Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([C:33](O)=[O:34])[CH:27]=[CH:26]2)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH2:20][CH3:21])[CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:22])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH2:37]([O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:44])[CH2:41][N:42]([C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:3]([CH2:1][CH3:2])([C:6]3[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH2:20][CH3:21])[CH:14]([OH:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[C:8]([CH3:22])[CH:7]=3)[CH2:4][CH3:5])[CH:24]=2)[CH:29]=1)=[O:34])[CH3:43])[CH3:38]
Reactant: CCOC(=O)CNC
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1ccc2cc(C(CC)(CC)c3ccc(OC(CC)C(O)C(C)(C)C)c(C)c3)ccc2c1
Yield: 88 %

Procedure:
Following a procedure analogous to Example 7E esterify the diastereomeric isomer pair 1 of 6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-naphthalene-2-carboxylic acid using N-methyl glycine ethyl ester hydrochloride to provide the title compound as a white foam (315 mg, 88%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.2 Hz, 6H), 0.93 (t, J=8.4 Hz, 3H), 0.93 (s, 9H), 1.31 (m, 3H), 1.68 (m, 1H), 1.80 (m, 1H), 2.12 (s, 3H), 2.17 (q, 4H), 2.60 (bs, 1H), 3.11 (s, 2H), 3.16 (s, 1H), 3.27 (s, 1H), 4.05 (s, 0.73H), 4.27 (m, 3H), 4.32 (s, 1.27H), 6.63 (d, J=8.8 Hz, 1H), 6.90 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.16 (d, J=10.0 Hz, 1H), 7.49 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.68 (m, 1H), 7.81 (s, 1H), 7.87 (m, 2H). High Res. ES-MS: 598.3488; calc. for C36H49NO5+Na: 598.3509. Analysis for C36H49NO5; Calcd: C, 75.10; H, 8.58; N, 2.43. Found: C, 75.04; H, 8.58; N, 2.43.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[OH:17]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[C:9]([CH3:16])[CH:10]=[C:11]2[OH:13])=[CH:6][CH:7]=1.[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C(C)Cc1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Product: CC(=O)Cc1ccc(Br)cc1
Product: Cc1cc(O)c2cc(Br)ccc2c1
Temperature: 50 °C

Procedure:
A flask containing the crude ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate from above (˜30 grams) was treated with concentrated H2SO4 (120 mL) and warmed to 50° C. for 2.5 h. The reaction was poured onto ˜500 mL of crushed ice. Once the ice had thawed, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated to ˜55 mL. The residue was treated with DCM and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (16.6 g, 60% yield over 2 steps from 1-(4-bromophenyl)propan-2-one. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=1.9 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.6, 2.0 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)NNC(=O)C(O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1c(C(=O)NNC(=O)C(=O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
172 mg of N′-[2-(3,5-difluorophenyl)-2-hydroxyacetyl]-4-benzyloxy-2-ethyl-3-methylbenzohydrazide (C3) are dissolved in 0.9 ml of dimethyl sulfoxide and 28 ml of dichloromethane under a dry nitrogen atmosphere. 185 mg of triacetoxyperiodinane (Dens-Martin reagent) are subsequently added. The suspension is stirred at room temperature for 1 h. For work-up, 100 ml of dichloromethane and 30 ml of 0.5 M Na2S2O3 solution are added. The organic phase is subsequently extracted with 50 ml of sat. NaHCO3 solution, dried over Na2SO4, filtered off with suction and evaporated to dryness. The residue is purified by means of flash column chromatography on silica gel (solvent gradient: cyclohexane/0-30% by vol. of methyl tert-butyl ether), giving 163 mg of the title compound as amorphous solid; MS: 452.7 (2M+H+); TLC: Rf=0.37 (cyclohexane/ethyl acetate 2:1, parts by volume).
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=[N:27][OH:28])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: Cc1ccc2c(c1)C(=O)CCC2C1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)C(=NO)CCC2C1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 5.20 grams (21.49 mmol) 4-cyclohexyl 7-methyl-1,2,3,4-tetrahydronaphth-1-one, 54 mL methanol, 3.25 grams (32.23 mmol) triethylamine, and 2.22 grams (32.23 mmol) hydroxylamine hydrochloride. The reaction was stirred at room temperature for 1.5 days, evaporated, partitioned between ethyl acetate and water, and the aqueous layer extracted with fresh ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated to an oil, which was used directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.N1CC=C([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[CH:24]=[CH:23]2)CC1.C(O[BH-](O[C:42](=O)[CH3:43])OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH:13]([N:22]3[CH2:43][CH:42]=[C:25]([C:24]4[C:25]5[C:30](=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[NH:22][CH:23]=4)[CH2:24][CH2:23]3)[CH3:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: Fc1ccc2ccn(C3=CCNCC3)c2c1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cccc2c(CC(C)N3CC=C(c4c[nH]c5cc(F)ccc45)CC3)coc12

