Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[S:34][C:35]([Cl:38])=[CH:36][CH:37]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[Cl:38][C:35]1[S:34][C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])=[CH:37][CH:36]=1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: O=C(CBr)c1ccc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(Cl)s3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(5-chloro-2-thienyl)ethanone (0.74 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.79 g, 56%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]3[CH3:25])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:32]>CO.[OH-].[OH-].[Pd+2]>[ClH:32].[CH3:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CC1CCCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1CCCCN1c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a solution of 8-benzyl-3-(2-methylpiperidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (0.65 g) in methanol (20 mL) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2.5 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (628 μL) and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.40 g, 73%) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=C(Nc1c(F)cncc1F)c1c(F)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccc(F)c1C(Cl)=Nc1c(F)cncc1F
Temperature: 25 °C

Procedure:
A mixture of 2-fluoro-N-(3,5-difluoropyridin-4-yl)-6-nitrobenzamide (10.81 g, 36.4 mmol) in thionyl chloride (95 mL) was heated under reflux for 3 days under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was azeotroped with toluene (×3) to afford the title compound as a yellow/pale brown solid (12.05 g, quantitative). LCMS (Method D): RT=3.64 min, m/z: 316 [M+H+].
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][CH2:5][N:4]=1.[C:8]1([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[C:8]1([C:14](=[O:19])[C:15](=[C:3]2[CH2:7][CH2:6][CH2:5][NH:4]2)[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC1=NCCC1
Solvent: CCCCCC
Product: CC(=O)C(C(=O)c1ccccc1)=C1CCCN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.9 g (0.1 mole) of 2-methoxy-1-pyrroline and 24.4 g (0.15 mole) of 1-phenyl-1,3-butanedione are mixed together and, in a nitrogen atmosphere, heated with stirring for 18 hours in an oil bath at 100°. The dark reaction mixture is cooled to 60° and 500 ml of hexane is added. Upon further cooling to room temperature, the reaction product crystallises out. Recrystallisation from ethyl acetate/hexane yields 1-phenyl-2-(2-pyrrolidinylidene)-1,3-butanedione m.p. 106°-108°.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3F)=[CH:8][CH:9]=2)[N:4]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:3]1.C([O-])(O)=O.[Na+].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[CH3:1][C:2]1([CH3:28])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:40][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([F:34])=[CH:36][CH:37]=3)=[CH:8][CH:9]=2)[N:4]([CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:3]1
Reactant: NCc1ccc(F)cc1
Reactant: CN1CCC(N2CC(C)(C)c3ccc(NC(=O)c4cccnc4F)cc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC(N2CC(C)(C)c3ccc(NC(=O)c4cccnc4NCc4ccc(F)cc4)cc32)CC1
Temperature: 85 °C

Procedure:
A solution of N-[3,3-dimethyl-1-(1-methyl-piperidin-4-yl)-2,3-dihydro-1H-indol-6-yl]-2-fluoro-nicotinamide (500 mg), 4-fluorobenzylamine (240 μL) and NaHCO3 (359 mg) was dissolved in IpOH (5 mL) and heated to 85° C. overnight. After cooling to RT, the mixture was dried under N2. The residue was partitioned between EtOAc and H2O, the organic layer was separated, washed with brine, dried over Na2SO4 and filtered. Silica was added to the filtrate and concentrated to a residue. It was purified by flash chromatography (10% MeOH/EtOAc) to yield a fluffy yellow solid. M+H 488.4. Calc'd for C29H34FN5O: 487.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.[OH-].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1

