Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([OH:9])=O.[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)=[O:9])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)C1CCCO1
Yield: 33.4 %

Procedure:
Proceeding as in Example 1, but substituting tetrahydrofuran-2-carboxylic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 92, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide (9.8 mg, 33.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.97 (s, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.21-7.15 (m, 7H), 6.93 (m, 2H), 4.55-4.43 (m, 2H), 3.73 (m, 2H), 2.64 (m, 3H), 2.03-1.90 (m, 4H), 1.86-1.76 (m, 4H). MS (EI) for C29H29FN2O4. found 489.5 (MH+).
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>CO>[C:30]1([S:36][C@H:5]2[NH:8][C:7](=[O:9])[C@H:6]2[NH:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N[C@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 5.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol are added under ice-cooling 1.6 ml of thiophenol and 15.5 ml of 1N aqueous solution of sodium hydroxide. The mixture is stirred for 20 minutes at the same temperature and for further 50 minutes at room temperature. The crystals separated out are collected by filtration to give 2.35 g of (3R,4R)-4-phenylthio-3-tritylamino-2-oxoazetidine (A). The filtrate is concentrated, and the residue is dissolved in ethyl acetate, washed with water, and concentrated. The residue is purified on a silica-gel column (ethyl acetate: n-hexane=1:1) to yield 2.65g of (3R,4S)-compound (B).
Reaction SMILES: Cl[CH2:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[OH:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCCCC(O)(CCl)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 94.4 %

Procedure:
A mixture of 40 g (0.14 m) of 1-chloro-2-(2,4-dichlorophenyl)hexan-2-ol and 38.6 g (0.57 m) of imidazole in 10 ml of dimethyl formamide is heated at 160° for one hour. The reaction mixture is cooled, poured into 300 ml of water and extracted with ether. The combined ether extracts are washed with water, then saturated sodium chloride solution and dried over MgSO4. Solvent is evaporated to give 42 g of a gummy brown solid, mp 78°-80°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.40-8.44 (m, 1H), 7.94-8.05 (m, 2H), 7.73-7.81 (m, 2H), 7.68 (dd, J=5.0, 1.5 Hz, 1H), 7.36-7.45 (m, 4H), 3.72 (s, 2H); MS (APCI+) M/Z 425 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[C:18](=O)([O-:20])[O-:19].[K+].[K+].[C]=O.O.[OH-].[Li+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CO>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:7]1[C:8]2[C:4](=[C:3]([CH2:2][C:18]([OH:20])=[O:19])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc2c1cnn2C1CCCCO1
Temperature: 80 °C
Yield: 86.3 %

Procedure:
A mixture of 4-bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (2.43 g, 8.232 mmol), dichlorobis(triphenylphosphine)palladium(II) (314 mg, 0.447 mmol), pulverized potassium carbonate (1.3 g, 9.406 mmol), THF (95 mL) and methanol (12 mL) was stirred at 25° C. in a sealed tube under 40 psi of carbon monoxide for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. To the resulting brown oil was added THF (20 mL), water (12 mL) and lithium hydroxide monohydrate (3.4 g, 81.03 mmol) at 25° C. and heated at 80° C. for 90 min. The reaction mixture was cooled, diluted with water (100 mL) and washed with ether (2×50 mL). The aqueous layer was acidified with aqueous 6N HCl, saturated with sodium chloride and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give [1-(Tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetic acid (1.85 g, 86.3%) as a yellow gum which solidified. MS m/e 261.3 (M+H+).
Reaction SMILES: [Cl:1][Si:2]([Cl:8])([Cl:7])C(C=C)=C.[SiH3]C=CC=C.[Cl:14][CH2:15][C:16]#[C:17][CH2:18][Cl:19].Cl[SiH](Cl)Cl>[Pt]>[Cl:14][CH2:15][C:16]([Si:2]([Cl:8])([Cl:7])[Cl:1])=[CH:17][CH2:18][Cl:19]
Reactant: ClCC#CCCl
Reactant: C=CC(=C)[Si](Cl)(Cl)Cl
Agent: [Pt]
Agent: C=CC=C[SiH3]
Agent: Cl[SiH](Cl)Cl
Product: ClCC=C(CCl)[Si](Cl)(Cl)Cl

