Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][S:7]1(=[O:12])=[O:11])([C:4]#[CH:5])[CH3:3].C[OH:14]>S(=O)(=O)(O)O.[Hg]=O>[O:11]=[S:7]1(=[O:12])[CH2:8][CH2:9][CH2:10][N:6]1[C:2]([CH3:1])([CH3:3])[C:4](=[O:14])[CH3:5]
Reactant: CO
Reactant: C#CC(C)(C)N1CCCS1(=O)=O
Agent: O=S(=O)(O)O
Agent: O=[Hg]
Product: CC(=O)C(C)(C)N1CCCS1(=O)=O
Temperature: 90 °C
Yield: 43 %

Procedure:
A mixture of 2-(2-methylbut-3-yn-2-yl)isothiazolidine-1,1-dioxide (3.500 g, 18.7 mmol) and mercury(II) oxide (0.810 g, 3.7 mmol) in methanol (100 mL) and 2 N aqueous sulfuric acid (50 mL) was heated at 90° C. for 3 hrs. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the desired product as a yellow oil (1.65 g, 43%). 1H NMR (300 MHz, CDCl3) δ 3.38 (t, 2H, J=6.6 Hz), 3.21 (t, 2H, J=7.5 Hz), 2.42-2.30 (m, 2H), 2.28 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([Br:26])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(-n2ccc(=O)c(OCc3ccccc3)c2)cc1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(benzyloxy)-1-(4-butylphenyl)pyridin-4(1H)-one (705 mg, 2.1 mmol) in AcOH (21 mL) was added N-bromosuccinamide (414 mg, 2.3 mmol) and the reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by flash chromatography (50 g Si02, 0-70% ethyl acetate/hexanes) to provide 3-(benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one. LC/MS (M+H)+ 412/414.
Reaction SMILES: O.[NH2:2][NH2:3].[SH:4][C:5]1[N:10]=[C:9](S)[CH:8]=[C:7]([CH3:12])[N:6]=1>C(O)C>[NH:2]([C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]([SH:4])[N:10]=1)[NH2:3]
Reactant: NN
Reactant: Cc1cc(S)nc(S)n1
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)nc(S)n1

Procedure:
Hydrazine monohydrate (6.4 ml) was added dropwise to a suspension of 2,4-dimercapto-6-methylpyrimidine (7.0 g) in 100 ml of ethanol at room temperature, the mixture was refluxed for two hours, and the crystals formed upon cooling were collected by filtration and washed with 100 ml of ethanol, giving 6.4 g of the objective compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:1]([O:8][C@@H:9]([CH3:14])[CH2:10][C:11]([N:17]([O:18][CH3:19])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CC(=O)O)OCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)butanoic acid (225 g) in DMF (1.5 L), N,O-dimethylhydroxylamine hydrochloride (111 g, 1.1 mol) and triethylamine (0.32 mL, 2.3 mol) were added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 1-hydroxybenzotriazole (112 g, 0.83 mol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (160 g, 0.83 mol) were successively added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was poured to ice-water, and it was extracted with diethyl ether. After it was successively washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) as a mixture. The present compound was used for the subsequent reaction without further purification.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15].CCN(CC)CC>CCOCC>[C:4]1([C:3]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:11]([O:19][CH3:20])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1onc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of (Z)-N-hydroxybenzimidoyl chloride (467 mg, 3 mmol) and dimethyl but-2-ynedioate (0.374 mL, 3.00 mmol) in Et2O (10 mL) at rt was added dropwise over 5 minutes Et3N (0.460 mL, 3.30 mmol). The reaction mixture became a thick suspension and was stirred at rt for 2 hr. After filtration, the filtrate was concentrated to an oil that was chromatographed on a 24 gm Isco silica gel cartridge, eluting with a 0-25% EtOAc/Hex gradient. The pure fractions were concentrated to afford dimethyl 3-phenylisoxazole-4,5-dicarboxylate (780 mg, 2.99 mmol, 100% yield) as a colorless oil. HPLC retention time=2.86 minutes (YMC Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=262.15. 1H NMR (500 MHz, CDCl3) d ppm 3.91 (s, 2H) 4.02 (s, 2H) 7.46-7.53 (m, 2H) 7.69 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N+:14]([O-])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(C2CC2)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C2CC2)c2ccccc12
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23 mmol) in ethanol (200 mL) was stirred under hydrogen in the presence of Pd/C (10% net, 1.8 g). The reaction mixture was shaken overnight, filtered over celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-amino-4-cyclopropylnaphthalene (3.1 g, 73%).
