Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[O:5][CH:6]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)[N:8]=1.[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][CH2:26][C:20]=2[C:19]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O.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]>[Cl:17][C:18]1[CH:34]=[CH:33][C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])[CH2:25][CH2:26][C:20]=2[C:19]=1[NH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:7]2[N:8]=[C:4]([NH:3][CH3:2])[O:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CNc1nc(-c2ccc(CN)cc2)co1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)co1
Temperature: 95 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
Slurry 4-(2-methylamino-oxazol-4-yl)-benzylamine hydrochloride (485 mg, 1.8 mmol) in toluene (10 mL) and DMF (1 mL) at 90° C. under a nitrogen atmosphere. Degass and place under vacuum then purge with nitrogen three times. Add 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0:5 g, 1.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (161 mg, 0.18 mmol), BINAP (219 mg, 0.35 mmol) and cesium carbonate (1.6 g, 4.9 mmol) to the slurry at 90° C. Stir the mixture at 95° C. for 16 h in a sealed flask. Cool the reaction to room temperature, dilute with EtOAc (100 mL), filter through Celite®, and concentrate in vacuo to an oil. Purify by chromatography on silica gel (10 g, pre-packed cartridge) eluting with hexane/THF (40:1 to 4:1 gradient) followed by SCX chromatography (10 g) eluting with DCM and DCM/2M ammonia in methanol (1:1, 50 mL) to obtain 7-chloro-6-[4-(2-methylamino-oxazol-4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 mg, 20%). MS (ES+) m/z: 479.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.C(=O)([O-])O>>[CH3:1][C:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1ccc(NC(C)=O)cc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Product: CCOC(=O)C(C)(Cc1ccc(N)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
Mix diethyl methyl-(4-acetamido)benzylmalonate (5.01 g, 15.6 mmol) and 2N hydrochloric acid (65 mL) and heat at reflux for several hours. Cool to room temperature, basify with solid hydrogen carbonate and extract into ethyl ether (3×). Dry (MgSO4) and evaporate the solvent in vacuo to give diethyl methyl-(4-amino)benzylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
A mechanically stirred mixture of 6-bromonaphth-2-ol (10.00 g, 0.04483 mol), benzyl bromide (6.97 g, 0.0408 mol), potassium carbonate (11.26 g, 0.08147 mol) and butan-2-one (350 ml) was heated under reflux for 24 hrs. (GLC and TLC analyses revealed a complete reaction). The potassium carbonate was filtered off and the filtrate was washed with water before being dried (MgSO4). The drying agent was filtered off and the solvent was removed in vacuo to give a pale orange solid. The crude product was crystallized twice from ethanol and was dried in vacuo (P2O5, CaCl2, paraffin wax, 48 h) to afford white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:13]([CH3:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[C:20]([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:13]1[CH3:27])(=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:24]
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCC(=O)[O-])c1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCC(=O)OCOC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of the compound 68 (100 mg, 0.230 mmol) and potassium carbonate (48.0 mg, 0.345 mmol) in N,N-dimethylformamide (1 mL) was added pivaloyloxymethyl iodide (61 mg, 0.252 mmol), and stirred at room temperature for 2 hours. The reaction mixture was partitioned between ice-water and ethyl acetate - hexane (1:1)). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ethyl acetate (1:1)) to give the compound 74 (111 mg, 88%) as pale yellow oil. Rf 0.15 (1:1 EtOAc-hexane).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([O:14]CC)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C[Al](C)C.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.Cl.[NH4+].[OH-]>ClCCl.O>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:28][CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)Cc1cccc2cnccc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: C[Al](C)C
Agent: Cl
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccc2cnccc12)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
The product from Example 70D (0.207 g, 0.96 mmol) in dichloromethane (10 mL) was treated with trimethylaluminum (1 mL, 2.0 mmol, 2M in toluene) dropwise. After 30 minutes, the mixture was teated with 4-(trifluoromethyl)benzylamine (0.350 g, 2.0 mmol) in dichloromethane (2 mL) and then refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, treated with 1M HCl (3 mL), basified to between pH 9 and 10 with concentrated NH4OH, treated with water and CH2Cl2 and the phases separated. The organic layer was washed with water (1×10 mL), brine (1×10 mL), dried (MgSO4), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (5% methanol/CH2Cl2) to provide a yellow residue which was triturated with diethyl ether to provide the title compound as a white solid (0.122 g, 37%). MS (ESI+) m/z 345 (M+H)+; MS (ESI−) m/z 343 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.00 (s, 2H), 4.37 (d, J 5.7, 2H), 7.46 (d, J 7.8, 2H), 7.67 (m, 4H), 7.93 (d, J 5.4, 1H), 8.03 (d, J 7.8, 1H), 8.52 (d, J 5.8, 1H), 8.80 (t, J 5.7, 1H), 9.31 (s, 1H); Anal. Calcd for C19H15F3N2O: C, 66.28; H, 4.39; N, 8.14. Found: C, 66.16; H, 4.27; N, 7.96.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:15]
Reactant: O=C(Cl)CCCCBr
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a typical run, 2.6 equivalents of phenyl magnesium bromide are added to 1.0 equivalent of 5-bromopentanoyl chloride dissolved in dried diethyl ether under inert atmosphere at 0° C. and stirred during 15 minutes. After this time the mixture is warmed up to room temperature, and then ammonium chloride is added slowly to the mixture, and worked up in the usual manner to produce 5-bromo-1,1-diphenyl-1-pentanol as a white solid. The crude product is then refluxed during 6 hours with p-toluenesulfonic acid (ratio 60:1) under benzene, and worked up in the usual manner to yield 5-bromo-1,1-diphenyl-1-pentene as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:13]([CH3:14])=[C:12]([CH3:15])[CH:11]=2)=[O:6])[CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Reactant: Cc1cc(C(=O)NC2CC2)cc(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cc(C(=O)NC2CC2)cc(-c2ccc(C(=O)NCC3CC3)cc2)c1C
Temperature: 90 °C

