Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Cl[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Ni](Cl)Cl.[Zn].C1(C)C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)#[N:19]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Into a 1 l four necked flask, 500 ml of dry pyridine, 44.3 g (0.259 mol) of 4-bromotoluene, 35.6 g (0.259 mol) of 2-chlorobenzonitrile, 3.24 g (0.025 mol) of anhydrous nickel chloride, 13.1 g (0.05 mol) of triphenylphosphine and 67.6 g (1.034 mol) of zinc powder were charged under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The temperature was raised to 80° C., and the mixture was reacted for 6 hours. Then, 400 ml of toluene was added thereto, and the solid was filtered off while it was still hot. The toluene layer was analyzed by gas chromatography. The results are shown in Table 1. Then, pyridine and toluene were recovered under reduced pressure. Then, 500 ml of toluene was added to the residue, and the solid was filtered off while it was still hot and washed with 100 ml of toluene. The warm toluene layer was washed with 300 ml of 5% hydrochloric acid, then with 300 ml of a 5% sodium hydrogencarbonate aqueous solution and further twice with 300 ml of warm water. The toluene layer was concentrated to obtain 54 g of a crude product. This product was distilled to obtain 28.4 g (yield: 57%, purity: 97.4%) of white crystals of 2-cyano-4'-methyl-1,1'-biphenyl.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[C:6]([N:14]=[CH:15]OCC)[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:10]([F:11])([F:12])[F:13])=[O:9])=[C:6]([NH:14][CH3:15])[N:5]([C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:23][C:24]=2[Cl:25])[N:4]=1)#[N:2]
Reactant: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 10 °C
Reaction time: 6.75 h
Yield: 23.3 %

Procedure:
A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 moles) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (350 g) as an off-white solid. (m.p. about 227° C.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([OH:36])[C@H:19]([CH3:37])[O:18][C:17]1=[O:38])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:16]1[C:17](=[O:38])[O:18][C@@H:19]([CH3:37])[C@H:20]([O:36][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[C@@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:22][O:23][CH2:24]1)=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1O
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@@H]1[C@@H](Cc2cccc3ccccc23)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-hydroxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (290 mg, 0.548 mmol) and DMAP (201 mg, 1.64 mmol) in CH2Cl2 (2.7 mL) was added isobutyryl chloride (86 μL, 0.821 mmol) slowly to the flask and the resulting solution was stirred at room temperature for 20 h. The reaction mixture was dissolved in CH2Cl2 (4 mL), treated with Celite®, the solvent evaporated, and the adsorbed crude material purified by flash chromatography (SiO2, 0→15% EtOAc/hexanes) to provide [(3S,6S,7R,8S)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-8-(1-naphthylmethyl)-4-oxo-1,5-dioxonan-7-yl]2-methylpropanoate (270 mg, 82%) as a white powder: mp 130-132° C.; 1H NMR (400 MHz, CDCl3) δ 8.01-7.93 (m, 1H), 7.84 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.54-7.41 (m, 2H), 7.37 (dd, J=8.2, 7.0 Hz, 1H), 7.28 (dd, J=7.0, 1.3 Hz, 1H), 5.20 (dd, J=8.7, 5.7 Hz, 1H), 5.11 (app t, J=9.3 Hz, 1H), 5.08-4.97 (m, 1H), 4.06 (dd, J=11.8, 5.7 Hz, 1H), 3.86 (dd, J=11.9, 8.7 Hz, 1H), 3.66 (d, J=11.0 Hz, 1H), 3.50 (dd, J=10.8, 6.4 Hz, 1H), 3.23 (dd, J=14.0, 3.1 Hz, 1H), 2.74-2.55 (m, 2H), 2.37-2.20 (m, 1H), 1.42 (s, 18H), 1.37 (d, J=6.2 Hz, 3H), 1.26 (app dd, J=7.0, 4.4 Hz, 6H); ESIMS m/z 622 ([M+Na]+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C@H:25]([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.CI.[NH4+].[Cl-]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]([CH3:1])([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: C[C@@H](Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(OC(C)(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of diisopropylamine (55.0 ml, 0.39 mmol) in THF (3 ml) at 0° C. was added nBuLi (2.5M, hex., 135 ml) slowly. After 20 minutes the mixture was cooled to −78° C. and (−)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (107 mg, 0.28 mmol) in THF (2 ml) was added. The resulting mixture was stirred for 45 minutes before CH3I (22 ml, 0.34 mmol) was added and the reaction mixture was stirred for 1 h at r.t. Sat. NH4Cl solution was added and the mixture was extracted with EA. The organic phase was washed with H2O and brine, dried and evaporated. Purification of the residue by silica gel chromatography using CHCl3:MeOH 50:1 followed by prep. HPLC gave the title compound (22 mg, 20%). 