Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=1.[CH:30]([O:33][C:34]1[CH:40]=[C:39]([CH:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:43][CH2:42]2)[C:38]([CH3:51])=[CH:37][C:35]=1[NH2:36])([CH3:32])[CH3:31]>CCN(C(C)C)C(C)C.CC(O)C>[Cl:8][C:6]1[C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:3]=[C:2]([NH:36][C:35]2[CH:37]=[C:38]([CH3:51])[C:39]([CH:41]3[CH2:42][CH2:43][N:44]([CH2:47][CH2:48][O:49][CH3:50])[CH2:45][CH2:46]3)=[CH:40][C:34]=2[O:33][CH:30]([CH3:32])[CH3:31])[N:7]=1
Reactant: COCCN1CCC(c2cc(OC(C)C)c(N)cc2C)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COCCN1CCC(c2cc(OC(C)C)c(Nc3nc(Cl)c(C(=O)c4ccccc4)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2C)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a 10 mL microwave reaction tube, (2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone (24.1 mg, 0.0548 mmol), 2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylaniline (16.8 mg, 0.0548 mmol), 2-propanol (4 mL) and Hunig's Base (3 drops) were added successively. The resulting mixture was stirred at 150° C. for 2 hours by using a microwave machine. The reaction solution concentrated in vacuo to afford crude (4-chloro-2-(2-isopropoxy-4-(1-(2-methoxyethyl)piperidin-4-yl)-5-methylphenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)(phenyl)methanone as a slightly yellow sticky oil. MS (ES+): 720.30 (MH+).
Reaction SMILES: [C:1]1([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[Br:30]N1C(=O)CCC1=O>C1(C)C=CC=CC=1>[Br:30][C:20]1[CH:21]=[CH:22][C:23]2[N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(-n3c4ccccc4c4ccccc43)cccc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2ccccc12
Yield: 99.4 %

Procedure:
5.9 g (20 mmol) of 9-(1-naphthyl)carbazole was put into a 500 mL Meyer flask, and 50 mL of ethyl acetate and 50 mL of toluene were added thereto, and the reaction mixture was stirred. Then, 3.6 g (20 mmol) of N-bromosuccinimide was slowly added to the solution, and the solution was stirred for about 170 hours (one week) at room temperature. After this solution was washed with water, the organic layer was dried with magnesium sulfate. Filtration and concentration of the reaction mixture gave 7.4 g of 3-bromo-9-(1-naphthyl)carbazole as white powder (99% yield). The Rf values (SiO2, eluent; hexane:ethyl acetate=2:1) of 3-bromo-9-(1-naphthyl)carbazole and 9-(1-naphthyl)carbazole were 0.43 and 0.35, respectively.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCSc1cccc[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCSc2cccc[n+]2[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 4.12 g of 2-β-aminoethylthio pyridine N-oxide hydrochloride in 60 cc of water, there are added 4 cc of 5 N soda, then 3.8 g of p-toluenesulfonyl chloride. The mixture is agitated for 5 hours at ambient temperature. The pH is maintained at 9.5 by the addition of normal soda. The precipitate is filtered and crystallized in aqueous ethanol. Yield=88%. Fusion point: 201° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:28]2([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC(C)C)(=O)C>O1CCCC1.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])[CH2:29][CH2:30][C:31](=[CH:9][C:7]#[N:8])[CH2:32][CH2:33]2)(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of potassium tert butoxide (1.0M in THF, 3.20 Kg, 3.55 mol) in tetrahydrofuran (2.1 L) was added diethyl (cyanomethyl)phosphonate (642 g, 3.62 mol), maintaining the temperature below 5° C. The resulting solution was aged for 2 h and a solution of 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (1.07 Kg, 2.78 mol) (Preparation 2) in tetrahydrofuran (3.9 L) was added. After the reaction was completed, isopropyl acetate (13.1 L) and water (26.3 L) were added. The organic layer was washed with brine and then concentrated to 1 L. Heptane (10.5 L) was added. The resulting solid was filtered, washed with heptane, dried in vacuo at 37° C. and then slurried in diethyl ether (5 L). Filtration and drying in vacuo afforded 989 g (87% yield) of [4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexylidene]acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.BrN1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>C1C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1
Reactant: Cc1nc2c(o1)CCc1ccccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(=O)c3ccccc3ccc2o1

