Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:23])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](O)=[O:21])=[N:12]3)[C:4]=2[O:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:46][NH:47][O:48][CH3:49].CCN(CC)CC>CN(C=O)C.O>[F:23][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([N:47]([O:48][CH3:49])[CH3:46])=[O:21])=[N:12]3)[C:4]=2[O:3]1
Reactant: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a mixture of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.8 g, 12 mmol), HOBt (2.7 g, 17 mmol) and WSC (3.4 g, 17 mmol) in DMF (50 mL) was added N,O-dimethylhydroxylamine hydrochloride (2.3 g, 23 mmol) and Et3N (4.9 mL, 35 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with AcOEt (250 mL×2). The combined organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give orange crystals. The crystals were washed with AcOEt/hexane (1/4) to give the title compound (2.7 g, 62% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.96 (3H, s), 7.12 (1H, dd, J=7.9, 1.1 Hz), 7.23 (1H, d, J=8.7 Hz), 7.57 (1H, dd, J=8.7, 1.1 Hz), 8.06 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([Br:6])[CH3:5].[CH2:7]1[N:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1>C(#N)C>[Br-:1].[Br:6][CH:4]([CH3:5])[CH2:3][CH2:2][N+:9]12[CH2:14][CH2:13][NH+:12]([CH2:11][CH2:10]1)[CH2:7][CH2:8]2.[Br-:1]
Reactant: C1CN2CCN1CC2
Reactant: CC(Br)CCBr
Solvent: CC#N
Product: CC(Br)CC[N+]12CC[NH+](CC1)CC2
Product: [Br-]

Procedure:
1,3-Dibromobutane (2.15 g, 1.2 ml, 10 mmol) was dissolved in acetonitrile (2 ml). DABCO (1.23 g, 11 mmol) was added. The reaction mixture was heated at 65° under nitrogen for 2 hr. The acetonitrile was removed under reduced pressure to give a white solid as the product.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1.C1COCC1.[N:26]#[C:27]Br.[CH2:29]([N:31](CC)CC)C>>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:27]#[N:26])=[C:5]([O:10][CH3:11])[CH:4]=2)=[CH:13][C:14]=1[O:19][CH3:20])[C:29]#[N:31]
Reactant: CCN(CC)CC
Reactant: COc1cc(CCc2ccc(O)c(OC)c2)ccc1O
Reactant: N#CBr
Solvent: C1CCOC1
Product: COc1cc(CCc2ccc(OC#N)c(OC)c2)ccc1OC#N
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A round bottom flask was charged with 1.05 g (3.8 mmol) of 4,4′-(ethane-1,2-diyl)bis(2-methoxyphenol), THF (40 mL), and CNBr (1.06 g, 10 mmol). The flask was cooled to −20° C. and triethylamine (1.16 mL) was added dropwise. A tan solid immediately precipitated from solution. The mixture was stirred at −20° C. for 10 min and was then removed from the cold bath and allowed to spontaneously warm. After stirring for an additional 30 min, the mixture was filtered on a medium glass-frit and the solid washed with water (3×20 mL) and then air dried to yield 0.71 g of crude product. Evaporation of the filtrate followed by water and ether washes vielded an additional 0.22 g of product for a total of 0.93 g (76%). Recrystallization from hot THF yielded 625 mg of tan needles. 1H NMR (DMSO-d6) δ 7.42 (d, 2H, J=8 Hz), 7.18 (s, 2H), 6.91 (d, 2H, J=8 Hz), 3.88 (s, 3H, OMe), 2.91 (s, 2H, CH2). Anal. Calcd for C18H16O4N2: C, 66.86; H, 4.97. Found: C, 66.67; H 4.96.
Reaction SMILES: CN1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([NH2:19])[CH:10]=2)CC1.N1C=CC=CC=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].Cl.[OH2:37]>C(Cl)Cl>[C:5]([NH:8][C:9]1[CH:10]=[C:11]([NH:19][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)(=[O:37])[CH:6]=[CH2:7]
Reactant: CN1CCC(Nc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dissolve the product obtained in Step 2 (168 mg, 0.73 mmol) in DCM (6 mL), add pyridine (115 mg, 1.46 mmol) and then cool to 0° C. on ice bath. Add slowly phenyl chloroformate (125 mg, 0.8 mmol), stir at 0-5° C. for 2 hrs. Pour the mixture into water (50 mL), adjust pH to neutral with 1M HCl and extract with EtOAc (15 mL×3). Combine the organic layers, wash with brine (100 mL) and dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (240 mg) which is used without further purification.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]I.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[I-:1].[I-:1].[CH2:2]([N+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc2ncccc2c1
Reactant: ICCCCCCI
Product: [I-]
Product: c1ccc2c(c1)ccc[n+]2CCCCCC[n+]1cccc2ccccc21
Temperature: 65 °C

