Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:35]>>[F:32][C:2]([F:33])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[CH2:40][CH2:41]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCOCCN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CCOCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-(2-ethoxy-ethyl)-piperazine following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([NH2:18])=O)=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]#[N:18])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(F)cc2c(=O)n2nc(C(N)=O)cc12
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1c2ccc(F)cc2c(=O)n2nc(C#N)cc12
Temperature: 65 °C

Procedure:
A mixture of 9.2 g of 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 25 ml of thionyl chloride and 175 ml of dimethylformamide is stirred and heated at 65° C. for 20 hours, then evaporated at reduced pressure. The residue is stirred with 1 liter of ice water and the resulting solid 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 331°-340° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+].Cl>O.CN(C)C=O>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[N:2]=[N:10][NH:11][N:12]=2)=[CH:4][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nn[nH]n2)cc1
Temperature: 0 °C
Yield: 71.8 %

Procedure:
A stirred solution of 117 grams (1.0 mole) of 4-cyanotoluene, 65.0 grams (1.0 mole) of sodium azide, and 12.0 grams (0.224 mole) of ammonium chloride 800 mL of N,N-dimethylformamide was heated at 130° C. for three hours. After this time the reaction mixture was cooled and then poured into 800 mL of water and 400 mL of ice. The resulting mixture was acidified to pH 2 with 3N hydrochloric acid, and the resulting solid was collected by filtration. The solid was washed with hexane, triturated with 300 mL of methanol, and dried under reduced pressure to a constant weight, yielding 115 grams of 4-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7]1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
To a solution of methyl 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (394 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (217 mg) as yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:24])[CH3:23])[C:17]=2[F:25])=[CH:12][C:11]1=[O:26])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+:30]>O1CCCC1>[Li+:30].[CH3:24][N:22]([CH3:23])[C:18]1[C:17]([F:25])=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([O-:27])=[O:3])[C:11](=[O:26])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)[O-])N1CC(Oc2cccc(N(C)C)c2F)=CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution containing (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.261 g, 0.001 mol) in tetrahydrofuran (4 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 2 mL, 0.001 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dried under high vacuum and rinsed with diethyl ether to afford (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid lithium salt (0.257 g, 100%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]([S:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CC[O:38]C(C)=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[CH2:10][CH:11]([S:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)(=[O:38])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(Cc1ccccc1)S(=O)N1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CC(Cc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 0 °C
Yield: 81 %

