Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25].C(OCC)(=O)C>ClCCl>[CH3:22][N:23]([CH3:27])[C:24]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:25]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 500 mg (2.50 mmol) of tert-butyl 4-piperidinyl-carbamate in 20 mL of dichloromethane was added 522 μL (3.74 mmol) of triethylamine and 276 μL (3.00 mmol) of dimethylaminocarbonyl chloride and the mixture was stirred for 2 hours at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 636 mg (94%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:8]=1)([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[NH2:1][C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:8]=1
Reactant: C=CCOC(=O)c1csc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)c1csc(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Allyl 2-nitro-4-thiophenecarboxylate was suspended in concentrated HCl (25 ml), at 0°. SnCl2.2H2O (7.44 g, 32.36 mmol) was added and after stirring for 4 hours at ambient temperature the pH was adjusted to 10 with NaOH. Extraction with ethyl acetate and purification by subjecting to flash silica gel chromatography using ethyl acetate/petroleum ether as eluant (25:75), gave the title compound (1.15 g, 55%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2].[C:37]([O:40][CH2:41][C:42]1[C:47]([N:48]2[CH2:59][CH2:58][N:57]3[C:50](=[CH:51][C:52]4[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=43)[C:49]2=[O:62])=[CH:46][C:45]([F:63])=[CH:44][C:43]=1B1OC(C)(C)C(C)(C)O1)(=[O:39])[CH3:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:37]([O:40][CH2:41][C:42]1[C:43]([C:24]2[CH:25]=[C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([N:4]4[CH2:5][CH2:6][N:7]([CH:9]5[CH2:10][O:11][CH2:12]5)[CH2:8][C@@H:3]4[CH2:1][CH3:2])=[CH:18][N:17]=3)[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=2)=[CH:44][C:45]([F:63])=[CH:46][C:47]=1[N:48]1[CH2:59][CH2:58][N:57]2[C:50](=[CH:51][C:52]3[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55][C:56]=32)[C:49]1=[O:62])(=[O:39])[CH3:38]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 39 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 114f (180 mg, 0.40 mmol), (2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 103g (198 mg, 0.40 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), K3PO4 (170 mg, 0.8 mmol), sodium acetate (66 mg, 0.8 mmol), acetonitrile (5 mL), and water (1.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 114g as a yellow solid (115 mg, 39%). MS: [M+H]+ 738.4
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.O[C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].N1CCOCC1>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:9]2[O:7][C:4]3([CH2:5][CH2:6][NH:1][CH2:2][CH2:3]3)[NH:13][C:11](=[O:12])[C:10]=2[CH:14]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc(O)c(C(N)=O)c1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)NC1(CCNCC1)O2

Procedure:
A mixture of 26 mg (0.083 mmol) of N-[4,8-dimethoxyquinoline-2-yl)carbonyl]-4-piperidone (prepared as described in Example 44), 14 mg (0.083 mmol) of 2-hydroxy-5-methoxybenzamide, and 0.020 mL of morpholine in a mixture of 0.2 mL of toluene and 0.6 mL of methanol is refluxed for 20 hr. The reaction mixture is diluted with ethyl acetate, and washed with water, brine, and dried over Na2SO4. After solvent removal by rotoevaporation, the crude product is purified by preparative TLC to give 17 mg (0.037 mmol, 45% yield) of 1′-[4,8-dimethoxyquinoline-2-yl)carbonyl]-6-methoxyspiro-[2H-1,3-benzoxazin-2,4′-piperidin]-4-(3H)-one (Compound 150): 1H NMR (DMSO-d6): δ 3.76 (s, 3H), 3.95 (s, 3H), 4.07 (s, 3H), 7.04 (d, 1H), 7.12 (d of d, 1H), 7.19 (s, 1H), 7.24 (m, 2H), 7.52 (d of d, 1H), 7.68 (d, 1H), and 8.85 ppm (s, 1H). MS m/z: 464.1 (M+H)+, 486.2 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH2:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=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>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:27][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([C:11]3[N:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:5][CH:6]=2)=[O:10])([CH3:25])[CH3:26])=[CH:22][CH:23]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: CC(C)(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (110 mg, 0.5 mmol), 2-(4-bromophenyl)propan-2-amine, 36-b, (70 mg, 0.32 mmol), HATU (290 mg, 0.76 mmol) and DIEA (82 mg, 0.64 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was washed with aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL). The organic layers were dried and concentrated in vacuo. The residue was washed with hexane to afford compound 36-c (80 mg, 57%). 1H NMR (300 MHz, CDCl3) δ11.62 (s, 1H), 9.55 (s, 1H), 9.41 (dd, J=1.5, 4.8 Hz, 1H), 9.00 (d, J=4.2 Hz, 1H), 8.63 (dd, J=1.5, 8.1 Hz, 1H), 7.78 (dd, J=5.1, 8.4 Hz, 1H)), 7.43 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 1.78 (s, 6H). LC-MS: (M+H)+ 414.
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[OH:19][CH:20]([CH3:27])[C:21](=[CH2:26])[C:22]([O:24][CH3:25])=[O:23].C1(NC2CCCCC2)CCCCC1>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:17]([CH2:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([CH:9]=1)[CH2:26][CH:21]([C:20](=[O:19])[CH3:27])[C:22]([O:24][CH3:25])=[O:23])#[N:18]
Reactant: C=C(C(=O)OC)C(C)O
Reactant: COc1ccc(CC#N)cc1Br
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C(Cc1cc(CC#N)ccc1OC)C(C)=O
Temperature: 80 °C