1H-NMR: 2.11 (s, 6 H) 3.63 (s, 3 H) 7.45 (d, 1 H) 7.52-7.57 (m, 1 H) 7.59 (d, 2 H) 7.98 (d, 1 H) 8.09 (s, 1 H) 8.72 (d, 2 H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[C:15]([CH:28]=2)[O:16][CH2:17][CH:18]([O:24]C(=O)C)[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH4+].[OH-]>CO>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:29]([F:35])([F:34])[C:30]([F:32])([F:33])[F:31])=[C:15]([O:16][CH2:17][C@@H:18]([OH:24])[N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:28]=1)=[O:9]
Reactant: CC(=O)OC(COc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F)N1CCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H](O)N2CCCC2)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid 2-(5-[(2-chloro-pyridine-3-carbonyl)-amino]-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-yl-ethyl ester (408 mg) was dissolved in MeOH (15 mL) and NH4OH (6 mL) was added and the mixture was stirred at RT for 6 h. The reaction was concentrated in vacuo and dried under high vacuum. The residue was purified over silica gel column (8:92:0.6 MeOH:CH2Cl2:NH4OH). The purified fractions were concentrated in vacuo and dried again to provide (R)-2-chloro-N-[3-(2-hydroxy-2-pyrrolidin-1-yl-ethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:38][C:39]1[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])=[CH:51][C:50]2[O:49][C:48]3[C:43](=[CH:44][C:45]([F:67])=[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH:47]=3)[C:42](=[O:68])[C:41]=2[CH:40]=1>C1COCC1.CC1CCCO1.C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:42]2([OH:68])[C:43]3[CH:44]=[C:45]([F:67])[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])=[CH:47][C:48]=3[O:49][C:50]3[C:41]2=[CH:40][C:39]([F:38])=[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])[CH:51]=3)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Reactant: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
The bromide 13 (807 mg, 1.59 mmol) was dissolved in 20 mL THF/2-methyltetrahydrofuran (1:1) and cooled to −105° C. in a liquid N2/diethyl ether bath. After stirring at −105° C. for 10 min, 4.5 mL of tert-butyllithium (1.1 M in pentanes) was added dropwise. Stirring was continued for another 15 min. 2,7-difluoro-3,6-bis-(2-methoxy-ethoxymethoxy)-xanthen-9-one 9 (912 mg, 2.07 mmol) dissolved in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at −105° C. for 30 min, the cooling bath removed, and the reaction solution was then stirred for an additional 15 min. The resulting mixture was added to 150 mL NH4Cl(sat) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 50% EtOAc in hexane (with 0.1% Et3N) to yield 956 mg (69%) of 14 as a orange-red oil. Rf=0.33 (in 50% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 5H), 6.97 (d, 2H, J=6.98 Hz), 6.86 (m, 3H), 6.72 (m, 2H), 5.30 (s, 4H), 5.05 (s, 2H), 4.02 (s, 4H), 3.85 (m, 4H), 3.56 (m, 4H), 3.36 (s, 6H), 1.38 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.8, 149.3, 147.6, 145.6, 145.5, 145.4, 145.2, 140.5, 138.4, 136.9, 128.3, 127.7, 127.5, 119.9, 119.8, 119.3, 118.4, 115.2, 114.9, 113.0, 104.9, 94.5, 81.0, 71.4, 70.6, 69.7, 68.1, 58.9, 54.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −139.0 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (MH+) 868.4, Found 867.8.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:15][CH2:14][CH2:12][OH:13]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CCO
Product: O=[N+]([O-])c1cccc(F)c1NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
