Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[N:3]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[C:6]3[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=23)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=C1OCCc2cc(-c3ccccc3)nc(Cl)c21
Product: O=C1OCCc2cc(-c3ccccc3)nc(N3CCOCC3)c21

Procedure:
128 mg (98%) of 8-morpholine-4-yl-6-phneyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid using the method same as in Example 35 except that 110 mg of 8-chloro-6-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was added with morpholine instead of 4-fluoro-aniline.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5](Cl)=[O:6].[CH3:21][NH2:22]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([NH:22][CH3:21])=[O:6]
Reactant: CN
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(I)c(Oc2ccc(OC)cc2)c(I)c1

Procedure:
3,5-diiodo-4-(4′-methoxyphenoxy)-N-methyl benzamide (Compound 8) was prepared by way of 3,5-diiodo-4-(4′-methoxyphenoxy)benzoyl chloride (see, Example 1.5). The acid chloride was reacted with excess methylamine in tetrahydrofuran at ambient temperature (1 hour), filtered to remove methylamine-hydrochloride precipitate, the solvent 5 evaporated and the product crystallized from 95% ethanol.
Reaction SMILES: C(O[C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:22])[C:13]3[C:14](=[C:16]([CH2:20][CH3:21])[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:6][N:5]=1)C.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:20]([C:16]1[N:17]([CH3:19])[N:18]=[C:13]2[C:12](=[O:22])[NH:11][C:10]([C:9]3[C:4]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[N:5][CH:6]=[C:7]([S:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]4)(=[O:24])=[O:25])[CH:8]=3)=[N:15][C:14]=12)[CH3:21]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(C)nc2c(=O)[nH]1
Reactant: COCCN
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3NCCOC)[nH]c(=O)c2nn1C
Yield: 69 %

Procedure:
A mixture of the title compound of Example 78 (200 mg, 0.42 mmol), and copper (II) sulphate pentahydrate (150 mg, 0.60 mmol) in 2-methoxyethylamine (2 ml) was heated under reflux for 2 hours, then cooled. The reaction was partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (5 ml), and the layers separated. The organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (98:2 to 95:5) to afford the title compound (150 mg, 69%). δ (CDCl3): 1.04 (3H, t), 1.40 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 2.92 (3H, s), 3.01 (2H, q), 3.13 (4H, m), 3.50 (4H, m), 3.48 (3H, s), 3.68 (2H, t), 3.88 (2H, t), 4.07 (3H, s), 8.34 (1H, s), 8.58 (1H, s). LRMS: m/z 519 (M+1)+
Reaction SMILES: [C:1]1([CH2:7][C:8]([O-:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C([N:18]2C=CC(C(F)(F)F)=N2)C=CC=1C(F)(F)CNC(C1C(C(F)(F)F)=CC=CN=1)=O.N>CO>[C:1]1([CH2:7][C:8]([NH2:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCC(F)(F)c1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)c1ncccc1C(F)(F)F
Reactant: O=C([O-])Cc1ccccc1
Agent: N
Solvent: CO
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-chloro-α,α-difluoro-4-[3-trifluoromethyl)-1H-pyrazol-1-yl]benzeneacetate (i.e. the product of Step B; 500 mg, 1.35 mmol in methanol was added dropwise ammonia in methanol (2 M, 3.37 mL, 6.75 mmol), and the resulting mixture was stirred for 24 h at room temperature. The solvent was removed under reduced pressure to afford crude 2-chloro-α,α-difluoro-4-[3-trifluoromethyl)-1H-pyrazol-1-yl]benzeneacetamide, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[C:14](Cl)(=O)[CH2:15][CH3:16]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:13]=[C:14]([CH2:15][CH3:16])[O:12][N:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: CCC(=O)Cl
Reactant: N=C(NO)c1cc(Cl)c(O)c(Cl)c1
Solvent: c1ccncc1
Product: CCc1nc(-c2cc(Cl)c(O)c(Cl)c2)no1
Reaction time: 4 h
Yield: 25.6 %