Procedure:
N,N-dimethylacetamide (200 mL) was added to Pd-118 (1.009 g) and tetrabutylammonium chloride hydrate (0.916 g), followed by 2-(3-bromo-4-methoxyphenyl)acetonitrile (7 g). Methyl 3-hydroxy-2-methylenebutyrate (5.64 mL) and dicyclohexylamine (9.25 mL) were added and the solution was heated at 80° C. for 3 days. The reaction mixture was diluted with EtOAc (200 mL) and extracted with water. The organic phase was dried, filtered and evaporated under reduced pressure. The crude product was purified by chromatography to afford the subtitle compound as an orange oil, 5.01 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].ClC1C=CC=C(C(OO)=[O:30])C=1.C(Cl)Cl>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]1[CH2:19][O:30]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=NN(CCCl)C(=O)N(CC1CO1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 5.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-(L-arabinopyranosyl)urea, 5.9 g of meta-chloroperbenzoic acid, 50 ml of methylene chloride and 50 ml of benzene is stirred at room temperature for 3 hours. After the reaction, the mixture is condensed under reduced pressure. The residue obtained is washed with ether and then purified by silica gel chromatography (Solvent: ethyl acetate). 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-(oxiran-2-yl-methyl)-3-(L-arabinopyranosyl)urea is thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]1C=C(O)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:26])[C:14]([C:24]#[N:25])=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[CH3:11]>>[C:24]([C:14]1[C:13](=[O:26])[O:12][C:10]2[C:6]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:11]=2)#[N:25]
Reactant: CCOC(=O)C(C#N)=Cc1cccc(OC)c1
Reactant: COc1cccc(O)c1
Product: COc1cccc(-c2c(C#N)c(=O)oc3cc(OC)ccc23)c1
Yield: 0.2 %

Procedure:
The title compound was prepared from 3-methoxyphenol and 3-(3-methoxyphenyl)-2-cyano-acrylic acid ethyl ester by a procedure similar to that described for Example 16 in 0.2% yield. 1H NMR (CDCl3): 7.50 (t, J=8.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.12 (dd, J=8.4, 2.4 Hz, 1H), 7.03-6.96 (m, 2H), 6.90-6.83 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>>[C:17]([NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1N
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(C)=O
Temperature: 2.5 °C
Reaction time: 0.3 h

Procedure:
Ortho anisidine (0.67 moles, 82 g.) was taken in a 1 L round bottom flask equipped with a liquid addition funnel and a guard tube; triethylamine (1.0 mole, 100 g) was added to it in one lot. Above mixture was cooled to 0-5° C. and acetyl chloride was added drop-wise maintaining temperature below 10° C. After addition of acetyl chloride cooling was removed and the reaction mixture was stirred at 25-28° C. for 0.3 hours. After the completion of reaction (TLC), the reaction mixture was poured on ice-water, and aqueous layer was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 96.5 g. of solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:14].[Na+].[Cl-].[Ca+2].[Cl-].Cl>O>[OH:14][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1cc(F)c(O)c(F)c1F
Temperature: 100 °C
Reaction time: 13.25 h

