Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 99.2 %

Procedure:
208 g of anthraquinone in 969 g of 97.5% nitric acid (mole ratio 15:1) are heated to 35° for 2 hours with stirring. The reaction is stopped by the addition of 103 ml of water. After removal of 265 g of 99% nitric acid by distillation (crystallisation acid 81%, γHNO3 = 0.520), the precipitated product is freed from nitric acid and dried and distilled at 30 Torr with head temperatures of 250° to 300°, together with about 800 g of silicone oil. The yield of 99.2% 1-nitroanthraquinone is 153 g (60% of the theoretical amount).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>ClCCl>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:24][O:25][CH3:26])[CH:5]=[CH:4][C:3]=1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: COCCl
Reactant: CCC(=O)c1ccc(O)c(C)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1ccc(OCOC)c(C)c1O
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a mixture composed of 1-(2,4-dihydroxy-3-methylphenyl)propan-1-one (5.00 g, 27.8 mmol) and dichloromethane (80 mL), diisopropylethylamine (5.26 mL, 30.5 mmol) was added under cooling with ice, and then a solution of chloro(methoxy)methane (2.30 mL, 30.5 mmol) in dichloromethane (20 mL) was added dropwise to the mixture over 20 minutes. After the completion of dropwise addition, the mixture was brought back to room temperature and stirred overnight. Dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=90/10→70/30) to obtain 5.73 g of the title compound (yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].[Na]>O1CCOCC1>[CH2:25]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:20][CH:19]=1)[N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CC(C)(C)C(O)C(Oc1ccc(Br)cc1)n1cncn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1COCCO1
Product: C=CCOC(C(Oc1ccc(Br)cc1)n1cncn1)C(C)(C)C
Yield: 78.9 %

Procedure:
34 g (0.1 mol) of 1-(4-bromophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol were suspended in 175 ml of dioxane and the suspension was added dropwise to a mixture of 3.5 g of 80% strength sodium hydride and 125 ml of dioxane while stirring. Thereafter, the mixture was heated under reflux for one hour. After cooling, 14.5 g (0.12 mol) of allyl bromide were added dropwise at room temperature to the sodium salt thus obtained. The mixture was then heated under reflux for 15 hours, allowed to cool and concentrated by distilling off the solvent. The oily residue was taken up in 600 ml of methylene chloride and the methylene chloride solution was washed twice with 1,000 ml of water each time, dried over sodium sulphate and concentrated. The residue was distilled under a high vacuum. 30 g (79% of theory) of 2-allyloxy-1-(4-bromophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butane of boiling point 152°-154° C./0.2 mm Hg were obtained.
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:35]([CH3:38])([O-:37])=[O:36].Cl>CCCCCCC>[N+:35]([CH2:38][C@:6]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:1]2[C@H:5]1[CH2:4][CH2:3][CH2:2]2)([O-:37])=[O:36]
Reactant: CCOC(=O)C=C1C[C@H]2CCC[C@@H]12
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCCCCCC
Solvent: O
Product: CCOC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Reaction time: 17 h
Yield: 87.6 %

Procedure:
The n-heptane solution (12.5 L) of the acrylic ester of Example 6 (0.921 Kg; 5.11 mol) was concentrated by distillation at atmospheric pressure to 36% of its original volume. The n-heptane was then replaced with tetrahydrofuran by atmospheric azeotropic distillation at constant volume. The reaction mixture was cooled to 20–25° C., then tetrabutylammonium fluoride trihydrate (2.10 Kg; 6.64 mol) and nitromethane (0.499 Kg, 8.18 mol) were added. The resulting brown solution was stirred at 20–25° C. for 17 hours. To the reaction mixture a 2M aqueous solution of hydrochloric acid (4.5 L) was added, causing the reaction temperature to rise by 8° C. n-Heptane (4.5 L) was added and the phases were separated. The organic layer was then washed with demineralised water (4.5 L) to give the title product (1.08 Kg) in 88% yield as an organic solution which is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Br-].[C:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][Zn+])#[N:18]>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.C1COCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([CH2:22][C:21]2[CH:20]=[C:19]([CH:26]=[CH:25][CH:24]=2)[C:17]#[N:18])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: N#Cc1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccc(C#N)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A screw cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (500 mg, 2.016 mmol), tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.202 mmol), and THF (5.04 mL). The mixture was sparged with N2, then (3-cyanobenzyl)zinc(II) bromide (0.5M in THF, 4.23 mL, 2.116 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then partitioned between EtOAc and water, and the organic layer washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography, eluting with a gradient of 0-15% EtOAc in hexane to give 3-((4-chloro-5,7-difluoro-3-methylquinolin-2-yl)methyl)benzonitrile. Mass Spectrum (ESI) m/e=329.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:15]3[CH:20]=[C:19]([F:21])[C:18]([CH3:24])=[C:17]([F:22])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(F)cc(F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1F
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
2-Chloro-4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.45 ml, 0.91 mmol) was added and the mixture stirred for 15 min at −75° C. Iodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3— solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10->20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=344.5 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][S:19][C:20]#[N:21])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)[N:21]=1)[CH2:7][OH:8]
Reactant: COC(=O)[C@@H](N)CO
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 60 °C
Yield: 77 %

