Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][O:56]CC1C=CC=CC=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=2[F:49])=[CH:38][CH:37]=1)=[O:17])C1C=CC=CC=1>[Pd].O1CCCC1>[OH:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=2[F:49])=[CH:40][CH:41]=1)=[O:17]
Reactant: O=C(OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCO)CCCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.8 %

Procedure:
First, 5.8 g of 16-[2,3-difluorobiphenyl-4'-yl]oxyhexadecyl 2,2-bis(6-benzyloxyhexyl)acetate, 1.8 g of 10% Pd-C, and 100 ml of tetrahydrofuran were placed in a 300 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=7/3) to obtain 3.9 g of 16-[2,3-difluorobiphenyl-4'-yl]oxyhexadecyl 2,2-bis(6-hydroxyhexyl)acetate (Y: 85.5%). The compound thus obtained had a purity of 99.2% by HPLC and an m.p. of 45.2° C. to 48.8° C.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]1([CH:55]=[CH:56][S:57](Cl)(=[O:59])=[O:58])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57](/[CH:56]=[CH:55]/[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)/C=C/c3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 66 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added 2-phenyl-ethenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 66% yield.
Reaction SMILES: [O:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:10][C:9](=[O:11])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CC(=O)COc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Temperature: 25 °C
Yield: 16.2 %

Procedure:
Phenoxyacetone (5.0240 g, 33.46 mmol) and diethyloxalate (4.52 mL, 33.29 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 11.1 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 40. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 1.3490 g (15.4%) of 40. 1H (CDCl3, 400 MHz): δ 7.31 (2H, t, J=7.5 Hz), 7.01 (1H, t, J=7.3 Hz), 6.91 (2H, d, J=8.8 Hz), 6.76 (1H, s), 4.67 (2H, s), 4.35 (2H, q, J=7.1 Hz), 1.38 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 199.61, 166.38, 161.55, 157.37, 129.63, 121.89, 114.48, 98.97, 70.13, 62.60, 13.90 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.90; CH2 carbons: 70.13, 62.60; CH carbons: 129.63, 121.89, 114.48, 98.97 ppm. HPLC: 10.180 min. (Starting material: 9.053 min)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>Cl.C(OCC)(=O)C.O>[CH2:1]([O:3][CH2:4][CH2:5][O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[CH3:2]
Reactant: CCOCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 28.4 %

Procedure:
Commercially available 2-bromoethyl ethyl ether (33.8 g, 221 mmol) was added to a solution of commercially available 3,4-dihydroxybenzaldehyde (30.5 g, 221 mmol) and sodium carbonate (35.1 g, 331 mmol) in NP-dimethylformamide (310 mL) under nitrogen atmosphere at mom temperature. The liquid mixture was stirred at room temperature for 5 days. The reaction liquid was cooled to 0° C. and diluted with 2 M hydrochloric acid, ethyl acetate, and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed serially with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The insoluble matters were separated by filtration with dichloromethane and the raw material was removed. The filtrate was purified with silica gel column chromatography (n-heptane:ethyl acetate=17:3-1:1) to obtain the title compound (13.2 g, 28%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:18]([C:20]1[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=1[O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][C@@H:28]([C:30]([O:32][CH3:33])=[O:31])[NH2:29])=[CH:25][CH:24]=1)#[N:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([NH:29][C@H:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[C:18]#[N:19])=[CH:35][CH:34]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccccc2C#N)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2C#N)cc1)NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a solution of 131 mg of N-Boc-2-(S)-methyl-(L)-proline, 190 mg 4-(2-cyanophenoxy)-phenylalanine, methyl ester hydrochloride, 297 mg PyBOP, and 4 mL of methylene chloride at 0° C. was added 300 μL of diisopropylethylamine via syringe. The reactants were allowed to warm to room temperature and said reaction was run over the weekend. The reaction was then diluted with methylene chloride, washed with water, 1N hydrochloric acid), saturated sodium bicarbonate solution, and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was purified via silica gel chromatography, eluted with 80% hexane:20% acetone to yield 263 mg of the title compound.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
475 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 15 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 0.45 ml of 1N aqueous hydrochloric acid was added, and the mixture hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 46 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 89.5 %

Procedure:
2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromo-succinimide (1.96 g, 11 mmol) and 2,2′-azobis(2-methyl-propionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 hours cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1-2%) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89%) of 2-bromomethyl-benzoic acid methyl ester as a solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]=[O:21].C(N(CC)CC)C.O>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[N:16]2[CH2:20][OH:21])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)NC(=O)CC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)N(CO)C(=O)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
7-(tert-Butyl-dimethylsilanyloxy)-3,4-dihydro-1H-quinolin-2-one (830 mg) was suspended in DMF (13 ml), formaldehyde (4.3 ml) and triethylamine (0.083 ml) were added, and the mixture was stirred at 80° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (36 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N+:22]([O-:24])=[O:23])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CCOCC>[C:32]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=[C:11]1[N+:22]([O-:24])=[O:23])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2nc([N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc([N+](=O)[O-])n(C(=O)c3ccccc3)c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3 g, 9.2 mmole) and triethylamine (3.9 ml., 27.6 mmole) in 30 ml. THF at 0° C. under N2 was dropwise added a solution of benzoyl chloride (1.2 ml., 10.1 mmole) in 5 ml THF. The reaction mixture was stirred for 8 hours at 0° C. and then left in the refrigerator overnight. The reaction was then diluted with 30 ml ether and filtered. The filtrate was concentrated on a rotary evaporator and chromatographed on Florisil. Recrystallization from methylcyclohexane gave 1.89 g of 1-benzoyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole, mp. 161°-163° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH3:23].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH3:23])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 96.8 %

