Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:26]N(C)C)=[CH:5][N:6]2[Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C.CI.C[Si]([C:36]#[N:37])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:26][C:36]#[N:37])=[CH:5][NH:6]2
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(Cl)c2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(Cl)c2c(CC#N)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4-Chloro-6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethyl-amine (0.73 g, 1.85 mmol) in benzene (20 ml) was added methyl iodide (0.52 g, 3.71 mmol). After stirring at ambient temperature for 16 hours, the solvent was removed under reduced pressure. The residue was suspended in anhydrous tetrahydrofuran (10 ml). To this solution was added, sequentially, trimethylsilyl cyanide (0.27 g, 2.78 mmol) and tetrabutylammonium fluoride (1.45 g, 5.56 mmol, 1M in tetrahydrofuran, after which the solution was stirred for an hour. After solvent was removed under reduced pressure, the residue was partitioned between water and ether. The ether extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give (4-Chloro-6-methoxy-1H-indol-3-yl)-acetonitrile as solid (0.41 g, quantitative). 1H NMR (CDCl3) δ: 3.82 (s, 3H), 4.10 (d, 2H, J+1.17 Hz), 6.79 (d, 1H, J=2.07 Hz), 6.79 (d, 1H, J=2.07), 7.16 (m, 1H), 8.11 (b, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: CCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 4-(5-trifluoromethyl-pyridin-2-yl)-benzaldehyde (1.0 g, 3.98 mmol) in andhydrous tetrahydrifuran (THF) (25 mL) that had been cooled to 0° C. in an ice bath is added n-butyl magnesium bromide (8.0 mL, 16.0 mmol) dropwise with stirring under nitrogen. The mixture is allowed to warm slowly to room temperature. The reaction is monitored by HPLC, and upon complete consumption of the aldehyde, quenched with 1N HCl. The mixture is diluted with ethyl ether and water, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The title compound is obtained after column chromatography (1.10 g or 3.20 mmol) at 80% yield.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][S:10](O)(=[O:12])=[O:11].P(Cl)(Cl)(Cl)=O>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)O
Reactant: COc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(C)(=O)=O)cc1
Temperature: 122.5 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
Anisole (2.16.3 g, 2.0 moles) was mixed in a flask with anhydrous methane sulfonic acid (64.8 g, 1.0 mole) and phosphorus oxychloride (54.1 g, 0.56 mole) and was heated while stirring at 120-125° C. for 5 hours. A nitrogen purge was used to sweep out HCl gas as it formed. Subsequent treatment of the reaction mixture after cooling was the same as in Example 1. The washed and dried product solution was then heated in a distillation unit with a fractionating column to remove unreacted anisole. Products remaining in the distillation unit were finally diluted with N-butanol and crystallized from this solvent. A yield of 35% of methyl p-methoxyphenyl sulfone was obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:34][CH2:33][C:32]([CH3:36])([OH:35])[CH2:31]2)[C:27]([F:37])=[C:26]([NH:38][NH2:39])[N:25]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:25]=[C:26]([NH:38][NH:39][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:37])=[C:28]([N:30]2[CH2:34][CH2:33][C:32]([OH:35])([CH3:36])[CH2:31]2)[N:29]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: CC1(O)CCN(c2nc(Cl)nc(NN)c2F)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC1(O)CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)C1

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.122 g, 0.4 mmol), racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-3-methyl-3-pyrrolidinol (0.104 g, 0.4 mmol), NMM (0.13 mL, 1.2 mmol), HOAt (0.054 g, 0.4 mmol), EDC (0.077 g, 0.4 mmol) and DMF (2 mL) were combined. When the reaction was complete, the mixture was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(3-hydroxy-3-methyl-1-pyrrolidinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a mixture of diastereomers (0.035 g, 16%). LCMS: (M+H)+=549.5.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][CH2:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:16]([CH2:15][Cl:14])(=[O:18])=[O:17])=[C:7]([CH3:12])[CH:6]=1
Reactant: O=S(=O)(Cl)CCl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Product: CNC(=O)Oc1ccc(NS(=O)(=O)CCl)c(C)c1

Procedure:
According to the procedure of Example 2, 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole) was reacted with chloromethanesulfonyl chloride (1.63g., 0.011 mole). The product, recrystallized from ethanol/water, was an orange-red solid (m.p. 136.5°-38.5° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][N:7]1[C@H:6]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:11][C:2]([C:2]4[CH:11]=[CH:10][CH:9]=[C:8]5[C:3]=4[CH:4]=[CH:5][CH:6]=[N:7]5)=[CH:3][C:19]=3[CH2:20][CH2:5]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: Brc1cccc2ncccc12
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5ncccc45)cc3CC[C@@H]12
Yield: 55 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0 ) (23 mg, 0.02 mmol), 5-bromoquinoline (135 mg, 0.65 mmol ), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 128 mg (55%) of the title compound as an amorphous foam. mp 100°-104°. FDMS: m/e=356. α[D]589 =+61.77 (c=0.35, chloroform).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].C1(C)C=CC=CC=1[CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C(O)C.[C:32]1(C)[C:33]([CH3:38])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:23]1[CH2:24][CH2:25][N:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:27][CH2:22]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: Cc1ccccc1C1CNCCN1
Reactant: Cc1ccccc1C
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](N1CCN(c3ccccc3C)CC1)C2
Temperature: 25 °C