Procedure:
For instance, 2-trichlorosilyl-1,3-butadiene [II-d]and 2-triloweralkoxy silyl-1,3-butadiene [II-a]can be synthesized by reacting 1,4-dichloro-2-butyne [IV]and trichlorosilane [V]in the presence of a platinum type catalyst to obtain 1,4-dichloro-2-(trichloro)silyl-2-butene [VI]is then reacted with Zn in a tetrahydrofuran solvent to prepare 2-(trichloro)silyl-1,3-butadiene[II-d], and further reacting the 2-(trichloro)silyl-1,3-butadiene II-d with a lower alcohol in the presence of a base, such as triethylamine, as shown by the following Formula (C): ##STR14##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1ccccc1F
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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccccc2F)cc1
Yield: 69.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(2-fluorobenzyl)benzamide was prepared according to method B with the N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 2-fluorophenylboronic acid (0.025 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.049 g (70%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([OH:15])=O)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[CH3:49]>CN(C=O)C.O>[CH2:48]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:15])[CH3:49]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a stirred solution of 5-phenyl-pyridine-2-carboxylic acid (0.3 g, 0.00151 mol) in DMF (5 mL) was added DIPEA (0.580 g, 0.00452 mol), HOBt (0.243 g, 0.00180 7 mol) and EDCI.HCl (0.346 g, 0.001807 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.252 g, 0.00181 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.32 g (75%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester. To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid ethyl ester (0.32 g, 0.00113 mol) in a mixture of THF (3.2 mL), methanol (2 mL) and H2O (1 mL) was added LiOH.H2O (0.142 g, 0.00338 mol) and the resulting mixture was stirred at ambient temperature overnight. Volatiles were removed by evaporation and the resulting residue was diluted with water and acidified with 10% HCl. The product was extracted with ethyl acetate, which was dried over sodium sulfate and concentrated under reduced pressure to afford 0.24 g (83%) of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:39](=[O:40])[CH2:38][O:37][C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.090 g, 0.23 mmol) and triethylamine (0.066 ml, 0.48 mmol) in dichloromethane (5 ml) was added acetoxy acetyl chloride (0.031 g, 0.25 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.073 g, 70%) as white solid. MS m/e: 461 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CC(O)=O>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:29]([CH2:28][C:27]4[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccc(F)cc1
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(F)cc1)C3=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(O'Reilly, N. J., Derwin, W. S., Fertel, L. B., Lin, H. C., Synlett., (1990) 609-610.) A solution of 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) and 4-fluorobenzylamine (0.15 mL, 1.3 mmol) in glacial HOAc (30 mL) was refluxed at 113° C. After 4 h, the reaction was cooled to r.t., concentrated, then azeotroped with toluene. The residue was diluted with water and basified with sat'd Na2CO3 (or sat'd NaHCO3) to pH>12. The solution was extracted with CH2Cl2 and the organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by using silica gel, eluting with 4:1 CH2Cl2/acetone+0.1 % MeOH, to give 101 as a light yellow oil that was converted to an HCl salt and recrystallized from MeOH/EtOAc to give a white solid (m.p. 251-253° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11](Cl)[CH:10]=2)=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1)CCC.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:30]3[S:31][CH:32]=[C:33]([CH3:35])[N:34]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nc(C)cs3)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of compound 274 (1 g, 1 eq.) and 2-(tributylstannyl)-4-methylthiazole (1.28 g, 1.2 eq.) in DMF (14 mL) were added PdCl2(PPh3)2 (193 mg, 10%) and potassium carbonate (455 mg, 1.2 eq.) and the resulting mixture was stirred at 90° C. overnight. DMF was concentrated under vacuum and water and dichloromethane were added. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on a silica gel to yield compound 275 as a white solid in 65% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.57 (s, 3H), 3.86 (s, 3H), 4.06 (s, 3H), 5.33 (s, 2H), 6.98 (d, J=8.64 Hz, 2H), 7.08 (s, 1H), 7.25 (d, J=9.25 Hz, 1H), 7.46 (d, J=8.64 Hz, 2H), 7.74 (s, 1H), 8.12 (d, J=9.25 Hz, 1H); MS (ESI, EI+): m/z=427.1 (MH+).
Reaction SMILES: CC(CCCCCOC(C1C(C(OCCCCCC(C)C)=O)=CC=CC=1)=O)C.[CH2:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(#N)C.[CH:40]#[N:41].CC#N>CCCCCCC.CCOCC.[Zn]>[C:31]1([CH:30]([CH3:29])[C:40]#[N:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C#N
Reactant: C=Cc1ccccc1
Agent: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Agent: [Zn]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCCCCCC
Product: CC(C#N)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 1.5 g (+) Diop (2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane, Aldrich Chemical Co.), 300 mg NiI2, 300 mg zinc dust, 2 ml commercial stabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr. then 250 μl HCN/CH3CN (11N) was added overnight by syringe pump. After addition of 2 ml styrene, 1 ml CH3CN and ca. 100 mg zinc dust another 400 μl HCN/CH3CN was added during eight hours. After addition of 4 ml styrene and 100 mg zinc addition of HCN/CH3CN at 50 μl/hr was continued overnight. The mixture was then diluted with 50 ml heptane and 25 ml ether. The mixture was filtered and the filtrate was concentrated to an oil which was diluted with an equal volume of toluene. The VPC analysis indicated that the two isomeric products PhCH(CN)CH3 and PhCH2CH2CN had been formed in approximately equal amounts. The PhCH(CN)CH3 was isolated by preparative VPC as described above to give 120 mg [α]D25 +1.1° C5.5% in CD3CN. An e.e. of about 10% is estimated based on the reported [α]D25 value of 10° for the pure isomer. The 1H nmr spectrum was as expected for PhCH(CN)CH3. The major product was apparently styrene polymer which hampered the isolation of the nitrile products.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2.Cl.[CH3:33][O:34][NH2:35]>>[OH:20][CH:16]([C:17]([NH:35][O:34][CH3:33])=[O:18])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2c(n1)CCCC2
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCC2

