Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].[Co:13](Cl)Cl>O>[Co:13].[CH3:3][C:4](=[O:12])[CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cl[Co]Cl
Agent: CCCCC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Co]
Reaction time: 0.17 h

Procedure:
Four grams (0.1 mol) of sodium hydroxide were dissolved in 150 cc of water. To this solution, 14.2 g (0.1 mol) of 2,4-octanedione were added slowly while stirring. After the dissolution had been completed, the obtained solution was dripped taking 10 minutes while vigorously stirring into a cobalt (II) chloride aqueous solution which had been prepared in advance by dissolving 11.9 g (0.05 mol) of hexahydrated cobalt (II) chloride in 200 cc of water. The produced rose-red-colored precipitate was separated by filtration and washed with water until the washing water became substantially colorless, followed by vacuum drying to obtain 15.1 g of the object: 2,4-octanedione cobalt complex.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10]CC(C)=C)[C:7]([Br:15])=[C:6]([OH:16])[CH:5]=1>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([OH:16])[C:7]([Br:15])=[C:8]([OH:10])[C:9]=1[CH2:5][C:4]([CH3:9])=[CH2:3]
Reactant: C=C(C)COc1cc(C(=O)OC)cc(O)c1Br
Solvent: CN1CCCC1=O
Product: C=C(C)Cc1c(C(=O)OC)cc(O)c(Br)c1O
Temperature: 25 °C
Yield: 188.4 %

Procedure:
A solution of 4-bromo-3-hydroxy-5-(2-methyl-allyloxy)-benzoic acid methyl ester (197b) (148 g, 0.49 mol) in NMP (1.5 L) was refluxed for 0.5 h. After TLC (petroleum ether/EtOAc=5/1) indicated complete consumption of 197b, the reaction mixture was cooled to room temperature and 20% aq. HCl was added until pH=1. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic phases were dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by column chromatography (petroleum ether/EtOAc=15/1) to give the title compound (139 g, 94% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CC[O-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>CCO>[C:19]([CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)#[N:20]
Reactant: N#CCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirred solution of 4-hydroxybenzoic acid (40 mmol) in absolute EtOH (350 mL) was added solid NaOEt (84 mmol). After 15 minutes, 4-bromobutyronitrile (40 mmol) was added and the mixture was heated overnight at 90° C. on an oil bath. The mixture was cooled to room temperature, volatiles were removed, the residue was taken up in ice and adjusted to pH 6 with 1N sulfuric acid. Solids were collected by vacuum filtration, washed with water and dried to give 4-(cyanopropyloxy)benzoic acid (4.8 g, 58%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[CH3:21][O-:22].[Na+].CO>CC(O)=O>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:13])[C:3]=2[CH2:2][O:22][CH3:21])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:15][CH:16]=1
Reactant: O=c1c(CBr)c(-c2ccc(O)cc2)oc2ccccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1c(-c2ccc(O)cc2)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.52 g, 1.57 mmol), sodium methoxide (1.36 mL, 6.28 mmol, 25% in MeOH) and anhydrous MeOH (10 mL) was stirred overnight at rt. The reaction mixture was neutralized by addition of AcOH and the solvent was removed. The residue was poured into water and the solid was collected and purified by column chromatography (hexane:EtOAc 2:1) to give 155 mg of 2-(4-hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one (35.0%). MS (ES) m/z: 283.95 (M+1), 282.93 (M); Mp. 237-239° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8])([O-])=O.[BH4-].[Na+].O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:7]#[N:8]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
3-Nitro-4-aminobenzonitrile (3.00 g) was dissolved in ethanol (300 ml) and added with stannous chloride dihydrate (20.7 g) and the whole was heated to 60° C. Sodium borohydride (348 mg) was gradually added thereto and the whole was stirred overnight at 60° C. After completion of the reaction, the resultant was added with water (300 ml) and neutralized with a 5 mol/l sodium hydroxide aqueous solution. After ethanol was distilled off under reduced pressure, the aqueous layer was added with ethyl acetate for extraction. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was recrystallized, thereby obtaining the subject compound (1.11 g) as a brown crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reactant: C1CCNCC1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and piperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 36%; MS: m/z=277 (M+H).
Reaction SMILES: [O:1]([CH2:9][C@H:10]([OH:12])[CH3:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][C:34](=[O:50])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([S:42][C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[CH:36]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OC(=O)C)C.O>[CH3:32][O:33][C:34](=[O:50])[C:35]1[CH:40]=[C:39]([O:12][C@@H:10]([CH3:11])[CH2:9][O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:38]=[C:37]([S:42][C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[CH:36]=1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)c1cc(O)cc(Sc2ccc(C)cc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(Sc2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
After adding 1.40 g (7.40 mmol) of (2R)-1-(t-butyldimethylsiloxy)-2-hydroxypropane and 2.00 g (7.40 mmol) of triphenylphosphine to a solution of 1.20 g (4.13 mmol) of the 5-hydroxy-3-(4-methylthiophenoxy)benzoic acid methyl ester obtained in Production Example 1 in tetrahydrofuran (10 ml), 3.20 ml (7.40 mmol) of diethyl azodicarboxylate was added while cooling on ice, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and then the organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=95:5) to obtain 1.63 g of 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methylthiophenoxy)-benzoic acid methyl ester (yield: 95%) as a colorless oil. After adding 2.06 g (12.0 mmol) of m-chloroperbenzoic acid to a solution of 1.84 g (3.97 mmol) of the obtained ester compound in chloroform (40 ml) while cooling on ice, the reaction mixture was stirred for 0.5 hour while cooling on ice. Aqueous sodium thiosulfate was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine, dried, and concentrated under reduced pressure to obtain a crude sulfone compound.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:45])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:46](Cl)(=[O:56])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([O:8][N:9]([C:16](=[O:45])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:22](=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:46](=[O:56])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Yield: 80 %