Procedure:
1,6-Diiodohexane (mmol) was added to a solution (30 mL) of dry quinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated. 1H NMR (300 MHz, DMSO-D6) δ 9.53 (1H, d, C2-H), 9.29 (1H, d, C3-H), 8.61 (1H, d, C8-H), 8.50 (1H, d, C4-H), 8.29 (1H, t, C7-H), 8.18 (1H, t, C5-H), 8.07 (1H, d, C6-H), 5.09 (2H, t, C′1-CH2), 1.96 (2H, m, C′2-CH2), 1.25 (2H, m, C′3-CH2).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>>[CH3:31][N:30]([CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:34])[F:35])=[CH:33][CH:32]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: CNCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)Cc1ccc(C(F)(F)F)cc1
Yield: 5 %

Procedure:
The title compound was prepared in 5% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-trifluoromethyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.22 (3H, s), 2.73 (2H, t, J=5.8 Hz), 3.62 (2H, s), 4.16 (2H, t, J=5.9 Hz), 7.12 (1H, m), 7.21 (1H, m), 7.38 (2H, d, J=7.8 Hz), 7.54 (2H, d, J=8.2 Hz), 7.75 (1H, s), 8.29 (1H, s), 8.54 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19F3N4O2, 405. Found, 405.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: COC(=O)c1cc(C=O)n(C)c1
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(Br)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-bromo-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccccc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-phenyl-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (40 mg, 0.290 mmol) similar to Example 77 and isolated as a tan solid (16 mg, 23%). 1H NMR (CDCl3): 8.44–8.40 (m, 2H), 7.50–7.45 (m, 3H), 7.02 (s, 1H), 6.91 (s, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.78 (dd, J=2.0, 8.3 Hz, 1H), 6.71 (s, 1H), 6.03 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]#N)[CH3:2].[OH-:16].[Na+].N.[OH2:19]>>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:8][C:9]([OH:19])=[O:16])[CH3:2]
Reactant: [OH-]
Reactant: O
Reactant: CCN(CC)c1cccc(CCC#N)c1
Agent: N
Agent: [Na+]
Product: CCN(CC)c1cccc(CCC(=O)O)c1

Procedure:
A mixture of 60.6 parts of 3-diethylamino-hydrocinnamonitrile, 250 parts by volume of methylated spirits of denatured alcohol, 100 parts of water and 60 parts by volume of a 35° Be solution of sodium hydroxide was heated under reflux until the evolution of ammonia ceased. After the evolution of ammonia had stopped, the mixture was cooled and then neutralized by addition of 19° Be hydrochloric acid. After filtering and drying, 3-diethylamino-hydrocinnamic acid was obtained of the formula:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:22].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:22])=[C:4]([F:21])[C:5]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Solvent: ClCCl
Solvent: CO
Product: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}naphthalene (0.96 g, 2.63 mmol) in dichloromethane (10 mL) was added 7N ammonia in methanol (20 mL, 140 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.769 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.37 (m, 1H), 7.94-8.03 (m, 1H), 7.60-7.71 (m, 4H), 7.56 (t, 1H), 7.36 (t, 1H), 6.56 (d, 1H), 4.13 (s, 2H). ES MS: m/z 302 (M+1).
Reaction SMILES: [B][B][B][B][B][B][B][B][B][B].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH3:27]>CO>[CH3:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[NH:11][CH:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])[CH3:27]
Reactant: CC(=O)c1ccccc1C
Reactant: Cc1cccc(N)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: Cc1cccc(NC(C)c2ccccc2C)c1
Reaction time: 20 h

