Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9]COC)=[CH:4][C:3]=1[CH3:13].Br[N:15]1C(=O)CC[C:16]1=O.[C-]#N.[Na+].CN(C)[CH:27]=[O:28]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:28][CH3:27])=[CH:4][C:3]=1[CH2:13][C:16]#[N:15]
Reactant: COCCOc1ccc(Cl)c(C)c1
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cl)c(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-chloro-5-(methoxyethoxy)toluene (5.00 g; 26.8 mmol), N-bromosuccinimide (4.77 g; 26.8 mmol) and 2,2-azobis(isobutyronitrile) (0.09 g; 0.53 mmol) in carbon tetrachloride (25 ml) was refluxed for 2 hours. After air cooling and filtration the precipitate, the filtrate was condensed under reduced pressure. To the residue were added sodium cyanide (2.77 g; 80.4 mol) and anhydrous N,N-dimethylformamide (30 ml). The mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel (hexane:ethyl acetate=6:1→4:1) to give [2-chloro-5-(methoxymethoxy)phenyl]acetonitrile as colorless oil (2.64 g; 47%).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][C:7]([O:10][C:11]([N:13]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[CH:21][O:22][C:18]=2[C:17](I)=[CH:16][N:15]=1)=[O:12])([CH3:9])[CH3:8].[Cl:47]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH3:6][C:7]([O:10][C:11]([N:13]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[CH:21][O:22][C:18]=2[C:17]([Cl:47])=[CH:16][N:15]=1)=[O:12])([CH3:9])[CH3:8]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(I)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c34)ccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(Cl)cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c34)ccc21
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
tBuLi (1.7 M in pentane) (0.59 mL, 1.003 mmol) was added dropwise to a solution of 1,1-dimethylethyl 5-[4-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-iodofuro[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (307 mg, 0.453 mmol) in THF (7 mL) at −78° C. under Nitrogen. The mixture was stirred at that temperature for 15 minutes, then a solution of hexachloroethane (217 mg, 0.917 mmol) in THF (3 mL) was added dropwise. The reaction was stirred and allowed to slowly warm from −78° C. to room temperature for 16 hours. The mixture was then quenched with saturated NH4Cl (25 mL), and extracted with ethyl acetate (2×20 mL). The extracts were washed with brine (1×20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2 [RediSep Gold column], 0%-25% EtOAc in hexanes gradient over 45 minutes). The second peak (1st big one) was collected to give 1,1-dimethylethyl 5-[4-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-7-chlorofuro[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (81 mg, 0.138 mmol, 30.5% yield) as a colorless oil. LC/MS (ES) m/z=586, 588 [M+H]+. The third peak to elute was also collected and found to be 1,1-dimethylethyl 5-[7-chloro-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)furo[3,2-c]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate (33 mg, 0.068 mmol, 14.99% yield), also as a colorless oil. LC/MS (ES) m/z=486, 488 [M+H]+.
Reaction SMILES: C([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C:5]1([CH3:19])[CH3:18])(=O)C.[N-]=[N+]=[N-].[Na+].CS(O)(=O)=O.[NH3:29].[CH2:30]([CH2:33]OC)[O:31]C>>[C:30]([NH:29][C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[C:5]1([CH3:18])[CH3:19])(=[O:31])[CH3:33]
Reactant: COCCOC
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Reactant: N
Agent: CS(=O)(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(=O)N[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
A stirred solution of (1S,3R)-benzyl 3-acetyl-2,2-dimethylcyclobutanecarboxylate (1.5 g, 5.76 mmol) in monoglyme (18.75 ml) at −45° C., NaN3 (1.12 g, 17.30 mmol), MeSO3H (10.5 ml), were added drop wise slowly and the reaction was allowed to stir at room temperature for about 48 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with aqueous ammonia solution. Solvent was evaporated and diluted with DCM. Organic layer was washed with water, brine dried over Na2SO4. The solvent was evaporated under reduced pressure and the resulting crude purified by silica gel column (60/120 mesh, elution: 30% EtOAc in Hexane) to afford the title compound as off white solid. Wt: 1.3 g; Yield: 82.2%; 1H NMR (300 MHZ, CD3OD): δ 7.42-7.31 (m, 5H), 5.59 (d, 1H, J=5.7 Hz), 5.12 (s, 2H), 4.13 (q, 1H, J=9.3 Hz), 2.69-2.63 (m, 1H), 2.38-2.34 (m, 1H), 2.13-2.06 (m, 1H), 2.05 (s, 3H), 1.30 (s, 3H), 0.86 (s, 3H). Mass: [M+1]+ 276 (100%), [M+Na]+ 298 (66%); IR (KBr, cm−1): 3270, 2963, 2866, 1728, 1647, 1571, 1455, 1303, 1151, 1071, 1019, 961, 755, 742; M.R: 85.6° C.-97.5° C.
Reaction SMILES: C1COCC1.[C:6]1([C@H:12]2[CH2:16][O:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][C:22](OCC)=[O:23])=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[BH4-].O>C(OCC)C>[C:6]1([C@H:12]2[CH2:16][O:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][CH2:22][OH:23])=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCCOc1cccc(C2=N[C@@H](c3ccccc3)CO2)c1
Reaction time: 4 h
Yield: 39.4 %

