Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:11]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1cncc(-c2ccccc2)c1
Yield: 67.2 %

Procedure:
Preparation H2, Step 1: 5-bromonicotinic acid (500 mg, 2.48 mmol, 1 eq.), phenylboronic acid (454 mg, 3.71 mmol, 1.5 eq.), tetrakis(triphenylphosphine)palladium(0) (143 mg, 0.124 mmol, 0.05 eq.), and sodium carbonate (787 mg, 7.43 mmol, 3 eq.) were mixed in ethanol (5 mL), toluene (25 mL), and water (5 mL) at room temperature under nitrogen. The reaction was then refluxed for 20 hours. Worked up by adding water then stripping off the ethanol. Rinsed the aqueous layer 2 times with diethyl ether. Adjusted the aqueous layer pH=3 with conc. HCl. The acidic aqueous layer was extracted 3 times with ethyl acetate and a little THF. The ethyl acetate/THF layers were combined, dried over sodium sulfate and stripped to give 5-phenylnicotinic acid (332 mg) as a white solid. Yield=67%. LCMS detects (M+H)+=198.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=3)[C:13]=2[CH:25]=1)=[O:8])=S.[OH-].[Na+].[I-].[K+].[K+].I[I-]I.II>C(O)C.O.C(OCC)(=O)C.CN(C)C=O>[CH3:1][NH:2][C:3]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=4)[C:13]=3[CH:25]=2)=[N:6][N:5]=1
Reactant: CNC(=S)NNC(=O)c1ccc2occ(-c3ccc(SC)cc3)c2c1
Agent: II
Agent: I[I-]I
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1nnc(-c2ccc3occ(-c4ccc(SC)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a solution of N-methyl-2-[[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]carbonyl]hydrazinecarbothioamide (0.58 g, 1.56 mmol) in ethanol (10 mL) was added 2 M sodium hydroxide to adjust to pH 9 at 0° C., and 5% potassium iodide-iodine aqueous solution was added at room temperature until the color of iodine started to remain. N,N-Dimethylformamide (10 mL) was added to the mixture, and the resulting mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction mixture, and insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/3-3/2) and recrystallized from hexane/tetrahydrofuran to give the title compound (0.13 g, yield 24%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: COC(=O)c1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1C

Procedure:
Methyl 2-methylpyridine-3-carboxylate (10 g, 66.2 mmol) was taken up in DCM (140 mL) and mCPBA (16.31 g, 72.8 mmol) was added. The resulting mixture was allowed to react at room temperature overnight and then purified directly by silica gel chromatography (0-20% MeOH-EtOAc) to afford the title compound as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]([CH2:17][CH2:18][CH3:19])([C:14]([O-:16])=[O:15])C([O-])=O)=[CH:4][CH:3]=1.[CH3:21][C:22](C)=O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[C:14]([O:16][CH2:21][CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: CCCC(CC(=O)c1ccc(Br)cc1)(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a 200 mL flask was added crude 2-[2-(4-bromophenyl)-2-oxoethyl]-2-propylmalonate (7.62 g, 19.2 mmol), acetone (21 mL), and ethanol (19 mL), followed by addition of 1 N aqueous sodium hydroxide solution (19.1 mL). The reaction mixture was heated to 55° C. for 3 h. The clear, orange-red reaction mixture was then concentrated under reduced pressure and the residue was redissolved in dimethoxyethane (30 mL). The mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (100 mL) and water (100 mL), and stirred for 15 minutes until almost all color was extracted into the organic layer. The layers were separated and the aqueous layer extracted with additional ethyl acetate (75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford an orange oil. The crude product was purified by flash chromatography (10:1 hexane:ethyl acetate) to afford ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 20%). LC-MS ret. time 3.60 min, m/z 326.05 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H), 1.25 (t, 3H), 1.29-1.43 (m, 2H), 1.57-1.73 (m, 2H), 2.90-3.08 (m, 2H), 3.34-3.47 (m, 2H), 4.15 (q, 2H), 7.59 (d, 4H), 7.82 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])=[O:15]
Reactant: CC(C)CCCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CC(C)CCCOC(=O)CCC(=O)CN
Reaction time: 2 h