Procedure:
50 g (0.258 mol) of 2,3,4,5-tetrafluorobenzoic acid and 41.4 g (1.04 mol) of sodium hydroxide are introduced first into 687 g of water, the resulting solution is heated to 100° C. and stirred at this temperature for 12 to 14.5 hours. The end point of the reaction is determined by gas chromatography. 57.2 g of calcium chloride are then added, and the pH is brought to 1 with 30% hydrochloric acid. The solutionis continuously extracted with MTBE (methyl tert.-butyl ether) for 16 hours, and the solvent is then distilled off. The dry residue (44.6 g) is recrystallized at 145° C. from 1,2-dichlorobenzene to give 42.1 g (0.219 mol, 85%) of white to slightly beige-colored 4-hydroxy-2,3,5-trifluorobenzoic acid which gives the expected values in all analytical tests. The 3-hydroxy-2,4,5-trifluorobenzoic acid content ofless than 5 mol % of the crude product also formed in the reaction is completely removed by dissolution and reprecipitation (recrystallization).
Reaction SMILES: [OH:1][C:2]1([CH3:10])[CH2:5][N:4]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][CH3:59])[N:55]=[C:54]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:53]=1.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:69][C:63]1[C:64]([F:68])=[CH:65][CH:66]=[CH:67][C:62]=1[CH2:61][S:60][C:54]1[N:53]=[C:52]([NH:9][S:6]([N:4]2[CH2:5][C:2]([OH:1])([CH3:10])[CH2:3]2)(=[O:8])=[O:7])[CH:57]=[C:56]([O:58][CH3:59])[N:55]=1
Reactant: CC1(O)CN(S(N)(=O)=O)C1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(NS(=O)(=O)N2CC(C)(O)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
A mixture of 3-hydroxy-3-methylazetidine-1-sulfonamide (0.25 g) (prepared according to patent WO 2004/011443), tris(dibenzylideneacetone)-dipalladium (0) (13 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (10 mg), cesium carbonate (0.68 g) was treated with a solution of 4-Chloro-2-[[(2,3-difluorophenyl)methyl] thio]-6-methoxypyrimidine (the product of example 35 step i) (0.4 g) in dioxane (10 ml) and the whole then heated at reflux for 30 min. H2O (10 ml) was added followed by 1N hydrochloric acid solution (5 ml) and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/DCM (1:4) as eluent to give the subtitle compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CN(C=O)C.COC(OC)(C)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:10][O:11][C:13]([CH3:18])([CH3:14])[O:12]2)=[CH:6][CH:7]=1
Reactant: OCC(O)Cc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Yield: 1994.1 %