Procedure:
To a flame-dried 100 mL round-bottom flask equipped with a magnetic stirring bar was added 260 mg of decaborane (260 mg, 2.1 mmol), dry methanol (52 mL), m-toluidine (780 μL, d=0.989 g/mL, 7.2 mmol), and 2′-methylacetophenone (1 mL, d=1.014 g/mL, 7.6 mmol), and the mixture stirred and monitored by TLC (product Rf=0.43-0.44 in 50% dichloromethane/hexanes). The solution gradually changed color from brown to pale yellow and the reaction proceeded. After 20 hours, the solution was colorless, decaborane (115 mg, 0.941 mmol) was added, at which time the solution became pale yellow again. Another portion of decaborane (103 mg, 0.843 mmol) was added after 4 days, and the reaction stirred an additional six days. After completion, the solvent was evaporated, the residue redissolved, loaded onto a short 2.5 inch columns of silica gel and eluted with 5% ethyl acetate/hexanes. The eluent was collected and concentrated, and the crude product purified by flash chromatography using a slow gradient of 10% dichloromethane/hexanes to 20% dichloromethane/hexanes. Fractions were combined and concentrated to give the desired product ZZZ (1.29 g, 79.6%) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1ccc(F)cc1
Solvent: CO
Product: COc1cc(C=Nc2ccc(F)cc2)cc(OC)c1O

Procedure:
3,5-Dimethoxy-4-hydroxybenzaldehyde (1 g, 5.46 mmol) was dissolved in methanol (30 ml) and to this solution was added 4-fluoroaniline (600 mg, 5.46 mmol, 0.51 ml). The resultant reaction solution was stirred for forty-eight (48) hours at room temperature under nitrogen. The reaction solution was then cooled in the freezer and the resultant precipitate was isolated by filtration and washed with cold methanol and ether. The isolated light yellow powder was the title product: 1H NMR (300 MHz, CDCl3); δ 8.31 (S, 1H) , 7.20-7.04 (m, 4H), 5.85 (S, 1H), 3.98 (S, 6H).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[S:6][C@@H:7]2[C@@H:24]([O:25][CH3:26])[C:23](=[O:27])[N:8]2[C:9]=1[C:10]([O:12]CC1C=CC([N+]([O-])=O)=CC=1)=[O:11])=[O:4])[CH3:2].C([O-])(O)=O.[Na+:32]>O1CCOCC1.O>[CH2:1]([S:3]([C:5]1[S:6][C@@H:7]2[C@@H:24]([O:25][CH3:26])[C:23](=[O:27])[N:8]2[C:9]=1[C:10]([O-:12])=[O:11])=[O:4])[CH3:2].[Na+:32]
Reactant: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)C1=C(C(=O)[O-])N2C(=O)[C@H](OC)[C@H]2S1

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-ethylsulfinyl-6-methoxy-pen-2-em-3-carboxylate (48 mg, 0.12 mmol) and 10% pd/C (100 mg) in dioxane (8 ml) and H2O (4 ml) is shaken under a H2 pressure of 45 psi for 60 minutes. The reaction mixture is diluted with H2O (20 ml) containing NaHCO3 (10 mg, 0.12 mmol) and filtered to remove the catalyst. The filtrate is washed with Et2O (3×20 ml), concentrated under vacuum to ca. 5 ml volume, and lyophilized to provide the crude product.
Reaction SMILES: C(N1C2C(=CC=C(N[C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)C=2)C(C)(C)C1)(=O)C.C(N1C2C(=CC=C([N+]([O-])=O)C=2)C(C)(C)C1)(=[O:32])C.O.O.[Sn](Cl)Cl.Cl>C(OCC)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:14]([OH:27])=[O:32])=[CH:22][CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a solution of 1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c), (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round-bottomed flask at 0° C., was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCl (0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (2:3 hexane:EtOAc), the title product. MP 121° C. MS (ESI, pos. ion) m/z: 391 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C(O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CSC(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 0 °C
Yield: 87 %

Procedure:
3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2 mmoles) of sodium acetate are dissolved in 75 ml of water. The solution is agitated vigorously during the addition by portions, of 3.10 g (20.5 mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. A white precipitate rapidly appears in this pale yellow solution which forms abundantly. Agitation is maintained for one hour, the reaction mixture is then cooled down to 0° C. and filtered. The precipitate is successively rinsed with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying. a white powder is obtained with a yield of 87%. Melting point: 120-121° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C.[Pd]>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3
Reactant: O=Cc1ccccc1O
Reactant: Nc1cccc2cccc(N)c12
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1C1=Nc2cccc3cccc(c23)N1
Reaction time: 18 h

