Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)#[N:2].C(O)(=O)C.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (5 g, prepared as described in J.Med.Chem. 29, 2194 (1986)), in ethanol (375 ml) and glacial acetic acid (75 ml) containing concentrated HCl (5 ml) was shaken in the presence of 10% Pd/C (1 g) in an atmosphere of hydrogen for 4 h. The catalyst was filtered off and the solution neutralised with 10% aqueous NaOH solution, and the solution evaporated to dryness. Acid-base extraction, and drying of a dichloromethane solution of the residue, furnished, after recrystallisation from ethyl acetate-pentane, 2.03 g of the required aminomethyl compound of example 4 of mp 191°-193° C. as the hemihydrate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>S([O-])([O-])(=O)=O.[Ni+].[NH4+].ClCCl>[Br:1][C:2]1[C:3]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: [Ni+]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)c(Br)cc(F)c1F
Reaction time: 0.42 h

Procedure:
To a round bottom flask containing 2-bromo-4,5-difluorophenol (2.7 g, 12.9 mmol) and ammonium nickel sulfate (2.6 g, 6.46 mmol) is added dichloromethane (15 mL) at RT. A solution of 70% nitric acid (1.2 ml) is added dropwise and the slurry is stirred for 20 to 30 min. The mixture is then quenched with excess MgSO4, filtered and concentrated. The product is used in the next step without purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Cl:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Cl:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NC(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)CO)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.96 g, 77%) as an off-white solid. MS (ISP) 272.2 [(M+H)+], mp 101° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].Cl>CN(C=O)C.C(O)C>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([P:17]([CH3:16])([CH3:19])=[O:18])=[CH:21][C:22]=2[O:27][CH3:28])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2)n1
Yield: 16 %

Procedure:
To a solution of 2,5-dichloro-N-phenylpyrimidin-4-amine (84 mg, 0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mL of DMF, was added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixture was heated in a sealed tube at 140 degrees over night. The reaction mixture was filtered through a syringe filter and purified by Prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield the desired product as a white solid. (23 mg, 16% yield). MS/ES+: m/z=403
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:11])[NH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20](Br)[CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH2:21][CH2:20][CH2:19][O:11][C:7]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH][nH]c1=O
Reactant: CC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c1OCCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
3-Oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (13.2 g, 84.5 mmol), potassium carbonate (50 g, 0.3 mol) and N,N-dimethylformamide (500 mL) were combined in a 250 mL round bottom flask, and the mixture was heated to 130° C. 1,2-Dibromo-propane (10.4 mL, 0.10 mol) was added. After 30 minutes, the mixture was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The yellow solid was purified by column chromatography (DCM/MeOH) to afford the ester (9.67 g, 58%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.62 (s, 1H), 4.41-4.38 (m, 2H), 4.13 (q, 2H), 4.08 (t, 2H, J=6.03 Hz), 2.21-2.15 (m, 2H), 1.21 (t, 3H, J=7.09 Hz).
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:5]=1.[Mg].[Cl-].[NH4+:17]>C1COCC1.CCC(=O)CC>[CH:12]1([CH2:11][O:10][C:6]2[CH:5]=[C:4]([C:4]([NH2:17])([CH2:9][CH3:8])[CH2:5][CH3:6])[CH:9]=[CH:8][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [NH4+]
Reactant: Brc1cccc(OCC2CC2)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCC(=O)CC
Product: CCC(N)(CC)c1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of magnesium (280 mg) in THF (2.5 mL), iodine (10 mg) was added at room temperature. Then, a small amount of a solution of 1-bromo-3-(cyclopropylmethoxy)benzene (2.27 g) obtained according to a method described in the document (Izvestiya akademi Nauk SSSR, Seriya Khimicheskaya, 12, 2752-2755 (1989)) in THF (3.5 mL) was added thereto, and the mixture was stirred at room temperature for 10 minutes until the iodine color disappeared. The remaining amount of the solution of 1-bromo-3-(cyclopropylmethoxy)benzene in THF was added thereto, and the mixture was stirred at room temperature for 1 hour until the magnesium disappeared. To the reaction mixture, a solution of 3-pentanone (1.02 g) in THF (3.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution (10 ml) was added at 0° C., and the aqueous layer was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane). The obtained compound was dissolved in chloroform (20 mL). To the solution, sodium azide (1.7 g) was added. To the reaction mixture, trifluoroacetic acid (3.2 mL) was added dropwise at 0° C., and the mixture was then stirred at room temperature for 1 hour. To the reaction mixture, water (20 mL) was added, and the resultant mixture was then extracted with chloroform (20 mL). The organic layer was washed with an aqueous saturated sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane). The obtained compound was dissolved in methanol (10 mL). To the solution, 10% palladium-carbon (260 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration through a pad of Celite and washed with methanol (100 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (1.70 g) as a crude product.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([O:5][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCCCCCCCCCCCCCO
Reactant: C=CC(=O)O
Product: C=CC(=O)OCCCCCCCCCCCCCCC
Temperature: 60 °C