Procedure:
3-Bromo-N-cyclopropyl-4,5-dimethylbenzamide (Intermediate 21, 30 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (28 mg), tetrakis(triphenylphosphine)palladium (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.5 ml) were mixed in propan-2-ol (2 ml) and heated at 90° C. under nitrogen for 24 hrs. The reaction was absorbed onto silica and applied to a SPE (Si, 10 g) and eluted with an ethyl acetate/cyclohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum and the residue recrystallised from ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-5,6-dimethyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[CH3:27][C:28]1([CH3:34])[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:27][C:28]1([CH3:34])[CH2:33][CH2:32][CH2:31][N:30]([CH2:15][C@H:12]([C@@H:11]2[C@:16]3([CH3:24])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:20]([C:19]=4[CH2:18][CH2:17]3)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:25])=[CH:9][CH2:10]2)[CH3:13])[CH2:29]1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: CC1(C)CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCCC(C)(C)C1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with 3,3-dimethyl-piperidine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(3,3-dimethylpiperidin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2].Br.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Agent: Br
Product: CCOC(=O)Cc1coc(-c2ccc(OCc3ccccn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64) and 2-(bromomethyl)pyridine hydrobromide. MS (m/e): 339.2 (M+1)
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[NH2:10][C:11]([CH3:18])([CH:15]([CH3:17])[CH3:16])[C:12]([NH2:14])=[O:13]>C(Cl)Cl>[CH3:9]/[C:3](=[C:2](\[CH3:1])/[C:7]([OH:6])=[O:8])/[C:4]([NH:10][C:11]([C:12]([NH2:14])=[O:13])([CH3:18])[CH:15]([CH3:17])[CH3:16])=[O:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: ClCCl
Product: C/C(C(=O)O)=C(\C)C(=O)NC(C)(C(N)=O)C(C)C
Yield: 96.3 %

