Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]1[S:13][C:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)=[CH:15][C:16]=1[OH:17].Br[CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]1[S:13][C:14]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:20]=2)=[CH:15][C:16]=1[O:17][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1
Reactant: COC(=O)CCc1sc(C(=O)c2cccc(C(=O)OC)c2)cc1O
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(C(=O)c2cccc(C(=O)OC)c2)cc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 81.9 %

Procedure:
804 mg of cesium carbonate is added to a solution of 430 mg of 3-[5-(3-Methoxycarbonylbenzoyl)-3-hydroxy-2-thienyl]-propionic acid methyl ester and 332 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 2.9 ml of dimethylformamide and the suspension is stirred for 21 hours at room temperature. The reaction mixture is filtered, the filtrate residue is washed with dichloromethane, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel with hexane. 542 mg of the title compound is obtained as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccnc(Cl)c1
Reactant: C1CCNC1
Product: Nc1ccnc(N2CCCC2)c1
Temperature: 200 °C
Yield: 79 %

Procedure:
A mixture of 2-chloro-4-aminopyridine 109 (2.29 g, 17.8 mmol) and pyrrolidine 68 (5.0 mL) was heated at 200° C. in a microwave reactor for 10 min. After cooling to room temperature, the solid was filtered and washed with dichloromethane (10 mL×3). The filter cake was dissolved in aqueous K2CO3 and extracted with CH2Cl2 (40 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to obtain 110 (2.30 g, 79% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol), 2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73 g, 0.53 mol) in NMP (200 mL) were stirred at 160° C. for 2 h. The reaction mixture was cooled to room temperature poured into water (250 mL) and extracted into EtOAc (2×100 mL). The organic layer was washed several times with water, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography eluting with hexane: EtOAc (95:5) to yield 66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid methyl ester (1A).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1.[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1O>ClCCl.O1CCCC1>[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1[O:42][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([I:34])[CH:36]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: OCc1cccc(I)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2cccc(I)c2)c(Cl)c1O
Reaction time: 18 h
Yield: 64.5 %

Procedure:
Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol) to a solution of (3-iodo-phenyl)-methanol (11.0 g, 47.0 mmol) and 1-(3-Chloro-2,4-dihydroxyphenyl)-ethanone (8.77 g, 47.0 mmol) in dichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18 hours, concentrate the reaction, and load directly onto silica. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (12.2 g, 64%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H), 7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([O:33][C:32]([F:31])([F:42])[F:43])[CH:35]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(OC(F)(F)F)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.5 g, 0.0012 mol) in DMF (10 mL), was added 3-(trifluoromethoxy)benzyl bromide (0.47 g, 0.0018 mol) and powdered potassium carbonate (1.16 g, 0.0084 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.61 g in 88% yield. 1H NMR (CDCl3) δ 7.20 (s, 1H), 7.19 (m, 11H), 7.04 (s, 1H), 7.01 (t, 2H), 6.88 (d, 1H), 6.69 (m 2H), 4.20 (t, 1H), 3.70 (s, 3H), 3.63 (s, 2H), 3.59 (s, 2H), 3.13 (d, 2H), 2.67 (t, 2H), 1.84 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.5, 149.6, 144.8, 136.7, 131.0, 130.9, 130.0, 129.8, 129.7, 129.6, 128.4, 127.8, 122.8, 122.7, 122.5, 120.6, 116.9, 114.5, 66.8, 61.3, 60.1, 53.4, 51.9, 51.2, 42.7, 28.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:20]#[C:21][NH2:22].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH:21]([NH2:22])[NH:20][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7]1
Reactant: N#CN
Reactant: COc1ccccc1CNNC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1CN1N=C(c2ccccc2)NC1N
Temperature: 120 °C
Reaction time: 4 h

Procedure:
Benzoic acid N′-(2-methoxybenzyl)hydrazide (200 mg, 0.78 mmol from 5.2) was dissolved in a mixture of 1.5 mL dioxane and 1 mL water, combined with 164 mg (3.9 mmol) cyanamide dissolved in 1 mL water, adjusted to pH 2 with 1 N HCl, then stirred for 4 hr at 120° C. in a microwave oven at 200 watts power. The pH was checked every 30 minutes and readjusted to pH 2 as necessary. The resulting solid was then suctioned off, washed with a small quantity of diethyl ether, and dried (65 mg target product in the form of a light yellow solid).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:9][CH:10]([CH3:14])[C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:8][C:11](=[O:12])[CH:10]([SH:9])[CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCC1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCC1