Procedure:
Following the procedure of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (525 mg, 2.02 mmol), 1-bromobutan-2-one (428 mg, 2.83 mmol), and triethylamine (0.480 mL, 3.44 mmol) were reacted in ethanol (20 mL) to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine (609 mg) as a yellow oil. The HCl salt was prepared according to Example 3, Step C, to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine hydrochloride (585 mg, 83%) as a white powder. 1H NMR (d6-DMSO) δ 7.97 (d, 1H), 7.59-7.61 (m, 3H), 7.35-7.42 (m, 3H), 7.12 (m, 1H), 6.86 (s, 1H), 5.34 (s, 2H), 2.67 (q, 2H), 1.23 (t, 3H). Mass spectrum (apci) m/z=312 (100) (M+H-HCl).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[CH3:31]>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:24][C:23]=1[CH3:31]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cc(C(=O)O)ccc1Cl
Agent: Cl
Product: Cc1cc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)ccc1Cl

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chloro-3-methylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][N:24]([CH:26](OC)OC)[CH3:25]>CN(C=O)C>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(OC)N(C)C
Reactant: Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Preparation 2A above, 57 g (0.195 mole) of 2-methyl-3(1-naphthylcarbonyl)nitrobenzene and 103 ml (0.784 mole) of DMF dimethyl acetal in 300 ml of DMF was heated under reflux for seventeen hours and then taken to dryness to give 2-(2-dimethylaminoethenyl)-3-(1-naphthylcarbonyl)nitrobenzene as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH2:25][C:26]([O:28]CC)=[O:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O[Li].O.O.ClCCl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH2:25][C:26]([OH:28])=[O:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)Cc1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)Cc1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1

Procedure:
To a solution of ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)acetate (0.010 g, 0.025 mmol) in THF (0.3 mL) were added LiOH.H2O (0.002 g, 0.05 mmol) and water (0.15 mL) were added. The mixture was stirred at room temperature for 2 h. dichloromethane (3 mL) was added to the reaction mixture and the organic layer washed with 1 N HCl (2×1.5 mL) and water (2×1.5 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure to give 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.90 (s, 1H), 8.42 (s, 1H), 7.57 (s, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.17 (s, 1H), 6.02 (s, 2H), 3.69 (s, 2H), 1.41-1.39 (m, 2H), 1.04-1.02 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)[CH3:2].[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[N:27]([C:14]2[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=2)[N:26]=1)[CH3:2]
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115 %

Procedure:
To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][S:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:2][C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:23]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: COC(=O)c1sccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(OCc2ccsc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Methyl 3-bromomethylthiophene-2-carboxylate (28.2 ml, 120 mmol) and potassium carbonate (36.6 g, 264 mmol) were added to a DMF (300 mL) solution of the compound obtained in Example 18 (28.1 g, 132 mmol), and the mixture was stirred overnight at room temperature. The solvents were distilled off under a reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvents were distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 35.1 g (80%) of the captioned compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:13][CH:14]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cn2)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cn2)c1
Temperature: 135 °C

Procedure:
A stirred mixture of methyl 3-hydroxy-5-(5-methylpyridin-2-yl)benzoate (290 mg, 1.2 mmol), 2-bromothiazole (410 mg, 2.5 mmol), potassium carbonate (346 mg, 2.5 mmol), and dimethyl sulfoxide (5 mL) was heated at 135° C. overnight. The reaction mixture was then cooled to room temperature and diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-30% EtOAc/hexane) to afford the title compound.
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])C.[Li+].[OH-]>C1COCC1.O>[F:14][C:11]1[CH:10]=[CH:9][C:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CCN(CC(=O)O)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1ccc(F)cc1

Procedure:
To a solution of 21.3 g (108 mmole) of ethyl N-(4-fluorophenyl)glycine in THF (100 mL) under nitrogen was added LiOH (5.44 g (130 mmol) monohydrate in 25 mL water. After 15 h the mixture was concentrated to half the volume and acidified to pH 3 with HCl. The precipitated solid was collected and washed with water (100 mL) to afford the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13](=[CH2:25])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:24]>C(Cl)Cl>[CH3:25][C:13]1([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][C:16]2=[O:24])[CH2:12][O:9]1
Reactant: C=C(C)Cn1c(=O)oc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(Cn2c(=O)oc3ccccc32)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
m-Chloroperbenzoic acid (1.66 g, 9.65 mmol) was added to a mixture of 3-(2-methyl-2-propenyl)-3H-benzoxazol-2-one (1.66 g, 8.77 mmol) in methylene chloride (30 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was washed with a 20% sodium sulfite aqueous solution, saturated sodium bicarbonate aqueous solution and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with methylene chloride/n-hexane, and the resulting precipitates were collected by filtration to afford 3-(2-methyl-2-oxiranylmethyl)-3H-benzoxazol-2-one (1.78 g, yield 99%) as a white powder.