Procedure:
3-Hydroxybenzoic acid is an important intermediate product for the preparation of plant protection agents. Thus, in accordance with U.S. Pat. No. 4,031,131, 3-hydroxybenzoic acid can be reacted with 3,4-dichlorobenzotrifluoride in methanolic solution and in the presence of potassium hydroxide and dimethyl sulphoxide, to give 3-(2-chloro-4-trifluoromethylphenoxy)-benzoic acid. Nitrating this benzoic acid with potassium nitrate in concentrated sulphuric acid then gives 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid which, according to U.S. Pat. No. 3,798,276, is an important herbicide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([CH2:25][CH3:26])=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[C:16]([CH2:25][CH3:26])=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: CCc1nnc(Cl)c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnc(Cc2c(Cl)cncc2Cl)c2ccc(OC)cc12
Yield: 35.2 %

Procedure:
Operating substantially as described in example 5 starting from 3,5-dichloro-4-methyl-pyridine (1.75 g, 10.77 mmoles), dry DMF (20 ml), 60% NaH in oil (0.26 g, 10.77 mmoles) and 1-chloro-4-ethyl-6-methoxy-phthalazine (1.2 g, 5.39 mmoles), prepared as described in example 10, in DMF (25 ml), 0.66 g of the title compound were obtained (yield: 36%). m.p.: 136-138° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29]>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.[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C:28]([OH:32])([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: Nc1nc(Cl)cc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3cc(Cl)nc(N)n3)c2c1)c1ncccn1
Temperature: 55 °C

