Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5](O)[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[N:35]=[C:34]([SH:40])[N:33]=1.C(=O)([O-])O.[Na+]>ClCCl.CN(C=O)C>[N:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:5]([S:40][C:34]1[N:33]=[C:32]([O:31][CH3:30])[CH:37]=[C:36]([O:38][CH3:39])[N:35]=1)[C:6]([O:8][CH3:9])=[O:7])=[N+:2]=[N-:3]
Reactant: COC(=O)C(O)C(C)(N=[N+]=[N-])c1ccccc1
Reactant: COc1cc(OC)nc(S)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(N=[N+]=[N-])c1ccccc1
Temperature: 0 °C

Procedure:
5.9 g (25 mmol) of methyl 3-azido-3-phenyl-2-hydroxybutyrate (Ex. 1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise with stirring. The mixture is stirred for 23 hours at room temperature, washed three times with 100 ml of water each time, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in 100 ml of DMF and added dropwise at 0° C. to a suspension of 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodium hydrogencarbonate in 100 ml of DMF. After stirring at room temperature for 2 hours and at 60° C. for a further 2 hours, the mixture is poured onto 1 l of ice water and the resulting precipitate is filtered off with suction.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([NH:10][C:11]1[O:15][N:14]=[CH:13][C:12]=1[C:16]1[CH2:17][N:18]([CH2:22]C)[CH2:19][CH2:20][CH:21]=1)[CH2:8][CH3:9].NC1ON=CC=1C1CN(CC)CCC=1.ICCC>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([NH:10][C:11]1[O:15][N:14]=[CH:13][C:12]=1[C:16]1[CH2:17][N:18]([CH3:22])[CH2:19][CH2:20][CH:21]=1)[CH2:8][CH3:9]
Reactant: CCCNc1oncc1C1=CCCN(CC)C1
Agent: CCN1CCC=C(c2cnoc2N)C1
Agent: O=C(O)C(=O)O
Solvent: CCCI
Product: CCCNc1oncc1C1=CCCN(C)C1

Procedure:
3-(5-propylamino-4-isoxazolyl)-1,2,5,6-tetrahydro-1-ethylpyridine oxalate from 3-(5-amino-4-isoxazolyl)-1,2,5,6-tetrahydro-1-ethylpyridine and iodopropane. M.p. 150-151° C. (Compound 21).
Reaction SMILES: [CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14]N(CC)CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N#C[Br:31].O.Cl>C(OCC)C>[CH:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[C:8]([O:10][C:11]([CH3:21])([CH3:20])[C:12]#[C:13][CH2:14][Br:31])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: N#CBr
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C#CCBr)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 9.5 g 4-diethylamino-1,1-dimethyl-2-butynyl α-cyclohexyl-α-phenylglycolate in diethyl ether, was added dropwise an etheral solution of 3.2 g cyanogen bromide, and the mixture was stirred for one hour under ice cooling and then for 18 hours under cooling with water. 2N-HCl (14 ml) was added to the reaction mixture under ice cooling, and the separated etheral layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue left was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 6.0 g of the objective compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][C:38]#C)[CH:31]=4)[CH2:26][CH2:25]3)=[O:19])[CH:12]=2)[C:9]([C:40]([O:42][CH3:43])=[O:41])=[C:8]([CH3:44])[NH:7][C:6]=1[CH3:45])=[O:4].[CH3:46]COC(C)=O>[Pd]>[CH3:45][C:6]1[NH:7][C:8]([CH3:44])=[C:9]([C:40]([O:42][CH3:43])=[O:41])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH:37]([CH3:38])[CH3:46])[CH:31]=4)[CH2:26][CH2:25]3)=[O:19])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCOC(C)=O
Reactant: C#CCOc1cccc(C2CCN(CCCNC(=O)Nc3cccc(C4C(C(=O)OC)=C(C)NC(C)=C4C(=O)OC)c3)CC2)c1
Agent: [Pd]
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)NCCCN2CCC(c3cccc(OC(C)C)c3)CC2)c1
Reaction time: 3 h

