30; H, 8.61; N, 12.38. Found: C, 73.91; H, 8.52; N, 12.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[CH2:21](C(CC)(CC)C([O-])([O-])[O-])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
A mixture of 2.9 g. of 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine, 50 ml. of ethanol, 2 ml. of triethylorthoacetate and 0.2 g. of p-toluenesulfonic acid was refluxed for 20 minutes. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and aqueous sodium carbonate solution. The organic phase was dried and evaporated. Crystallization from methylene chloride/hexane yielded 8-bromo-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine, having a melting point of 245°-248°. Chromatography of the mother liquor on 60 g. of silica gel using 10 percent ethanol in methylene chloride afforded additional product, m.p. 248°-250°.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[C:10]3[C:13](=O)[C:14](=[O:16])[NH:15][C:9]3=[CH:8][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.[BrH:31]>O.CCO>[BrH:31].[O:16]=[C:14]1[NH:15][C:9]2=[CH:8][C:7]3[CH2:6][CH2:5][NH:4][C:12]=3[CH:11]=[C:10]2[C:13]1=[N:25][NH:24][C:23]1[CH:22]=[CH:21][C:20]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCc2cc3c(cc21)C(=O)C(=O)N3
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Br
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cc4c(cc32)NCC4)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
A solution of 0.10 g (0.44 mmol) of 5-acetyl-1,5,6,7-tetrahydro-pyrrolo[2,3-f]indole-2,3-dione in 3 mL of conc. HBr was heated to 100° C. for 18 h. The mixture was cooled to ambient temperature, diluted with 10 mL of water and filtered. The filtrate was concentrated in vacuo and added to a solution of 0.05 g (0.2 mmol) 4-sulfonamidophenylhydrazine hydrochloride in 5 mL of EtOH. The mixture was heated to 80° C. for 1 h and cooled to ambient tempurature. The resulting solid was collected by vacuum filtration, washed with water and dried in a vacuum oven at 70° C. to afford the title compound as a tan solid (0.026 g, 17%): mp>250° C.; 1H NMR (DMSO-d6): δ 3.17 (t, J=7.8 Hz, 2H), 3.69 (t, J=7.8 Hz, 2H), 6.96 (s, 1H), 7.25 (s, 2H), 7.52 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 10.65 (bs, 2H), 11.24 (s, 1H), 12.73 (s, 1H); APCI-MS: m/z 356 (M−H)−. Anal. Calcd for C16H15N5O3S.0.9 HBr.0.5 H2O: C, 43.75; H, 3.88; N, 15.94; S, 7.30. Found: C, 44.01; H, 4.14; N, 15.70; S, 7.12.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[C@H:4]([NH:11][CH3:12])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33]>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:11]([C@@H:4]([C@H:3]([O:2][CH3:1])[CH3:13])[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH3:12])=[O:29])=[CH:26][C:25]=1[CH3:33]
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H](C)[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(F)c(C)c1
Yield: 73.6 %

Procedure:
To a solution of (2R,3R)-3-methoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M6) (80 mg, 0.43 mmol) in DCM (1.5 mL) was DIPEA (0.090 mL, 0.52 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.061 mL, 0.43 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 74%).
Reaction SMILES: C(N(CC)CC)C.CC1C2C(=CC=CC=2)CCN1.[Cl:19]C1C(C)=C(C)N=C(NC2C=CC(F)=CC=2)N=1.[CH3:36][C:37]1[C:38]([N:52]2[CH2:61][CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]2[CH3:62])=[N:39][C:40]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:41][C:42]=1[CH3:43]>C(O)CO.C(O)CCC>[ClH:19].[CH3:36][C:37]1[C:38]([N:52]2[CH2:61][CH2:60][C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]2[CH3:62])=[N:39][C:40]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=[N:41][C:42]=1[CH3:43]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Agent: CC1NCCc2ccccc21
Agent: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: OCCO
Product: Cl

Procedure:
8.12 g (11.2 ml, 80.3 mmole) of triethylamine, 30 ml of n-butanol and 6.58 g (44.1 mmole) of 1-methyl-1,2,3,4-tetrahydroisoquinoline were added to 40 ml of ethylene glycol. 10.1 g (40.1 mmole) of 4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine was added thereto and then reacted at 130° C. for 30 hours under refluxing to prepare 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-pyrimidine. This product was treated according to the procedure detailed in Example 14 to obtain 14.7 g of purified 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride.