Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[CH3:11][N:12]1[C:16]([O:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20](OC3N(C)N=C(C(F)(F)F)C=3)[N:19]=2)=[CH:15][C:14]([C:37]([F:40])([F:39])[F:38])=[N:13]1>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[CH3:11][N:12]1[C:16]([O:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])[N:19]=2)=[CH:15][C:14]([C:37]([F:40])([F:39])[F:38])=[N:13]1
Reactant: COc1cc(Oc2cc(C(F)(F)F)nn2C)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: O=S1(=O)CCCC1
Product: COc1cc(OCC(F)(F)C(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 110 °C
Reaction time: 3.7 h
Yield: 99.2 %

Procedure:
To a mixture of 2,2,3,3-tetrafluoropropan-1-ol (0.29 g, 2.2 mmol) in dry sulfolane (2 ml) is added NaH (60% in oil, 0.09 g, 2.2 mmol) and 2,6-bis-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methoxypyridine (0.8 g, 1.8 mmol). After stirring at 110° C. for 3.7 h the mixture is cooled to ambient temperature. The resulting mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 10 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (0.72 g, 57% yield) of m.p. 73-74° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[C:4]([O:14]COC)[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])[CH:7]=1
Reactant: COCOc1cc(Br)cc(S(=O)(=O)C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)S(=O)(=O)c1cc(O)cc(Br)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
To a solution of 1-bromo-3-methoxymethoxy-5-(propane-2-sulfonyl)-benzene (840 mg, 2.59 mmol) in THF (24.4 mL) and methanol (40 mL) was added p-toluenesulfonic acid hydrate (150 mg, 0.78 mmol) at room temperature. Then, the resulting solution was heated to 70° C. and stirred for 2 days. Then, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude residue which was purified by using an ISCO 40 g column chromatography, eluting with 5-30% ethyl acetate in hexanes to isolate 3-bromo-5-(propane-2-sulfonyl)-phenol (354 mg, 49%) as a viscous oil: ES(+)-HRMS m/e calcd for C9H11BrO3S (M+Na)+ 300.9504, found 300.9505.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][CH:16]3[C:21]#N)=[CH:9][CH:8]=1.[OH2:25]>>[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][CH:16]3[C:21]([OH:2])=[O:25])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1CCc2c(Cc3ccc(Cl)cc3)cccc21
Reactant: O
Product: O=C(O)C1CCc2c(Cc3ccc(Cl)cc3)cccc21

Procedure:
To 60 ml. of 60% sulfuric acid is added 3.0 g. of 4-(p-chlorobenzyl)indan-1-carbonitrile and the mixture is refluxed in a current of nitrogen gas for 2 hours. After cooling, water is added and the mixture is extracted with ether. The ethereal solution is washed with water and extracted with a 5% aqueous solution of potassium carbonate. The extract is rendered acidic with hydrochloric acid and the resultant precipitate is extracted with chloroform. The chloroform layer is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is crystallized from cyclohexane. The described procedure gives 4-(p-chlorobenzyl)indan-1-carboxylic acid as crystals melting at 127°-129° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CO)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Solvent: C1CCOC1
Product: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 41.2 %

Procedure:
To a suspension of Example 105 (14.7 mg, 0.033 mmol) in THF (3 mL) was added 3,3,3-triacetoxy-3-iodophthalide (42.2 mg, 0.10 mmol). The mixture was stirred at rt under nitrogen for 4 d. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF and purified by HPLC using a gradient of 20-90% MeCN in water to yield 6.0 mg (41%) of the title compound. 1H-NMR (DMSO-d6) 10.34 (s, 1 H), 9.90 (bs, 1 H), 9.75 (bs, 1 H), 8.15 (s, 1 H), 8.06-7.99 (m, 2 H), 7.59 (d, J=8.6, 2 H), 7.51 (dd, J=7.0, 1.1, Hz, 1 H), 7.46 (d, J=8.5 Hz, 2 H), 7.25 (s, 1 H); MS [M+H]+=442.1; LCMS RT=3.29 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:3]=1.[K+].[C:16]([C:18]1[N:19]=[C:20]([C:31]([O-])=[O:32])[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=1)#[N:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:31]([C:20]2[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]([C:16]#[N:17])[N:19]=2)=[O:32])=[C:4]([C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 4-bromo-2-cyclohex-1-enyl-phenylamine (as prepared in the previous step, 1.23 g, 4.88 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d), 1.49 g, 4.88 mmol) and PyBroP (2.27 g, 4.88 mmol) in 25 mL of DMF was added N,N-diisopropylethylamine (DIEA) (2.55 mL, 14.6 mmol). After stirring at RT for 16 h, the mixture was treated with 100 mL of EtOAc and washed with H2O (2×30 mL), brine (30 mL) and dried (Na2SO4). The organic solvent was evaporated and the residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to give 2.21 g (90%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.70 (s, 1H), 8.26 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.36 (dd, 1H, J=8.6, 2.3 Hz), 7.31 (d, 1H, J=2.3 Hz), 5.94 (s, 2H), 5.86 (m, 1H), 3.66 (t, 2H, J=8.3 Hz), 2.19-2.33 (m, 4H), 1.75-1.88 (m, 4H), 0.97 (t, 2H, J=8.3 Hz), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[C:13](OCC)(=O)[CH3:14]>>[CH3:13][CH:14]1[CH:5]([C:4]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:7])[CH2:8][C:1](=[O:3])[CH2:2]1
Reactant: CCOC(C)=O
Reactant: CCO
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C1C(=O)CC(=O)CC1C