Procedure:
A stirred mixture of 9,10-dihydro-2-methyl-4H-benzo[5,6]cyclohepta[1,2-d]oxazol-4-one (9.52 g) (J. Med. Chem., 1974, 17, 1316) and N-bromosuccinimide (7.95 g) in benzene (200 ml) was irradiated with a 500 Watt halogen lamp for 2 h. The mixture was then treated with N,N-diisopropylethylamine (15.5 ml) and set at reflux for 1 hour. The mixture was then partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by recrystallisation from ethyl acetate to give a buff solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]Br>ClCCl>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([Br:28])=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: COc1ccc(Cn2c(C)cc3cnnc(OCc4ccccc4)c32)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2c(C)c(Br)c3cnnc(OCc4ccccc4)c32)cc1
Yield: 78 %

Procedure:
1.8 g (5 mmol) of 7-benzyloxy-l-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine and 282 μl (5.5 mmol) of bromine are reacted in a total of 65 ml of dichloromethane and purified as described for Example 3a. Yield: 78%, m.p.: 149°-152° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[H-].[Na+]>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:34]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[C:3]2[C:15]([CH3:16])=[N:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 53, the product of Example 65 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 148°-150° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:5]([NH2:13])[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61]([NH:63][C:64]1[S:68][C:67]([C:69]2[C:74]([F:75])=[CH:73][CH:72]=[CH:71][C:70]=2[F:76])=[N:66][C:65]=1[C:77](O)=[O:78])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[F:76][C:70]1[CH:71]=[CH:72][CH:73]=[C:74]([F:75])[C:69]=1[C:67]1[S:68][C:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])=[C:65]([C:77](=[O:78])[NH:13][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:66]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1C1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:21][CH2:16][CH2:17][F:25])=[C:17]([F:25])[CH:18]=1
Reactant: Nc1ccc(B(O)O)cc1F
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: FCCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F

Procedure:
The title compound was prepared first using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-amino-3-fluorophenyl)boronic acid and then using General Experimental Procedure S for alkylation. 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-N-(3-fluoropropyl)aniline was obtained as a orange solid. 1H NMR (400 MHz, methanol-d4): δ 9.12 (d, J=7.6, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.86 (t, J=8.4 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 4.50 (t, J=5.6 Hz, 1H), 3.41 (t, J=6.8 Hz, 1H), 2.03 (m, 2H); MS (ESI) m/z [M+H]+339.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>CC(C)=O>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccccc1COc1cc(Nc2nccs2)ccc1Cl
Yield: 58 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol) and Cs2CO3 (72 mg, 0.22 mmol) in acetone (4.4 mL) was treated with 2-methylbenzyl bromide (41 mg, 0.22 mmol) at RT. Reaction control by TLC showed full conversion after 3 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/1) in 58% yield (42 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:39])[NH:22][C:9]4[CH:10]=[C:11]([C:20]#[N:21])[C:12]([N:14]5[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[O:37][N:36]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCCC5)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-piperidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M99) (0.41 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (226 mg, 70%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[O:17]([CH2:24][CH2:25][CH2:26][Br:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[BrH:27].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:26][CH2:25][CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: BrCCCOc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Br
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCOc2ccccc2)CC1
Yield: 54.4 %