Procedure:
A mixture of 14.1 parts of 3,5-dichloro-N,4-dihydroxybenzenecarboximidamide, 6.5 parts of propanoylchloride and 98 parts of pyridine was stirred for 4 hours at reflux temperature. The reaction mixture was concentrated and the residue was partitioned between water and dichloromethane. The organic layer was separated and washed successively with water (2×) and NaCl (dil.). The combined aqueous layers were washed with dichloromethane and then filtered over diatomaceous earth. After acidifying with acetic acid, the precipitate was filtered off and taken up in dichloromethane. This solution was dried, filtered and evaporated. The residue was crystallized from a mixture of ethanol and water. The product was filtered off and dried in vacuo at 50° C., yielding 4.25 parts (25.6%) of 2,6-dichloro-4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenol; mp. 125.7° C. (interm. 11).
Reaction SMILES: [CH3:1][C:2]([C:9]([OH:11])=[O:10])([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[NH2:3].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:3][C@:2]([CH3:1])([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)(CCC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@@](CCC(=O)O)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a stirred solution of α-methyl-D,L-glutamic acid (10 g, 62 mmol) in 2 N sodium hydroxide (62 mL) at 0.5° C. was added benzyl chloroformate (12.7 g, 74.4 mmol) over 30 min. After the addition was complete the reaction mixture was stirred at room temperature for 3 hours. During, this time the pH was maintained at 11 by addition of 2N sodium hydroxide (33 mL). The reaction mixture was then extracted with ether (60 mL). The aqueous layer was cooled in an ice bath and then acidified with 4N hydrochloric acid (34 mL) to pH=1. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (60 mL) and dried (MgSO4). The solvent was removed in vacuo to give 15.2 g (83%) of N-benzyloxycarbonyl-α-methylglutamic acid as an oil: 1H NMR (CDCl3) δ 8.73(m, 5H), 5.77(b, 1H), 5.09(s, 2H), 2.45-2.27(m, 4H), 2.0(s, 3H).
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].C([Li])CCC.[C:40](=[O:42])=[O:41].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C.O>[C:26]([O:25][C:24]([NH:23][C@H:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[C:5]2[CH:31]=[CH:32][C:2]([C:40]([OH:42])=[O:41])=[CH:3][C:4]=2[O:8][N:7]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:30])([CH3:28])([CH3:29])[CH3:27]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(Br)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(=O)O)ccc12
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 1-(S)-(2-(6-bromobenzo[d]isoxazol-3-yl)phenyl)-2-(pyridin-2-yl)ethylcarbamate (Compound 16a) (1.72 g) in diethyl ether (30 mL) at 5° C. was added a 60% dispersion in mineral oil of sodium hydride (3.34 g). The suspension was stirred at 5° C. for 10 min and then cooled to −65° C. and a 2.5M solution of n-butyllithium in hexanes (5.57 mL) was added. The suspension was stirred at −70° C. for 30 min and then poured onto solid carbon dioxide pellets and left to stand until the mixture reached room temperature. To this was added water and acidified with citric acid and extracted with ether (3×200 mL), the organic layers were dried over anhydrous magnesium sulfate and evaporated. Flash chromatography eluting with 10% methanol in dichloromethane to give the title product (0.71 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:31]C(=O)OC(C)(C)C)[C:17](=[O:30])[NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:20]=2)=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:31][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)[C:17]([NH:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:20]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
To a 100 ml flask was (S)-tert-butyl 3-(4-chlorophenyl)-1-oxo-1-(3-(pyridin-4-yl)isoxazol-5-ylamino)propan-2-ylcarbamate TFA salt 3.1.B (200 mg, 0.54 mmole), 10 ml of CH2Cl2, and 10 ml of TFA. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed to give (S)-2-amino-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide TFA salt 3.1.C as a light yellow solid (250 mg, 100% yield).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:43][C:44]1[CH:53]=[CH:52][C:51]2[CH2:50][NH:49][CH2:48][CH2:47][C:46]=2[N:45]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:43][C:44]1[CH:53]=[CH:52][C:51]2[CH2:50][N:49]([C:5](=[O:7])[CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:48][CH2:47][C:46]=2[N:45]=1
Reactant: O=C(O)CC1CC1
Reactant: Clc1ccc2c(n1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC1)N1CCc2nc(Cl)ccc2C1
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To a stirred solution of cyclopropylacetic acid (24 mg, 0.24 mmol) in DMF (1 ml) at room temperature was added HBTU (185 mg, 0.49 mmol) and HOBt (72 mg, 0.53 mmol) sequentially and the resulting solution stirred for 15 mins. 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (50 mg, 0.24 mmol) and DIPEA (89 μl, 0.53 mmol) in DMF (1 ml) were then added and the resulting mixture stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and the residue was purified by FCC on silica gel (99:1:1 DCM/MeOH/NH3) to provide the title compound (56 mg, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.[Cl:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([SH:26])[NH:25][C:21]=2[CH:20]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH:25][C:21]=2[CH:20]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NCCCCCSc1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 133.2 %

