Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:57][CH2:58][CH2:59][CH2:60]O.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Br:57][CH2:58][CH2:59][CH2:60][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]2[O:23][C:22]1[C:14]([F:13])=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:37])=[CH:16]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Diethyl azodicarboxylate (0.847 g, 4.86 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1.5 g, 4.42 mmol), (prepared as described for the starting material in Example 1), triphenylphosphine (1.74 g, 6.63 mmol) and 3-bromo-1-propanol (0.923 g, 6.63 mmol) in methylene chloride. After stirring for 1 hour at ambient temperature, triphenylphosphine (1.16 g) and DEAD (0.770 g) was added. After stirring for 30 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatograhy eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (1.5 g, 73%).
Reaction SMILES: I[CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][C:3]1=O.[CH3:17][O-:18].[Na+].[OH2:20]>C(OCC)C>[CH3:17][O:18][C:3]1[CH:2]=[CH:7][C:6]([C@H:8]2[CH2:9][CH2:10][C@H:12]([C:11]([O:14][CH3:15])=[O:20])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(C2CCC(=O)C(I)C2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)[C@H]1CC[C@H](c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 2-iodo-4-(4-methoxyphenyl)cyclohexanone (Step A) (363 mg, 1.099 mmol) in diethyl ether (3 ml), under nitrogen, was added sodium methoxide (77 mg, 1.429 mmol) and the resulting mixture was stirred at RT for 30 minutes. Water was added and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.15 (d, J=8.6 Hz, 1H); 6.84 (d, J=8.6 Hz, 1H); 3.79 (s, 3H); 3.70 (s, 3H); 3.17 (p, J=8.6 Hz, 1H); 3.06-2.91 (m, 1H); 2.34 (ddd, J=13.2, 8.1, 4.7 Hz, 1H); 2.19-2.06 (m, 2H); 2.03-1.80 (m, 2H); 1.70-1.58 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:13][CH:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[C:29]([S:30][C:31]2[CH:36]=[C:35]3[O:37][CH2:38][O:39][C:34]3=[CH:33][C:32]=2I)=[N:28][C:22]2[C:23]([NH2:27])=[N:24][CH:25]=[N:26][C:21]1=2)[CH3:15].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:32]2[C:31]([S:30][C:29]3[N:20]([CH2:19][CH2:18][CH2:17][NH:16][CH:14]([CH3:15])[CH3:13])[C:21]4[C:22]([N:28]=3)=[C:23]([NH2:27])[N:24]=[CH:25][N:26]=4)=[CH:36][C:35]3[O:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(N(C)C)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 85.5 %

Procedure:
4-(Dimethylamino)phenylboronic acid (14.5 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 25.3 mg (85%) of DZ2-392. 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.93 (s, 1H), 6.83 (s, 1H), 6.67 (d, J=8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J=6.7 Hz, 2H), 2.97 (s, 6H), 2.78 (septet, J=6.3 Hz, 1H), 2.44 (t, J=6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4, 152.4, 151.5, 149.9, 148.5, 148.0, 147.1, 139.6, 130.0, 127.8, 120.5, 119.7, 112.8, 111.7, 111.0, 101.7, 49.3, 43.1, 40.9, 40.4, 28.9, 21.9; HRMS (ESI) m/z [M+H]+ calcd. for C26H32N7O2S, 506.2338; found. 506.2330; HPLC: method A Rt=5.72, method B Rt=5.12.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[C:16](=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]=[CH:24][CH:25]=3)[CH2:18][CH3:19])[C:15]3[CH:27]=[CH:28][CH:29]=[N:30][C:14]=3[CH2:13][O:12][C:11]=2[CH:31]=1
Reactant: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=C1c2ccc(F)cc2OCc2ncccc21)c1cccc(NS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.34 mL, 4.36 mmol) is added dropwise to a solution of 3-[1-(8-fluoro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-phenylamine (1.37 g, 3.96 mmol) and pyridine (0.35 mL, 4.36 mmol) in dichloromethane (10 mL) at 0° C. After 2 h, 7% aqueous sodium bicarbonate (20 mL) is added and the mixture stirred for 30 min, decanted, and the layers separated. The aqueous phase is washed with dichloromethane (2×20 mL). The organic phases are collected and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1.98 g of crude product. The material is purified by flash chromatography, using Biotage® and eluting with hexane:ethanol (9:1) to afford 1.35 g (80%) of the title compound. LCMS m/e 425 [M−H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH:5]([OH:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].O.NN>C(O)C.