Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:54][C:53]3[C:48](=[C:49]([O:61]C)[C:50]([O:59][CH3:60])=[C:51]([O:57][CH3:58])[C:52]=3[O:55]C)[CH2:47]2)=[CH:42][CH:41]=1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:54][C:53]3[C:52](=[O:55])[C:51]([O:57][CH3:58])=[C:50]([O:59][CH3:60])[C:49](=[O:61])[C:48]=3[CH2:47]2)=[CH:42][CH:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C2(C(=O)OCC)CC3=C(C2)C(=O)C(OC)=C(OC)C3=O)cc1
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A water (1.0 ml) solution of CAN (795 mg, 1.45 mmols) was dropwise added to an acetonitrile (6.0 ml) solution of ethyl 2-[4-(4-ethoxycarbonyl-1-oxabutyl)phenyl]-4,5,6,7-tetramethoxy-2-indancarboxylate (300 mg, 0.581 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain the entitled compound (200 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:15]1([NH:21][C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]([CH3:23])=[N:11][C:6]=2[CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 58.6 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 4-Bromo-3-nitrobenzoic acid methyl ester (130 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as colorless crystals (78 mg, 59%). mp 108-110° C. 1H NMR (DMSO) δ 2.55 (s, 3 H), 3.78 (s, 3 H), 7.30 (d, J=8.2 Hz, 1 H), 7.52-7.71 (m, 5 H), 7.92 (d, J=8.2 Hz, 1 H), 8.30 (br s, 1 H); 13C NMR δ 13.6, 52.1, 110.8, 118.5, 124.7, 124.8, 127.0, 129.7, 130.1, 134.0, 137.9, 153.7, 157.8, 166.2. HRMS (FAB): cal. for C16H15N2O2 [M+H]+: 267.1134; found: 267.1128.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:25][C:26]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:25][C:26]1[CH:33]=[C:32]([CH:31]=[CH:30][C:27]=1[C:28]#[N:29])[O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:24]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(Cl)c3)ccc21
Reaction time: 14 h
Yield: 64.7 %

Procedure:
To a solution of the compound obtained in Step 2 (500 mg, 1.54 mmol) and 2-chloro-4-fluorobenzonitrile (240 mg, 1.54 mmol) in THF (15 mL) was added potassium t-butoxide (432 mg, 3.85 mmol) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (458 mg, 0.996 mmol, 64.6%) as a colorless powder.
Reaction SMILES: [Br:1]Br.N1C=CC=CC=1.[C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)#[N:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:15]1[CH:16]=[N:17][C:18]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:9]#[N:10])=[CH:20][CH:19]=2
Reactant: BrBr
Reactant: N#Cc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc2ncc(Br)cc2c1
Reaction time: 2 h

Procedure:
In an amount of 37.8 mg of 6-cyanoquinoline (Justus Liebigs Ann. Chem., 1966, 699, 98-106) was dissolved in 1 ml of carbon tetrachloride, added with 13 μl of bromine, and then stirred under reflux. After 2 hours, the reaction mixture was added with 20 μl of pyridine, and further stirred for 23 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate (4:1)) to obtain 34.8 mg of the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=2)=[CH:57][C:56]=1[CH3:68]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 67 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 65% yield: LCMS (ESI) m/z 470 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]([CH3:33])[C:20]3[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:22][C:21]=3[CH:32]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:34].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[C:19]([CH3:33])[C:20]2[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:22][C:21]=2[CH:32]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:35])[C:2]([CH3:36])([CH3:37])[CH3:1])=[C:7]([CH3:34])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 99.5 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carbonyl)-amino]-acetic acid (210 mg, 0.414 mmol) is reduced with NaBH4 (31 mg, 0.827 mmol) analogous to Example 3 to give the title product (210 mg, 100%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:24][C:22]1[CH:21]=[CH:20][C:19]([C:25]2[C:26]([N:36]3[CH2:37][CH2:38][CH2:39][O:33][CH2:34][CH2:35]3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:32])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5F)ccc(F)c43)ccc21
Reactant: C1CNCCOC1
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5N5CCCOCC5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(2-fluoro-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and [1,4]oxazepane following a procedure analogous to that described for Example 128. LC (method 9): tR=0.87 min; Mass spectrum (ESI+): m/z=505 [M+H]+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1O)[CH:20]=[O:21].O>N1C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Br:26])[C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH:20]=[O:21]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1cc(Br)c(OS(=O)(=O)C(F)(F)F)c(Br)c1
Reaction time: 1 h