Procedure:
From 4-methyl-1-pentanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 2 h. The yield was 1.32 g (87%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=2[CH2:10]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]=3[CH2:10]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2.99 g of potassium carbonate, 20 ml of ethyl acetate and 40 ml of water are added to 2.09 g of ethyl (+)-6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate 1/2 (+)-D-dibenzoyltartrate, and a solution of 1.28 g of 4-chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added thereto at room temperature under stirring. After the mixture is stirred at room temperature for 1.5 hour, the organic layer is separated therefrom, washed, dried and evaporated to revove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.10 g of ethyl (+)-6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([OH:10])=O)=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1.C(N(CC)CC)C>O1CCCC1.O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)nn1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (109 mg, 0.78 mmol) in tetrahydrofuran (4.0 mL) were added N,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (135 μL, 1.55 mmol), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and a solution of the residue in tetrahydrofuran (2.0 mL) was added dropwise to a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and triethylamine (360 μL, 2.59 mmol) in tetrahydrofuran (4.0 mL). After stirring at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4→ethyl acetate) and precipitated from hexane/ethyl acetate to give the title compound (118 mg, 42%) as a white powder.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=1)=[O:9]>CO>[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)=[O:9]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (3.9 mL, 11.8 mmol) was added to a THF (10 mL) and MeOH (5 mL) solution of methyl 2′-formyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (1.2 g, 3.9 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][C:13]([CH3:42])([CH3:41])[CH2:14][CH:15]1[NH:19][CH:18]([C:20]([OH:22])=O)[CH:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])[C:16]1([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[F:40])[C:31]#[N:32])=[N+:9]=[N-:10].[CH3:43][C:44]1([CH3:52])[O:48][C@@H:47]([CH2:49][CH2:50][NH2:51])[CH2:46][O:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:43][C:44]1([CH3:52])[O:48][C@@H:47]([CH2:49][CH2:50][NH:51][C:20]([CH:18]2[CH:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:16]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:15]([CH2:14][C:13]([CH3:42])([CH3:41])[CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[NH:19]2)=[O:22])[CH2:46][O:45]1
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 90.6 %

Procedure:
In a manner similar to the method described in Examples 42c, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 120c (0.54 g, 0.85 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.37 g, 2.54 mmol), HATU (0.58 g, 1.5 mmol) and iPr2NEt (0.74 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide as a light yellow solid (0.5 g, 91%).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20]N(C)C)=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CC(C)=O>[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH3:20])=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]1
Reactant: CN(C)Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Solvent: CI
Solvent: CC(C)=O
Product: Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Methyl iodide (38 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (168 mg) in acetone (4 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in tetrahydrofuran (5 ml) was added a 1N aqueous sodium hydroxide solution (3 ml), followed by stirring with heating at 60° C. for 3 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. Then, a solution of the resulting residue in dichloromethane (6 ml) was added dropwise to an ice-cooled solution of triethylsilane (144 μl) and methanesulfonic acid (60 μl) in dichloromethane (10 ml), and the resulting mixture was stirred at 0° C. for 1 hour. A 10% aqueous potassium carbonate solution was added thereto, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (101 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[N:20]1[CH:25]=[CH:24][C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][CH:21]=1.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:20]1[CH:25]=[CH:24][C:23]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(-c3ccncc3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
3,4-Dihydro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone (4.41 g, 15.0 mmol) was dissolved in 40 ml of N,N-dimethylformamide in an argon atmosphere, and 6.77 g (18.4 mmol) of 4-pyridyltributyltin, 1.90 g (45.0 mmol) of lithium chloride and 0.53 g (0.75 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature, and ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 30% ethyl acetate and hexane) to obtain 2.32 g of the above-mentioned compound (yield 69%).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH:7]([NH:12]C(OCC2C=CC=CC=2)=O)[C:8]([O:10][CH3:11])=[O:9])=[N:4][N:3]=[N:2]1.[ClH:23]>CO>[ClH:23].[NH:4]1[C:5]([CH2:6][CH:7]([NH2:12])[C:8]([O:10][CH3:11])=[O:9])=[N:1][N:2]=[N:3]1
Reactant: COC(=O)C(Cc1nnn[nH]1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)Cc1nnn[nH]1
Reaction time: 2 h