Procedure:
A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 8.8 g of o-tolylpiperazine, and 2 ml of absolute ethanol in 100 ml of xylene is refluxed for 4 days. The reaction mixture is cooled to room temperature, and the resulting crystalline solid filtered off and washed with ether to give 15.2 g of crude product. Recrystallization from ethanol/methanol gives 4 g of the title compound, melting point 217°-219° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34](OS(C)(=O)=O)[CH2:35][CH3:36])=[N:21]2)=[O:16].C(N(CC)CC)C>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][N:20]2[C:25]=1[C:24](=[O:26])[N:23]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([CH:34]([NH:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:35][CH3:36])=[N:21]2)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCC(OS(C)(=O)=O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 75 °C
Yield: 12.4 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (Fluka, 0.054 ml, 0.31 mmol) was added to a solution of 3-benzyl-2-(1-methanesulfonyloxy-propyl)-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxyic acid methyl ester (0.086 g, 0.21 mmol) and triethylamine (0.086 mL, 0.616 mmol) in DMF (1.0 mL) and the reaction mixture was heated to 75° C. for 4 h. The reaction mixture was quenched with saturated NaHCO3 (2 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with 10% LiCl (4×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.013 g, 14%) as a solid: 1H NMR (CDCl3) δ 6.98–7.26 (m, 8H), 5.75 (m, 1H), 4.95 (m, 2H), 3.86 (s, 3H), 3.65 (m, 1H), 3.00 (m, 2H), 2.45 (m, 1H), 2.00 (m, 1H), 1.50–1.75 (m, 4H) 1.36 (s, 9H), 0.88 (m, 3H); MS (ESI+) 498 (M++H); HRMS (ESI+) calculated: 498.2716 (M++H), found: 498.2720 (M++H).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)#[CH:9].C(N(CC)CC)C.CN(C)C=O>[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:7][N:6]1[C:2]([C:9]#[C:8][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[CH:3][CH:4]=[N:5]1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1nccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nccc1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 5-iodo-1-methyl-1H-pyrazole (8.00 g), 1-ethynyl-4-(trifluoromethyl)benzene (6.54 g), copper(I) iodide (110 mg), bis(triphenylphosphine)palladium(II) dichloride (1.35 g), triphenylphosphine (504 mg), triethylamine (8.00 mL) and dimethylformamide (70 mL) was stirred at 75° C. for 2 hours. Thereafter, the reaction solution was added to water, and the obtained mixture was then extracted with ethyl acetate. The organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=85:15 to 75:25), so as to obtain the title compound (7.74 g) in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]CC4C=CC5C(=CC=CC=5)N=4)=[CH:13][CH:14]=3)[C:9]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:4][CH:3]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reaction time: 7 h

Procedure:
To a solution of methyl 3-[1-(4-chlorobenzyl)-3-trimethylacetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (EP 419,049, March 27, 1991, Example 8, Step A) (11.5 g) in 150 mL DMF at 100° C. was added CuCl2.2H2O (4.9 g) in 26 mL H2O. After 7 hours, the solution was cooled, poured onto aqueous NH4OAc, and extracted with EtOAc. The organic phase was washed twice with NH4OAc (aq), washed with brine, dried (MgSO4), and evaporated. Purification of the residue by chromatography on silica gel (8% EtOAc in toluene) gave the title compound as a brown gum.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40]>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2[nH]ccc2c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1nc2c(ccn2Cc2cc(F)ccc2F)c(-c2ccc3c(c2)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27 from (S)-methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1,4-difluorobenzene, except that the racemic mixture obtained in Step G was purified by preparative HPLC using an IC column (250 mm×30 mm I.D.; 5 um) from Chiral Technologies (West Chester, Pa., USA). The mobile phase was comprised of 80% hexanes containing 0.1% formic acid (v/v) and 20% isopropanol, operating at 42.5 ml/min, with triggered collections at 280 nm (Rt=6.80 minutes) to give to give (S)-2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid. (S)-2-(Tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid was then used as in Example 27, Step H to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) d=7.50-7.41 (m, 1 H), 7.23-7.17 (m, 1 H), 7.14 (t, J=3.4 Hz, 1 H), 7.06 (td, J=4.5, 9.3 Hz, 1 H), 7.01-6.92 (m, 3 H), 6.32 (dd, J=3.5, 11.3 Hz, 1 H), 5.64-5.53 (m, 3 H), 4.29 (t, J=4.6 Hz, 2 H), 2.96-2.80 (m, 2 H), 2.79 (s, 3 H), 2.09 (d, J=5.3 Hz, 2 H), 1.03-0.90 (s, 9 H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-][CH2:18]C.[Na+].[Na].Cl[CH2:23][CH2:24][S:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:26]>C(O)C.O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:23][CH2:24][S:25]([CH2:27][C:28]([O:30][CH2:31][CH3:18])=[O:29])=[O:26])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: COC(=O)CS(=O)CCCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CS(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (2.97 g, 0.0125 mole) was added to sodium ethoxide, freshly prepared from sodium (0.29 g, 0.0125 mole) in ethyl alcohol (75 ml), and stirred for 1.5 hours. A solution of the title compound of Example 11 (2.3 g, 0.0125 mole) in ethyl alcohol (50 ml) was added dropwise over one hour and the resulting solution stirred for 20 hours at room temperature. Water (100 ml) was added and the ethyl alcohol removed using a rotary evaporator. The aqueous residue was extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and the product purified by chromatography on silica. The yellow solid was recrystallized from ethyl acetate/hexane to give 1.1 g, m.p. ca. 110° C.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(Cl)([Cl:31])=O.[CH2:33](O)[CH3:34]>>[ClH:31].[CH2:33]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH2:15])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:2][CH:3]=1)[CH3:34].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCO
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Product: Cl
Temperature: 65 °C
Reaction time: 2 h

