Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[CH3:17]OS(OC)(=O)=O>O1CCCC1>[F:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:17])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (4.5 g, 1 eq) is added in small portions to a solution of 4-fluoro-3-nitrobenzoic acid (20 g, 1 eq) in tetrahydrofuran (100 ml). After stirring for 1 hour at approximately 20° C., dimethylsulphate (10.2 ml) is added dropwise to the yellow precipitate. The reaction mixture is then heated under reflux for 8 hours then concentrated under reduced pressure at 40° C. The residue is diluted in dichloromethane and Na2CO3 saturated water. After decanting and extracting, the combined organic phases are washed with salt water, dried over sodium sulphate and concentrated under reduced pressure at 40° C. The yellow solid obtained is recrystallized from a diethyl ether/petroleum ether mixture in order to produce the expected compound in the form of a light yellow powder (16.7 g, 78% yield). Melting point=59° C.
Reaction SMILES: C[O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:19](=[CH:20][CH:21]=1)[O:18][C:11]1([CH2:14][N:13]([C:15](=[O:17])[CH3:16])[CH2:12]1)[CH2:10][C:9]2=[O:22].[OH-].[Na+]>>[C:15]([N:13]1[CH2:12][C:11]2([CH2:10][C:9](=[O:22])[C:8]3[C:19](=[CH:20][CH:21]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:23])=[O:2])[CH:7]=3)[O:18]2)[CH2:14]1)(=[O:17])[CH3:16]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(C)=O)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Yield: 46.9 %

Procedure:
(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (270 mg, 0.85 mmol) was hydrolyzed with 1 M NaOH (1.1 ml) following the procedure described in Example 30, Step A, giving (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (120 mg, hydrochloride salt) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].C(O)(C)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: OC1CCNCC1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: OC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
To a mixture of 2-(4-((3-chloropyrazin-2-yl)oxy)piperidin-1-yl)quinoline (see PREPARATION P1.1; 0.1 g, 0.29 mmol) and piperidin-4-ol (0.029 g, 0.29 mmol) and K2CO3 (0.08 g, 0.58 mmol) was added isopropyl alcohol (i-PrOH) (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.02 g, 0.04 mmol, 17% yield) as white solid. ESI-MS (M+1): 406 calc. for C23H27N5O2 405.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[C:12]([CH:13]=[CH:14][CH:23]=3)[C:4]#[N:3])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.088 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 7.21 (s, 1 H) 7.29 (d, J=5.15 Hz, 1 H) 7.55 (m, 2 H) 7.65 (d, J=8.09 Hz, 1 H) 7.78 (m, 3 H) 7.94 (m, 2 H) 8.22 (d, J=5.52 Hz, 1 H) 14.19 (s, 1 H) 14.83 (s, 1 H). MS (ESI−) m/z 476(M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (35 g, 0.114 mol) and stannous chloride dihydrate (128.5 g, 0.569 mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (250 ml, 10/1, v/v), and the reaction solution was refluxed for 4 hours. The solution was cooled to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (35 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.[H-].[Na+]>>[Cl:10][C:11]1[N:16]=[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2ccnc(Cl)n2)cc1

Procedure:
The 2-chloro4-(4-methoxyphenylsulphanyl)pyrimidine was prepared in a similar manner to the analogous starting material of Example 1, from 4-methoxybenzenethiol (1.90 g, 13.4 mmol), 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) and sodium hydride [60% dispersion in oil] (590 mg, 14.8 mmol) as an off-white solid m.p. 69-70°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH2:5][NH2:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][C:23](=[O:30])/[C:22]/2=[CH:31]/OC.O>CN(C)C=O>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[NH:24][C:23](=[O:30])/[C:22]/2=[CH:31]\[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccc(O)c(O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
According to general procedure 1, an amount of 3, 4 dihydroxybenzylamine (0.596 g, 4.3 mmol), is dissolved in N,N-dimethylformamide (61 mL). 1.8 ml (12.9 mmol) of triethylamine is added followed by 1.21 g (4.3 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 30 min, water (5 mL) is added and the reaction mixture is stirred for 60 min. The precipitate is filtered and washed several times with anhydrous ether. The crude solid is then purified by high performance liquid chromatography to give 910 mg of a white solid. MS (ESI) m/z 389.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:26]#[N:27])[C:8]([CH3:25])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:18])[CH3:17])[CH2:12]2)[N:6]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl.O>[C:26]([C:7]1[C:5]2[N:6]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[O:3][C:4]=2[C:10]([N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:17])[CH3:18])[CH2:12]2)=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]=1[CH3:25])#[N:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N)nc2c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NS(C)(=O)=O)nc2c1C#N