Procedure:
A solution of 3-(4-bromo-phenyl)-propane-1,2-diol (1.41 g, 6.10 mmol) and p-toluenesulfonic acid (50 mg) in DMF (10 mL), 2,2-dimethoxypropane (10 mL) is stirred at rt for 2 h. The reaction mixture is diluted with sat. aq. NaHCO3 (150 mL) and extracted with diethyl ether (2×200 mL). The organic extracts are washed with water (200 mL), dried over MgSO4 and evaporated to give 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g) as a pale brownish oil; LC-MS: tR=1.00 min.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=O)[CH3:3].C(O)C.[S-:18][C:19]#[N:20].[K+]>O>[CH2:2]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:20]=[C:19]1[SH:18])[CH3:3]
Reactant: CCNCC(=O)c1ccc(O)cc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCn1cc(-c2ccc(O)cc2)nc1S
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred and refluxing mixture of 21.5 parts of 2-(ethylamino)-1-(4-hydroxyphenyl)ethanone hydrochloride, 60 parts of ethanol and 75 parts of water is added dropwise a solution of 12 parts of potassium thiocyanate in a small amount of water. Upon completion, stirring is continued overnight at reflux temperature. Another portion of 4 parts of potassium thiocyanate in a small amount of water is added and the whole is stirred for 8 hours at reflux temperature. The reaction mixture is concentrated. The product is filtered off and crystallized from a mixture of ethanol and water, yielding 10 parts (91%) of 4-(1-ethyl-2-mercapto-1H-imidazol-4-yl)phenol; mp. 251.7° C.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[C:9]([NH:17][C:18]1[CH:30]=[C:29]([N:31]2[CH:35]=[CH:34][CH:33]=[CH:32]2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22]C(C)(C)C)=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(OCC)(=O)C.O.CO>[C:9]([NH:17][C:18]1[CH:30]=[C:29]([N:31]2[CH:35]=[CH:34][CH:33]=[CH:32]2)[CH:28]=[CH:27][C:19]=1[C:20]([OH:22])=[O:21])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2cccc2)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(-n2cccc2)ccc1C(=O)O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.24 mL of 2.0 mol/L aqueous sodium hydroxide was added to a mixed solution of 1.0 mL of dioxane and 1.0 mL of methanol containing 58 mg of tert-butyl 2-(benzamido)-4-(1H-pyrrol-1-yl)benzoate and stirred at 50° C. for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature, water was added and after pH was adjusted to pH 3.0 with 1.0 mol/L hydrochloric acid, ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with water and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 41 mg of 2-(benzamido)-4-(1H-pyrrol-1-yl)benzoic acid as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.[BH4-]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1NC(=O)C1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
A solution of 2.0 g (8.2 mmole) of methyl 3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate in 20 ml of tetrahydrofuran is cooled in ice and a solution of 0.75 g (20 mmole) sodium borohydride in 10 ml of water is added. The mixture is stirred 20 min at 0° and then 1.5 hr at room temperature. Acetic acid is added dropwise to decompose the excess borohydride and the mixture is concentrated in vacuum. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCO3 ; dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128°-131°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.C([O-])([O-])=O.[Na+:36].[Na+].CCCCCCC>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([O-:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.[Na+:36]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)[O-])c2)n1
Reaction time: 15 h

Procedure:
A solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [540 mg, 1.17 mmol, Example 49(b)] in MeOH (60 mL) is treated with Na2CO3 (187 mg, 1.78 mmol) and the mixture is stirred for 15 hours. The reaction mixture is filtered and the filtrate is concentrated to dryness. To the residue is added a mixture of methanol, EtOAc and acetone. The insoluble material is filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. The residue is again treated with a mixture of methanol, EtOAc and acetone, the insoluble material filtered off and the filtrate is evaporated. To the residue is added MeOH (1 mL) and EtOAc (5 mL), followed by heptane until the solution turned cloudy and a solid is formed slowly. Heptane is repeatedly added until the solution stay clear. The mixture is filtered affording sodium 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionate as a crystalline. LC/MS: RT=2.34 minutes, MS: 460 (M-Na+2H)+. 1H NMR [300 MHz, (CD3)2SO]: □ 7.97 (1H, br s), 7.24-7.7 (7H, m), 6.57 (1H, s), 3.86 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.4 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[C:33]([OH:35])[CH:32]=[C:31]([OH:36])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+].O>O1CCCC1.CO>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[C:33]([OH:35])[CH:32]=[C:31]([OH:36])[CH:30]=2)=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cc(O)cc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cc(O)cc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 8.7 %

Procedure:
A solution of N-[2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[thiophene-2-carbonyl]amino-L-alanine, methyl ester (250 mg, 0.47 mmol), and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in tetrahydrofuran (30 mL), methanol (10 mL), and water (10 mL) was stirred at room temperature overnight. The solution was concentrated to remove methanol and tetrahydrofuran, and then water (50 mL) and 1 M HCl (20 mL) were added. The mixture was extracted with ethyl acetate (2×30 mL), and the solvent was evaporated from the extracts. The residue was dissolved in methanol (30 mL) and 10 mL of this solution was purified by HPLC to give N-[2-chloro-4-[[[(3,5-dihydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[thiophene-2-carbonyl]amino-L-alanine (21.2 mg, 26%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[C:8]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(N)C(=O)O
Reactant: CCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)NC(C)(C)C(=O)O
Yield: 48.7 %

Procedure:
2-Aminoisobutyric acid (2.0 g, 19.4 mmol) and n-hexanoyl chloride (3.0 g, 22.4 mmol) were reacted in the presence of NaOH (1.6 g, 40 mmol) in a mixture of ether and water using the method described in Example 5, Part A. The title compound (1.90 g, 49%) was obtained after crystallization from benzene, m.p. 141°-143° C.