Procedure:
Pentadecyl acrylate was prepared by esterification of acrylic acid with 1-pentadecanol under standard conditions. Crude monomer was recrystallized from three volumes of ethanol and dried in vacuo. Ten grams of pentadecyl acrylate was dissolved in 20 ml of oxygen free ethylacetate containing 0.10 grams of azobis-isobutylnitrile (hereinafter AIBN) and stirred in a sealed bottle maintained at 60° C. for 24 hours. The resulting polymer was isolated by precipitation into cold ethanol and dried in vacuo. Analysis of the polymer showed it to have a first order transition temperature of 29° C., a heat of fusion of 59 J/g and a molecular weight of about 175,000 in an uncured state.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[OH:14][C:15]1[CH:16]=[C:17]([C:21](=[O:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1>C(O)(=O)C.C(Cl)Cl>[C:21]([C:17]1[CH:18]=[CH:19][C:20]([C:9]2([OH:13])[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[C:15]([OH:14])[CH:16]=1)(=[O:23])[CH3:22]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(=O)c1cccc(O)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 110 °C
Yield: 79.4 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 hrs at 110° C. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (White, 1.32 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:4]1[CH:3]=[C:2](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[C:6]([Cl:8])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (100 mg, 0.27 mmol) and ethyl acrylate (3.06 mL, 30.58 mmol) in dimethylformamide (3 mL) was stirred at room temperature. Triethylamine (0.15 mL, 1.08 mmol) was added followed by triphenylphosphine (42.6 mg, 0.16 mmol) and palladium acetate (18.16 mg, 0.008 mmol). The reaction mixture was purged with argon and heated under reflux for about 20 hours. The reaction mixture was cooled to room temperature and the residue was poured into water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. Ethyl (2E)-3-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]prop-2-enoate (64.8 mg, 61.59%) was isolated by silica gel column chromatography using ethyl acetate in hexane (15-17%) as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].C[Si](C)(C)[C:25]#[C:26][C:27]1([CH3:31])[CH2:30][O:29][CH2:28]1.CN(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.[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:25]#[C:26][C:27]4([CH3:31])[CH2:30][O:29][CH2:28]4)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8]
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(Br)c(F)cc2O3)COC1
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A vial charged with Pd(PPh3)4 (0.73 g, 0.63 mmol), copper(I) iodide (0.48 g, 2.52 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (3.0 g, 6.30 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.06 g, 6.30 mmol) and 13 mL DMF was degassed with argon and treated with DIPA (4.49 mL, 31.5 mmol). The resulting slurry was allowed to stir at RT for 18 h at which point an additional portion of copper(I) iodide (0.48 g, 2.52 mmol) was added. After stirring for an additional 4 h the reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×100 mL). The resulting suspension was filtered through a glass frit and the filtrate was dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.18 g, 2.66 mmol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1O
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cc(C(=O)Cn2cc(Cl)cnc2=O)ccc1O

Procedure:
A solution of 5-chloropyrimidin-2-one hydrochloride (508 mg) and methyl 5-bromoacetylsalicylate (827 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 13/4 hours, by which time a precipitate had formed. This suspension was chilled in ice, and the collected solid was crystallised from chloroform-ethanol to give the title pyrimidinone: yield 442 mg: m.p. 203°-204° dec: λmaxEtOH 228.5 nm (ε 40720), 269.5 nm (ε 16930), 312.5 nm (ε 6320).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 94.8 %