Procedure:
2-Amino-7-[3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#76) was suspended in dichloromethane (3.4 ml), then triethylamine (94.9 μl, 681 μmol) and methanesulfonyl chloride (52.7 μl, 681 μmol) were added with cooling with ice, then dichloromethane (10 ml) was added, followed by stirring with cooling with ice for 5 hours. Further, triethylamine (94.9 μl, 681 μmol) and methanesulfonyl chloride (52.7 μl, 681 μmol) were added with cooling with ice, followed by stirring at room temperature for 15 hours. Aqueous 1 N sodium hydroxide solution (5 ml) and water (5 ml) were added to the reaction liquid, and the aqueous layer was washed with diethyl ether (20 ml×2).
Reaction SMILES: [C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2].[H][H]>CO.[Pd]>[C:1]([C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5](=[O:17])[CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccc2)C=CN(Cc2ccc(F)cc2)C(=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#CC1(c2ccccc2)CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
To a solution of 4-cyano-1-(4-fluorobenzyl)-4-phenyl-1,2,3,4-tetrahydropyridin-2-one (3.98 g, 13.0 mmol) in degassed methanol was added 10% Pd/C (0.8 g). The reaction shaken under an atmosphere of 33 psi of hydrogen for 18 hours. More 10% Pd/C (0.4 g) was added and the mixture was shaken under 45 psi of hydrogen for 48 hours. The mixture was filtered through a bed of celite and the filtrate was concentrated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J=7.7 Hz, 2H), 7.46 (t, J=7.9 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.28 (t, J=3 Hz, 2H), 7.16 (t, J=2.4 Hz, 2H), 4.58 (s, 2H), 3.44 (m, 1H), 3.25 (m, 1H), 3.07 (q, J=16 Hz, 2H), 2.41 (s, 2H) ppm. ES MS M+1=309.
Reaction SMILES: [NH2:1][C:2]1[C:22]([CH:23]2[CH2:25][CH2:24]2)=[CH:21][C:5]2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Br:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(N(CC)CC)C>CCOC(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:26][C:27]1[CH:32]=[C:31]([NH:1][C:2]2[C:22]([CH:23]3[CH2:25][CH2:24]3)=[CH:21][C:5]3[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)[O:8][C:4]=3[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(C3CC3)cc12
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(Nc3cccc(Br)c3)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
A mixture of ethyl 6-amino-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (1.00 g, 2.95 mmol), (3-bromophenyl)boronic acid (1.184 g, 5.89 mmol), copper(II) acetate (0.803 g, 4.42 mmol), triethylamine (1.232 mL, 8.84 mmol) and 4 A molecular sieves (2 g) was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane:EtOAc) to give ethyl 6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (740 mg, 51%). LCMS (m/z, ES+)=494, 496 (M+H, M+2).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH2:2][CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(O)(=O)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=[O:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH2:2][CH3:3]
Reactant: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a stirred solution of the title compound from Example 12 (25 mg) in acetic acid (5 ml) was added potassium dichromate (25 mg), and stirring was continued overnight. The solution was then evaporated to dryness. Chromatography on silica using ether as eluant gave the title compound (15 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])[CH2:25][CH2:24]1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[N:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1ccccc1N1CCOCC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2N2CCOCC2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 2-morpholinobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-morpholinobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 519.3 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][NH2:14])=[O:12])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1>C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:7]([C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]3[O:12][C:37](=[O:38])[NH:14][N:13]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)n1c(-c2ccccc2C(=O)NN)nc2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)n1c(-c2ccccc2-c2n[nH]c(=O)o2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzoic acid hydrazide (310 mg, 0.8 mmol) in THF (4 mL), followed by the addition of triethylamine (2 mL) and CDI (390 mg, 2.405 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with EtOAc/water. The organic layer is separated, washed with brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-5% MeOH/CH2Cl2 as the eluent to afford 5-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-3H-[1,3,4]oxadiazol-2-one (140 mg, 42%) as a light brown solid. LCMS (ESMS): m/z 413.07, 415.04 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]([F:22])([F:21])[C:15]([F:20])([F:19])[C:16](O)=O>>[CH3:8][C:5]1[S:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]2[C:6]=1[NH:7][C:16]([C:15]([F:20])([F:19])[C:14]([F:22])([F:21])[F:13])=[N:1]2
Reactant: COC(=O)c1sc(C)c(N)c1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: COC(=O)c1sc(C)c2[nH]c(C(F)(F)C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3,4-diamino-5-methylthiophene-2-carboxylate (1.0 g) in pentafluoropropionic acid (8.9 g) was stirred at 100° C. for 6 hr. The reaction solution was concentrated to dryness and the residue was suspensed in water. The mixture was made basic with aqueous solution of K2CO3, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether-hexane gave colorless plates (0.86 g, 51%). m.p. 156°-157° C.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[S:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)(C)C.[F-].[Cs+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([S:5][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=[C:8]([O:16][CH3:17])[C:9]=1[O:14][CH3:15]
Reactant: COc1cc(S[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CCOC(=O)CCCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1cc(OC)c(OC)c(OC)c1
Reaction time: 3 h