Procedure:
3-{1-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-6-fluoro-1H-indole was prepared by generally following the procedure outlined in example 41, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 3 (1,2,3,6-tetrahydro-4-pyridinyl)-6-fluoro-1H-indole (216.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it with 80% ethyl acetate:hexane. Brown solid; Yield: 60 mg (14%); 405 (M+H); 1HNMR (400 MHz, CDCl3): δ 8.31 (broad, s, 1H, NH); 7.92˜6.88 (m, 7H); 6.25 (s, 1H); 3.85 (s, 3H), 3.50˜2.60 (m, 10H); 1.03˜1.05 (d, J=8.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O-])=[O:7])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[O:20]1[CH2:3][CH:2]1[CH2:1][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][OH:7]
Reactant: C=CCOC(C(=O)[O-])c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OCC(OCC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Dissolve 2-(allyloxy)-2-phenylacetate (850 mg, 4.77 mmol) in DCM (40 mL) and add m-chloroperoxybenzoic acid (1.5 g, 8.69 mmol) in a single portion. Stir at ambient temperature overnight. Concentrate under reduced pressure and purify via flash column chromatography using 10% MeOH in DCM to elute. Remove the solvents under reduced pressure to give the product as a colorless oil (900 mg, 97.2%). MS (m/z): 195 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:6][C:5]2([CH3:31])[CH3:30].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:3]([OH:32])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=1[CH:16]=[CH:17][NH:18][C:19]3=[O:24])[C:7]([OH:29])([C:25]([F:28])([F:26])[F:27])[CH2:6][C:5]2([CH3:30])[CH3:31]
Reactant: COc1c(Cl)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2c(c(O)c1Cl)C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)[nH]ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
40 mg (0.083 mmol) of (rac.) 5-{[6-chloro-2-hydroxy-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-isoquinolin-1(2H)-one is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since starting material is still present, another 0.8 ml of boron tribromide solution is added, and it is stirred for 16 hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate solution (pH 8) at −30° C. The batch is mixed with ethyl acetate, and the cold bath is removed. After 10 minutes of vigorous stirring at room temperature, the batch is extracted twice with ethyl acetate. The organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane) after the solvent is spun off 19.9 mg (51.2%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:8](=[O:9])[NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].O>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:8](=[O:9])[N:7]1[C:32](=[O:33])[NH:31][CH:28]([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(=O)n(-c2cc(Cl)cc(Cl)c2)c(=O)n1C(=O)NC(C)C
Yield: 75 %

Procedure:
To a solution of 3.2 g of 1-ethoxycarbonyl-4-(3',5'-dichlorophenyl) urazole in 10 ml of N,N-dimethylformamide were added, in sequence, a drop of triethylamine and 0.85 g of isopropyl isocyanate dropwise at room temperature with agitation. After maintaining the same conditions for one hour, the reaction mixture was mixed with water to precipitate crystals which were filtered and recrystallized from ethanol to obtain 1-ethoxycarbonyl-2-(isopropyl carbamoyl)-4-(3',5'-dichlorophenyl) urazole in an amount of 3.0 g, a yield of 75%.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:2].[ClH:1].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[CH:12][C:11]=1[CH3:17]
Reactant: Cc1cc(N)ccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N2CCNCC2)ccc1F
Reaction time: 24 h
Yield: 12.1 %

Procedure:
A solution of 56.3 g (0.315 mol) of bis(2-chloroethyl)amine hydrochloride and 35.9 g (0.287 mol) of 4-fluoro-3-methylbenzeneamine in 500 mL of absolute ethanol was heated at reflux for 24 h under a nitrogen atmosphere. The mixture was cooled and 65.3 g (0.473 mol) of anhydrous potassium carbonate was added and heating was continued for 24 h. The hot mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to yield a crude solid. This solid was converted to the base and purified by column chromatography using 500 g of silica gel on a 30 cm×10 cm column, eluted with methanol. The fractions containing the product were combined and concentrated. The residue was partitioned between water and ethyl ether. The ethyl ether layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 9.3 g (14%) of a light-pink oil. A portion of the oil was converted to the dihydrochloric acid salt and the solid was recrystallized from 2-propanol to yield a white solid, mp 188°-191° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.O.[NH2:11][NH2:12]>CCO>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:11][NH2:12])=[N:6][CH:7]=1
Reactant: NN
Reactant: Cc1cc(Cl)ncc1Br
Solvent: O
Solvent: CCO
Product: Cc1cc(NN)ncc1Br
Temperature: 120 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Combined 5-bromo-2-chloro-4-methylpyridine (15.0 g, 72.46 mmol) and EtOH (60 mL) and added hydrazine hydrate (85%, 45 mL) and stirred at 120° C. overnight. The reaction mixture was concentrated to give a residue which was extracted with EtOAc (50 mL×2) and water (50 mL×2). Then combined organic layers were extracted with brine, dried over Na2SO4 to and concentrated to give a residue which was purified by flash chromatography (petroleum ether:EtOAc=10:1 to 1:5) to give the title compound (7.8 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine and 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound was prepared as a solid having a melting point of 243-244° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[CH3:22][S:19]([OH:21])(=[O:20])=[O:18].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: C1CNCCN1
Product: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Product: CS(=O)(=O)O
Temperature: 115 °C

