Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Furoic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52 min, MH+ 328. NMR: δH [2H6]-DMSO 9.92,(1H, b), 8.36,(1H, d), 8.23,(1H, d), 7.80,(1H, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H, s).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:22]3[CH:27]=[CH:28][C:19]([O:18][CH3:17])=[CH:20][C:21]=3[O:26][CH2:25][CH2:24]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1ccc2c(c1)OCCN2
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCOc3cc(OC)ccc32)c1=O

Procedure:
Prepared in a similar fashion as described for Example aaa using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3) δ 6.91 (d, J=9.5 Hz, 1H), 6.69 (s, 1H), 6.46–6.41 (m, 2H), 4.92–4.82 (m, 1H), 4.34–4.31 (m, 2H), 4.20–4.16 (m, 2H), 3.76 (s, 3H), 2.64–2.50 (m, 1H), 2.24–2.12 (m, 1H), 1.96–1.40 (m, 7H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 390.1595 [(M+H)+, calcd for C20H25N3O3Cl 390.1584].
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O:28][C:29](=[O:39])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:38][C:34]3[CH:33]=[C:32](/[CH:31]=[CH:30]/[C:29]([OH:28])=[O:39])[CH:37]=[CH:36][CH:35]=3)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)/C=C/c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 3-(3-amino-phenyl)-acrylic acid methyl ester (prepared in two steps from 3-nitro-benzaldehyde) according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.55 (1H, br s), 8.00 (1H, s), 7.86 (1H, m), 7.57 (1H, d), 7.36 (2H, m), 6.50 (1H, d), 2.89 (2H, m), 2.68 (1H, m), 1.94 (5H, br s), 1.80-1.51 (17H, m), 1.39-1.19 (5H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.52; H, 8.50; N, 7.59%. C38H56N4O8.3.0 mols H2O requires: C, 60.78; H, 8.32; N, 7.46%.
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][N:12]([CH2:8][P+:3]1([CH2:1][N:12]([CH3:11])[C:13]([NH:15][CH3:16])=[O:14])[CH2:4][N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[CH2:6]1)[C:13]([NH:15][CH3:16])=[O:14]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+]1(CN(C)C(=O)NC)CN(C)C(=O)N(C)C1
Yield: 67.5 %

Procedure:
Reaction of THPC (19.06 g, 0.1 mol) with 1,3-dimethylurea (26.44 g, 0.3 mol) in toluene (75 ml), following Example 19, gave 25.85 g (67.5%) of 5,5-bis(1,3-dimethylureidomethyl)-1,3-dimethyl-2-oxo-1,3-diaza-5-phosphoniacyclohexane chloride (IV, R=R'=CH3, X=Cl) as a white, crystalline solid, mp 191°-192.5° C. dec. The remainder (11.89 g) was a viscous yellow oil. Two recrystallizations from 2-propanol (5 ml/g), followed by thorough drying in a vacuum at 100° C., gave pure product, mp 196°-197° C. dec.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](I)=[C:8](F)[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(NCC)C.[Cu]I>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCc1ccc(I)c(F)c1
Agent: [Cu]I
Solvent: CCNCC
Product: CCCCCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.1 mol of 4-pentyl-2-fluoro-iodobenzene, 0.12 mol of trimethylsilylacetylene, 0.0014 mol of bis(triphenylphosphine)-palladium(II) chloride Pd(PPh3)2Cl2 and 0.7 mmol of copper (I) iodide in 250 ml diethylamine is stirred at room temperature for 20 hours. After evaporation of the solvent the crude product is purified by chromatography on alumina (4:1 petrol/difluoromethane) to give 2-(4-pentylphenyl)-1-trimethylsilylacetylene. Removal of the trimethylsilylgroup is accomplished by treatment this acetylene in methanol with 1M KOH for 1 hour at room temperature. Evaporation of the methanol and either extraction yields 4-pentyl-2-fluoro-phenylacetylene.
Reaction SMILES: [OH:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH2:8]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:4][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-hydroxy-4-benzyl piperidine (0.66 g, 3.5 mmol) in 1M NaOH (7 mL, 7 mmol) and dioxane (5 mL) at 0° C. was treated with BOC2O (0.76 g, 3.5 mmol), warmed to room temperature, stirred for 16 hours, adjusted to pH<7 with 10% citric acid, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH:6]([OH:27])[CH2:7][NH:8][C:9]([CH3:26])([CH3:25])[CH2:10][NH:11][C:12]1[N:17]=[N:16][C:15]([NH:18][NH:19]C(OCC)=O)=[CH:14][CH:13]=1.[ClH:32]>>[ClH:32].[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH:6]([OH:27])[CH2:7][NH:8][C:9]([CH3:26])([CH3:25])[CH2:10][NH:11][C:12]1[N:17]=[N:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)NNc1ccc(NCC(C)(C)NCC(O)COc2ccccc2C)nn1
Agent: Cl
Product: Cc1ccccc1OCC(O)CNC(C)(C)CNc1ccc(NN)nn1