Procedure:
150 g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) are added to 1500 ml ethanol at room temperature. The mixture is then warmed to an internal temperature of 60-70° C. 42.8 ml Thionyl chloride is then added over a period of 1 h to the reaction mixture. The mixture is then stirred for a further 2 h. 810 ml of the solvent is removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. 1310 ml of solvent is then removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. 520 ml of solvent is then removed by distillation under reduced pressure. 1460 ml Heptane fraction is then added. The mixture is then cooled to room temperature over a period of 1 h. The mixture is then stirred at room temperature for 2 h. The solid is then collected by filtration. The solid is then washed with heptane fraction (600 ml) and dried to give (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=H, R3=Et). Spectroscopic data as given in Example 9-1 Method 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Reaction time: 4 h

Procedure:
A 6.0 gram (0.02 mole) portion of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared in Example I (Compound No. 75) was dissolved in approximately 80 milliliters of ethanol and 1.2 grams (0.03 mole) of sodium hydroxide pellets were added to the resulting mixture. The mixture was stirred for four hours and then allowed to stand overnight. The mixture was then evaporated to dryness and water added to give a yellow cloudy solution. This solution was extracted with methylene chloride and then acidified with 10% hydrochloric acid causing a white precipitate to form. The white precipitate was worked up to give 1.8 grams (0.01 mole) of 3[(4-bromo-2-methylphenyl)amino]-3-oxopropanoic acid as a white solid having a melting point of 163° C.-165° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nn2)CC1
Yield: 42.6 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and oxazolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (52 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[N+]([O-])(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Clc1ccn(-c2cccnc2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, round bottom flask was charged 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) and concentrated sulfuric acid (4 mL). This suspension was cooled to 5° C. and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by adding the concentrated sulfuric acid to a stifling and cooling solution of the nitric acid) was added dropwise at a rate such that the internal temperature was maintained <15° C. The reaction was allowed to warm to 20° C. and stirred for 18 hours. A sample of the reaction mixture was carefully diluted into water, basified with 50 wt % sodium hydroxide and extracted with ethyl acetate. Analysis of the organic layer indicated that the reaction was essentially complete. The reaction mixture was carefully added to ice cold water (100 mL) at <20° C. It was basified with 50% sodium hydroxide at <20° C. The resulting light yellow suspension was stirred for 2 hours and filtered. The filter cake was rinsed with water (3×20 mL) and dried to afford an off-white solid (2.5 g, quantitative): mp 141-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76, 127.22, 124.31; EIMS m/z 224 ([M]+).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[Br:7][C:8]1[S:9][C:10]2[CH2:11][CH2:12][C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[C:15](=[C:18]3[CH2:23][CH2:22][N:21](C)[CH2:20][CH2:19]3)[C:16]=2[CH:17]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:7][C:8]1[S:9][C:10]2[CH2:11][CH2:12][C:13]3[CH:28]=[CH:27][CH:26]=[CH:25][C:14]=3[C:15](=[C:18]3[CH2:23][CH2:22][N:21]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[CH2:20][CH2:19]3)[C:16]=2[CH:17]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3CCc3sc(Br)cc32)CC1
Yield: 62 %

Procedure:
Ethyl chlorocarbonate (32 mL, 336 mmol) was added to a toluene (200 mL) solution of the compound obtained in Example 1 (21.0 g, 56 mmol), and the mixture was refluxed while heating for 6 hours. The mixture was allowed to cool in the air, and the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=19:1), to give 15.0 g (62%) of the captioned compound in the form of an oily product.