Procedure:
A suspension of the product of Example 51 (316 mg, 0.519 mmol) and 81 mg of 10% Pd/C in EtOAc (65 mL) was shaken under 50 psi of H2 on a Parr Hydrogenator for 3 h. The suspension was then filtered through Celite and the filtrate concentrated in vacuo to give 325 mg of the product as a clear oil. This residue was purified by preparative HPLC (Zorbax-RX-C8 column; 45% MeCN/55% 0.1% TFA H2O; 4.2 mL/min) and the free base subsequently converted to the HCl salt to furnish the product as a colorless foam: mp 110°-130° C. (sintered); 1H NMR (CDCl3) δ10.62 (br s, 1H). 8.53 (br s, 1H), 7.34 (d, 1H, J=7.6 Hz), 7.12 (m, 3H), 7.00 (t, 1H, J=7.6 Hz), 6.86 (d, 1H, J=7.5 Hz), 6.68 (m, 4H), 4.90 (s, 1H), 3.82 (t, 2H, J=6.5 Hz), 3.54 (s, 6H), 3.45 (m, 2H), 3.20 (m, 2H), 2.75 (m, 4H), 2.62 (m, 3H), 2.25 (s, 6H), 1.92 (m, 4H), 1.72 (h, 2H, J=6.8 Hz), and 0.95 (t, 3H, J=7.3 Hz); 13C NMR (CDCl3) δ168.4, 159.4, 157.1, 148.8, 145.5, 144.4, 139.6, 129.8, 128.5, 122.0, 118.7, 118.1, 117.2, 113.6, 112.5, 102.9, 69.5, 55.2, 53.3, 51.0, 40.2, 39.1, 36.7, 30.2, 25.1, 22.6, 19.2, and 10.5. Anal. Calcd for C35H46N4O6.HCl.0.45H2O: C, 63.37; H, 7.28; N, 8.45. Found: C, 63.37; H, 7.40; N, 8.28.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:41])[CH3:40])[CH3:38])[C:32]([O:34]CC)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:40])[CH3:41])[CH3:38])[C:32]([OH:34])=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1)N(C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Temperature: 60 °C
Yield: 55 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 28 (400 mg, 0.642 mmol), THF (5 mL) and ethanol (5 mL). A solution of lithium hydroxide (124 mg, 10.2 mmol) in water (5 mL) was added, and the mixture was heated at 60° C. for 48 h. After this time, the reaction was cooled to room temperature, and the mixture was slowly acidified to pH 4.0 with 10% aqueous citric acid. The resulting precipitate was filtered, and the filter cake was washed with water (20 mL), then triturated with a 1:10 mixture of methylene chloride/ethyl acetate (20 mL). The resulting residue was dried to a constant weight under vacuum at 45° C. to afford 29 in 55% yield (210 mg) as an off-white solid: mp 197-198° C.; 1H NMR (500 MHz, DMSO-d5) δ 9.91 (s, 1H), 9.29 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.39 (d, 2H, J=8.5 Hz), 7.35 (dd, 1H, J=7.0, 1.5 Hz), 7.32-7.28 (m, 2H), 7.24 (s, 1H), 4.23 (s, 1H), 3.56 (s, 3H), 3.30 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.33 (s, 9H), 1.13 (d, 3H, J=6.5 Hz), 1.10 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 596 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[Br:13][C:11]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:2]3[S:18][C:17]([NH:16][NH2:15])=[N:19][C:3]=3[C:4]=2[CH:12]=1
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Reactant: NNC(N)=S
Product: NNc1nc2c(s1)CCOc1ccc(Br)cc1-2

Procedure:
Following the procedure for 449, Step 2, 4,7-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one was reacted with thiosemicarbazide to afford the title compound as a beige solid. LCMS (Method E): RT=3.85 min, [M+H]+=312 and 314. 1H NMR (DMSO-d6): 10.13 (2H, bs), 9.80 (1H, bs), 8.49 (1H, d, J=2.6 Hz), 7.37 (1H, dd, J=8.6, 2.6 Hz), 6.97 (1H, d, J=8.6 Hz), 4.29 (2H, t, J=5.0 Hz), 3.21 (2H, t, J=5.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]#N)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:19].[Na+].N.Cl.[OH2:23]>C(O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:23])=[O:19])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Reactant: O
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 67 %

Procedure:
A mixture of 129 g. (0.52 mole) of 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile and 88 g. (1.1 moles) of 50% sodium hydroxide solution in 800 ml. of ethanol and 500 ml. of water is stirred and refluxed for about 18 hours with slow evolution of ammonia. The solution is then cooled to about 50° C. and acidified by adding 110 ml. of concentrated hydrochloric acid. The mixture is cooled, and the precipitated product, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid, is filtered and recrystallized from methanol, m.p. 193-195° C. (dec.). A second crop is obtained upon concentration of the mother liquor for a total yield of about 67% of theoretical. Analysis: Calcd. for C14H11ClNO3 : N, 5.05%. Found: N, 5.06%.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:20][C@@H:10]([O:11]C2C=CC(OC)=CC=2)[C@H:9]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C@@H:8]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:7]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:3])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@H:6]1[O:20][CH:10]([OH:11])[C@H:9]([N:21]2[C:22](=[O:31])[C:23]3=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]3[C:25]2=[O:26])[C@@H:8]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:7]1[O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2N2C(=O)c3ccccc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)OC[C@H]1OC(O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.4 %