Procedure:
Reaction: ##STR128## Into a 50 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 11.4 grams cycloheptanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 10 hours. At the end of the 10 hour period, the reaction mass is distilled on a micro distillation apparatus to yield the compound having the structure: ##STR129##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]2[NH:65][CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]=2[CH:67]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:65]2[CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]3[CH:67]=[C:53]([Cl:52])[CH:54]=[CH:55][C:56]2=3)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid from Example E9 (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (0.70 ml, 4.0 mmol), PyBrop (2.40 g, 5.1 mmol), and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc) to yield the title compound (775 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]2[C:21]([CH3:30])=[C:22]([C:26]([F:29])([F:28])[F:27])[C:23]([CH3:25])=[CH:24][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.N1C=CC=CC=1.[CH3:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50]>ClCCl>[CH3:46][O:47][C:48](=[O:52])[C:49]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]2[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[C:15]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:27])([F:28])[F:29])=[C:21]([CH3:30])[C:16]1=2)=[O:50]
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)c(C)c21
Reaction time: 8 h
Yield: 81.2 %

Procedure:
Dissolve (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 148, Step 2) (0.200 g, 0.353 mmol) in dichloromethane (4 mL), cool the solution down with an ice-water bath. Add pyridine (0.143 mL, 1.77 mmol) followed by chloro-oxo-acetic acid methyl ester (0.162 mL, 1.77 mmol) dropwise. Warm up the reaction to room temperature and stir overnight. Dilute the reaction mixture with more dichloromethane (10 mL), and wash with aqueous NaHCO3 (10 mL). Extract back the aqueous layer with dichloromethane (10 mL). Combine the organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound (0.187 g, 81%). MS (ES+): 653 (M+H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C:11]2[N:12]=[C:13](Br)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:9])=[CH:3][CH:2]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][C:11]2[N:12]=[C:13]([C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:35][CH:34]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:9])=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(Br)n1
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: COCCOC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(-c2ccc(C(F)(F)F)cc2)n1
Yield: 86.4 %

Procedure:
A mixture of Example 14 (0.1 g, 0.24 mmol), 3-trifluoromethylphenylboronic acid (0.14 g, 0.72 mmol), Pd(PPh3)4 (0.028 g, 0.024 mmol) and 2N Na2CO3 solution (0.1 ml) in DME was heated at 75° C. for 12 h under nitrogen. The reaction mixture was cooled, and the solvent was evaporated. The resulting residue was purified by flash column chromatography (SiO2, 10% ethyl acetate in hexane) to provide the title compound (0.1 g, 87%) as a light yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH:12]1([CH2:11][C@H:2]([OH:1])[C:3]([N:5]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[O:4])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C([C@@H](O)CC1CCCCC1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
2 (1.02 g, 5.39 mmol, 1 eq) is dissolved in 60 mL of dry DCM and cooled to 0° C. Trichioroisocyanuric acid (1.32 g, 5.65 mmol, 1.05 eq) is added and mixed for 10 minutes resulting in a white slurry. TEMPO is added (8.8 mg, 0.056 mmol, 0.01 eq) to the chilled reaction mixture which immediately turns orange and additional precipitate is formed. The reaction vessel is removed from the cold bath and the mixture is stirred for additional 45 minutes. The reaction mixture is then filtered through a pad of celite, washed with 5% citric acid followed by saturated bicarbonate, dried over MgSO4, filtered, and stripped to yield pure 3 (0.979 g, 97% yield) which was used immediately in step C.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:23]([O:25][C:26](=O)[C:27]#[C:28][CH2:29][O:30]C)C>C(Cl)(Cl)Cl>[CH3:23][O:25][CH2:26][C:27]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:29](=[O:30])[CH:28]=1
Reactant: CCOC(=O)C#CCOC
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Solvent: ClC(Cl)Cl
Product: COCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)CC(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and 4-methoxy-but-2-ynoic acid ethyl ester (see Example 106) employing the procedure described in Example 95. [α]D25 −14.80 (c 0.5, CHCl3).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>ClCCl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)C(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 87.8 %