Procedure:
A mixture of 4-(2-keto-1-benzimidazolinyl)piperidine (980 mg. 4.51 mmol) and 3-phenoxypropyl bromide (1.02 g, 4.73 mmol) was reacted in the presence of K2CO3 in CH2CN by refluxing under N2 for about 4 h to obtain the hydrobromide as a pale beige solid (1.06 g, 54%); mp 136-138° C. (foams); 1H NMR (CD3OD) δ 2.12 (d, J=13 Hz, 2H), 2.25-2.40 (m, 2 H), 2.81-2.99 (m, 2 H), 3.22-3.49 (m, 4 H), 3.82 (d, J=12 Hz, 2 H), 4.14 (t, J=8.4 Hz, 2 H), 4.55-4.70 (m, 1 H), 6.91-7.41 (m, 9 H).
Reaction SMILES: [C:1]1([N:7]([CH2:30]CC(OC)=O)[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].[C:43]([O:46][CH2:47][CH3:48])(=[O:45])[CH3:44].C(O)C.N>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][CH2:44][C:43]([O:46][CH2:47][CH3:48])=[O:45])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][S:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:41])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1cnc2c(c1)nc(CSc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 88 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[(4-cyanophenyl)thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 88% of theory, C27H28N6O3S (516.63) Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU106##
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3].[OH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=O)[O:27]1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH:28]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:26](=[O:25])[O:27]4)[CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3]
Reactant: O=C1OC(O)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 76.9 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.9 g (0.005 mole), 3-hydroxyphthalide 0.75 g (0.005 mole), triethylamine 0.5 g (0.005 mole) and DMF 10 ml was heated at 100°-110° C. for 8 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in dichloromethane, washed with water and dried with anhydrous Na2SO4. After removing the solvent, the residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.8 g (78%) of 1-ethyl-6-chloro-7-(4-phthalidyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless powders.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](OC)=[O:25].Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:25])[NH2:32]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (310 mg, 0.77 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 25 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 145 mg (49%) of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.2 (m, 6H), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.25 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3460, 3360, and 1589. MS (ES) m/e 383, 385.
Reaction SMILES: [NH2:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>O1CCOCC1.O>[C:12]1([CH2:11][O:10][C:8]([NH:1][CH:2]([PH:4](=[O:5])[OH:6])[CH3:3])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)[PH](=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(NC(=O)OCc1ccccc1)[PH](=O)O
Temperature: 20 °C
Yield: 73.8 %

Procedure:
To a solution of 1.7 g (15.6 mmol) of 1-aminoethyl phosphinic acid in 35 ml of a mixture of dioxane and water, in the presence of an equivalent of soda (624 mg), there is added, 0° C., dropwise and simultaneously, a solution of 3.1 g (18.3 mmol) of benzyl chloroformate in 9 ml of dioxane and, so as to maintain the pH of the reaction about 9, a solution of 1 g of soda in 8.7 ml of water. At the end of the addition, the mixture is maintained at a temperature about 20° C. for 2 hours. The aqueous phase is then washed 3 times with 20 ml of diethyl ether. The aqueous phase is acidified, at 0° C., with brisk agitation, with 11 ml of a 6N hydrochloric acid solution. An abundant white precipitate forms, which is filtered, washed with water and dried. There is recovered 2.8 g of product (yield=73.9%).
Reaction SMILES: Br[CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].[I-].[K+]>S(=O)(=O)(O)O>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C@H:2]([C:3]([OH:5])=[O:4])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Reactant: Cc1ccccc1N
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Product: Cc1ccccc1N[C@H](C(=O)O)C(C)C
Temperature: 0 °C

Procedure:
To m-phenoxybenzyl α-bromoisovalerate (2 g, 0.0055 mole), 24°, is added 2-methylaniline (2.95 g, 0.0275 mole) followed by a catalytic amount of potassium iodide (20 mg). The reaction mixture is heated, 110°-115°, for about 36 hours, and then poured into ice-water (30 ml) and 2 N sulfuric acid (10 ml) and extracted with ether (3×30 ml). The combined ether extracts are washed with water (2×30 ml) until neutral and with brine (10 ml) followed by drying over calcium sulfate. The reaction product is concentrated under vacuum and isolated by preparative TLC to yield 3-phenoxybenzyl ester of N-(2-methylphenyl)valine. MS m/e 389.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[CH:20]1([NH:23][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:35](=[O:36])[C:34]5[CH:33]=[CH:32][C:31]([N:28]6[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]6)=[CH:39][CH:38]=5)=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:12][CH:13]=2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc4c(ccn4-c4ccc(C(=O)NC5CC5)cc4)c3)cc2)CC1

Procedure:
Compound 961 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 4-(4-methylpiperazin-1-yl)benzoic acid. [M+H]+ calcd for C30H31N5O2: 494.25; found 494.06.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:26]([NH:29][CH:30]([C:36]([OH:38])=[O:37])[CH2:31]SC(=O)C)(=O)[CH3:27]>>[C:6]([O:38][C:36](=[O:37])[C@@H:30]1[CH2:31][CH2:27][CH2:26][N:29]1[C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])([CH3:10])([CH3:7])[CH3:5]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)O)cc1
Product: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1

Procedure:
By substituting 2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoic acid for the N,S-diacetyl-D,L-cysteine in the procedure of Example 53, N-[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline tert-butyl ester is obtained.