Procedure:
Compound 22 (9.0 g, 14.1 mmol) was dissolved in acetonitrile:water (4:1, 400 ml). Ammonium cerium (IV) nitrate (20.1 g, 36.7 mmol) was added thereto, and the mixture was stirred vigorously for 40 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica, gel column chromatography (toluene:ethyl acetate=2.5:1) to obtain Compound 23 (6.1 g, 81%).
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15](=[S:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([CH3:3])[CH3:2].CI.[CH:27](N(C(C)C)CC)(C)C.O>C(O)C>[CH:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:20]=[CH:19][C:10]([CH:11]=[C:12]2[S:16][C:15]([S:17][CH3:27])=[N:14][C:13]2=[O:18])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccccc1Oc1ccc(C=C2SC(=S)NC2=O)cc1
Solvent: CCO
Solvent: O
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2ccc(Oc3ccccc3C(C)C)cc2)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
To a solution of 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-thioxo-thiazolidin-4-one (0.4 g, 1.12 mmol) in Ethanol (14 mL) was added CH3I (0.32 g, 2.25 mmol) and diisopropylethylamine (0.17 g, 1.35 mmol). The reaction mixture was stirred at room temperature for 4 h. It was then added water (40 mL) and the slurry was stirred at room temperature for 30 minutes. The solid was filtered, washed with water to yield the 5-[4-(2-Isopropyl-phenoxy)-benzylidene]-2-methylsulfanyl-thiazol-4-one as a yellow solid (0.42 g, 94%)
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20](Cl)=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>O1CCCC1.C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([NH:5][CH3:3])=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CC1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylamine in tetrahydrofuran (THF) (2.0 M, 3.5 mL) was mixed with triethylamine (2.1 mL, 15 mmol). The resulting mixture was added to a solution of 1-(4-chlorophenyl)cyclopropanecarbonyl chloride in methylene chloride (15.0 mL) at 0° C. The resulting mixture was stirred at room temperature (about 25° C.) for 30 min, and was then quenched with saturated sodium bicarbonate (25 mL). The quenched mixture was extracted with ethyl acetate (3×40 mL). The combined ethyl acetate extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the product, 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide, which was used in next step without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>ClCCl>[C:5]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([Br:9])=[CH:15][CH:14]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH2:21]1)(=[O:7])[CH3:6]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)C1(c2ccc(Br)cc2)C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a reaction flask under nitrogen atmosphere there was placed 26.6 g (0.2 Mol) of aluminum chloride, which was then covered with 150 ml of dichloromethane. There was then added dropwise 15.6 g (0.2 Mol) of acetyl chloride in 200 ml of dichloromethane, while cooling the reaction mixture. To this was added dropwise 23.3 g (0.1 Mol) of 4-bromobiphenyl in 200 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, and it was then heated to reflux for 4 hours, after which it was left at room temperature overnight under nitrogen atmosphere. There was then added 50 g of ice and the aqueous layer was separated. The organic layer was washed twice with 50 ml of saturated sodium chloride solution, then dried over magnesium sulfate and evaporated. The crude product was crystallized from 3:1 petroleum ether:benzene to give 16.9 g in the first crop, m.p. 126°-128° C.; and 3.9 g in the second crop.
Reaction SMILES: [NH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[NH2:2].C(O)(=O)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25](=O)/[CH:26]=[CH:27]/N(C)C)[CH:24]=1>C(O)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([OH:32])=[C:23]([C:25]2[N:1]([CH:3]3[CH2:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]3)[N:2]=[CH:27][CH:26]=2)[CH:24]=1
Reactant: CN(C)/C=C/C(=O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC(NN)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(Cl)ccc2O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 88.37 g, 0.4247 mol) was dissolved in ethanol (883.7 mL) and the solution was cooled to 0° C. in an ice bath. Acetic acid (97.36 mL, 1.70 mol) was added followed by (2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one, (Preparation 852, 95.86 g, 0.4247 mol) and the resulting slurry was allowed to warm to room temperature then stirred at room temperature for 2 days. The resulting suspension was cooled to 0° C. and the solid was filtered off, washed with cold ethanol (2×40 mL) and dried to give the title compound as a white granular solid, (83.23 g).
Reaction SMILES: [CH3:1][O:2]C1C=CC([N+]([O-])=O)=C(C=1)N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:20](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[C:23]=2[CH:24]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2c1