Procedure:
The product from Step D (430 mg, 0.91 mmol) was taken up in acetonitrile (1.5 mL) with stirring and cooled to 0° C. RuCl3.3H2O (0.5 mg) and NalO4 (290 mg, 1.37 mmol) were added followed by water (2 mL). The resulting mixture was stirred at room temperature for 2½h until tlc (hex/EtOAc 1:1) indicated the absence of starting material. The reaction was diluted with DCM, the layers separated and the aqueous layer was further extracted with DCM. The organic extracts were combined, dried, filtered and concentrated in vacuo to give the product as an oil (360 mg, 81%). 1H-NMR δ (CDCl3) 7.37-7.09 (15H, m), 4.96 (1H, d, J=12.2 Hz), 4.94 (1H, d, J=12.1 Hz), 3.91 (1H, m), 3.89-3.68 (2H, m), 3.31 (1H, dd, J=4.5, 14.0 Hz), 2.88-2.45 (7H, m 1.72-1.50 (3H, m) and 1.29-1.15 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)\[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.00 g), methyl 4-oxo-4-phenylbutyrate (619 mg), acetic acid (0.553 ml), sodium acetate (528 mg) and methanol (20 ml) was heated to reflux for 19 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.18 g, yield 76%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([NH2:60])[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([NH:60][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:23])[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: O=C(O)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CC(C)(C)OC(=O)N1CCN(N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 1.3 ml NEM in 8 ml DCM, 914 mg TOTU were added and the mixture was stirred for 30 min at RT. Then 673 mg 4-Amino-piperazine-1-carboxylic acid tert-butyl ester were added and the reaction was stirred over night. After removal of the solvent under reduced pressure the residue was directly purified by chromatography on silica gel eluting with an ethyl acetate/heptane gradient. Yield: 1.1 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].[H-].[Na+].[CH3:34]N(C)C=O.CI>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:10][C:11]=2[N:13]([CH3:34])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (1.07 g), 60% sodium hydride (0.10 g) and N,N-dimethylformamide (14 mL) was stirred at room temperature for 40 min. A solution of methyl iodide (0.20 mL) in tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-15:85) to give the title compound (0.75 g, yield 68%) as pale-yellow needle crystals.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[CH3:28][O:29][CH:30]([O:34][CH3:35])[C:31]([NH2:33])=[S:32].C(OCC)(=O)C>CN(C)C(=O)C.ClCCl>[CH3:28][O:29][CH:30]([O:34][CH3:35])[C:31]1[S:32][CH:2]=[C:3]([C@@H:5]2[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[N:33]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(OC)C(N)=S
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(OC)c1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.0 g) in a mixture of N,N-dimethylacetamide (10 ml) and dichloromethane (5 ml) was added 2,2-dimethoxythioacetamide (1.28 g) at room temperature. After stirring at room temperature for 12 hours, the mixture was poured into ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated. The obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (20:1, V/V) to give (2S,4R)-2-[2-(dimethoxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.6 g).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)[CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>CCOC(C)=O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=6)=[O:21])=[CH:17][CH:18]=5)[CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:44]=2)[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-amide (prepared below, 70 mg, 0.175 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (66.8 mg, 0.349 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and then diluted with EtOAc (2 mL). The solution was washed with water (2 mL) and the water layer was re-washed with additional EtOAc (2 mL). The combined organic layers were then concentrated in vacuo affording the crude product. The crude product was further purified by silica gel column chromatography with 5% methanol in chloroform as eluant to give the desired product as a solid in 55% yield (55 mg, 0.96 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([NH:22][CH:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:24](O)=[O:25])=[O:21])=[CH:14]2>>[CH2:27]([CH:23]([NH:22][C:20]([C:15]1[NH:16][C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:10])=[CH:19][CH:18]=2)=[O:21])[C:24]([N:6]1[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Dimethylaminopiperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A. The residue was purified by chromatography on silica gel eluted with 5-30% ethanol in dichloromethane containing 0.5% ammonium hydroxide, followed by trituration with ether: Yield 21 mg, 5%; PBMS 453/455 (MH+, 100%);
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3]/[C:4](/[CH2:7][CH3:8])=[CH:5]\[CH3:6].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[O:13].C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:13][CH:12]([CH:7]([CH3:8])[C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])=[CH:5][CH3:6])[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCOC(=O)C=O
Reactant: C/C=C(/CC)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC=C(O[Si](C)(C)C)C(C)C(O)C(=O)OCCCC
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 21.6 mg (0.05 mmol) of a chiral titanium complex, (R)-1, in 3 ml of methylene chloride were added 157 mg (1 mmol) of Z-3-(trimethylsilyl)oxy-2-pentene and subsequently a solution of 130 mg (1 mmol) of freshly distilled butyl glyoxylate in 0.5 ml of methylene chloride at 0° C. After stirring for 30 minutes at that temperature, the resultant mixture was poured into 10 ml of a saturated sodium hydrogencarbonate aqueous solution at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. Separation by silica gel chromatography (eluent: hexane/ethyl acetate=15/1 by volume) gave 181 mg (0.63 mmol; yield 63%) of butyl 2-hydroxy-3-methyl-4-(trimethylsilyl)oxy-4-hexenoate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]2=[O:27])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Na+].Cl>C1COCC1.O>[F:30][C:2]([F:1])([F:29])[CH:3]([CH3:28])[CH:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:18]2=[O:27])=[CH:14][CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C(C(=O)O)c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.80 g (6.43 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-{[2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]methyl}phenyl)butanoate were dissolved in 18.2 ml each of THF, methanol and water, and 51.5 ml (128.6 mmol) of 10% strength aqueous sodium hydroxide solution were added. The mixture was stirred at RT overnight. The reaction mixture was then diluted with water, acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This gave 2.82 g of product, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CC1C=CC(S(O[CH2:18][C@@H:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:23][O:22]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2cc(I)cn2)O1
Temperature: 100 °C

Procedure:
A mixture of 4-iodopyrazole (1.00 g, 5.16 mmol), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.624 g, 5.671 mmol), Cs2CO3 (2.52 g, 7.73 mmol) and DMF (5 mL, 60 mmol) was heated to 100° C. for 2 h. The solution was extracted with EtOAc, and washed with water (2×). The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 2-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.34 (d, J=8.8 Hz, 6H), 3.76 (dd, J=8.6, 6.1 Hz, 1H), 4.08 (dd, J=8.6, 6.3 Hz, 1H), 4.23-4.37 (m, 2H), 4.39-4.46 (m, 1H), 7.50-7.55 (m, 1H), 7.77 (s, 1H). MS (ES+): m/z=309.01 (100) [MH+]. HPLC: tR=1.34 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:10]=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:11]1[CH2:23][CH2:24][O:25][CH:10]1[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: OCCO
Reactant: O=Cc1ncccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1C1OCCO1
Temperature: 120 °C

Procedure:
3-Nitro-2-pyridinecarbaldehyde (22 g, 144.74 mmol) was dissolved in toluene (500 mL). To the mixture was added catalytic amount of p-TSA (2 g) and ethylene glycol (40 mL) and the reaction flask equipped with Dean-Stark assembly was refluxed for 12 h at 120° C. After the reaction was complete, the reaction mixture was treated with water and ethyl acetate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a thick oily mass. The oily mass was then purified by silica gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 2-(1,3-dioxolan-2-yl)-3-nitropyridine: 1H-NMR (CDCl3) δ: 4.2 (d, 5H), 6.5 (s, 1H), 7.5 (m, 1H), 8.3 (d, 1H), 8.9 (brs, 1H).