Procedure:
The same procedure used above is modified using an equivalent amount of anhydrous ethanol as the solvent and ethyl acetoacetate; yield 93.4 g (47%); mp 89-91° C. (from ethyl acetate: petroleum ether, bp 54° C.).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O>C1(C)C=CC=CC=1>[CH2:1]([NH:7][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNCc1ccco1
Yield: 64.3 %

Procedure:
Furfurylamine (15.0 g) and 17.2 g of triethylamine were dissolved in 75 mL of toluene, 20.8 g of ethyl chloroacetate was added thereto and the mixture was heated to reflux for 3 hours. After the reaction solution was cooled, 100 mL of water was added thereto and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 18.2 g of an objective compound as yellow liquid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1[C:17]2[N:16]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:15]3[CH2:14][CH2:13][NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH:1]1([C:4]([N:12]2[CH2:13][CH2:14][CH:15]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][N:16]3[C:17]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]2=3)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3NCCC2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of cyclopropylcarbonyl chloride (0.072 mL, 0.79 mmol) CH2Cl2 (1 mL) was added to an ice-cooled solution of the product of Example 72A (218 mg, 0.716 mmol) in CH2Cl2 (5 mL). The reaction was stirred with ice cooling under nitrogen for 45 minutes and then it was allowed to warm to room temperature for 4 hours. The reaction was quenched by addition of methanol (2 mL) and the solution was stirred for 10 minutes. The reaction mixture was then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous (NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: MS (DCI) m/z 373 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([OH:26])=O)=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=2[CH:76]=1>CN(C=O)C.CC(=O)OCC>[OH:75][B:70]1[C:69]2[CH:76]=[C:65]([CH2:64][NH:63][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:26])[CH:66]=[CH:67][C:68]=2[C:72]([CH3:74])([CH3:73])[O:71]1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(Cl)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
To a solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)indolizine-8-carboxylic acid (24 mg, 0.05 mmol), HATU (29 mg, 0.075 mmol) and Et3N (0.03 mL, 0.15 mmol) in DMF (10 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (23 mg, 0.1 mmol). The mixture was stirred at rt overnight. EA (30 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxamide (8 mg; yield 25%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (t, J=6.0 Hz, 1H), 9.05 (s, 1H), 8.54 (s, 1H), 7.90 (s, 2H), 7.67 (s, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.29 (s, 2H), 7.06-7.12 (m, 2H), 4.54-4.68 (m, 4H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=649.7 (M+1, ESI+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.BrC1C=CC2[N:26]=[C:27]([C@H:29]3C[C@H:31]([N:33]4CCC[C@H]4C)[CH2:30]3)SC=2C=1.[OH-:41].[NH4+].CO>ClCCl>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:33]5[C:31](=[O:41])[CH:30]=[CH:29][CH:27]=[N:26]5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1
Reactant: [OH-]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: O=c1cccnn1-c1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 44A for the product of Example 1E. In this preparation, two isomeric products were obtained which represented the cis- and trans-configurations of the cyclobutane ring. The product that had a RF of 0.28 on TLC (TLC conditions 0.5% ammonium hydroxide and 5% methanol in dichloromethane on silica gel) was separated and purified by column chromatography on silica gel, eluting with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give an off-white solid, which corresponded to the trans isomer: mp 139-140° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (d, J=2.14 Hz, 1H) 8.05 (d, J=8.85 Hz, 1H) 7.93 (dd, J=3.81, 1.68 Hz, 1H) 7.70 (dd, J=8.85, 2.14 Hz, 1H) 7.24-7.31 (m, 1H) 7.09 (dd, J=9.46, 1.83 Hz, 1H) 3.80-3.92 (m, 1H) 3.10-3.19 (m, 1H) 2.53-2.70 (m, 4H) 2.21-2.47 (m, 4H) 1.58-1.72 (m, 4H) 1.42-1.55 (m, 2H). MS: (M+H)+=367.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH2:21])[CH3:2].N1C=CC=CC=1.[Cl:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([CH2:30][Cl:29])[CH:32]=1)[CH3:2]
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
2-Amino-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (compound A) (2.5 g) produced by the above process was dissolved in anhydrous methylene chloride (40 ml). Pyridine (1.4 ml) and 3-(chloromethyl)-benzoyl chloride (compound B) (1.3 ml) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 2-(3-chloromethylbenzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (2.3 g, yield 62%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.4 g (4.692 mmol) cyclopentylamine is stirred for 6 h at 115° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile/water and drying under HV (8 h, 100° C.); m.p. 163-165° C.; ESI-MS: (M+H)+=305.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(C)CCN(C)C.[Li]C(CC)C.[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28]Br>C1COCC1>[Br:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH2:28][CH2:11][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: Cc1c(F)cccc1C(=O)O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CCc2c(F)cccc2C(=O)O)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A solution of 3-fluoro-2-methylbenzoic acid (5.00 g, 32 mmol, 1 equiv) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) (9.7 mL, 64 mmol, 2 equiv) in THF (100 mL) was cooled to −78° C. under an atmosphere of argon. s-BuLi (1.3 M in hexanes, 52 mL, 26 mmol, 2.1 equiv) was added dropwise and the solution was allowed to stir for 1 hr. A solution of 2-bromo-5-methoxybenzylbromide (22 g, 80 mmol, 2.5 equiv) in THF (10 mL) was added dropwise. The solution was allowed stir for 1 hr at −78° C. hr and then quenched by the addition of H2O and 1N HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. After column chromatography (SiO2) followed by trituration from MeOH/DCM, 2-[2-(2-bromo-5-methoxy-phenyl)-ethyl]-3-fluoro-benzoic acid (3.3 g, 9.4 mmol, 80%) was obtained as a white powder. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=7.8 Hz, 1H), 7.12-7.33 (m, 4H), 6.78 (d, J=9.0 Hz, 1H), 3.76 (s, 3H), 3.24 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H). LCMS: ES− 351 (M−1), 353 (M+1), 355 (M+3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=[O:8].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH2:16].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:16][CH2:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:8]
Reactant: C=Cc1ccccn1
Reactant: O=C(O)C(c1cccs1)c1cccs1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: O=C(OCCc1ccccn1)C(c1cccs1)c1cccs1