Procedure:
1.5 g of the compound obtained in Example 17a and 0.93 g of 5-chloro-2-mercaptobenzimidazole were refluxed for 5 hours in 20 ml of acetonitrile containing 0.55 g of triethylamine. The reaction mixture was cooled to room temperature, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 1.81 g of the title compound (yield: 91%). Subsequently, the product was added with 0.85 g of hydrazine hydrate and 25 ml of methanol and refluxed for 5 hours. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated, washed with chloroform and then concentrated again to obtain 1 g of the title compound (crude product).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:28][CH2:29]O>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:29]
Reactant: CCO
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give (3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[OH-].[Li+].C(O)C.Cl.C[O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5]([N:7]([CH3:19])[C@@H:8]([C:16]([NH:34][C@H:33]([C:32]([OH:31])=[O:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1

Procedure:
Coupling of N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine (derived from the corresponding methylester described in example 78 by hydrolysis with lithium hydroxide in methanol/water: [a]D =+88° (c=1.0, ethanol)) with (L)-phenylalanine methyl ester hydrochloride according to example 1 followed by hydrolysis of the methyl ester moiety according to example 12 gives N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanyl-(L)-phenylalanine; FAB-MS m/e 457 (M-H)-.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:19]=[CH:18][C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[C:26](=O)([O:29]C)[O:27][CH3:28]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:19]=[CH:18][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:26]([O:27][CH3:28])=[O:29])[C:16](=[O:17])[C:10]=3[CH:9]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)OC
Reactant: Cc1ccc(COc2ccc3c(c2)C(=O)CCCC3)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCCc2ccc(OCc3ccc(C)cc3)cc2C1=O
Temperature: 110 °C
Yield: 88 %

Procedure:
To 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.67 g, 9.52 mmol) dissolved in dimethyl carbonate (40 ml) was added sodium methoxide (2.57 g, 47.6 mmol), and the resulting mixture was stirred at reflux with heating (110° C.) for 6 hours. The reaction mixture was mixed with 1 N hydrochloric acid (60 ml) under ice cooling and was concentrated under reduced pressure to remove the organic solvent, and then the aqueous layer was extracted with ethyl acetate (30 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 40 g, ethyl acetate/hexane=1/30). The objective fractions were concentrated under reduced pressure to obtain methyl 3-(4-methylbenzyloxy)-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.84 g, 8.39 mmol, 88%).
Reaction SMILES: C(C1[CH:24]=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[CH:5][CH:4]=1)C.ClCC1C=C[N:30]=CC=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[CH:23]=[CH:24][N:30]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: ClCc1ccncc1
Product: COCOc1cc(SCc2ccncc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 4-chloromethylpyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:17][OH:18]>>[OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:18][CH3:17]
Reactant: CO
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Agent: Cl
Product: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Temperature: 5 °C
Reaction time: 20 h