Procedure:
A suspension of 1.78 g of the compound obtained in Step A, 0.835 g of CsF and 1.1 g of ethyl 4-bromobutyrate in 80 ml of dimethylformamide is stirred, under argon, for 3 hours. After removal of the solvent by distillation, the residue is taken up in a mixture of water/dichloromethane, decanted and then dried over sodium sulphate. Chromatography over silica gel eluted with dichloromethane enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][Br:27])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Temperature: 90 °C
Yield: 27.6 %

Procedure:
A mixture of 3-[(6-bromo-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (8.1 g, 23.78 mmol), NBS (5.08 g, 28.5 mmol) and AIBN (0.195 g, 1.189 mmol) in CCl4 (240 ml) was heated at 90° C. for 16 h under an atmosphere of nitrogen. The mixture was cooled to 0° C., filtered thru Celite and concentrated. The crude yellow oil was purified on silica gel (hexanes/ethyl acetate) to give 2.75 g (26%) of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.44 (dd, 1H), 7.34 (t, 1H), 7.18-7.32 (m, 1H), 7.13 (t, 1H), 6.89-7.05 (m, 1H), 4.45 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](NCCC3C=CC(OCC(OCC)=O)=C(OCC(OCC)=O)C=3)=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 197 %

Procedure:
The solution of the compound prepared in (a) (1.2 g) in dichloromethane (20 ml) was added pyridinium chlorochromate (1.1 g), and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated and purified by column chromatography on silica gel to give 1.07 g of the title compound from the fraction eluted with ethyl acetate:n-hexane=1:3 (yield, 89.8%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1.[C:20]1([CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]#[C:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:41][CH:40]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[OH:1][CH:2]([C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1)[CH2:3][N:27]([CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]#[C:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])=[CH:43][CH:44]=1
Reactant: CCCCC(=O)NCc1ccc(C#CCCOCCCCCCNCc2ccccc2)cc1
Reactant: c1ccc(C2OCc3nc(C4CO4)ccc3O2)cc1
Solvent: CO
Product: CCCCC(=O)NCc1ccc(C#CCCOCCCCCCN(Cc2ccccc2)CC(O)c2ccc3c(n2)COC(c2ccccc2)O3)cc1
Yield: 52 %

Procedure:
A solution of 6-oxiranyl-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine (0.712 g) and N-[[4-[4-[[6-[(phenylmethyl)amino]hexyl]oxy]-1-butynyl]phenyl]methyl]pentanamide (1.25 g) in methanol (10 ml) was refluxed for 1l h. The methanol was evaporated to leave an oil which was purified by FCC eluting with ER to give the title compound as a yellow oil (1.02 g), t.l.c. ER:triethylamine (100:1) Rf 0.2
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[N:34]1C=CC=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH2:34])=[O:25])[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: c1ccncc1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(N)=O

Procedure:
Using tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 15, step A (using pyridine instead of triethylamine), the title compound was obtained.