Procedure:
To a THF (40 ml) solution of ethyl 3-(4,5-dihydro-4(S)-phenyloxazol-2-yl)phenoxyacetate (2.77 g, 8.5 mmol) was added LiBH4 (0.37 g, 17 mmol) in one portion. After stirring for 4 h, water (40 ml) was added and the mixture diluted with diethyl ether (40 ml). The aqueous layer was separated and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with 0.5 N aqueous HCl (20 ml), brine (20 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (=2:1) to afford title compound (0.95 g, 40%) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:28])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (89 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.099 ml) and phenyl chloroformate (0.089 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 45 min. To the reaction mixture was added morpholine (0.249 ml), followed by stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1). Fractions containing the target compound was concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (80.2 mg, 62.0%) as a colorless solid.
Reaction SMILES: ClC1C=CC=CC=1C[O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])NC1SC(SCC(C)(C)C(O)=O)=CN=1.Br[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[F:45].C([O:48][C:49](=[O:60])[C:50]([S:53][C:54]1[S:58][C:57]([NH2:59])=[N:56][CH:55]=1)([CH3:52])[CH3:51])C>>[F:45][C:39]1[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:38]=1[CH2:37][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:9](=[O:24])[NH:59][C:57]1[S:58][C:54]([S:53][C:50]([CH3:51])([CH3:52])[C:49]([OH:48])=[O:60])=[CH:55][N:56]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccc(F)cc2F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl -2,4-difluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([O:14]CC3C=CC=CC=3)=[C:9]2[OH:22])=[CH:4][CH:3]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([OH:14])=[C:9]2[OH:22])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC1(c2ccc(Cl)cc2)OC(=O)C(O)=C1O
Yield: 45.8 %

Procedure:
Hydrogenolysis of 330 mg of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 110 mg (46% yield) of 5-(4-chlorophenyl)-3,4-dihydroxy-5-methyl-2(5H)-furanone a light tan solid: mp 154-155° C. dec. (benzene/hexanes) 1H NMR (acetone-d6) δ 7.52-7.34 (m, 4H), 1.82 (s, 3H). 13C NMR (acetone-d6) δ 169.0, 156.6, 139.8, 134.3, 129.2, 127.8, 117.9, 80.8, 24.6. Anal Calcd for C11H9ClO4 : C, 54.90; H, 3.77. Found: C, 54.74; H, 4.08.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:22]#[N:23])=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1C(c2ccc(C#N)cc2)COC1(C)C
Yield: 55 %

Procedure:
A stirred solution of (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg, example 1(e)), zinc cyanide (66 mg) and tetrakis(triphenyl-phosphine)palladium (57 mg) in DMF (4 ml) under an argon atmosphere in a sealed tube was heated at 160° C. for 15 minutes under microwave irradiation. The mixture was then poured onto ice-water and the mixture extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-(4-cyano-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (82 mg, 55%) as a colourless viscous oil. MS (ISP): 325.4 ([M+Na]+), 303.4 ([M+H]+), 247.3 ([M+H—C4H8]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15][C:14]3=[O:23])[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.[CH3:25][N:26](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[O:23]=[C:14]1[N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]#[N:26])=[CH:3][CH:4]=3)[N:9]=2)[CH:17]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:16][O:15]1
Reactant: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2csc(N3C(=O)OCC3CC(F)(F)F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-2-one (0.53 g, 1.3 mmol), prepared in step 3 of Example 67, and zinc cyanide (91 mg, 0.78 mmol) were dissolved in 15 mL of DMF. The mixture was purged with nitrogen for 15 min, tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) was added, and the mixture was heated at 120° C. for 3 h. The mixture was cooled and diluted with ethyl acetate and poured into 200 mL of water. The mixture was extracted with ethyl acetate, the organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (25% hexane in methylene chloride) afforded racemic 4-{2-[2-oxo-4-(2,2,2-trifluoroethyl)-1,3-oxazolidin-3-yl]-1,3-thiazol-4-yl}benzonitrile (364 mg, 79%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][CH:71]=2)=[N:68][N:67]=[N:66]1>C(Cl)Cl>[NH:68]1[C:69]([C:70]2[CH:75]=[CH:74][C:73]([NH:76][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]3)=[O:30])=[CH:72][CH:71]=2)=[N:65][N:66]=[N:67]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 130 mg, 0.344 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-(1H-tetrazol-5-yl)-phenylamine (Alfa, 55 mg, 0.344 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (24 g column, eluent, 30% EtOAc/methylene chloride) to give a yellow solid. 21 mg.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=2[N:32]=1)[C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:39][Mg]Cl>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[C:37]([C:34]1[CH:35]=[CH:36][C:30]2[O:29][C:28]([C:8]([C:9]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]4[C:10]=3[CH:11]=[CH:12][N:13]4[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([NH:7][S:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])[CH3:39])=[N:32][C:31]=2[CH:33]=1)#[N:38]
Reactant: C[Mg]Cl
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1

