Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Sn](C)(C)C)=[CH:6]1)(=[O:4])=[O:3].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C)C=O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc([Sn](C)(C)C)c2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(-c3cn(S(C)(=O)=O)c4ccccc34)c2cc1OC
Temperature: 90 °C

Procedure:
A solution of 1.33 g (4.01 mmol) of N-methylsulfonyl-3-trimethylstannylindole, 750 mg (3.34 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.19 g (5 mol % 0.16 mmol) of Pd (PPh3)4 in 10 ml of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is diluted with methylene chloride washed with 10% ammonium hydroxide and stirred vigorously and then washed with water and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to dryness. Recrystallization from ethyl acetate yields 4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline (m.p.>220° C.).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17]COC)=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].Cl>CCO>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[OH:17])=[C:8](/[CH:21]=[C:22](\[CH2:28][C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]3[CH2:33][CH2:34][O:35][C:31]=3[CH:30]=2)/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1OCOC
Agent: Cl
Solvent: CCO
Product: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1O
Yield: 64 %

Procedure:
To a solution of Ethyl (E)-3-[1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate (4.50 g, 8.10 mmol) in EtOH (60 mL) was added 0.6 mL of conc. HCl. After heating at reflux for 3 h, the mixture was concentrated and then diluted with EtOAc. The resulting mixture was washed with 5% NaHCO3, brine and dried (Na2SO4). After removing the solvent, column chromatography of the residue with 25% EtOAc in hexane gave 2.65 g (64%) of the title compound as a solid: m.p. 158-160° C.; MS (ESI) m/z 511 (M+H)+ ; 1H NMR (400 MHz, CDCl3) d 7.58 (s, 1H), 7.47 (s, 1H), 7.02 (d, 1H), 6.78 (s, 1H), 6.62 (dd, 1H), 6.59 (d, 1H), 6.48 (s, 2H), 5.50 (bs, 1H), 4.48 (t, 2H), 4.12 (m, 2H), 3.85-3.95 (m, 4H), 3.83 (s, 3H), 3.81 (s, 3H), 3.16 (t, 2H), 1.67 (m, 2H), 1.20 (t, 3H), 1.17 (m, 2H), 0.80 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[NH:39]1[CH2:44][CH2:43][CH2:42][CH:41]([C:45](O)=[O:46])[CH2:40]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:45]([CH:41]3[CH2:42][CH2:43][CH2:44][NH:39][CH2:40]3)=[O:46])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: O=C(O)C1CCCNC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 85 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and piperidine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (85% yield). LCMS: 532.35 (M+1)+; HPLC: 99.84% (@ 254 nm) (Rt;5.059); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 8.83 (t, 1H), 8.44 (bs, 2H), 8.30 (s, 1H), 7.86 (s, 1H), 6.92 (bs, 1H), 5.89 (s, 1H), 5.21-5.18 (m, 1H), 4.38 (d, 2H, J=4.4 Hz), 4.31 (bs, 1H), 4.23 (bs, 1H), 3.74 (m, 2H), 3.14 (m, 4H), 2.97 (m, 1H), 2.82 (m, 1H), 2.70 (m, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 1.89 (m, 1H), 1.74 (m, 2H), 1.60 (m, 1H), 1.51 (d, 6H, J=6.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:23])([CH2:20][CH:21]=[CH2:22])[CH2:9][CH2:10][NH:11][N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25]>C(N(CC)CC)C.C1(C)C=CC=CC=1.C(Cl)(Cl)=O>[CH2:20]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:23][C:24](=[O:25])[N:11]([N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[CH:21]=[CH2:22]
Reactant: O=C(Cl)Cl
Reactant: C=CCC(O)(CCNN(C)c1ccccc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCC1(c2ccc(F)cc2)CCN(N(C)c2ccccc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(4-fluorophenyl)-1-(2-methyl-2-phenylhydrazinyl)hex-5-en-3-ol (14 mg, 0.04 mmol) and triethylamine (3 drops) was dissolved in toluene (1 mL). The solution was cooled to 0° C. and phosgene (3 drops, 20% toluene solution) was added. After 1 h, more phosgene was added (3 drops, 20% toluene solution) and the reaction was allowed to warm to rt overnight. The solvent was evaporated and the residue was redissolved in toluene. DBU (5 drops) was added and the solution heated to reflux for 4 h. The solvent was evaporated and the residue was purified by preparative HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-(methyl(phenyl)amino)-1,3-oxazinan-2-one (8.8 mg). LC-MS Method 1 m/z=341 (M+1). 1H NMR (CDCl3) δ 7.43-7.37 (br m), 7.25-7.26 (m), 7.19-7.12 (m), 6.99 (t), 6.85 (m), 6.72-6.66 (m), 6.07 (d), 6.73 (m), 5.15-5.05 (m), 3.42 (m), 3.33 (m), 3.14 (s), 2.85 (s), 2.65-2.55 (m), 2.50-2.34 (m).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:34][CH2:18]2)[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[N:15]=[CH:14][NH:13]C2=O)(=[O:7])[CH3:6].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:4][C:1]1[C:11]2[C:16](=[CH:17][C:18]([O:19][C:20](=[O:22])[CH3:21])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: CC(=O)Oc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 27.5 °C