Procedure:
20 g (97.5 millimoles) of cis-2-(p-aminobenzoyl)-cyclopropanecarboxylic acid, 5.9 g (118 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 5 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 18.6 g (95% of theory) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]-hept-2-en-5-one are obtained as pale yellow crystals, which are identical with the compound from Example 8a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1>CO.O.[Pt]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1N
Agent: [Pt]
Solvent: O
Solvent: CO
Product: COc1cc(Br)cc(N)c1N
Yield: 85.3 %

Procedure:
A solution of 2.0 g (8.1 mmol) 4-Bromo-2-methoxy-6-nitro-phenylamine [Zhou, Q-T., et al. Huaxue Xuebao 1980, 38(5), 507-10] in 50 ml methanol/water (2:1) is hydrogenated in the presence of 200 mg Pt/C (Engelhard 4709) at normal pressure for 3 h. Then the catalyst is filtered off and the filtrate is concentrated in vacuo to afford 1.5 g of the title compound as an oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccccc4)cc3)cc21
Yield: 58.4 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), benzoylchloride (126 mg), triethylamine (263 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (247 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(N(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:10])[CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)NCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 6-methyl-5-nitropyridine-2-carboxylic acid (0.500 g, 3.0 mmol) in DCM (7 mL) were added 2-morpholin-4-ylethanamine (1.0 mL, 7.7 mmol), TBTU (0.992 g, 3.1 mmol), and DMA (1.34 mL, 7.7 mmol). The reaction mixture was allowed to stir at rt overnight and then quenched with water. The organic solution was separated and the aqueous solution was extracted with DCM. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 6-methyl-N-(2-morpholin-4-ylethyl)-5-nitropyridine-2-carboxamide (0.27 g, 30%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.[CH3:30][O:31][C:32]1[CH:41]=[C:40]([CH3:42])[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[C:40]([CH3:42])=[CH:41][C:32]([O:31][CH3:30])=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of the above prepared 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (assumed 0.211 mmol), methyl 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.078 g, 0.253 mmol), (Ph3P)4Pd (0.024 g, 0.021 mmol) and cesium carbonate (0.103 g, 0.317 mmol) in a mixture of H2O (0.2 mL)/1,4-dioxane (1 mL) was stirred at 95° C. for 2 hours 30 min. The mixture was left standing at r.t. overnight. The mixture was diluted with 3.5 ml 1,4-dioxane, filtered through a Whatman PVDF 0.45 um disk (with 3×1 ml washing). The filtrate was concentrated. The mixture was added with 3.5 ml 1N HCl, and then 6 ml H2O (yellow solid deposited on the wall of the flask). The aqueous was decanted, and the residue washed with 3×2 ml H2O and dried. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=466.27, HPLC Rt=1.708 min.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:16][C:15]3[C:10]([N:9]=2)=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: Nc1ncccc1O
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3ncccc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 5 mL of trimethylsilyl polyphosphate was added 2-aminopyridin-3-ol (175 mg, 1.59 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (344 mg, 1.50 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with MTBE (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,3]oxazolo[4,5-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.72 (d, 1H), 8.58 (d, 1H), 8.30 (d, 1H), 8.05–7.91 (m, 4H), 7.88 (t, 1H), 7.51 (dd, 1H), 7.40 (dd, 1H), 4.02 (s, 3H); MS (ESI) 304 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[CH:22]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Reactant: Fc1cccc(Br)c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2cccc(Br)c2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-bromo-3-fluoro-benzene were converted to yield Allyl-{5-[1-(3-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine as light brown oil, MS: 411 (MH+, 1Br).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:20]=[C:21]=S)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]1[NH:2][C:3]2[CH:7]=[C:6]([Cl:8])[S:5][C:4]=2[S:9](=[O:10])(=[O:11])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=NCc1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: O=S1(=O)N=C(NCc2ccccc2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and benzyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 223°-226° C.; 1H-NMR (DMSO-d6): δ 4.42 (d, 2H), 7.05 (s, 1H), 7.30 (m, 5H), 7.78 (br t, 1H), 11.22 (br s, 1H).