Procedure:
To a solution of 1-(2-amino-6-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (750 mg, 1.81 mmol) in 1:1 triethylamine/dry THF (12 mL) was introduced bis(triphenylphosphine)palladium(II) chloride (127 mg, 0.18 mmol), copper(I) iodide (34 mg, 0.18 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (535 mg, 3.61 mmol). The reaction mixture was warmed to 55° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo to furnish the crude title compound: 1H NMR (500 MHz, DMSO) delta 1.92 (3H, s), 6.26 (1H, s), 7.09 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.51 (1H, t, J=4.9 Hz), 8.23 (1H, d, J=8.6 Hz), 8.82 (1H, s), 8.90 (2H, d, J=4.9 Hz); LC-MS: m/z=+436.05/437.70 (M+H)+. This compound, with LC-MS purity=91% UV, was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]([NH:40][CH2:41][CH2:42][NH2:43])[N:32]=1>>[NH2:30][C:31]1[N:32]=[C:33]([NH:40][CH2:41][CH2:42][NH:43][C:13]2[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=3[N:12]=2)[CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-amino-3-nitro-6-(2-aminoethylamino)pyridine gave tert-butyl 2-({2-[(6-amino-5-nitro(2-pyridyl))amino]-ethyl}amino)-4-(2,4-dichlorophenyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:5]([Cl:23])=[CH:4][N:3]=1.Br[C:25]1[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:23][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[CH:7][C:2]([NH:1][C:25]2[CH:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)=[N:3][CH:4]=1
Reactant: N#Cc1cnc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(N)ncc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2Cl)CC1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
Dry dioxane (0.45 mL) was added to a microwave reaction vial containing tert-butyl 4-((2-amino-5-chloropyridin-4-ylamino)methyl)piperidine-1-carboxylate (23 mg, 0.067 mmol), 5-bromopyrazine-2-carbonitrile (8.3 mg, 0.045 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (1.9 mg, 4 mol %), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2.2 mg, 8 mol %) and sodium tert-butoxide (6.1 mg, 1.4 eq.) under nitrogen. The vial was sealed and nitrogen gas was bubbled through the suspension with stirring for 5 min. The mixture was heated at 90° C. for 30 min under microwave irradiation. The mixture was diluted with methanol and adsorbed onto Isolute SCX-II acidic resin (2 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and the residue was further purified by preparative thin layer chromatography, eluting with 5% MeOH in dichloromethane, to give tert-butyl 4-((5-chloro-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (12 mg, 60%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])(CCO)[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[C:52](F)(F)[C:53]([O:55][C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:52][CH2:53][O:55][C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(=O)C(F)(F)F)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
To a mixture of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (150 mg, 0.214 mmol) and dichloromethane (15 mL) were added trifluoroacetic acid anhydride (36 μL, 0.258 mmol), triethylamine (89 μL, 0.642 mmol), and DMAP (1.3 mg, 0.0107 mmol), and the mixture was stirred at room temperature. After being stirred for 3 hours, trifluoroacetic acid anhydride (72 μL, 0.516 mmol) was added again. After confirming the consumption of No. 5217614 by LCMS, formic acid (5.0 mL) was added and the mixture was stirred overnight. The solvent was distilled off under reduced pressure to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-2-[2-(2,2,2-trifluoro-acetoxy)-ethyl]-nonadec-4-enoic acid (ESI (LC/MS positive mode) m/z 740 (M+H); Rt 2.64 min.). To the obtained (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-2-[2-(2,2,2-trifluoro-acetoxy)-ethyl]-nonadec-4-enoic acid (16 mg, 0.0216 mmol) were added toluene (3.0 mL), methanol (1.0 mL), and trimethylsilyldiazomethane (0.6 M in n-hexane, 54 μL, 0.0324 mmol), and the mixture was stirred at room temperature. After being stirred for 1.5 hours, trimethylsilyldiazomethane (0.6 M in n-hexane, 54 μL, 0.0324 mmol) was added. After stirring for 1 hour, the organic solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain the title compound (17 mg, 99% yield, white solid).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C)ccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent—hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent—hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C.CCO>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 10) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 209 to 210° C./DMF-EtOH.
Reaction SMILES: [O:1]=O.[CH2:3]([C:5]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6]1)[CH3:4]>>[CH2:3]([C:5]1([C:9]([OH:1])=[O:10])[CH2:8][O:7][CH2:6]1)[CH3:4]
Reactant: O=O
Reactant: CCC1(CO)COC1
Product: CCC1(C(=O)O)COC1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
The procedure as in Example 10 is carried out, but at an oxidation temperature of 40° C. After 2 hours, 0.8 mol of oxygen have been taken up per mol of 3-ethyl-3-hydroxymethyl-oxetane. After working up, 3-ethyl-oxetane-3-carboxylic acid is obtained in a yield of 86.2% of theory.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[NH:14][C:15](=[O:24])[CH:16]=[C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:18]=1.[OH-].[Na+].O>CC(C)=O>[NH2:12][C:13]1[N:18]=[C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[C:15]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Nc1cc(=O)[nH]c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.08 g (11 mmol) of p-toluenesulfonyl chloride in 20 ml of acetone are added dropwise to a solution of 1.47 g (8 mmol) of methyl 2-amino-1,6-dihydro-6-oxo-4-pyrimidinecarbamate, 12 ml of 1N sodium hydroxide, 5 ml of water and 50 ml of acetone. The mixture is stirred at room temperature for 18 hours. After filtration of the precipitate, the solvent is evaporated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate and water, the organic phase is separated, dried and evaporated under reduced pressure. Crystallization from methylene chloride/methanol yields pure methyl 2-amino-6-[(p-toluenesulfonyl)oxy]-4-pyrimidinecarbamate of meltig point 188°-189°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:13].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: N#Cc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At room temperature, to a tetrahydrofuran solution (60 ml) of 5-bromo-3-nitropyridine-2-carbonitrile (6.00 g) was added a tetrahydrofuran solution (1 M, 52.8 ml) of tetrabutylammonium fluoride, followed by stirring for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 5-bromo-3-fluoropyridine-2-carbonitrile. To a mixed solvent solution of this in 1,2-dimethoxyethane (120 ml) and water (30 ml) were added 2-hydroxyphenylboronic acid (4.37 g), sodium carbonate (8.39 g) and tetrakis(triphenylphosphine)palladium (1.52 g), followed by stirring under heating at reflux for 2 hours. The reaction solution was brought back to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 3-fluoro-5-(2-hydroxyphenyl)pyridine-2-carbonitrile (2.73 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C:34](=[O:36])[CH3:35])[C@@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-((S)-indan-1-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and acetyl chloride.