Procedure:
DL-Alanine methyl ester hydrochloride (13.96 g; 0.1 mol) is dissolved in 800 ml of dichloromethane and placed at 0° C. Triethylamine (2.3 eq.; 230 mmol; 32 ml) is added dropwise, along with portionwise addition of 2-nitrobenzenesulfonyl chloride (1 eq.; 100 mmol; 22.16 g), and the reaction medium is allowed to return to room temperature overnight. The reaction medium is washed with water and then dried over sodium sulfate, filtered through silica and evaporated to dryness to give 25.3 g of solid corresponding to the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N1C=CN=C1>C(Cl)Cl.CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a stirred solution of p-bromophenol (5) (4.0 g, 23.1 mmol) in DCM (40 ml) was added triisopropylsilyl chloride (5 ml, 23.4 mmol). The reaction mixture was cooled to 0° C. and imidazole (3.94 g, 57.9 mmol) was added and the mixture was stirred at 0° C. for 30 minutes then allowed to warm to ambient temperature over 12 hours. The reaction mixture was diluted with ether and sequentially washed with 0.5 M HCl (2×), sat. aq. NaHCO3, water and brine then dried over MgSO4. The crude product was purified by bulb to bulb distillation (boiling point: 149-150° C. at 2.0 mmHg) to give 6 as a clear oil (6.23 g, 82% yield): 1H-NMR (400 MHz, chloroform-d) δ 7.30 (d, J=8.8 Hz, 2 H), 6.75 (d, J=8.8 Hz, 2 H), 1.24 (septet, J=7.2 Hz, 3 H), 1.09 (d, J=7.2 Hz, 18 H); 3C-NMR (100 MHz, chloroform-d) δ 155.2, 132.2, 121.7, 113.2, 17.8, 12.6; FTIR (thin film) 2945, 2892, 2867, 1586, 1487, 1274, 909, 883, 828, 732 cm−1; HRMS (EI+) for C15H25BrOSi calcd. 328.0858 found 328.0844.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:16][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: CC(C)c1cccc(-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 67 %

Procedure:
700 mg (3.28 mmol) of 2-isopropyl-6-phenylphenol and 236 mg (9.84 mmol) of sodium hydride were dissolved in 10 ml of toluene, and then refluxed for 4 hours. The refluxed solution was cooled to room temperature, and then a solution of 930 mg (3.21 mmol) of trichloro(pentamethylcyclopentadienyl)titanium (IV) was slowly added dropwise thereto, and the mixture was refluxed for 24 hours. After completion of the reflux reaction, volatile components were removed from the reaction solution, and the residue was washed with purified hexane, recrystallized from a mixed solvent of toluene/hexane −35° C., filtered, and then dried in a vacuum, thus obtaining 1.0 g of a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 156.7 %

Procedure:
A mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.20 g), aminoguanidine hydrochloride (0.085 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (20 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 61) (0.21 g) as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([CH2:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:28][N:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([CH2:30][CH2:31][P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])=[CH:28][N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CCc1cn(-c2ccccc2)nc1O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.38 g), diethyl 2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethylphosphonate (0.47 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature. The mixture was stirred at room temperature for 6 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethylphosphonate as a colorless oil (0.60 g, yield 80%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v).
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH:12]C1C(C(F)(F)F)=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38]Cl.[H-].[Na+]>C1COCC1.C(Cl)(Cl)(Cl)Cl>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38][NH2:12]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Reactant: ClSc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: NSc1nc2ccccc2s1
Reaction time: 3 h

Procedure:
The sulfenylated diphenylamine was prepared from N-[2-chloro-5-(trifluoromethyl)phenyl]-2,4-dinitro-6-(trifluoromethyl)benzenamine (4.3 g, 0.010 mol) in dry THF (20 ml), 2-benzothiazolesulfenyl chloride [2.0 g, 0.010 mol, Zh. Obshch. Khim. 45, 1127 (1975)] in carbon tetrachloride (45 ml) and 50% NaH (0.53 g, 0.011 mol) as outlined in Example 1 with the following exception: the reaction mixture was stirred at 0° for 3 hours and then at room temperature for 16 hours. Purification by dry column chromatography (silica gel, hexane/ethyl acetate, 8.5/1.5) gave N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-trifluoromethyl)phenyl]-2-benzothiazolesulfenamide as a red-orange glass: mp 46°-53°; NMR (CDCl3) δ 7.20-8.25 (m, 7H, Ar-H), 8.8-9.05 (AB quartet, 1.6H, Ar-H); IR(KBr) 1600, 1540, 1500, 1330, 1270, 1170, 1150, 1130 and 1070 cm-1.