Procedure:
Free base of the titled compound was prepared from 5-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 417.42; mp: 172.0-174.0° C.; 1H-NMR (DMSO) δ: 8.78-8.76 (1H, m), 8.18 (1H, td, J=7.8, 2.1 Hz), 7.78 (1H, d, J=16.1 Hz), 7.74 (1H, d, J=8.1 Hz), 7.66-7.55 (4H, m), 7.41-7.32 (3H, m), 7.11 (1H, d, J=15.8 Hz), 6.98-6.91 (2H, m), 3.75 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.[Fe]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)C(=O)OC2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 2000 mL 3-necked round-bottom flask, was placed a solution of 6-nitroisobenzofuran-1(3H)-one (prepared as described in the previous step, 136 g, 759.78 mmol, 1.00 equiv) in water (50 mL), Fe (126.4 g), ethyl acetate (500 mL), acetic acid (180 mL). The reaction mixture was stirred for 2 h at 60° C. in an oil bath. The resulting mixture was added sodium bicarbonate 500 mL. The resulting solution was extracted with 5×500 mL of ethyl acetate. The combined organic layer was washed with 500 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (46 mg, 79%), MS (ISP) m/z=313.4 [(M+H)+], mp 249.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 3,4-difluoro-phenylboronic acid (38.2 mg, 0.24 mmol).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:63][C:64]([NH2:66])=[S:65]>ClCCl.CO>[NH2:66][C:64]1[S:65][CH:2]=[C:1]([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[N:63]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Acetylfuran (5.10 g, 46.0 mmol) was dissolved in a mixed solvent of dichloromethane (50 mL) and methanol (50 mL), and N,N,N,N-tetra-n-butylammonium tribromide (22.3 g, 46.0 mmol) added thereto, then the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue, then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was dissolved in acetonitrile (60 mL), and thiourea (3.5 g, 46.0 mmol) added thereto, then the solution was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, and to the resulting solid was added saturated sodium bicarbonate aqueous solution and ethyl acetate added, then the mixture was extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 2-amino-4-(2-furyl)thiazole (1.53 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].F[C:40]1[CH:41]=C(C=C[C:75]=1F)CN1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(O)=O)C=4)NC=3)C=CC=2)=O)C1=O.C(N)CC>>[CH2:75]([NH:33][C:31]([C:28]1[CH:29]=[C:30]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:8]4[C:7](=[O:34])[N:6]([CH2:5][C:4]5[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:10][CH:9]=4)=[O:13])[CH:17]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:32])[CH2:40][CH3:41]
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Solvent: CCCN
Product: CCCNC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid propylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and 1-Propanamine (20 mg, 0.00034 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3) d ppm 12.514 (s, 1H) 10.791 (m, 1H) 9.331 (s, 1H) 9.039 (s, 1H) 8.617 (m, 1H) 8.274 (m, 1H) 7.881-7.566 (m, 3H) 7.566-7.320 (m, 3H) 7.196-7.088 (m, 2H) 7.055-6.991 (m, 1H) 6.534 (t, J=6.5 Hz, 1H) 5.164 (s, 2H) 4.757 (d, J=5.3 Hz, 2H) 3.503 (m, 2H) 1.736 (m, 2H) 0.999 (t, J=7.4 Hz, 3H); MS m/z=556.36 M+H.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:7]1=[O:19].O>CN(C=O)C.CCOCC>[N:1]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)[C:7]1=[O:19])=[N+:2]=[N-:3]
Reactant: O=C1C(Br)CCN1c1ccc(F)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(c2ccc(F)c(Cl)c2)C1=O
Reaction time: 8 h
Yield: 120.6 %

Procedure:
Sodium azide (0.45 g) was added to a solution of 3-bromo-1-(3-chloro-4-fluorophenyl)-2-pyrrolidinone (2.00 g) in DMF (16 ml) and the mixture left to stand overnight. A further portion of sodium azide (0.15 g) was added and the mixture again left to stand overnight. The mixture was poured into water giving a white solid which was isolated by filtration, dissolved in ether, dried (MsSO4) and concentrated in vacuo to give the sub-title compound as an off-white solid (2.10 g) which was used directly in the next step.