Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18](O)[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]([N:27]3[C:26](=[O:28])[C:25]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]4[C:23]3=[O:33])[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC[C@H](c1nc(-c2ccccc2)c(-c2ccccc2)o1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (4S)-4-(4,5-diphenyloxazol-2-yl)-4-hydroxy-1-butene (9.2 g) in THF (100 ml) were added phthalimide (7.0 g) and triphenylphosphine (12.5 g) and diethyl azodiformate (7.5 ml) at room temperature. The mixture was stirred for 2 hours at room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (4R)-4-(4,5-diphenyloxazol-2-yl)-4-phthalimido-1-butene (9.7 g). MS (m/z): 421 (M+ +1) IR (Nujol): 1760, 1710 cm-1NMR (CDCl3, δ): 3.1-3.4 (2H, m), 5.0-5.3 (2H, m), 5.63 (1H, dd, J=6.0, 10.0 Hz), 5.7-6.0 (1H, m), 7.2-8.0 (14H, m) HPLC; chiralcel OD, 10% isopropanol/hexane, 32.2 ml/min
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCC(O)c1ccc(C)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCC(c1ccc(C)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a flame-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 980 mg of 1-(4-methylphenyl)-butan-1-ol of Preparation 20 in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 660 mg of the title product as a white solid.
Reaction SMILES: [I-:1].[Na+].[CH3:3][C:4]1([CH3:13])[O:9][C:8](=[O:10])[CH:7]=[C:6]([CH2:11]Cl)[O:5]1>CC(C)=O>[I:1][CH2:11][C:6]1[O:5][C:4]([CH3:13])([CH3:3])[O:9][C:8](=[O:10])[CH:7]=1
Reactant: [I-]
Reactant: CC1(C)OC(=O)C=C(CCl)O1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C=C(CI)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Sodium iodide (2.16 g) was dissolved in 16 mL of acetone, 2.00 g of 2,2-dimethyl-6-chloromethyl-1,3-dioxin-4-one diluted with 4 mL of acetone was added, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was removed from the reaction mixture by filtration and the filtrate was concentrated. The residue was dissolved in 20 mL of chloroform, the insoluble matter was again filtered off and the filtrate was concentrated. The thus-obtained residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate =1/1 (volume ratio)) to give 2.65 g of 6-iodomethyl-2,2-dimethyl-4H-1,3-dioxin-4-one as a yellow liquid. The NMR spectrum of this compound is shown below.
Reaction SMILES: O[CH:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4].C(Cl)[Cl:25].Cl>O>[Cl:25][CH:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][CH2:10][NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCC(O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: O
Product: CCC(Cl)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 26.7 g. (75.4 mmole) 4-chlorobenzenesulphonic acid-4-(1-hydroxypropyl)-phenethyamide], 200 ml. methylene chloride and 100 ml. concentrated hydrochloric acid is vigorously stirred for 1 hour, then diluted with water and the methylene chloride phase is separated off. It is washed with water and sodium bicarbonate solution, dried with anhydrous sodium sulphate and evaporated. Yield quantitative; m.p. 90°-91° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]1C=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1N.O.[CH3:21][N:22]([CH3:25])[CH:23]=O>>[F:9][C:10]1[CH:11]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:23]=1[N:22]([CH3:25])[CH3:21]
Reactant: CN(C)C=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN(C)c1cc([N+](=O)[O-])ccc1F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (4.15 g, 30 mmol) and methyl iodide (1.49 mL, 24.0 mmol) were added to a solution of 2-fluoro-5-nitroaniline (1.56 g, 10.0 mmol) in N,N-dimethylformamide (30 mL) at room temperature and the mixture was stirred at 100° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford 2-fluoro-N,N-dimethyl-5-nitroaniline as a pale yellow oil (290 mg).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[N:30]=[CH:31][CH:32]=[CH:33][N:34]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-pyrimidin-2-yl-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.18 (d, 1H), 10.94 (s, 1H), 9.28 (s, 1H), 8.52 (d, 1H) 8.08 (d, 1H), 7.99 (d, 1H), 7.84 (d, 1H), 7.6 (d, 1H), 7.13 (d, 1H), 7.06 (m, 1H), 7.01 (m, 1H),; APCI−MS m/z 449 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][CH2:24][NH2:25]>>[CH3:17][N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][CH2:24][NH:25][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: CN1CCCC1CCN
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CN1CCCC1CCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 25.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (100 mg, 0.43 mmol) and 2-(1-methyl-pyrrolidin-2-yl)ethanamine (0.25 mL, 1.73 mmol) to provide 475 (35 mg, 25% yield) as a white powder. LC-MS (M+H=322, obsd.=322). 1H NMR (400 MHz, DMSO-D6) δ 11.47 (s, 1H), 8.65 (d, J=8.1, 1H), 8.43 (d, J=4.7, 1H), 7.99 (d, J=8.8, 1H), 7.18 (m, 2H), 6.89 (d, J=8.8, 1H), 6.65 (s, 1H), 3.24 (s, 2H), 2.98 (m, 1H), 2.25 (d, J=1.4, 3H), 2.02 (m, 2H), 1.97 (s, 2H), 1.66 (s, 2H), 1.52 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
tert-Butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate (7.15 g, 0.021 mol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (68.3 mL) and stirred at rt for 1 hour and concentrated to give the desired product (6.32 g, 96%) as an off-white powder. LCMS for C13H14N3O2 (M+H)+: m/z=244.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:32][N:33]([CH3:43])[S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:40]3[CH2:41][CH2:42][N:37]([S:34](=[O:35])(=[O:36])[N:33]([CH3:32])[CH3:43])[CH2:38][CH2:39]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1