Procedure:
Piperazine (149.2 g, 8 mol equiv) was heated to a melt and 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see (International Patent Application Publication No. WO93/19059) (54.5 g, 217 mmol)was then added. The mixture was heated at 115° C. for 24 hours, then cooled and the excess piperazine removed in vacuo. The residue was purified by flash chromatography (silica, methanol:dichloromethane, 1:19) to give the title compound (51 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH3:34].C(OCC)(=O)C>C(#N)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:34])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(SC)cc1OC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(SC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
510 mg (3.15 mmol) of N,N'-carbonyldiimidazole were added to a solution of 1.142 g (2.42 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxy-4-methylthiophenyl)octanamide (prepared as described in Preparation 31A) in 10 ml of acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour, after which 0.79 ml (12.1 mmol) of 28% w/w aqueous ammonia. The reaction mixture was stirred for 5 hours, after which it was diluted with water, and the diluted aqueous mixture was freed from the organic solvent by distillation under reduced pressure. The aqueous concentrate was extracted with ethyl acetate. The extract was washed with 2 N aqueous hydrochloric acid, with a 0.5 N aqueous solution of sodium hydroxide, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 962 mg (yield 84%) of the title compound as crystals, melting at 171-172° C. (from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=NO)[C:11]=2[CH:12]=1.CC(C)=[O:17]>Cl>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cn1)CCCC2=NO
Reactant: CC(C)=O
Agent: Cl
Product: COc1cc2c(cn1)CCCC2=O
Temperature: 25 °C

Procedure:
A solution of 3-methoxy-7,8-dihydro-5(6H)-isoquinolinone oxime (1.20 g, 6.25 mmol) in a mixture of acetone (40 ml) and 6M hydrochloric acid (27 ml) was refluxed for 4 h then allowed to cool to room temperature. The mixture was concentrated to remove acetone then basified with sodium carbonate and extracted four times with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated and the residue subjected to column chromatography (silica, ethyl acetate-hexane, 1:4) to afford the title compound (0.81 g) as a white solid m.p. 7981°. MS (ES+) 178 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH3:17].C(=O)([O-])[O-].[K+].[K+].O.[CH2:25](O)[CH3:26]>>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O:14][CH2:25][CH3:26])=[O:13])=[CH:10][C:9]=1[CH3:17]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: CCO
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc(OCC(C)(C)O)c(C)c1
Temperature: 80 °C

Procedure:
A mixture of 1-chloro-2-methyl-propan-2-ol (10 mL), 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13.15 mmol), potassium carbonate (7.3 g, 52.71 mmol), water (6 mL) and ethanol (60 mL) was heated at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between 1N NaOH and EtOAc and the layers were separated. The organic layer was washed with 1N NaOH (2×10 mL) and the combined aqueous layers were washed with EtOAc. The combined organic layers were dried and concentrated in vacuo to give ethyl 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoate. The ester was dissolved in ethanol (15 mL) and water (2 mL), sodium hydroxide (1.1 g, 26.30 mmol) was added and the reaction mixture was stirred at 40° C. for 4 hours. The reaction mixture was poured into 1N NaOH solution and extracted with ether (2×10 mL). The aqueous layer was acidified to pH 2-3 using 6N HCl solution and extracted with EtOAc (3×10 mL). The organics were separated and washed with brine solution. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting material was triturated with ether to give 4-(2-hydroxy-2-methyl-propoxy)-3-methyl-benzoic acid (2.2 g, 75%) as a white solid. ESI-MS m/z calc. 224.1. Found 225.5 (M+1); Retention time: 1.06 minutes (3 min run) 1H NMR (400 MHz, DMSO) δ 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.73-7.70 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 4.67 (s, 1H, OH), 3.76 (s, 2H), 2.20 (s, 3H), 1.22 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([O:30]C(=O)C)=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:35])[C:5]([CH3:34])=[C:6]([CH2:12][C:13]2[C:14]([OH:30])=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2O)=C(C)C1=O
Yield: 63.3 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-methoxyaniline (0.040 g, 0.0834 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) to obtain the titled compound (0.025 g, 0.0528 mmol, 69%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)c1cccs1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)c3cccs3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, thiophene-2-carbonyl chloride (29 mg, 197 mmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (9.6 mg, 28% of theory).
Reaction SMILES: O[CH2:2][C:3]1[C:8](Cl)=[CH:7][CH:6]=C[C:4]=1[C:10]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:20].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:40]([Cl:42])Cl>>[Cl:42][C:40]1[CH:2]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:4]([C:10]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20]
Reactant: ClCCl
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(O)c1cccnc1-c1cccc(Cl)c1CO
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cccnc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
2-(Hydroxymethyl-3-chlorophenyl)-3-carboxypyridine was dissolved in a solution of methylene chloride/glacial acetic acid (5:1). Pyridinium dichromate (10.95 g, 29 mmoles) was added and the solution was stirred at room temperature under an inert atmosphere. The solvent was removed yielding 2-(3-chlorobenzoyl)-3-carboxypyridine.