Procedure:
Compound (8) (1.20 g, 1.95 mmol) was reacted with decanoyl chloride (0.565 g, 2.96 mmol) in CH2Cl2 and 1N NaOH following the procedure used for (3). Purification by silica gel column chromatography with 2:1 EtOAc/hexane as the eluant provided 1.20 g (80%) of (10) as an oil: NMR δ 0.90 (t, 3H, J=6), 1.13-1.40 (m, 14H), 1.47-1.90 (m, 12H), 2.23-2.53 (m, 8H), 3.50-3.77 (m, 6H), 4.77 (s, 6H), 7.33 (s, 15H). Anal. (C46H64N4O6) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]2[CH2:14][CH2:15][C:16]3[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[O:9][C:10](=[O:17])[C:11]=3[CH2:12]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccc(Cl)cc1)CC3
Yield: 70 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-chlorobenzaldehyde. Yield 70%; mp 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([OH:22])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH:20]([O:22][CH2:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])[CH2:19][CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: OC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(COC1CCc2nc(-c3ccc(OCC4CC4)c(Cl)c3)oc2C1)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-6-ol (6.61 g) and 4-(chloroacetyl)morpholine (5.38 mL) in THF (50 mL) was added potassium tert-butoxide (4.64 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (9.24 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([N:8]([CH3:31])[C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)C(=O)c1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 43.9 %

Procedure:
In a manner similar to that of Example 1(g), starting with 400 mg (0.9 mmol) of N-benzyl-N-methyl-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-carboxamide in 5 ml of dioxane, 170 mg (43%) of the desired product, with a melting point of 66° C., are obtained.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[CH:61][C:60]=1[NH:65][C:55]([C:43]1[N:44]=[C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])[S:46][C:42]=1[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:56]
Reactant: Cn1ncc(N)c1Cl
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A solution of PyBOP (4.08 g, 7.84 mmol) and 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (2.20 g, 6.16 mmol) in DCM (50 mL) was stirred at room temperature for 30 min. A solution of 5-chloro-1-methyl-1H-pyrazol-4-amine (737 mg, 5.60 mmol) and DIPEA (1.6 mL, 9.0 mmol) in DCM (50 mL) was then added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (3×50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-100% EtOAc/isohexane) followed by trituration with MeCN gave tert-butyl 4-(5-chloro-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (1.71 g, 65%). 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.42-7.33 (m, 1H), 7.09-7.01 (m, 2H), 3.87 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: CO.[OH-].[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[C:15](=[O:41])[O:16][C:17]([OH:40])([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:18]=3[CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1>O>[O:5]1[C:9]2[CH:10]=[CH:11][C:12](/[C:14](=[C:18](/[CH2:19][C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)\[C:17]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[O:40])/[C:15]([OH:41])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)/C(Cc2cc(OC)c(OC)c(OC)c2)=C(/C(=O)O)c2ccc3c(c2)OCO3)cc1
Yield: 9 %