Reaction SMILES: O=[As:2]O[As]=O.C([O-])(=O)CS.[NH4+].[CH2:12]([C:14]([CH2:19][SH:20])([CH2:17][SH:18])[CH2:15][SH:16])[CH3:13]>C(O)C>[CH2:12]([C:14]12[CH2:19][S:20][As:2]([S:18][CH2:17]1)[S:16][CH2:15]2)[CH3:13]
Reactant: O=[As]O[As]=O
Reactant: CCC(CS)(CS)CS
Agent: O=C([O-])CS
Agent: [NH4+]
Solvent: CCO
Product: CCC12CS[As](SC1)SC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Arsenic trioxide (0.101 g, 0.506 mmol) was dissolved in ethanol (95%, 20 mL) and ammonium thioglycolate (827.2 μL of 5.5 M aqueous solution, 4.55 mmol) were stirred vigorously while heating to 50° C. After 60 minutes 4 (0.184 g, 1.01 mmol) was added, stirring continued for 20 minutes, cooled, and then filtered to remove insoluble material. The filtrate was taken to dryness, washed with water (2×15 mL), dissolved in dichloromethane (10 mL), dried over anhydrous magnesium sulfate, filtered, and taken to dryness to yield light yellow crystals. X-ray quality crystals were grown by slow evaporation from chloroform. Yield: 0.135 g, 50.3%. 1H NMR (CDCl3; 500 MHz) δ ppm: 0.89 (t, 3H, CH3), 1.39 (q, 2H, CH2) 2.94 (s, 6H, SCH2). 13C NMR (CDCl3 d6; 125.8 MHz) δ ppm: 8.17 (CH3), 31.29 (C), 31.65 (SCH2), 37.39 (CCH2). ESI-MS (m/z) 254.69 (254.93 calcd for [M+H]+ of [C6H11S3As]). Elemental Anal. calc'd (found) for C6H11S3As: C, 28.34 (31.42); H, 4.36 (4.70).
Reaction SMILES: Cl.[C:2]1([N+:8]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=CC=CC2C(=O)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([O:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH3:41])[CH:36]=[C:35]3[CH2:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][C:44]=2[O:52][CH3:53])=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24]1.[OH-:54].[Na+]>C(O)C>[C:17]1([N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]([O:48][C:47](=[O:49])[C:46]2[CH:50]=[CH:51][C:43]([CH2:42][C:35]3[C:34]4[C:38](=[CH:39][CH:40]=[C:32]([NH:31][C:29]([O:28][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)=[O:30])[CH:33]=4)[N:37]([CH3:41])[CH:36]=3)=[C:44]([O:52][CH3:53])[CH:45]=2)=[O:54])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: [OH-]
Reactant: NC(=O)C1C=CC=C[N+]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(=O)OC(=O)N(c2ccccc2)c2ccccc2)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reaction time: 0.25 h

Procedure:
N,N-Diphenylcarbamoylpyridinium hydrochloride (0.132 g.) was added to a stirred solution of 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3 -ylmethyl]-3-methoxybenzoic acid (obtained as described in Example 9) (0.15 g.) and sodium hydroxide (0.35 ml. of 1M aqueous solution) in absolute ethanol (6 ml.), under an atmosphere of nitrogen. The mixture was stirred for 15 minutes, and was then partitioned between ethyl acetate (50 ml.) and water (30 ml.). The organic layer was washed successively with 1M hydrochloric acid (20 ml.) and saturated brine (20 ml.), then dried (MgSO4), and evaporated to give 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride, as a white foam. This foam was dissolved in N,N-dimethylformamide (DMF) (3 ml.), and added to a stirred solution of the sodium salt of benzenesulphonamide (0.19 g.) in DMF (6 ml.), under an atmosphere of nitrogen. The mixture was stirred for 1 hour and then poured into 1M hydrochloric acid (40 ml.). The acid mixture was extracted with ethyl acetate (2×30 ml.). The combined extracts were dried (MgSO4) and evaporated. The yellow oil obtained was purified by the following successive procedures:
Reaction SMILES: [CH2:1]([CH:8]1[C:31](=[O:32])[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21][CH:20]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:19](=[O:53])[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:68][N:69]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][C:70]1=[O:76].C(=O)(O)[O-].[Na+]>FC(F)(F)S(O)(=O)=O>[CH2:46]([CH:20]1[C:19](=[O:53])[N:18]([CH3:54])[CH:17]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:16](=[O:59])[O:15][CH:14]([CH3:60])[CH2:13][N:12]([CH3:61])[CH:11]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:10](=[O:66])[O:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:68][N:69]3[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][C:70]3=[O:76])=[CH:6][CH:7]=2)[C:31](=[O:32])[N:30]([CH3:33])[CH:29]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:28](=[O:38])[O:27][CH:26]([CH3:39])[CH2:25][N:24]([CH3:40])[CH:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:22](=[O:45])[O:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C1CCCCCN1CO