2,3-Difluoronitrobenzene (15 g, 94.3 mmol) is dissolved in 200 mL of ethanol. Ethanolamine (11.4 ml, 188.7 mmol, 2 equiv) is added and the mixture stirred at room temperature overnight (reaction complete by TLC). Ethanol is evaporated and the resulting residue is dissolved in ethyl acetate, washed with water (to eliminate excess ethanolamine), dried over magnesium sulphate, filtered and evaporated to dryness, giving the desired product as a deep orange oil (18.3 g, 97%). This crude material was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][C:9]=2[C:19]=1[NH:20][C:21](=[O:37])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:23]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][C:19]2[C:9]3[O:10][CH:11]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[CH2:12][O:13][C:8]=3[CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:37])=[CH:23][CH:24]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCOc1ccc(C(=O)Nc2c(C(=O)OC)ccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCOc1ccc(C(=O)Nc2c(C(=O)O)ccc3c2OC(c2nnn[nH]2)CO3)cc1

Procedure:
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic acid methyl ester (332 mg; synthesized in example 2 (107) was dissolved in methanol (1.5 ml). To the solution, a 1N aqueous solution of sodium hydroxide (1.36 ml), and the mixture was stirred for 50 min at room temperature and for 2 hrs at 40° C. After cooling, 1N hydrochloric acid (2 ml) was added to the solution. The mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to give the title compound (263 mg) having the following physical data:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[N:18]([CH3:43])[C:19]3[C:24]([N:25]=2)=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:22]=[C:21]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH2:41][CH3:42])[N:20]=3)([OH:16])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:33]1[N:32]([C:21]2[N:20]=[C:19]3[C:24]([N:25]=[C:17]([C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)([OH:16])[CH3:15])[N:18]3[CH3:43])=[C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:22]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=1)[CH3:42]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Reaction time: 1 h

Procedure:
To a solution of 4-{1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-hydroxyethyl}piperidine-1-carboxylic acid tert-butyl ester (104 mg, 0.18 mmol) in DCM (1 mL) was added TFA (1 mL) and the resulting mixture stirred for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with DCM affording 1-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol. LCMS (method A): RT 1.88 min, [M+H]+ 491.2
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([F:20])=[CH:17][C:18]=1[I:19])([CH3:6])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[C:3]([O:7][C:8](=[O:21])[N:9]([CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([F:20])=[CH:17][C:18]=1[I:19])[CH3:22])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCOc1cnc(F)cc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1cnc(F)cc1I)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
Add sodium hydride (620 mg, 26 mmol) to a solution of [2-(6-fluoro-4-iodo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (0.33 g, 0.86 mmol) in 3 mL of DMF. Stir the mixture at RT for 1 h and add methyl iodide (0.37 g, 2.59 mmol). Stir the reaction mixture at RT overnight. Add water and extract with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify the residue by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a light yellow solid (0.13 g, 38%). 1H NMR (400 MHz, CD3CN) δ 1.45 (s, 9H), 3.08 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 4.20 (t, J=5.6 Hz, 2H), 5.07 (s, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[CH:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 100.1 %

Procedure:
To a solution of 1H-indol-6-ol (1.5 g, 11.4 mmol) and acetic anhydride (1.2 mL, 12.6 mmol) in DCM (114 mL) was added Et3N (3.18 mL, 22.8 mmol) and the reaction mixture was stirred (rt, 64 h). The reaction mixture was washed with H2O (4×25 mL) and brine (50 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound (2.0 g, 100%). MS (ESI): mass calculated for C10H9NO2, 175.1; m/z found, 176.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.23 (s, 1H), 7.62 (d, J=8.5, 1H), 7.21 (dd, J=3.2, 2.4, 1H), 7.18-7.15 (m, 1H), 6.87 (dd, J=8.5, 2.1, 1H), 6.55 (ddd, J=3.1, 2.0, 0.9, 1H), 2.35 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH2:27])[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:13][C:14]1[S:15][C:16]([C:19]2[CH2:26][S:25][CH:24]3[N:21]([C:22](=[O:28])[CH:23]3[NH:27][C:7](=[O:8])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:20]=2[C:29]([O:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])=[CH:17][N:18]=1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