Procedure:
Serine methyl ester hydrochloride (1.02 g, 4 mmol) was dissolved in 50 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate (0.686 g, 4.4 mmol), prepared in step 1 of Example 1, was added followed by triethylamine (0.63 mL, 4.4 mmol). The mixture was heated to 60° C. for 18 h and then cooled and concentrated under reduced pressure. Flash chromatography (1% methanol/chloroform) afforded 1.1 g of 2-[4-(4-bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 79%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]#[N:25])[CH:19]=[CH:20][CH:21]=1>>[C:24]([CH:23]=[CH:22][C:18]1[CH:17]=[C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=[CH:20][CH:19]=1)#[N:25]
Reactant: N#CC=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: N#CC=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Carboxylic acid (56) (120 mg, 0.64 mmol) was coupled to aniline (88) (92 mg, 0.64 mmol), using Method C to give the title compound.
Reaction SMILES: Br.Br.[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[OH:16].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: Cc1cc(N2CCNCC2)ccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)ccc1O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of 123.8 parts of 2-methyl-4-(1-piperazinyl)phenol dihydrobromide, 49.4 parts of 1-fluoro-4-nitrobenzene, 58.2 parts of sodium carbonate and 300 parts of dimethyl sulfoxide was stirred over weedend at room temperature. The reaction mixture was poured into water. The product was filtered of, washed with 2-propanol and dried, yielding 101.2 parts (92.3%) of 2-methyl-4-[4-(4-nitrophenyl)-1-piperazinyl]phenol as a solid residue (compound 1.12).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:23]=[CH2:24])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 130 °C
Yield: 81.7 %

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (1.5 g, 3.84 mmol), tributyl(vinyl)tin (2.436 g, 7.68 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.270 g, 0.384 mmol) were combined in 1,2-dichloroethane (4 mL) and heated at 130° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (1.06 g, 82% yield): mp 145-147° C.: 1H NMR (CDCl3) δ 7.64 (m, 1H), 7.22 (m, 1H), 6.84 (dd, 1H), 5.68 (m, 2H), 5.43 (br s, 2H), 3.99 (d, 3H), 3.95 (s, 3H).
Reaction SMILES: O[CH:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:14][C:15]([O-:17])=[O:16].S(=O)(=O)(O)O.N>>[CH3:13][O:12][C:8]1[N:9]=[CH:10][C:11]2[CH2:2][CH:3]([CH2:14][C:15]([OH:17])=[O:16])[CH:4]=[CH:5][C:6]=2[CH:7]=1
Reactant: COc1cc2c(cn1)C(O)C(CC(=O)[O-])CC2
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc2c(cn1)CC(CC(=O)O)C=C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11 Parts of 8-hydroxy-3-methoxy-5,6,7,8-tetrahydro-2-azanaphthalene-7-acetate described in Example 25 is added to 110 parts by volume of sulfuric acid at room temperature and stirred for 15 minutes. 200 Parts of ice water are added and the solution is made basic with 300 parts by volume of aqueous ammonia. The solution is filtered through celite and then extracted three times with chloroform. Removal of the chloroform and crystallization from methanol provides 3-methoxy-7,8-dihydro-2-azanaphthalene-7-acetic acid, melting at 151°-152° C. This compound is also an active anti-inflammatory agent, as is the alkylated derivative, 3-methoxy-7,8-dihydro-2-azanaphthalene-7-α-methylacetic acid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].Cl.[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[OH:19]>O.C(OCC)C>[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]=1[OH:19]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(Br)c(O)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C
Reaction time: 7 h