Procedure:
The crude product of newly synthesized dithiophenyl acetic acid (10 g, 59 mmol theoretically), freshly distilled 2-vinylpyridine (6.25 g, 59 mmol), and 1 mol % toluene sulfonic acid were dissolved in benzene and placed in a round bottom flask equipped with a vigreaux column and magnetic stirbar. The reaction was then heated to reflux and allowed to react for 16 hours. The viscous liquid that remained after the solvent was removed was then purified by column chromatography (silica 2/1 v/v hexane/ethyl acetate). Yield=3.9 g. 1H NMR (CDCl3) δ=3.042 (t, 2 H), δ=3.573 (t, 2 H), δ=4.233 (s, 2H) δ=6.968–7.476 (m, 8H), δ=8.467, (d, 1H). 13C NMR (CDCl3) δ=35.627 (CH2), δ=36.180 (CH2), δ=58.323 (CH2), δ=121.93 (CH), δ=123.383 (CH2), δ=127.501 (CH), δ=128.818 (CH), δ=129.346 (CH), δ=137.272 (C), δ=149.668 (CH), δ=159.305 (C), δ=235.369 (C═S).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]1[CH2:45][O:44][C:13]([CH2:32][O:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(/[CH:14]=[CH:15]/[C@H:16]2[C@H:23]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:22][C@H:21]3[C@@H:17]2[CH2:18][C:19](=[O:31])[O:20]3)[O:12]1.C1(C)C=CC=CC=1.C(O)(C)C>O>[CH2:45]1[CH2:11][O:12][C:13]([CH2:32][O:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(/[CH:14]=[CH:15]/[C@@H:16]2[C@@H:17]3[C@@H:21]([O:20][CH:19]([OH:31])[CH2:18]3)[CH2:22][C@H:23]2[O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[O:44]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 0.5 h

Procedure:
Under argon at -70°, 1.5 ml. of a 20% solution of diisobutylaluminum hydride was added to a solution, cooled to -60°, of 150 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 5[b]) in 15 ml. of absolute toluene. After 30 minutes, the mixture was combined with 0.75 ml. of isopropanol and 0.75 ml. of water and agitated for 30 minutes at 0°, diluted with 150 ml. of methylene chloride, filtered off from the precipitated aluminum compound, and evaporated under vacuum, thus obtaining 146 mg. of the title compound as a colorless oil. IR: 3600, 1630, 1600, 970 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([O:27][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (2.72 g, 7.54 mmol) and 0.5 M sodium methoxide in methanol (40 mL) were heated under nitrogen at 60° C. for 2 days, cooled, evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with brine, dried and solvent evaporated to afford crude material, purified by flash chromatography on silica (gradient 25 to 100% EtOAc hexane) to give the desired compound as a solid. The solid was stirred with approx. (10 mL) 2:1 isopropyl acetate:hexane and filtered to give the title compound as white solid. M.S.(M+1): 357.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].O.[OH-].[Li+]>C1COCC1.O>[C:15]([O:14][C:5]1[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:19])=[O:2])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To 5.52 mmol 2-tert-butoxy-5-methanesulfonyl-benzoic acid methyl ester in 25 ml THF was added a solution of 8.34 mmol lithium hydroxide monohydrate in 25 ml water and the reaction mixture was stirred at room temperature for 4 hours. After such time the THF was removed in vacuo and to the remaining aqueous solution was added 8 ml of 1 N aq HCl leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (67%) as a white solid. MS (m/e): 289.9 (M+NH4+).