Procedure:
A mixture of 46 g of dimethylmaleic acid anhydride, 48 g of 2-amino-2,3-dimethylbutyric acid amide and 70 ml of methylene chloride was heated at its boiling point for 15 minutes. After some of the solvent had been distilled off, the residual mixture was stirred with 300 ml of diethyl ether, and the product precipitated thereby was suction-filtered off. The desired compound (II) (90 g; 96%) was isolated as a crystalline solid, melting point 70°-72° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:23](=[O:28])[CH2:24][S:25]([CH3:27])=[O:26])=[C:17]([CH:22]=1)[N:18]([CH3:21])[CH:19]=[O:20]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:23](=[O:28])[CH2:24][S:25]([CH3:27])(=[O:6])=[O:26])=[C:17]([CH:22]=1)[N:18]([CH3:21])[CH:19]=[O:20]
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (0.63 g) was added to a solution of 5'-fluoro-N-methyl-2'-methylsulphinylacetylformanilide (0.78 g), prepared in a similar manner to that described in Example 8, in dichloromethane (25 ml). The mixture was stirred at ambient temperature for 2 hours and then washed with saturated aqueous sodium hydrogen carbonate solution (2×20 ml) and water (2×20 ml). Evaporation in vacuo gave an oil which was crystallised from toluene gave to give 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide, m.p. 95°-97° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[NH2:86][C:87]1[S:88][CH:89]=[CH:90][N:91]=1>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:86][C:87]1[S:88][CH:89]=[CH:90][N:91]=1)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: Nc1nccs1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C(=O)Nc3nccs3)ccc2c1)c1c[nH]cn1
Yield: 93.7 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (570 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with 2-aminothiazole (150 mg) in a similar manner as described in Example 24-(i) to give the titled compound (370 mg) as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])#[N:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C#N)c1
Yield: 99 %

Procedure:
tert-Butyl bromoacetate (9.01 g, 46 mmol) was dropwise added to a mixture of 3-cyanophenol (5.0 g, 42 mmol), potassium carbonate (13.82 g, 100 mmol) and DMF (40 ml) while stirring. After stirring for 8 hours, the mixture was poured onto ice water followed by extraction with ethyl ether. The extract was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was applied to column chromatography using silica gel (200 g) and eluted with hexane-ethyl acetate (3:1, v/v) to give the title compound (9.70 g, 99%) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[C:13][Si](C)(C)C)[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)#[CH:13]
Reactant: Cc1ccc2cc(C#C[Si](C)(C)C)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 2-methyl-6-trimethylsilanylethynyl-quinoline (2.1 g, 1.03 mmol, 1 eq) in solution in MeOH (5 mL) was added K2CO3 (5.69 g, 4.12 mmol, 4 eq), and the resulting mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and water was then added. The aqueous layer was extracted twice with cyclohexane, and then the combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration under reduced pressure the crude product was purified by column chromatography on silica gel (Cyclohexane-EtOAc 99:1) to afford 169 mg of 6-ethynyl-2-methyl-quinoline as a yellow crystal (98%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[S:11])[S-:10])[CH:5]=[CH:4][CH:3]=1.C([NH+](CC)CC)C.Cl[CH2:20][C:21](=[O:24])[CH2:22][CH3:23]>O>[CH2:22]([C:21]1([OH:24])[CH2:20][S:11][C:9](=[S:10])[N:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:23]
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CCC(=O)CCl
Agent: CC[NH+](CC)CC
Solvent: O
Product: CCC1(O)CSC(=S)N1c1cccc(C)n1
Reaction time: 3 h
Yield: 71.1 %