[Ni]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH:5]([OH:17])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: CCN(CC)CC(O)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)CC(O)COc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A suspension of 1-diethylamino-3-(4-nitro-phenoxy)-propan-2-ol (2.41 g, 8.99 mmol) in absolute ethanol (60 mL) was heated to 50° C. To the resulting solution was added hydrazine monohydrate (2.62 mL, 6 equiv.) followed by addition of a small portion of Raney nickel. The reaction mixture was heated at 50° C. with stirring for 1 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated in vacuo to give the 1-(4-Amino-phenoxy)-3-diethylaminopropan-2-ol as a light yellow oil (2.13 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:25][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:15]=[CH:16][CH:17]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(CNCCCN3CCN(CCCNCc4ccnc5ccccc45)CC3)ccnc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 4-quinolinecarboxaldehyde (824 mg, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 249.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[Br:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[Br-:23].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:9])[C:10]2[CH:11]=[CH:12][N+:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CC#N
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cc[n+](Cc2ccccc2)cc1
Product: [Br-]
Reaction time: 22 h
Yield: 99.2 %

Procedure:
To a stirred mixture of 89.2 parts of α,α-bis(4-fluorophenyl)-4-pyridinemethanol and 720 parts of acetonitrile were added dropwise 56.5 parts of (bromomethyl)benzene at reflux temperature. Upon completion, stirring was continued for 22 hours at reflux. The reaction mixture was allowed to stand over week-end at room temperature. The product was filtered off and set aside. The filtrate was concentrated to a volume of 50 parts. The product was allowed to crystallize. It was filtered off and washed, together with the product which was set aside (see above), with 2,2'-oxybispropane and dried, yielding 139.5 parts (99.2%) of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)pyridinium bromide (intermediate 27).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.O[CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52].N12CCCN=C1CCCCC2.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[C:51]([O:50][C:49]([NH:48][CH2:47][CH2:46][C:1]([O:44][CH2:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25])=[O:2])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 1.0 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 400 mg of tert-butyl N-(2-hydroxyethyl)carbamate and 400 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[OH-].[Na+]>O>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(NS(=O)(=O)c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1ccc(NS(=O)(=O)c2ccccc2C(=O)O)cc1
Temperature: 85 °C

Procedure:
Reaction scheme II is carried out by slowing adding the cooled reaction mixture into a 4 liter beaker containing 250 ml water and 300 ml of hydrochloric acid (37%), and equipped with an efficient stirrer, taking care that the mixture does not foam over. The dispersion is chilled in a refrigerator over night. The crude N-(p-n-butylphenyl)-o-carbomethoxy benzene sulfonamide settles on the bottom of the beaker as a brownish, viscous mass. The water layer is poured off and replaced by a solution of 80 g sodium hydroxide in 1.5 liter of water. The resulting solution is heated for 2 hours at 85° C. to hydrolize the methyl ester (reaction scheme III). ##STR39##
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[CH2:11]([N:13]1[C:17](O)=[CH:16][C:15]([CH3:19])=[N:14]1)[CH3:12]>O>[Cl:8][C:17]1[N:13]([CH2:11][CH3:12])[N:14]=[C:15]([CH3:19])[C:16]=1[CH:3]=[O:4]
Reactant: CCn1nc(C)cc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c(C=O)c1Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 28.7 ml of anhydrous N,N-dimethylformamide at 0° C. were added slowly 80.7 ml of phosphorus oxychloride then 15.6 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol. The mixture was stirred under nitrogen at 80° C. for 1 hour, poured into 700 ml of water at 0° C. then extracted six times with 350 ml of diethyl ether. The combined extracts were dried over magnesium sulphate, filtered and evaporated to leave 9.3 g of 5-chloro-1-ethyl-3-methyl-1H-pyrazole-4-carbaldehyde as an orange liquid which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:32]([C:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=3[O:36][CH3:37])(=[O:33])=[O:34])=[CH:16][CH:15]=2)=[O:13])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester (140 mg, 0.43 mmol) in dichloromethane (5 ml) and pyridine (0.15 ml) was treated with 5-chloro-2-methoxy-benzenesulfonyl chloride (159 mg, 0.66 mmol, 1.5 equiv.) and stirred at room temperature for 17 hours. The solvent was then evaporated and the residue purified by flash chromatography (dichloromethane/ether 9:1) to yield 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester as a white foam, 227 mg (100%). MS (ISP): m/e=527.2 (M−H); δH (300 MHz; d6-DMSO) 10.5 (1H, s), 8.02 (1H, d), 7.96 (2H, d), 7.93 (2H, d), 7.85 (1H, d), 7.72 (1H, dd), 7.67 (1H, dd), 7.30 (1H, d), 7.23 (1H, d), 4.30 (2H, q), 3.78 (2H, m), 2.75 (2H, t), 1.74 (2H, m), 1.32 (3H, t).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[N:16][OH:17].[CH2:19]([OH:22])[C:20]#[CH:21]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[C:20]([CH2:19][OH:22])[O:17][N:16]=1