Procedure:
Sodium nitrate (361 mg, 4.25 mmol) was dissolved in water (4 mL) and LaNO3 *6H2O (18 mg, 0.04 mmol) and HCl (12M, 4 mL) were added. The solution was cooled to 0° C. and a slurry of 4-bromo-3-hydroxy-6-methoxybenzoic acid in diethyl ether (20 mL) was added to the reaction mixture in portions during 10 min. After slowly raising the temperature to room temperature the mixture was stirred for 7 h. Extraction between H2O (20 mL) and CH2Cl2 (3×30 mL), drying the organic phase with MgSO4, filtration and evaporation under reduced pressure gave a mixture of products. Purification by silica gel chromatography (HOAc-EtOAc-toluene 1:2:8) gave the title compound (0.6 g). 1H NMR (CD3OD): δ7.57 (s, 1H), 3.85 (s, 3H). MS (EI, 70 eV): m/z (rel. int.) 291/293 (M+, 21/19).
Reaction SMILES: [OH-].[K+].[C:3]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[N:15]=[C:16]([O:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=4)[C:24]([O:26]C)=[O:25])[NH:17][C:12]3=[CH:11][C:10]=2[Cl:30])=[CH:5][CH:4]=1>CO>[C:3]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]3[N:15]=[C:16]([O:18][C:19]4[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=4)[C:24]([OH:26])=[O:25])[NH:17][C:12]3=[CH:11][C:10]=2[Cl:30])=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2N KOH (1.1 mL, 2.2 mmol) was added to a methanol (10 mL) solution of methyl 5-{[5-(biphenyl-4-yl)-6-chloro-1-H imidazo[4,5-b]pyridin-2-yl]oxy}-2-methylbenzoate (104 mg, 0.22 mmol) and the reaction was stirred at 80° C. for 2 h. The reaction was partitioned between EtOAc and 10% aqueous citric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography of the resulting residue utilizing a Biotage™ 10G SNAP cartridge and employing a gradient: 0-100% EtOAc/hexane afforded the title compound as a white solid. LC-MS: calculated for C26H18ClN3O3 455.89, observed m/e: 456.2 (M+H)+ (Rt 2.0/4 min). 1H NMR δ (ppm) (DMSO-d6): 8.00 (1H, s), 7.82 (1H, m) 7.79-7.69 (7H, m), 7.48 (2H, m), 7.38 (2H, m), 2.56 (3H, s).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:31][C:32]1N=CO[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([CH2:31][N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)#[N:33]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: ClCc1ncon1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C3=NCC4(CCN(CC#N)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of N-Methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg), 3-(chloromethyl)-1,2,4-oxadiazole (35 mg), potassium carbonate (44 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was purified by preparative HPLC to give the title compound (55 mg, yield 47%) as white crystals. melting point 211° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 5, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and diethanolamine were converted to yield 2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 451 (MH+, 1Br).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](/[C:33](/[C:40]2[N:45]=[C:44]([O:46][CH3:47])[C:43]([CH2:48][CH3:49])=[CH:42][CH:41]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:29][C:28]=1[Cl:50])(C(C)(C)C)(C)C.O.Cl>O1CCCC1>[Cl:50][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[CH:41]=[CH:42][C:43]([CH2:48][CH3:49])=[C:44]([O:46][CH3:47])[N:45]=2)=[CH:34]\[CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:31]=[CH:32][C:27]=1[OH:26]
Reactant: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c2)nc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(/C(=C/C2CCCC2)c2ccc(O)c(Cl)c2)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.73 mL) was added to a solution of 6-[(E)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-chlorophenyl)-2-cyclopentylethenyl]-3-ethyl-2-methoxypyridine (409 mg) in tetrahydrofuran (3 mL) under ice-boiling, and the mixture was stirred at room temperature for two hours. The reaction solution was poured into water and made acidic with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give 2-chloro-4-[(E)-2-cyclopentyl-1-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]phenol as a yellow oil (306 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1.[C:24]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:23])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]([CH3:24])[C:16](=[O:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[CH:8]=2)[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Cc2ccc(C#N)cc2C(Oc2cc[nH]c(=O)c2)C1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cn1ccc(OC2c3cc(C#N)ccc3CC(C)(C)C2O)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 310 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethylsulfate is boiled for 2 hours. The mixture is filtered and the filtrate is worked up in the customary manner to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-1,2,3,4-tetrahydro-3-naphthol.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccccc1-c1cccnc1

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 0.307 mmol) and 3-bromopyridine (73 mg, 0.460 mmol) provides the title compound. Purify further via silica gel chromatography to obtain 14.9 mg (14%) of material that is 98% pure by HPLC. MS (ES) 360 (M+H).
Reaction SMILES: N1C=CC=C(COC(=O)[NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C:21]3[C:26]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:24]=[C:23]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:22]=3)=[O:19])=[CH:14][CH:13]=2)C=1.C(O)=O>CCO.[Pd]>[C:31]([O:30][C:28](=[O:29])[NH:27][C:26]1[C:21]([NH:20][C:18](=[O:19])[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH2:10])=[CH:17][CH:16]=2)=[N:22][C:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:24][CH:25]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
pyridin-3-ylmethyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (1.5 g, 2.71 mmol) was taken up in EtOH (10.84 mL) at 0° C., evacuated and backfilled with N2. Pd/C (0.288 g, 0.27 mmol) was added and the reaction was again purged and backfilled with N2. Formic acid (2 mL, 53 mmol) was added and the reaction was stirred at RT and monitored by LC/MS. Reaction was complete in 2 h. The reaction was filtered through Celite and evaporated. The residue was taken up in DCM and washed with satd NaHCO3 solution (2×50 mL). The combined organic fractions were dried over Na2SO4, filtered and evaporated in vacuo to provide tert-butyl(2-{[4-(aminomethyl)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate. MS: cal'd 419 (MH+), exp 419 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](Cl)(=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[C:6]([CH:2]([NH:1][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:21])=[O:27])[CH:3]([CH3:5])[CH3:4])([OH:8])=[O:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Product: CC(C)C(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)O)C(C)C)C(=O)O

Procedure:
Using the method employed in Preparation 30, 17.8 g (0.15 mol) of D,L valine was reacted with 17.2 g (0.05 mol) of 2,2'-dithiobisbenzoyl chloride to produce 11.4 g of the title compound after recrystallization from acetic acid, mp 226.5°-227.5° C.