Procedure:
14.73 ml of triflic anhydride is added, under inert gas and at 0° C., to 19.0 g of 3,5-dibromo-4-hydroxy-benzaldehyde in 100 ml of pyridine. Agitation is carried out for 1 hour while allowing the temperature to return to ambient, the reaction medium is poured into water and the aqueous phase is extracted with 3 times 150 ml of dichloromethane. The organic phases are dried and evaporated to dryness under reduced pressure. 23.83 g of crude product is obtained which is purified by filtration chromatography using a cyclohexane/ethyl acetate mixture 1/1 as eluant. In this way 23.83 g of expected product is obtained. Rf: 0.71, cyclohexane/ethyl acetate 1/1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](OCC)=[O:27])=[CH:22][N:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:41])=[C:9]([CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[CH2:26][OH:27])=[CH:22][N:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:20]=3)=[CH:15][C:14]=2[O:39][CH3:40])[N:10]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoate (0.55 g) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (0.95 M hexane solution, 6.3 mL) at 0° C., and the mixture was stirred at room temperature for 3 hrs. Sodium sulfate decahydrate (1.91 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propen-1-ol as colorless crystals (0.30 g, yield 59%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si](C(C)C)(C(C)C)C(C)C)=[CH:4][C:3]=1[C:21]([OH:23])=[O:22].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)O)c(F)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.5 %

Procedure:
6-Fluoro-1-(triisopropylsilyl)-1H-indole-5-carboxylic acid (4.36 g, 13.00 mmol) was treated with THF (30 mL) and tetra-n-butylammonium fluoride (1.0 M in THF, 13.0 mL, 13.00 mmol) and stirred at RT for 15 min. The reaction mixture was diluted with Et2O (30 mL) resulting in a suspension which was collected by filtration affording 6-fluoro-1H-indole-5-carboxylic acid (2.41 g) as a white crystalline solid. MS (ESI, pos. ion) m/z: 180.1 (M+H)+. The crude material was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH:13]=[CH2:14])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16]>C(OCC)(=O)C.[Pd]>[CH2:13]([C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:15])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:17])[CH3:14]
Reactant: C=Cc1cc(OC)cc2c1C(=O)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(OC)cc2c1C(=O)CCC2(C)C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
A solution of 8-vinyl-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 155, 1.12 g, 4.86 mmol) in ethyl acetate (10 mL) was treated with 10% palladium on carbon (100 mg) and the resulting reaction mixture was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered over a bed of celite and the filtrate was evaporated to afford the title product (1.1 g, 98%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.S(=O)(=O)(O)O.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][N:3]=[CH:4]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ncncc2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2ncncc2c1
Reaction time: 1 h

Procedure:
Quinazoline (2 g) was nitrated with 25 mL of mixture of nitric acid 90%, 10 mL) and sulfuric acid (+20% SO3, 15 mL) at 0° C. for 20 minutes, and then at ambient temperature for 1 hour. The mixture was then poured on ice, neutralized with KOH and the pH was adjusted to 8 with K2CO3 (pH 8). Filtration and recrystallization from EtOH yielded the crystalline product 6-nitroquinazoline (1.7 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1C(OCC)=O.ClC1C=CC2SC=C(C)C=2C=1>>[Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][CH:7]=1
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Agent: Cc1csc2ccc(Cl)cc12
Product: Clc1ccc2scc(CBr)c2c1
Yield: 57 %

Procedure:
Using the general procedure of Example 1, Method A, (iv), replacing ethyl 5-chloro-3-methylbenzo[b]thiophene-2-carboxylate with 5-chloro-3-methylbenzo[b]thiophene gave 2.78 g (57%) of 3-bromomethyl-5-chloro-benzo[b]thiophene: mp 126°-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][Br:30])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(F)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.98 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 7.30 (s, 1H), 7.14-7.18 (m, 1H), 7.01-7.05 (m, 1H), 4.36 (s, 2H).
Reaction SMILES: CCO[C:4]([C:6]1[C:12](C)=[CH:11][C:9](=[O:10])[O:8][C:7]=1C)=O.[OH-:15].[Na+].Cl>O>[CH3:4][CH:6]1[C:7](=[O:15])[O:8][C:9](=[O:10])[CH:11]=[CH:12]1
Reactant: [OH-]
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1C=CC(=O)OC1=O

Procedure:
The procedure found in J. Am. Chem. Soc. 75, 2377-9 (1953) was generally followed. Ethyl isodehydroacetate (100 g, 0.51 mol) was added to a warm solution of sodium hydroxide (68.5 g., 0.71 mol) in water (500 mL) and stirred for an hour until the mixture became clear. The solution was acidified with concentrated hydrochloric acid (200 mL) and was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was mixed with acetic anhydride (250 mL) and the resulting mixture was heated at reflux for 20-30 min. The solvent was removed by evaporation under reduced pressure and the residue obtained was crystallized from ether to obtain 60.8 g (94 percent of theory) of the title compound as a tan powder melting at 70°-72° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[N:8]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][OH:28]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[C:7]2[N:8]=[C:4]([C:1]3([CH3:2])[O:28][CH2:27][CH2:26][O:3]3)[O:5][C:6]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2oc(C(C)=O)nc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2oc(C3(C)OCCO3)nc12
Temperature: 25 °C