Procedure:
Prepared in 55% (338 mg) yield as described in general procedure (B) from 4-[1-cyclohexyl-3-(5-formyl-thiazol-2-yl)ureido]-piperidine-1-carboxylic acid tert-butyl ester (436 mg, 1.0 mmol) and piperazine-1-sulfonic acid dimethylamide hydrochloride (230 mg, 1.0 mmol).
Reaction SMILES: [CH2:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=N)[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C[O:20]CCO>Cl.O>[CH2:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:20])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Cc1ccc(CC2SC(=N)NC2=O)cc1
Reactant: COCCO
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-(4-Acetonylbenzyl)-2-iminothiazolidine-4-one (1g) was heated under reflux in a mixture of 2-methoxyethanol 20 ml and 2N HCl (5 ml) for 8 h. The cooled mixture was diluted with water and the resulting precipitate filtered and dried under vacuum to give 5-(4-acetonylbenzyl)thiazolidine-2,4-dione as a white solid, mp 133°-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[CH3:2].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[C:8]([F:11])=[CH:7][C:6]=1[F:12])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4-Difluorobenzoic acid ethyl ester (5.33 g) was cooled to 0° C. and treated with concentrated sulfuric acid (3.5 mL) and then fuming nitric acid (3.5 mL). The mixture was stirred for 2 hours at 0° C. and then partitioned between dichloromethane (2×50 mL) and water (25 mL). The organic phase was back extracted with water (25 mL) and then dried over magnesium sulfate and concentrated in vacuo. This provided the desired compound as a white solid (5.00 g) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].CS[C:9](=[NH:11])[NH2:10].OS(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])[C:9]([NH2:11])=[NH:10]
Reactant: CSC(=N)N
Reactant: NCCCCN
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)NCCCCN
Reaction time: 12 h

Procedure:
To 1.8 g. of 1,4-diaminobutane dissolved in 50 ml. of H2O was added, dropwise, a solution of 2 g. of S-methylthiopseudourea.H2SO4 in 20 ml. of H2O. Throughout the addition, the solution was stirred vigorously and continued for 12 hours after the completion of addition. Then H2O was lyophilized, giving viscous colorless oil, which upon addition of 50 ml. of methanol precipitated 1.05 g. of white powder. Mass spec. (FD.) ions at m/e 228 and 130 for H2N--(CH2)4 --NHC(=NH)--NH2.H2O4 and H2N--(CH2)4 --NHC(=NH)--NH2, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1F)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was added 3-nitro-4-fluorotoluene (1.55 g, 10 mmol), 4-amino-1-N-Boc-piperidine (2.40 g, 12 mmol), powder K2CO3 (2.76 g, 20 mmol) and dry DMF (30 mL). The mixture was stirred at 85° C. overnight. Solvents were evaporated under reduced pressure. The residue was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4 and filtered. Removal of solvents under reduced pressure gave an oil residue. 4-(4-methyl-2-nitrophenylamino)-piperidine-1-carboxylic acid tert-butyl ester was isolated as a solid (3.13 g, 94%) from Biotage flash column chromatography using hexanes and ethyl acetate (3/1 ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[N:25]=1>>[CH3:31][C:26]1[N:25]=[C:24]([N:14]2[CH2:15][CH:16]3[CH2:17][N:10]([C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:18]4[N:22]=[CH:21][CH:20]=[N:19]4)=[O:9])[CH2:11][CH:12]3[CH2:13]2)[CH:29]=[C:28]([CH3:30])[N:27]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Reactant: Cc1cc(Cl)nc(C)n1
Product: Cc1cc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)nc(C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and 4-chloro-2,6-dimethyl-pyrimidine. MS (ESI): mass calculated for C21H22FN7O, 407.45, m/z found 408.2 [M+H]+. 1H NMR (CDCl3) 7.97 (dd, J=9.0, 4.8 Hz, 1H), 7.73 (s, 2H), 7.25-7.19 (m, 1H), 7.16-7.10 (m, 1H), 5.94 (s, 1H), 3.95-2.88 (m, 10H), 2.50 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)[CH3:2].[OH-].[K+]>ClCCl.O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6]>[CH2:22]([N:3]([CH2:1][CH3:2])[C:4](=[O:21])[CH:5]=[C:6]1[CH:11]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:9](=[O:16])[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7]1)[CH3:23]
Reactant: CCN(CC)C(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Fe+6]
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
4.80 g (0.015 Mol) of N,N-diethyl-2-(3,5-di-tert-butyl-4-hydroxy-phenyl)acetamide are dissolved in 60 ml of dichloromethane. To this solution a solution of 15 g (0.046 mol) of potassium hexacyanoferrate (IlI) and 6.0 g (0.11 mol) of potassium hydroxide in 120 ml of water is added, and the mixture is stirred one hour at room temperature under nitrogen. The organic layer is separated, washed with water and evaporated in vacuo. The solid residue is recrystallized from acetonitrile to give 3.6 g of the title compound as yellow needles, melting at 109°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[OH:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[O:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(C(O)c2cc(OC)cc(OC)c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cccc(C(=O)c2cc(OC)cc(OC)c2)c1