Procedure:
0.53 g (1.74 mmol, 1 equiv.) of the compound of Example 52 (3-tetrazolyl-2-benzyloxymethanamidopropionic acid, methyl ester) was dissolved in 30 mL of methanol and 1 mL of conc. HCl was added. The reaction was flushed with nitrogen and 80 mg of 10% palladium on carbon was added. The solution was hydrogenated for 2 hours at 40 psi. Filtration of the catalyst followed by concentration in vacuo yielded 354 mg of the title compound. 1H-NMR (CD3OD): 4.7 p.p.m. (m, 1H); 3.8 p.p.m. (s, 3H); 3.6 p.p.m. (m, 2H).
Reaction SMILES: O.[N:2]#[C:3]Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[C:5]1([O:11][C:3]#[N:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CBr
Reactant: Oc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: N#COc1ccccc1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
The title compound was prepared by a modification of the procedure described in Organic. Syntheses, 61, 35 (1983). A 3-necked, 2 L R.B. flask, equipped with a 500 ml pressure equalized dropping funnel, a mechanical stirrer and a thermometer, was charged with water and coled in an ice-salt bath. Cyanogen bromide (189.1 g, 1.78 mol) was added and the mixture was stirred for 5 min. Phenol (160.0 g., 1.7 mol) in carbon tetrachloride (535 ml) was added in one portion. The mixture was stirred vigorously while triethylamine (236.9 ml, 172.0 g, 1.7 mol) was added dropwise at a rate such that the reaction temperature did not exceed 5° C. (total addition time=45 min.). The mixture was stirred for a further 15 min. then transferred to a 2 L separatory funnell The organic layer was separated and the aqueous layer was extracted with carbon tetrachloride (2×90 ml). The combined organic layers were washed with water (3×90 ml) then dried by stirring with phosphorus pentoxide (10 g) for 15 min. The mixture was filtered and the solvent was evaporated under reduced pressure (water aspirator) at 20° C. to give a yellow oil. Polyphosphate ester (Y. Kanaoka, et al., Chem. Pharm. Bull., 13, 1065-1072 (1965)) (0.2 ml) was added and the mixture was distilled under reduced pressure through a 15 cm vigreux column to give phenyl cyanate (165.8 g, 82%) as a colorless oil, b.p. 79°-82° C. (16 mmHg)1. The product was stored under nitrogen at -10° C. (freezes).
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.O>[CH3:20][C:3]1[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=2[O:35][CH3:36])=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(Br)c1C
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCCCNC(=O)c1cccc(-c2ccc(OC)cc2OC)c1C
Yield: 77.6 %

Procedure:
The procedure of the step 1 in Example 92 was repeated except that the methyl 6-(3-bromo-2-methylbenzamido)hexanoate (34 mg, 0.10 mmol), tetrakis(triphenylphosphin)palladium (12 mg, 0.010 mmol), sodium carbonate (21 mg, 0.20 mmol), and 2,4-dimethoxyphenyl boronic acid (27 mg, 0.15 mmol) instead of phenyl boronic acid were dissolved in 3 mL of dioxane/H2O (4:1, v/v) to obtain the title compound (31 mg, 80%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.17 mmol) was used in general procedure 3 with 1-ethylpiperazin (0.868 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 482.3 (M)+
Reaction SMILES: N#N.[CH2:3]([NH:10][C:11](=[O:29])[C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][C:13]=1[O:27][CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]([CH3:42])[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:3]([NH:10][C:11](=[O:29])[C:12]1[CH:17]=[C:16]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34](=[O:41])[N:33]([CH3:42])[CH:32]=2)[CH:15]=[CH:14][C:13]=1[O:27][CH3:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)NCc1ccccc1
Reactant: Cn1cc(Br)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Product: COc1ccc(-c2cn(C)c(=O)c3ccccc23)cc1C(=O)NCc1ccccc1
Reaction time: 0.05 h
Yield: 107.7 %

Procedure:
For about 3 min, N2 was bubbled through a mixture of N-benzyl-2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (51 mg, 0.14 mmol), 4-bromo-2-methylisoquinolin-1(2H)-one (30 mg, 0.13 mmol), aqueous 1M K3PO4 (0.3 mL) and Pd(dppf)Cl2 (10 mg, 0.013 mmol) in dioxane (1.15 mL) which was then microwaved at 100° C. for 1 h. Work up similar to Example 15 and purification by silica gel chromatography, eluting with 5-50% EA in hexane over 4 min and continuing 50% isocratic EA gave the title compound (37 mg, 0.14 mmol) as a tan solid in 71% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.57 (s, 3H), 3.97 (s, 3H), 4.52 (d, J=6.06 Hz, 2H), 7.21-7.37 (m, 6H), 7.47-7.51 (m, 2H), 7.56 (td, J=5.37, 2.15 Hz, 2H), 7.68-7.73 (m, 1H), 7.79 (d, J=2.27 Hz, 1H), 8.33 (d, J=7.83 Hz, 1H), 8.79 (t, J=6.06 Hz, 1H). LCMS (M+H)+ 399.