Procedure:
The procedure of Example 1 is followed but starting with triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (71.0 g) and 1-chlorobutan-2-one (26.6 g) in distilled water (300 cc) at 20° C. The reaction is carried out for 3 hours at 20° C. After recrystallisation of the product from ethanol (250 cc), there is obtained 4-ethyl-4-hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (45.0 g) melting at 118° C.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.CN(C=O)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:10]1[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
8-Chloro-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (2.0 g, 9.3 mmol) was dissolved in DMF (50 ml) K2CO3 (2.57 g, 18.6 mmol) and benzyl bromide (1.75 g, 10.3 mmol) were added and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was evaporated in vacuo the residue was dissolved in DCM:H2O (1:1) (100 ml) the water phase was extracted with DCM (50 ml) the combined organic phase was dried with MgSO4 filtered and evaporation gave 4A as a white crystalline compound. Yield: 2.92 g. Mp: 145.7–147.1° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1)[CH3:3].[C-]#N.[Na+]>[Cl-].[NH4+]>[CH3:22][C:2]([CH3:3])([O:4][C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:1]
Reactant: COC(=O)C(C)Cc1ccc(NCC(=O)OC(C)(C)C)cc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(Cc1ccc(NCC(=O)OC(C)(C)C)cc1)C(=O)O
Temperature: 70 °C

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]-alpha-methyl-benzenepropanoic acid, methyl ester (9.95 g, 32.4 mmol) in anhydrous hexamethylphosporamide (160 mL) and treat with sodium cyanide (1.59 g, 32.4 mmol). Heat at 70° C. for 48 hours, cool and dilute with saturated ammonium chloride (300 mL). Extract with ethyl ether (400 mL), wash with water (2×300 mL), then brine (300 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to give the title compound.
Reaction SMILES: [C:1]1([C:20]([OH:22])=[O:21])[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=2[C:4]([C:17]([OH:19])=O)=[CH:3][CH:2]=1.[Na][Na]>O.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+]>[C:6]12[C:14](=[O:16])[O:15][C:17](=[O:19])[C:4]3[C:5]1=[C:10]([C:1]([C:20]([OH:22])=[O:21])=[CH:2][CH:3]=3)[C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)c1ccc2c3c(ccc(C(=O)O)c13)C(=O)OC2=O
Yield: 97 %

Procedure:
After cooling to a temperature of 20° to 30° C., the suspension, which was present after the letting down, of the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid (NTC) was worked up by a process analogous to that described in Example 3 c) , by a procedure in which the disodium salt of NTC was first formed by acidification to pH 4.8 to 4.5 and was isolated, this salt was then dissolved in water by conversion into the tetrasodium salt, insoluble impurities were separated off by filtration, and the 1,8-monoanhydride of NTC was then precipitated by acidification with hydrochloric acid and was isolated. 13.1 kg of naphthalene-1,4,5,8-tetracarboxylic acid 1,8-monoanhydride of 96% purity, corresponding to a yield of 97% of theory, were obtained.
Reaction SMILES: C1COCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1>O>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH2:14][CH:41]1[CH2:42][CH2:43][CH:44]([CH:47]2[CH2:48][CH2:49][CH:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:62])([F:63])[F:64])=[CH:57][CH:56]=3)[CH2:51][CH2:52]2)[CH2:45][CH2:46]1
Reactant: O=C1CCC(C2CCC(CCc3ccc(C(F)(F)F)cc3)CC2)CC1
Reactant: c1ccc([PH](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Reaction time: 3 h
Yield: 41.9 %

Procedure:
THF (70 ml) was added to 1,3-dioxan-2-ylethyltriphenylphosphinebromide (6.80 g, 14.9 mmol), followed by adding to the mixture, potassium-t-butoxide (1.68 g, 14.9 mmol) at 0° C., stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 10 ml THF solution of the above 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (2.7 g, 7.7 mmol), stirring the mixture at the same temperature for one hour, further stirring at room temperature for 3 hours, adding water (50 ml) to the reaction solution, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting residue according to column chromatography treatment using heptane/ethyl acetate (3/1) as a developing solvent, on silica gel, distilling off the solvent, hydrogenating the residue (3.2 g) in the presence of a catalyst of 5% Pd/C (0.15 g), in ethanol solvent, filtering off the catalyst distilling off the solvent under reduced pressure, and recrystallizing the residue from heptane/ethanol (5/1), to obtain 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane (1.46 g, 3.23 mmol). The yield of this product from 4-(4-oxocyclohexyl)-1-(2-(4-trifluoromethylphenyl)ethyl)cyclohexane was 42%.