Procedure:
To 1,8-diaminonaphthalene (31.6 g, 0.2 mole) suspended in 200 ml absolute ethanol is added salicylaldehyde (24.4 g, 0.2 mole) and 7 g 10% palladium-on-carbon. The mixture is stirred and heated under reflux for 45 min., after which it is allowed to stand for 18 hours at ambient temperature. The mixture is then filtered and the filtrate is washed with ethanol and ether. The green solid is treated with heated dimethylformamide (charcoal) and filtered hot. The catalyst is removed from the product by filtration along with the charcoal. The yellow-orange filtrate is cooled, and upon addition of water, yields the desired product, 2-(o-hydroxyphenyl)perimidine, orange crystals, m.p. 258°-260° dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].C.[CH2:18]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[S:24])[CH2:19][CH2:20][CH3:21]>CC(C)=O>[ClH:16].[CH2:1]([O:3][C:4]([C:6]1[C:7]([S:24][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][CH2:18][CH2:19][CH2:20][CH3:21])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCCCNC(=S)NCCCC
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Agent: C
Solvent: CC(C)=O
Product: CCCCN=C(NCCCC)Sc1nc2ccccc2nc1C(=O)OCC
Product: Cl
Temperature: 25 °C
Yield: 47.5 %

Procedure:
2-Chloro-3-quinoxalinecarboxylic acid ethyl ester (7.10 g., 0.03 mole) was dissolved in 125 ml. of acetone treated with Norit and filtered. The filtrate was added to 5.650 g. (0.03 mole) of 1,3-di-n-butylthiourea in 100 ml. of acetone. The solution was stirred at reflux under a nitrogen atmosphere for 6 hours, allowed to cool to room temperature, and stirred an additional 17 hours. The red solution was treated with Norit, filtered, and concentrated to a volume of 100 ml. The yellow solid that crystallized out was collected by filtration, washed and dried to give the 6.05 g. (47.5% yield) of product, m.p. 138°-139° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22]C)[C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1)[CH3:2].Br.[OH-].[Na+]>C(O)(=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[S:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CC1)c1ccccc1Sc1c(OC)cccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCC2(CC1)c1ccccc1Sc1c(O)cccc12
Reaction time: 5 h

Procedure:
A solution of 1'-ethyl-4-methoxythioxanthene-9-spiro-4'-piperidine (1.625 g.) in glacial acetic acid (20 ml.) is added to 48% w/v hydrobromic acid (20 ml.) and refluxed with stirring for 5 hours. The mixture is cooled, diluted with water (500 ml.), cooled in ice and basified with 19N-sodium hydroxide solution and the solution washed with ether (× 3). The aqueous alkaline layer is acidfied to pH 1 with concentrated hydrochloric acid, neutralised with solid sodium bicarbonate and extracted with ethyl acetate (× 3). The combined ethyl acetate extracts are washed with water (× 3), dried over MgSO4 and the ethyl acetate removed by distillation in vacuo. The resulting sticky solid is triturated with ether to give 1'-ethyl-4-hydroxythioxanthene-9-spiro-4'-piperidine, m.p. 223°-225° C. on recrystallisation from dimethyl formamide/methanol/water.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:39]([CH3:41])[CH3:40])[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:28])=[C:19]2[OH:38])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:8][CH:9]([CH:39]([CH3:41])[CH3:40])[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:28])=[C:19]2[OH:38])=[O:11]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate from Example No. 146 (0.13 g) is stirred in a mixture of 4 mL trifluoroacetic acid and 7 mL CH2Cl2 at 0° C. for approximately 1.5 h. Once the reaction is complete, the mixture is partitioned between CH2Cl2 and saturated NaHCO3. After the TFA is neutralized, any undissolved material is filtered off. The organic layer is washed once with water. The combined aqueous layers are back-extracted with CH2Cl2 and EtOAc. The organics are combined, dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. The solid is recrystallized from a minimal amount of EtOH. (0.040 g, 0.082 mmol, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([O:12]CC)=[O:11])[CH3:9])=[O:6].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:35])[C:17]=1[C:18]([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[C:23]=2[CH:22]=[CH:21]1)=[O:19])[C:5]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:6]
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A mixture of ethyl N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alaninate (20 mg, 0.038 mmol) in tetrahydrofuran and water (1:1, 1 mL) was treated with sodium hydroxide (1.5 mg) and stirred at room temperature for about 1 hour. Tetrahydrofuran was removed under vaccuo and the residue was acidified with hydrochloric acid solution (1N, up to pH 2). The solid was filtered and dried to get pure N-[3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)benzoyl]alanine (12 mg, 66%).