Procedure:
Into a 3.0 L four necked round bottomed flask, equipped with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and thermometer socket are charged chloroform (1000 ml), 6,7-diacetoxy-4(3H)-quinazolinone (50 g) obtained by the process described in step (ii) above and dimethylformamide (2 ml). Oxalyl chloride (50 g) was slowly added in about 20-30 minutes. The reaction mass was slowly heated to reflux temperature and maintained at reflux temperature for 6 hours. Reaction was found to be over by HPLC. Cooled the reaction mass to 25-30° C. and slowly quenched into saturated sodium bicarbonate solution at less than 10° C. Separated the organic layer and dried over anhydrous sodium sulfate. The dried organic layer thus obtained was directly used in the next step without any purification.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CCCCCC.C(OCC)C>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:14])[C:9]=2[CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1csc2ccc(Cl)cc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1C
Temperature: 0 °C
Yield: 65.4 %

Procedure:
n-Butyllithium in hexane (2.6M, 2.3 ml) was added to a solution of 5-chloro-3-methylbenzo(b)thiophene (1,0 g, 6 mmol) in ethyl ether (20 ml) stirred at 0° C. under argon. The mixture was stirred for 30 minutes and transferred slowly under argon pressure to a stirred solution of ethyl chloroformate (0.63 g, 6 mmol) in ethyl ether (20 ml). The mixture was stirred at 0° C. for 30 minutes and at 25° C. for 1.5 hours. The mixture was treated with water and the organic phase was dried, concentrated and triturated with hexane to give 1.0 g (67%) of ethyl 5-chloro-3-methylbenzo(b)thiophene-2-carboxylate: mp 92.5°-94° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[N:67]1([C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH:71]=[CH:70][CH:69]=[N:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:76]4[CH:77]=[C:72]([N:67]5[CH:71]=[CH:70][CH:69]=[N:68]5)[CH:73]=[CH:74][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccn2)ccn1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(-n4cccn4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-pyrazol-1-yl-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=442.
Reaction SMILES: [N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].OO.O[Li].O.[O-:40]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[N:1]([C@@H:4]([CH:20]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:5]([OH:6])=[O:40])=[N+:2]=[N-:3]
Reactant: O=S([O-])[O-]
Reactant: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 3-[2-(S)-azido-3,3-bis-(4-chloro-phenyl)-propionyl]-4-(S)-benzyl-oxazolidin-2-one (1.53 g, 3.1 mmol) in 3:1 THF/water (60 mL) at 0° C. was added 30% aq. H2O2 (1.4 mL, 12.3 mmol) and LiOH.H2O (259 mg, 6.2 mmol). The mixture was stirred for 1 h at 0° C. Na2SO3 (2.52 g, 20 mmol) was added, and the mixture was stirred for 30 min at 0° C., then warmed to rt, and stirred for 1 h. The mixture was concentrated without external heating, and the residue was diluted with water and extracted with DCM (3×). The aqueous layer was acidified with conc. HCl and extracted with EtOAc (4×). The combined EtOAc extracts were dried (Na2SO4) and concentrated to provide the desired azidoacid as a colorless solid (0.98 g, 94%). 1H NMR (500 MHz, CDCl3): 7.33-7.24 (m, 6H), 7.21-7.18 (m, 2H), 4.52 (d, J=8.3, 1H), 4.49 (d, J=8.3, 1H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:31]1[N:32]=[N:33][NH:34][N:35]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:22]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:24]([CH3:26])=[CH:25][C:9]1=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:52][CH2:53][OH:54]>CN(C=O)C>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=2)[C:31]2[N:32]=[N:33][N:34]([CH2:52][CH2:53][OH:54])[N:35]=2)[C:9]2[CH:25]=[C:24]([CH3:26])[C:23]([C:27]([F:28])([F:29])[F:30])=[CH:22][C:10]1=2)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: OCCBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
Dissolve (S)-tert-Butyl 5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 16) (0.252 g, 0.395 mmole) in DMF (4 mL), add potassium carbonate (0.0929 g, 0.672 mmole) in one portion. Inject 2-bromoethanol (0.0420 mL, 0.593 mmole) dropwise. Stir at room temperature overnight. Partition the reaction mixture between ethyl acetate (50 mL) and water (50 mL). Extract aqueous back with more ethyl acetate (20 mL). Combine organic layers, Dry over sodium sulfate, filter and concentrate the solution. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as a colorless oil (0.0700 g, 26%). MS (ES+): 705 (M+Na).
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)[CH3:3].Cl.[CH2:14]([O:16][NH2:17])[CH3:15]>CO>[ClH:1].[CH2:14]([O:16][N:17]=[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:3])[CH3:15]
Reactant: CCON
Reactant: CC(=O)C1CN2CCC1CC2
Agent: Cl
Solvent: CO
Product: CCON=C(C)C1CN2CCC1CC2