A solution of (thien-2-yl)-acetyl chloride (0.55 cc) in dry tetrahydrofuran (5 cc) is added, in 5 minutes, to a solution of 3-(2-acetamido-thiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.27 g) in dry tetrahydrofuran (27.5 cc) at 2° C., and after 30 minutes a solution of triethylamine (0.63 cc) in dry tetrahydrofuran (5 cc) is added. After 1 hour's reaction at 2° C., the reaction mixture is filtered and the filtrate is diluted with a mixture of ethyl acetate (200 cc) and half-saturated sodium bicarbonate solution (200 cc). The organic layer is washed with water (100 cc) followed by a saturated sodium chloride solution (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is chromatographed on a column (height: 30 cm; diameter: 5 cm) of silica (0.04-0.06 mm), elution being effected under 0.4 bar (40 kPa) with a 30:70 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 15 to 22, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 3-(2-Acetamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.92 g) is obtained in the form of a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:13]2[O:15][CH2:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCC1CO1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A mixture of 4-nitrophenol (0.6 mole, 82.3 grams), epichlorohydrin (1.8 mole, 167 g.) and piperidene (3 ml.) is stirred at 100° C. for 17 hours. The solution is evaporated and to the residue is added sodium hydroxide (2 mole) in 500 ml. of water. After 24 hours of stirring, the solution is extracted with chloroform. After washing with dilute sodium hydroxide, the dried chloroform solution is evaporated yielding 3-(4-nitrophenyloxy)-1,2-epoxypropane. A solution of the epoxide (1.0 g.) in 50% aqueous acetic acid (15 ml.) is heated at 90° C. for five hours and then evaporated and chromatographed on silica acid plates (chloroform-methanol 9:1). The band with an Rf of about 0.5 is eluted and crystallized from chloroform and ethyl acetate to yield 1,2-dihydroxy-3-(4-nitrophenyloxy)-propane.
Reaction SMILES: O.O.O.[I-].[Li+].C[O:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][C:13]=1[O:14]C>C(OCC)(=O)C.O>[OH:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(CCNC(=O)C(C)(C)C)cc1OC
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Mix 2.2 g. of lithium iodide trihydrate and 0.53 g. of N-[β-(3,4-dimethoxyphenyl)-ethyl]-2,2-dimethylpropionamide, as prepared in Example 5, step A, heat under nitrogen to 180° and hold for 6 hours. Allow the melt to cool to room temperature, then dissolve the solid mixture by shaking with an ethyl acetate-water mixture. Separate the layers and wash the ethyl acetate layer with 2N hydrochloric acid, water, saturated aqueous sodium thiosulfate, saturated sodium bicarbonate and water in the order set forth. Dry the ethyl acetate solution over anhydrous sodium sulfate, filter and evaporate to a residue. Crystallize the residue from a 9:1 mixture of toluene:ethanol to obtain the title product.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5].CCN(CC)CC.C[O:25][C:26](=O)[C:27]1[C:32]([NH:33][C:34]([CH:36]2[CH2:38][CH2:37]2)=[O:35])=[CH:31][CH:30]=[C:29]([Cl:39])[C:28]=1[CH2:40]Br>CN(C=O)C>[Cl:39][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])=[C:27]2[C:28]=1[CH2:40][N:1]([CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][C:4]#[N:5])[C:26]2=[O:25]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC#N)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 75.5 %

Procedure:
To the DMF solution (20 ml) of 3-Amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.55 g, 7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (2.42 g, 7 mmol). The mixture was heated at 90° C. for 12 hrs then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {7-chloro-2-[2-cyano-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (2.4 g, 80%): mp 200-202° C.; 1H NMR (CDCl3)δ 0.90-0.94 (m, 2H, c-CH2), 1.09-1.14 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.64-1.70(m, 1H, c-CH), 3.12-3.32(m, 2H; CH2CN), 3.89(s, 3H), 3.99-4.12 (m, 3H, OCH2CH3+CHHN), 4.37 (d, J=18 Hz, 1H. CHHN), 5.62-5.68 (m, 1H, NCH), 6.87-6.98 (m, 3H, Ar), 7.40 (d, J=9 Hz, 1H, Ar), 8.47 (t, J=9 Hz, 1H, Ar), 10.34 (s, 1H, NH); 3C NMR (CDCl3) δ 8.5, 14.7, 16.2, 21.2, 46.4, 51.8, 56.0, 64.7, 111.7, 112.2, 116.9, 118.4, 119.1, 119.8, 121.9, 127.9, 133.3, 136.9, 138.9, 149.9, 150.0, 169.0, 172.7; Anal Calcd for C24H24ClN3O4: C, 63.50; H, 5.33; N, 9.26. Found: C, 63.43; H, 5.31; N, 9.01