Procedure:
2-Acetyl-4-methoxybenzoxazole (200 mg), p-toluenesulphonic acid (239 mg), ethylene glycol (0.29 ml) and toluene (10 ml) were heated to reflux under Dean-Stark conditions for 2 h. After cooling to room temperature, the toluene was evaporated, and the residue partitoned between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (40 ml), aqueous sodium bicarbonate (2×40 ml) and water (40 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as a white solid (129 mg).
Reaction SMILES: [C:1]1(O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([O:15]CC)([O:12][CH2:13][CH3:14])(OCC)[CH3:8]>C(O)(=O)C(C)(C)C>[CH2:3]([C:1]1[C@@H:5]([CH2:8][C:7]([O:12][CH2:13][CH3:14])=[O:15])[CH2:4][CH2:3][CH:2]=1)[CH2:2][CH2:1][CH2:5][CH3:4]
Reactant: CCOC(C)(OCC)OCC
Reactant: OC1=CCCC1
Agent: CC(C)(C)C(=O)O
Product: CCCCCC1=CCC[C@@H]1CC(=O)OCC
Yield: 73 %

Procedure:
A mixture of the cyclopentenol obtained according to Example 1 (5 g, 32.5 mmol) with triethyl orthoacetate (47.2 ml=42.1 g, 260 mmole, 8 eq.) was heated to 145° (temp. of oil bath 160°) under a nitrogen current in a reactor which was equipped with a Vigreux column and a condenser, while adding continuously, over 4 h, pivalic acid (232 mg, 2.28 mmole, 7 mol %) in triethyl orthoacetate (5.9 ml=5.26 g, 32.5 mmole, 1 eq.). During the reaction, the formed ethanol, as well as the ethyl acetate and a little orthoacetate, were removed by distillation. The reaction mixture was heated for 1 more hour, then cooled to 20°, hydrolyzed with diluted aqueous NaHCO3 and extracted with ether. The organic layer was washed 2x with water and once with brine, dried over Na2SO4 and evaporated, to give 15.4 g of crude product. After distillation of the heads (6.6 g, 50°/1.1×102 Pa), 5.30 g (95°/1.1×102 Pa) of (+)-ethyl (1 R)-2-pentyl-2-cyclopentene-1-acetate were obtained (yield 73%), having an enantiomeric purity of 90% e.e. (chiral column of the type Megadex® 5).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a stirring solution of 4-iodophenol (100 g, 0.5 mol) and K2CO3 (70 g, 0.5 mol) in DMF (400 mL) was added 1,4 dibromobutane (100 mL, 0.84 mol) over a period of 1 hr. The solution was stirred overnight at room temperature under Ar. H2O (1000 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer was then washed with 1000 mL of brine, dried over MgSO4, concentrated to gave a white solid (100 g); 1H NMR (CD3Cl): δ 2.15-1.87 (m, 6H), 3.50-3.20 (m, 4H), 3.94 (t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)(O)[O-].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[OH:1]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(C)cc1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
Commercially available 2-hydroxy-4-methylbenzoic acid (1.0 g, 7.0 mmol) and potassium bicarbonate (841 mg, 8.4 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (10 ml) and methyl iodide (0.65 ml, 10.5 mmol) were added thereto. The resulting mixture was stirred at 40° C. for 4 hours. The reaction solution was diluted with ethyl acetate (200 ml), and sequentially washed with water (70 ml), with a saturated aqueous sodium bicarbonate solution (70 ml), twice with water (70 ml), and with a saturated aqueous sodium chloride solution (70 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to yield 2-hydroxy-4-methylbenzoic acid methyl ester (1.1 g) as a pale yellow oily material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])[CH2:10][C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([N+:23]([O-])=O)=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:23][C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[CH2:14]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc(N)cc2C1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product (0.43 g) from Step A above in 4 mL of methanol was added 20% palladium hydroxide on carbon (Pearlman's catalyst, 0.04 g). The reaction was placed under a balloon of hydrogen and allowed to stir at room temperature overnight. The reaction flask was purged, the mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 55% ethyl acetate/hexanes) to afford the title compound. LC/MS: 328 (M−100).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=2)[CH2:17][CH2:16][CH2:15]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][CH2:15][N:14]2[CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:19][CH:20]=1
Reactant: CN(CCN1CCCc2ccc([N+](=O)[O-])cc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(CCN1CCCc2ccc(N)cc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of compound 2 (1.85 g, 5.205 mmol) in dry ethanol (30 mL) was treated with Pd—C (˜0.2 g) and purged with hydrogen gas. The reaction was stirred at room temperature under hydrogen (balloon pressure) for 3 h. The reaction was filtered through celite bed and washed with methanol (3×20 mL). The combined organic layer was evaporated to obtain crude compound 3 (1.67 g, 99%) as a syrup. ESI-MS (m/z, %): 326 (MH+, 100).