Reactant: ON=C(Cl)c1ccccc1Cl
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: OCc1cc(-c2ccccc2Cl)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triethylamine (48 mL) in diethyl ether (0.5 L) was added over two hours to a 0° C. solution of the compound prepared in Example 5 (50.0 g) and propargyl alcohol (31 mL) in diethyl ether (1.2 L). The reaction was stirred at room temperature overnight, washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (50.0 g) having the following physical data.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])=[O:18].N1C=CC=CC=1.[NH:32]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([CH:41]=O)[C:35]=2[CH:34]=[CH:33]1>O1CCCC1>[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][N:23]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][CH2:33][NH:32]3)[CH2:22][CH2:21]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(Cc2cccc3c2CCN3)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.92 g of sodium triacetoxyborohydride, 2.26 of 1-methanesulfonylpiperazine hydrochloride and 545 mg of pyridine are successively added to a solution of 1 g of indole-4-carboxaldehyde in 40 ml of tetrahydrofuran under argon. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled to 15° C., and then 1.30 g of sodium cyanoborohydride are added in portions. The reaction medium is stirred for 2 hours while allowing it to rise to ambient temperature, poured into a water/ice mixture, treated with 28% aqueous ammonia until the pH is neutral, and extracted with dichloromethane (4×30 ml). The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane/ethyl acetate, from 0 to 100% of ethyl acetate), so as to give 890 mg of 4-(4-methanesulfonylpiperazin-1-ylmethyl)-2,3-dihydro-1H-indole in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[CH2:23][CH2:24][O:25]C(=O)C)[CH:8]=2)[N:3]=1.[N+:38]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45])([O-:40])=[O:39]>>[CH3:1][C:2]1[NH:11][C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([NH:45][CH2:44][C:43]4[CH:46]=[CH:47][CH:48]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=4)=[O:34])=[CH:36][CH:37]=3)[CH2:23][CH2:24][OH:25])[CH:8]=2)[N:3]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OCCN(Cc1ccc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Product: Cc1nc2ccc(CN(CCO)c3ccc(C(=O)NCc4cccc([N+](=O)[O-])c4)cc3)cc2c(=O)[nH]1
Yield: 46 %

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-2-methyl-4-oxo-3-pivaloyloxymethylquinazolin-6-ylmethyl)-N-(2-acetoxyethyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(2-hydroxyethyl)amino]-N-(3-nitrobenzyl)benzamide (containing 1 equivalent of water) in 46% yield, m.p. 230°-232° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:18]=2)=[N:6][C:7]([Cl:12])=[C:8]([CH2:10][CH3:11])[N:9]=1)(=[O:3])[NH2:2].C(OCC)(=O)C.C(OC(=O)C)C.Cl>C(O)C>[Cl:12][C:7]1[N:6]=[C:5]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][C:8]=1[CH2:10][CH3:11]
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a mixture of tert-butyl 4-{4-[(3-carbamoyl-6-chloro-5-ethylpyrazin-2-yl)amino]-1H-pyrazol-1-yl}piperidine-1-carboxylate (1.69 g), ethyl acetate (10 mL), and ethanol (10 mL) was added a 4 M hydrogen chloride ethyl acetate solution (20 mL), followed by stirring at room temperature for 2 hours. The mixture was subjected to liquid separation by the addition of a 1 M aqueous sodium hydroxide solution and chloroform. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (1.32 g) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:19][NH2:20])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A mixture of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 80 mmol) and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirred for 16 h at 25° C. Then the solvent was concentrated to yield an off white solid of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 72.2 mmol, 90% yield): 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES-LCMS m/z 250 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:14][CH2:15][CH2:16][Cl:17])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N)cc1OCCCCl
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a solution of methyl 4-amino-2-hydroxybenzoate (500 mg, 2.99 mmol) and 1-bromo-3-chloropropane (0.294 mL, 2.99 mmol) in DMF (3 mL) was added CESIUM CARBONATE (1462 mg, 4.49 mmol). The resulting mixture was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated. The crude product was purified by silica gel chromatography using a gradient of 20-50% EtOAc/Hexanes to give 686 mg (94%) methyl 4-amino-2-(3-chloropropoxy)benzoate.