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 3-[2-(4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid and O-methylhydroxylamine hydrochloride.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C(O)c1ccc(C(=O)c2cccc(Cl)c2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(C(=O)N2CCc3occc3C2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.114 g (0.720 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.175 g (0.67 mmol) of 4-(3-chlorobenzoyl)benzoic acid and 0.4 ml (2.9 mmol) of triethylamine in 30 ml of dichloromethane, 0.18 g (1.1 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The-resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=3/1/1). The resulting purified product was recrystallized from methanol-hexane to yield the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C1OCCOCCOCCOCCOCCOC1.C([N-:32]C=O)=O.[Na+].Cl>C(#N)C.O.C(O)C>[ClH:11].[NH2:32][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C[N-]C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: NCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-4'-chloroacetophenone (10.34 g, 43.40 mmol) and 18-crown-6 (1.16 g, 4.34 mmol) in acetonitrile (150 mL) at room temperature (RT) is added sodium diformylamide (12.51 g, 131.6 mmol). After 3 h at RT and 2 h at 40° C., the suspension is diluted with water (100 mL) and extracted with ethyl acetate (4×150 mL). The combined organics are washed with brine, dried (magnesium sulfate), and concentrated to afford waxy yellow solids. These are taken up in absolute ethanol (150 mL), the stirred solution is treated with concentrated hydrochloric acid (15.00 mL, 174 mmol), and the mixture is heated to reflux for 1.5 h. The suspension is cooled to RT, filtered, and the solids are washed with ethyl acetate. Drying in vacuo at RT afforded the title compound as white solids.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C@H:3]([OH:7])[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:5][C:4](=[O:6])[C@@H:3]([OH:7])[C:2]([CH3:9])([CH3:8])[CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](O)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
(S)-3,3-dimethyl-2-hydroxybutyric acid (2.1 grams, 15.9 mmol) and triethylamine (3.3 mL, 23.8 mmoL) were dissolved in 15 mL DMF. Benzylbromide (2.8 mL, 23.8 mmol) was added and the mixture was stirred overnight. Ethyl acetate was added and the mixture was washed with water (3×) and sat'd NaCl then dried over sodium sulfate and concentrated. Flash chromatography (150 g silica, 7/1Hexane/EtOAc) afforded 3.4 grams (96%) of the title compound. 1H NMR (300 MHz, CDCl3). δ 0.98 (s, 9H), 2.75 (d, 1H), 3.85 (d, 1H), 5.23, (s, 2H), 7.27-7.3 (m, 5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([NH:17][S:18](Cl)(=[O:20])=[O:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].O>C1COCC1>[C:10]([NH:17][S:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:19])=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
TEA (4.2 mL, 30 mmol) was added to a solution of indole (1.17 g, 10 mmol) in dry THF (12.0 mL) at 0° C. and stirred for 10 min. N-Boc sulfamoyl chloride (4.31 g, 20 mmol) was added, the mixture allowed to warm to RT, and stirred overnight. The reaction mixture was poured into water, and the crude product extracted into EtOAc. The organic layer was evaporated to dryness, and dried under vacuum overnight to provide N-Boc 1H-indole-3-sulfonamide (1.57 g, 53% yield).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]([C:9]([O:11]CC)=[O:10])[CH2:6][N:5]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][O:2]1.O.[OH-].[Li+]>O.CO>[C:17]([O:16][C:14]([N:5]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[CH2:8][C:4]21[CH2:3][O:2][CH2:1]2)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)C2(COC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)CC12COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 5-tert-butyl 7-ethyl 2-oxa-5-azaspiro[3.4]octane-5,7-dicarboxylate (514 mg, 1.80 mmol) and lithium hydroxide monohydrate (378 mg, 9.0 mmol) in 1 mL of H2O and 10 mL of MeOH was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was stirred with saturated aqueous solution of 2-hydroxypropane-1,2,3-tricarboxylic acid (15 mL) and then extracted with DCM (15 mL×2). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo to afford 5-(tert-butoxycarbonyl)-2-oxa-5-azaspiro[3.4]octane-7-carboxylic acid (444 mg, yield: 95.9%) as a white solid.