Reactant: CC(C)CC1C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CC(C)CC1C(=O)OC(Cc2ccc(CN3CCCCCC3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
At 0° C., 200 ml of trifluoromethanesulfonic acid were initially charged and 20 g (0.0217 mol) of 8,20-dibenzyl-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (1-b) (for example from Ex. 1) and 6.2 g (0.0434 mmol) of N-hydroxymethyl-ε-caprolactam were added successively, and the mixture was stirred at room temperature for 20 h. The mixture was then poured onto ice, neutralized by addition of solid sodium bicarbonate and subsequently extracted with dichloromethane. The combined extracts were washed with little water, dried and concentrated. The resulting 26 g of crude product were separated by MPLC. The first main fraction gave 1.22 g of singly amidoalkylated compound 20-benzyl-8-[4-(2-oxoazepan-1-ylmethyl)benzyl]-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (20-a). After intermediate fractions of a total of 4.21 g, 5.59 g of doubly amidoalkylated compound 8.20-bis-[4-(2-oxoazepan-1-ylmethyl)benzyl]-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (20-b) were obtained.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.C[O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([OH:31])=[O:22])=[CH:11][CH:12]=1)([OH:3])=[O:20]
Reactant: COC(=O)c1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2C(=O)O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].[H-].[Na+].Cl[CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:21][CH:22]=[C:23]([Cl:25])[CH3:24])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CC(Cl)=CCCl
Reactant: CCCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1(CC=C(C)Cl)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
6,7-Dichloro-2,3-dihydro-5-methoxy-2-propyl-1H-inden-1-one (13.66 g, 0.05 mole) dissolved in toluene (80 ml) was added over 15 minutes with stirring under N2 to a suspension of 56% sodium hydride (2.36 g, 0.055M) in dimethylformamide (65 ml) and toluene (15 ml) at 25°. The mixture was stirred without external heat for 11/2 hours, at 50° C. for 1/2 hour and then cooled to 30° C. A solution of 1,3-dichloro-2-butene (7.81 g, 0.0625 mole) in toluene (10 ml) was added, and the mixture was heated at 50°-55° for 2 hours, poured into ice water, and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and chromatographed on silica with elution with 1/1 hexane/methylene chloride to obtain 14.5 g of product as an oil which was a mixture of cis-trans isomers.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH:14](C)[CH2:15][C:16](O)=O)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:20](=[O:23])([O-])[O-:21].[K+].[K+].[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]=1.CN(C)C=O>O>[N:26]1([C:2]2[O:3][C:4]([CH2:14][CH2:15][CH2:16][C:20]([OH:21])=[O:23])=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[N:6]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C([O-])[O-]
Reactant: CC(CC(=O)O)c1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]butanoic acid (2.03 g), potassium carbonate (2.76 g), benzimidazole (1.18 g) and N,N-dimethylformamide (30 mL) was stirred at 120° C. for 4 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed with water and dried to give 4-[2-(1H-benzimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]butanoic acid (2.22 g, yield 82%). Recrystallization from tetrahydrofuran-ethanol gave colorless needle crystals. melting point: 199–200° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]>>[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/methanolic ammonia=9.5/0.4/0.1 as eluant.
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39])C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][C@H:4]1[N:7]([C:8](=[C:22]([S:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:37])[C@@H:5]1[C@H:38]([OH:40])[CH3:39]
Reactant: ClCl
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2Cl)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a stirred solution of 1 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-{1(R)-hydroxyethyl}-azetidin-2-on-1-yl]-3-(4-methylthiophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -40° was added a solution of 1.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the reaction was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound as a pale yellow foam (0.66 g, 68%).