Procedure:
To a solution of tert-butyl 4-((tert-butylsulfinyl)imino)(5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 130-A) (0.56 g, 1.047 mmol) in THF (10.47 mL), MeMgCl (3M in THF, 1.047 mL, 3.14 mmol) was added at 0° C. After 10 minutes the mixture was diluted with sat. aq. NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc:Heptanes) to provide the title compound. MS (ESI+) m/z 551.2 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)[CH:26]=1)C.CCOC(C)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[CH:36]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]3[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=3)[CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(C)c2)c(OCCO)c(-c2cc(C)cc(C)c2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCO)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a cooled solution (0° C.) of 8-phenyloctyl amine (1.56 g, 7.58 mmol, 1.51 ml) in 10 mL anhydrous THF was added n-BuLi (5.1 mL, 7.96 mmol) as a solution in hexanes dropwise. After the addition, the reaction was warmed up to room temperature and was stirred for one-half hour at room temperature. Then the lithiated amine was cooled back down to 0° C. and was added to a cooled (0° C.) solution of 3,5-bis-(3,5-dimethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (1.04 g, 2.49 mmol) in 10 mL anhydrous THF. The resulting reaction mixture was stirred for 5 min at 0° C. then allowed to warm up to room temperature. At that point, additional n-BuLi was added (2.04 mL, 3.18 mmol). When the reaction appeared to be practically complete (by TLC), it was worked up as in Step 2 of Example 135. After flash chromatography (25% EtOAc:75% Hexanes), there yielded 850 mg, 59.4% of the amide as a yellow oil. 1H NMR (CDCl3) δ1.25-1.40 (m, 8H); 1.40-1.64 (m, 5H); 2.37 (s, 12H); 2.57 (t, J=8.18 Hz, 2H); 3.25 (t, J=4.09 Hz, 2H); 3.36-3.47 (m, 4H); 6.06 (t, J=6.54 Hz, 1H); 7.02 (s, 2H); 7.11-7.19 (m, 4H); 7.20-7.48 (m, 5H); 7.69 (s, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH2:26])[CH:15]=3)=[CH:13][C:6]=12.C(N(CC)CC)C>ClCCl>[N:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][CH2:24][CH2:25][NH:26][C:1](=[O:3])[CH3:2])[CH:15]=3)=[CH:13][C:6]=12
Reactant: CC(=O)Cl
Reactant: NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetyl chloride (31 μl) was added dropwise to a solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylamine [100 mg, Example 3(a)] and triethylamine (52.2 μl) and dichloromethane (20 mL) at ambient temperature under a nitrogen atmosphere. After stirring for 24 hours at ambient temperature the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give the title compound (82 mg) as a yellow solid, m.p. 260° C. MS: 334 (MH+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[CH:9][CH:8]=1.O>CN(C)C=O>[C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:18]3[NH:19][N:3]=[N:2][N:1]=3)[CH:20]=[CH:21][CH:22]=2)=[CH:9][CH:8]=1
Reactant: N#Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(COc3cccc(-c4nnn[nH]4)c3)cc2)cc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride (1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)benzonitrile (8.0 g, 28.04 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. To the cooled reaction mixture water (100 mL) was added and the reaction mixture stirred for 0.75 hour. The precipitate was filtered off and washed with water, 96% ethanol (2×50 mL), and dried in vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.C(OCC)(=O)C.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>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C=C(c2ccc(N)nc2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 72.4 %

Procedure:
A mixture of (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (1.55 g, 4.13 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.00 g, 4.54 mmol), Pd(PPh3)4 (0.239 g, 0.21 mmol) and Cs2CO3 (3.36 g, 10.32 mmol) in THF (10 mL) and water (2 mL) was microwave heated to 100° C. for 10 min. The reaction was then diluted with ethyl acetate (50 mL) and water (25 mL). The layers were separated and the organics were washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated, then purified by flash chromatography [0-8% methanol/DCM eluent] to provide (S)-1-tert-butyl 2-methyl 4-(6-aminopyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (0.955 g, 72% yield). LCMS (m/z): 320.4 (MH+), 0.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: COC(=O)C=Cc1ccc(Cl)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
A mixture of 290 g of p-chlorocinnamic acid, methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with ethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-chlorophenyl)butanoic acid methyl ester.