Procedure:
A suspension of 14.1 g (0.071 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzonitrile (prepared in example 1.1 above) in 400 ml of methanol is cooled to -45° C. and saturated with gaseous hydrochloric acid. The suspension is allowed to return to 10° C. and gaseous hydrochloric acid is bubbled through the suspension for 4 hours more at that temperature. The suspension is cooled to 5° C. and kept at that temperature for 20 hours. The precipitate which has formed is filtered off and 11.4 g of methyl 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidate are obtained in the form of a white solid which is used as such in the following step.
Reaction SMILES: Cl.CC1(C)[O:7][C@@H:6]2[CH2:8][CH2:9][CH2:10][C@@H:11]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:33]=[CH:32][C:31]6[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=6[CH:25]=5)[N:23]=4)[CH2:15][CH2:14]3)[C@@H:5]2[O:4]1>CO>[CH3:34][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:37])[C:26]2[CH:25]=[C:24]([C:22]3[N:23]=[C:19]([N:16]4[CH2:17][CH2:18][CH:13]([NH:12][C@@H:11]5[CH2:10][CH2:9][CH2:8][C@@H:6]([OH:7])[C@H:5]5[OH:4])[CH2:14][CH2:15]4)[S:20][CH:21]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CC1(C)O[C@H]2[C@H](NC3CCN(c4nc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)cs4)CC3)CCC[C@H]2O1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N[C@@H]5CCC[C@@H](O)[C@H]5O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 ml of 1.25 N HCl in methanol are added to 45 mg of ((3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-yl)-{1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-yl}amine, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated and dried under high vacuum. The product is in the form of the hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(OP(=[S:18])(O)OCC)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[S:18])=[CH:4][CH:3]=1
Reactant: CCOP(O)(=S)OCC
Reactant: N#Cc1ccc(O)cc1
Solvent: O
Product: NC(=S)c1ccc(O)cc1
Temperature: 80 °C
Yield: 86.3 %

Procedure:
In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol), diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml) were heated with stirring to about 80° C. for about thirty minutes. An additional 10 ml of water was then added to the suspension, and the reaction was heated for about another one hour. The mixture was then allowed to stir for about sixteen hours at room temperature and was then extracted with water and 1:1 ether/ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (silica gel; hexanes to ethyl acetate). The product was isolated as a yellow solid (5.54 g, 87% yield). 1H NMR (CD3OD): δ6.74 (d, 2H, J=9.1 Hz), 7.83 (d, 2H, J=8.7 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:22][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: NC1CCCCC1
Solvent: CC#N
Product: O=C(CNC1CCCCC1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm3 of acetonitrile and 0.7 cm3 of cyclohexylamine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a methylene chloride/methanol/aqueous ammonia mixture (97/2.5/0.25 by volume). The fractions containing the expected product are combined and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 492 mg of N-(6-chloro-1H-indazol-3-yl)-2-(cyclohexylamino)acetamide in the form of a white powder melting at 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7]C)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].CO>O>[C:13]1([N:19]([C:5](=[O:7])[C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NN(C(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 71.8 g. (0.35 mole) methyl 3,4-dichlorobenzoate, 37.9 g. (0.35 mole) phenylhydrazine, 21.6 g. (0.40 mole) sodium methoxide, and 175 ml. methanol was heated at the reflux temperature for 22 hrs. After cooling the reaction mixture to about 25° C., it was poured into 500 ml. water. The aqueous mixture was filtered and the solids that collected on the filter were dissolved in 500 ml. ethanol. Refrigeration caused crystals to form which were recovered by filtration. There was thus obtained 3,4-dichlorobenzoic acid phenylhydrazide melting at 169° to 172° C. An analytical sample melting at 171.5° to 173° C. was obtained by recrystallization from ethanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[OH:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>CC(C)=O>[OH:19][C:20]1[CH:27]=[C:26]([O:28][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:8]([F:18])([F:17])[F:7])=[CH:10][CH:11]=2)[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: O=Cc1ccc(O)cc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium carbonate (16.51 g) and 4-trifluoromethylbenzylbromide (18.47 ml) were added to an acetone solution of 2,4-dihydroxybenzaldehyde (15 g). The mixture was stirred at room temperature for 15 hours and further stirred at 60° C. for 7 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a white powder (12.76 g).