Reaction SMILES: C1(C(=CC=CC=1)O)O.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C@@:16]12[CH:25]3[CH2:26][CH2:27][C@:28]4([CH3:34])[C:32](=[O:33])[CH2:31][CH2:30][C@H:29]4[C@@H:24]3CC[C@@H]1C[C@H](O)[CH2:18][CH2:17]2.[I:36]I>C(Cl)Cl>[I:36][C@@H:10]1[CH2:18][CH2:17][C@@:16]2([CH3:15])[C@H:12]([CH2:13][CH2:14][C@@H:24]3[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:34])[C@H:29]3[CH2:30][CH2:31][C:32]2=[O:33])[CH2:11]1
Reactant: c1ccncc1
Reactant: II
Reactant: C[C@]12CCC3[C@@H](CC[C@@H]4C[C@H](O)CC[C@]34C)[C@@H]1CCC2=O
Agent: Oc1ccccc1O
Solvent: ClCCl
Product: C[C@]12CC[C@@H](I)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-α-methyl-5-β-androstan-17-one was synthesized by the addition of catechol phosphochloridate (35 g, 200 mmol) and pyridine (15 g, 189.6 mmol) to 3-α-hydroxy-5-β-androstan-17-one (50.1 g, 173.0 mmol) in 1000 ml of methylene dichloride. The solution was magnetically stirred for 0.5 hour at room temperature (25° C.). Iodine (70 g, 275 mmol) was then added slowly to the solution and the stirring continued for an additional 2 hours at 25° C. The solution was washed with aqueous sodium sulfite (5%), dilute HCl, water, and dried over magnesium sulfate. It is important that the sodium sulfite solution not be saturated to prevent formation of emulsions. Approximately half of the aqueous solvent was removed under reduced pressure. Ether (2000 ml) was then added, and the entire solution passed through a short column of neutral alumina to remove colored impurities. The ether/solvent was evaporated from the column effluent under reduced pressure to yield 3α-iodo- 5β-androstan-17-one. This product was pure enough to be used in the next step without recrystallization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:30](O)=[O:31])=[N:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:23]3[C:22]([Cl:21])=[CH:27][C:26]([C:28]#[N:29])=[CH:25][N:24]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I yielded the 3-chloro-5-cyano-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as a white solid. MS (ISP): m/z=452.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][O-:13].[Na+].[CH3:15][OH:16]>>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[C:6]([O:16][CH3:15])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CO
Reactant: CSc1nc(Cl)c(C)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(SC)nc(OC)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of 4,6-dichloro-5-methyl-2-(methylthio)pyrimidine (607 mg, 2.903 mmol) in MeOH (7 mL), NaOMe (1.25 g, 23.23 mmol) was added portionwise. The brown suspension was slowly allowed to reach rt, stirred at rt for 18 h and refluxed (85° C.) for 3 h. Due to the fact that the reaction was not completed, 0.4 eq. of NaOMe was added and the dark yellow suspension was refluxed (85° C.) for another 18 h. The reaction mixture was allowed to reach rt, then the solvent was removed and the residue was redissolved in EtOAc. The org. layer was washed with water, the aq. layer was reextracted with EtOAc (100 mL) and the combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (EtOAc/hept 3:97) yielded 4,6-dimethoxy-5-methyl-2-(methylthio)pyrimidine as a solid. LC-MS conditions A: tR=0.93 min, [M+H]+=201.12.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([CH:15]2[CH2:17][CH2:16]2)[N:12]=[C:11]([NH:18][CH:19]2[CH2:21][CH2:20]2)[C:10]=1[CH3:22]>COCC(O)C.ClCCl>[CH:1]1([NH:7][C:9]2[C:10]([CH3:22])=[C:11]([NH:18][CH:19]3[CH2:21][CH2:20]3)[N:12]=[C:13]([CH:15]3[CH2:16][CH2:17]3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(Cl)nc(C2CC2)nc1NC1CC1
Reactant: NC1CCCCC1
Solvent: COCC(C)O
Solvent: ClCCl
Product: Cc1c(NC2CCCCC2)nc(C2CC2)nc1NC1CC1
Temperature: 125 °C
Reaction time: 120 h
Yield: 17.5 %

Procedure:
A mixture of cyclohexylamine (1.78 g, 18 mmol) and 6-chloro-N,2-dicyclopropyl-5-methyl-4-pyrimidinamine 33 (0.70 g, 3 mmol) in 1-methoxy-2-propanol (2 ml) is stirred at 125° C. for 120 hours. After cooling, the brown solution is diluted with dichloromethane, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated under high vacuum to afford a brown oil. The crude oil is purified by column chromatography (dichloromethane/methanol: 97.3/2.7) to give pure N4-cyclohexyl-N6,2-dicyclopropyl-5-methyl-4,6-pyrimidinediamine 141 (0.150 g, 17%).