Procedure:
To a stirred solution of (3,5-dimethoxyphenyl)-(3-methoxyphenyl)methanol (2.47 g, 9.0 mmol) in CH2Cl2 (20 ml) at rt was added activated MnO2 powder (3.91 g, 45 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed at least 98% conversion occurred. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3,5-dimethoxy-phenyl)-(3-methoxy-phenyl)methanone was an oil (2.35 g, 92%): 1HNMR (CDCl3) δ 7.38-7.35 (m, 3H, Ar), 7.15-7.13 (m, 1H, Ar), 6.93 (d, J=2 Hz, 2H, Ar), 6.67 (t, J=2 Hz, 1H, Ar), 3.86 (s, 3H, single OCH3 group), 3.83 (s, 6H, 2OCH3), 0.99 (s, 9H, 3OCH3). The product was carried over to the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.O[Li].O>>[C:4]([C:6]1([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])[CH2:7][CH2:8][CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OCC)CCC1
Agent: [Li]O
Solvent: O
Product: CC(C)(CCCCC(=O)CCCCC1(C(=O)O)CCC1)C(=O)O

Procedure:
Compound 107e was prepared likewise Method D starting from 106e (8.83 g, >90% pure by 1H NMR, 20.8 mmol) and LiOH.H2O (2.91 and 1.94 g after 18 h, 69.4 and 46.2 mmol) to give, after recrystallized from iPr2O/heptane, 7e (5.19 g, 76%) as a white solid. mp=53-55° C. 1H NMR: δ 10.80 (br s, 2H), 2.50-2.35 (m, 2H), 2.39 (t, J=7.2 Hz, 4H), 1.98-1.74 (m, 6H), 1.65-1.49 (m, 6H), 1.31-1.11 (m, 4H), 1.18 (s, 6H). 13C NMR: δ 210.6, 184.3, 183.4, 47.6, 42.7, 42.6, 42.2, 40.5, 37.8, 30.1 (2×), 25.1 (2×), 24.8, 24.7, 24.2, 24.1, 15.7.
Reaction SMILES: [H-].[Na+].[C:3](=[N:13][OH:14])([NH2:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:15]1([C:21]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:27][CH:26]([C:28](OC)=O)[CH2:25][N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:38]1([C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:22]2[CH2:27][CH:26]([C:28]3[O:14][N:13]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:12]=3)[CH2:25][N:24]=[CH:23]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCCCCCCCC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 104 mg, 2.6 mmol) and n-nonanamidoxime (448 mg, 2.6 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (1.0 g, 2.6 mmol) was added dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-octyl-1,2,4-oxadiazol-5-yl)pyrimidine 780 mg (60%). This product was dissolved in triflouroacetic acid (2 ml), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 182 mg (30%) white crystals, mp 97°-99° C. identified by 300 MHz nmr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
7 g (31.6 mmol) of 3-bromobenzylamine, 100 ml of THF and 9.6 ml (69.2 mmol) of triethylamine are placed in a three-necked flask under a stream of nitrogen. 4 ml (34.6 mmol) of benzoyl chloride are added dropwise and the mixture is stirred for 1 hour at room temperature. The reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. 9.2 g (100%) of the desired product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Oc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(Oc3ccccc3)c2)CC1
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(O)[O-].[O:8]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C>O.CN(C)C=O.C(O)(=O)C>[C:1]([CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=1)#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 1 %

Procedure:
A solution of 0.765 Kg of sodium cyanide in 3.8 liters of water was added with stirring at 5° C. over 10 minutes to a mixture of 3.700 Kg of combination bisulfite of m-phenoxy-benzaldehyde (98% titer) in 7.4 liters of dimethylformamide and 3.8 liters of acetic acid were added thereto over 30 minutes at 5° C. The mixture was stirred for 30 minutes at 10° C. and the reaction mixture was then poured into a mixture of water and ethyl acetate. The mixture was stirred and decanted and the aqueous phase was extracted twice more with ethyl acetate. The combined ethyl acetate phases were washed with water, dried and stirred with 0.37 Kg of activated charcoal and 0.37 Kg of sodium sulfate. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 2.770 Kg of α-cyano-3-phenoxy-benzyl alcohol containing 1% of dimethylformamide.