Procedure:
1.9 g of 3-acetyl quinuclidine hydrochloride and 0.98 g of O-ethylhydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol, followed by concentrating to dryness and purifying by chromatography on alumina (eluant: methylene chloride-methanol 9-1). The reaction medium is acidified using gaseous hydrochloric acid, then evaporated to dryness. After crystallizing from ethanol, filtering, and rinsing with ether, 1.3 g of expected product is recovered. M.p.=198°-200° C.
Reaction SMILES: C1(NC(C)C)CCCCC1.[Li]CCCC.[C:16]([O:20][C:21](=[O:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[C:16]([O:20][C:21](=[O:23])[CH2:22][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][CH:27]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of cyclohexyl-isopropyl-amine (1.0 eq.) in THF (2.0M) at −78° C. was added dropwise n-BuLi (0.95eq.). The mixture was stirred at −78° C. for 20 min then a solution of acetic acid tert-butyl ester (1.0 eq.) in THF (5.0M) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h. A solution of 4-bromobenzyl bromide (0.9eq.) in THF (5.0M) was then added dropwise and the final mixture was warm slowly to rt and stirred for 12 h. The reaction was quenched with cold aqueous HCl (1M), diluted water and extracted with Et2O (2×). The combined organic extracts were washed with HCl (1M), brine, dried over Na2SO4, filtered and concentrated. The residue was distilled under vacuum (95° C., 0.4 mmHg) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@H:11]1[F:38].[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@H:11]1[F:38]
Reactant: [H][H]
Reactant: CCCCCC(C)(/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](F)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CCOC(C)=O
Product: CCCCCC(C)(/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@H](F)C[C@H]1OC1CCCCO1)OC1CCCCO1

Procedure:
A solution of 400 mg of (5Z,13E)-(9R, 11R,15RS)-11,15-bis(tetrahydropyran-2 -yloxy)-9-fluoro-15-methyl-5,13-prostadienoic acid methyl ester in 50 ml of ethyl acetate is shaken with 40 mg of pa 11adium/10% strength on carbon under a hydrogen atmosphere at 0° C. After absorption of 1 equivalent of hydrogen, the product is filtered off from the catalyst and evaporated under vacuum. The residue is absorbed on silica gel. With hexane/5-20% diethyl ether, 300 mg of the title compound is eluted as a colorless oil.
Reaction SMILES: OC1C=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([OH:19])=O.[C:20]([O-])([O-])=O.[K+].[K+].C[CH2:27][O:28][C:29]([CH3:31])=[O:30]>CC(C)=O>[CH3:27][O:28][C:29]([C:31]1[CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:4]=[CH:3][C:17]=1[O:19][CH3:20])=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1OC

Procedure:
To a solution of 4-Hydroxy-4′-nitro-biphenyl-3-carboxylic acid (2.0 g, 7.71 mmol) in acetone was added K2CO3(2.34 g, 16.9 mmol) and Mel (4.3 g, 30.8 mmol) and refluxed for 12 h. Reaction mixture was diluted with EtOAc and filtered, filtrate was washed with water brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography gave pure 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid methyl ester (1.9 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)[CH3:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.C([O-])([O-])=O.[Na+].[Na+].[O:46]1[C:50](B(O)O)=[CH:49][C:48]2[CH:54]=[CH:55][CH:56]=[CH:57][C:47]1=2>COCCOC.O>[C:1]([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:16](=[O:25])[N:17]([C:47]2[O:46][C:50]3=[CH:49][CH:48]=[CH:54][C:55]3=[CH:56][CH:57]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH3:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)Nc1ccc(I)cc1)c1ccc(C(C)(C)C)cc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-methyl-amino}-benzoic acid tert-butyl ester (120 mg, 0.19 mmol) was taken up in 8 mL of DME, 4 mL of ethanol and 2 mL of water. Na2CO3 (81 mg, 2.4 mmol), PdCl2(O-tolyl)2, (15 mg, 0.0019 mmol) and benzo[B]furan-2-boronic acid (62 mg, 0.38 mmol) were then added, flushed with nitrogen and heated to reflux for 1 h. Cooled to RT, EtOAc (20 mL) was added, and filtered through a plug of celite. The solvents were removed under reduced pressure to give a yellow viscous solid. Water was added to the solid to give a yellow precipitate, which was filtered and triturated with methanol to give 140 mg of a white solid. LCMS (M+1=589.6)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH3:21])[CH2:10][C@H:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:39]=[CH:38][C:29]([O:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:22](=[O:23])[NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:38]=[CH:39][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:37][CH:36]=3)[CH2:10]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A mixture of (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluoro-2-methylbenzyl)pyrrolidine-2-carboxylic acid (540 mg, 1.54 mmol), prepared as in Reference 4, 4-(4-fluorophenoxy)aniline (313 mg, 1.54 mmol), DIEA (0.4 mL) and HATU (586 mg, 1.54 mmol) in DMF (3 mL) was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (20 mL) and then brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified from the residue by flash column (eluted with a 3:1 hexanes/ethyl acetate mixture) to give (2S,4R)-tert-butyl 4-(4-fluoro-2-methylbenzyl)-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate (826 mg, 1.59 mmol, 103%) as a reddish oil.