Procedure:
To 150 mL methanol to which 3.95 mL 1.00N NaOH had been added was added 3-benzo[1,3]dioxol-5-yl-5-hydroxy-5-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 2.00 g (3.95 mmol). The suspension was stirred to give solution and was placed in a 400 mL Pyrex™ beaker and diluted with 150 mL water. The beaker was covered with a quartz evaporating dish (100 mm o.d.×15 mm h., QRD 100; Quartz Scientific, Inc., Fairport Harbor, Ohio). The covered solution was irradiated for 30 hours in an Atlas Sunchex™ simulated sunlight exposure instrument (Xenon arc lamp, set to 0.35 W/m2 at 340 nm, filtered to exclude wavelengths less than 280 nm; Atlas Electric Devices Co., Chicago, Ill.). The mixture was filtered to remove insoluble solids, and the filtrate was evaporated in vacuo to remove methanol. The residual aqueous solution was extracted repeatedly with ethyl ether, while the pH of the aqueous phase was adjusted incrementally between 7.5 and 8 by addition of 3N HCl. The aqueous phase was then acidified to pH 1 with HCl and extracted with ethyl ether. The ether phase was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Addition of petroleum ether gave a crystalline solid which was filtered and dried under vacuum at 40° C., giving a solid melting at 192-193° C., 180 mg. The product was identified by 1H NMR, MS, [M-H]+ =505.3 Da. and microanalysis.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:46]/[O:47]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:45])[N:26]([C@@H:29]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[O:39][C:40](=[O:44])[O:41][C:42]=5[CH3:43])=[O:35])[CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(OCC)C>ClCCl>[CH3:43][C:42]1[O:41][C:40](=[O:44])[O:39][C:38]=1[CH2:37][O:36][C:34]([N:31]1[CH2:30][C@H:29]([N:26]2[C:25](=[O:45])/[C:24](=[CH:23]/[C:15]3[CH2:14][S:13][C@@H:12]4[C@H:11]([NH:10][C:8](/[C:7](/[C:4]5[N:3]=[C:2]([NH2:1])[S:6][N:5]=5)=[N:46]/[OH:47])=[O:9])[C:18](=[O:19])[N:17]4[C:16]=3[C:20]([OH:22])=[O:21])/[CH2:28][CH2:27]2)[CH2:33][CH2:32]1)=[O:35]
Reactant: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N/O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1

Procedure:
90 mg of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]-thiadiazol-3-yl)-2-triphenylmethyloxyiminoacetyl-amino]-8-oxo-3-[(E)-(R)-2-oxo-1′-(5-methyl-2-oxo-1,3-dioxol-4-ylmethoxycarbonyl)-[1,3′]bi-pyrrolidinyl-3-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 10 ml of dichloromethane, 0.5 ml of triethylsilane and 2 ml of trifluoroacetic acid and stirred at room temperature. After 30 minutes the mixture is added dropwise to 150 ml of diethyl ether. The precipitate is filtered, washed with diethyl ether and dried in vacuo.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17].Cl>CS(C)=O>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]2[C:2]=1[N:19]([CH:16]([CH3:18])[CH3:17])[C:13](=[O:15])[CH2:12]2
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Reactant: CC(C)N
Agent: Cl
Solvent: CS(C)=O
Product: CC(C)N1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl)acetic acid (16, 1.00 g, 0.00461 mol) and isopropylamine (6 eq., 2.35 ml, 0.0276 mol) are mixed in DMSO (5 ml) and stirred at 45° C. for 1 hour. 2N Hydrochloric acid (20 ml) is added in one portion and the mixture stirred at room temperature for 1 hour. The resulting precipitate is filtered, washed with water and ether, and dried under vacuum (0.39 g, 35%); HPLC r.t. 5.31 min.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37](Cl)=[O:38])[C:25]=2[CH2:40][CH3:41])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:38])[C:25]=2[CH2:40][CH3:41])=[CH:22][CH:23]=1
Reactant: CCc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A mixture of 3.2 g of tert-butyl hydrazinecarboxylate and 3.9 ml of triethylamine in 100 ml of DCM is cooled to 0° C., a solution of 10.5 g of the compound obtained in stage A in 100 ml of DCM is added dropwise and the mixture is left stirring while allowing the temperature to rise to AT. The reaction mixture is washed with water, with a pH=2 buffer solution and with a saturated NaHCO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. 12.7 g of the expected compound are obtained.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([C:45]1([C:48](O)=[O:49])[CH2:47][CH2:46]1)=[O:44].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:48]([C:45]4([C:43](=[O:44])[NH:42][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[F:35])[CH2:46][CH2:47]4)=[O:49])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2F)CC1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4F)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (410 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (223 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (90.6 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:18].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:18]
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)OC)sc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (260 mg, 0.85 mmol) in THF/H2O (4 mL/1 mL) was added KOH (478 mg, 8.52 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give a crude acid, which was used directly without further purification.