Procedure:
A solution of 66 mg of 1-(2-methylphenoxy)-3-[1,1,-dimethyl-2-(3-ethoxycarbonylhydrazino-6-pyridazinylamino)ethylamino]-2-propanol in 5 ml of 10% hydrochloric acid was refluxed for 5 hours. After the solvent was evaporated under reduced pressure, the residue was recrystallized from ethanol to give 31 mg of 1-(2-methylphenoxy)-3-[1,1-dimethyl-2-(3-hydrazino-6-pyridazinylamino)ethylamino]-2-propanol hydrochloride as colorless crystals.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C@@H:10]([CH3:27])[CH2:11][N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[C:18]=2[CH3:26])=[N:13]1>>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:8])[CH3:27])[N:13]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: O=C(O)c1cocn1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cocn3)n2)ccc(C#N)c1Cl
Yield: 0.81 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 4-oxazolecarboxylic acid (0.181 g, 1.596 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.430 g, 1.330 mmol). The product was purified by Flash-chromatography. Yield 0.813%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.57 (s, 3H), 4.31 (dd, 1H), 4.43 (dd, 1H), 4.54-4.63 (m, 1H), 6.44 (d, 1H), 7.50 (d, 1H), 7.51-7.55 (m, 2H), 7.60 (dd, 1H), 7.85 (d, 1H), 8.22 (d, 1H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C:1]([Cl:4])=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Phosgene (2.95 mL, 5.69 mmol, 1.93 M in toluene) was added dropwise to a cooled mixture of triethylamine (1.3 mL, 9.4 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (0.80 g, 1.88 mmol, example 6) in methylene chloride (15 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and evaporated. The residue was kept under high vacuum for 30 min. Chromatography of the residue over silica gel using 60-80% methylene chloride in hexanes gave 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.71 g, 77%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][N:28]1[CH2:29][CH2:30][N:25]([C:23]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)=[O:24])[CH2:26][CH2:27]1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: O=C(C1CCCCO1)N1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(=CN1CCN(C(=O)C3CCCCO3)CC1)C(=O)N2

Procedure:
5.00 g. of 5,6-dimethoxy-3-hydroxymethylene oxindole, 5,6 g. 1-(tetrahydropyran-2-carbonyl)piperazine and 2.1 g. acetic acid in 60 ml. benzene was reacted as described in Example 5 to give 6.18 g. of product, m.p. 208°-210° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1.[Mg].II.[C:25](=[O:27])=[O:26].Cl>C1COCC1>[CH3:20][C:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:25]([OH:27])=[O:26])([CH3:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C=O
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
The 4-bromo-2-(1,1-dimethyldecyl) anisole (15.72 g, 44.2 mmoles) obtained in Example 11(a), above, is dissolved in THF (50 ml). This solution is slowly added to magnesium (1.18 g, 48.7 mmoles) and an iodine crystal, while being maintained at reflux by heating. Once the addition is complete, the reaction mixture is maintained at reflux for 30 minutes and then cooled to -40° C. 300 ml of THF are added and a stream of CO2 is passed therethrough for 2 hours. The reaction mixture is then poured into a solution of HCl (4N, 300 ml) and the product is extracted with ether (3×300 ml). The organic phase is washed with water until neutral, dried on MgSO4, and the solvents are evaporated. The residue is pulverized in isooctane to produce 7.25 g (51% yield) of 3-(1,1-dimethyldecyl)-4-methoxy benzoic acid which melts at 112° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19]([N:14]2[C:13](=[O:15])[CH2:12][O:11][CH2:10][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:20])=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1COCC(c2ccc(F)c(F)c2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.34 g, 1.57 mmol) in 10 mL of THF was added NaH (0.05 g, 1.9 mmol) and the resulting solution was stirred for 30 min. It was then transferred via a syringe into a solution of 4-nitrophenyl chloroformate in 20 mL of anhydrous THF at −78° C. under argon. The resulting solution was stirred for 2 hours after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 to obtain 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl ester as a colorless thick oil (0.31 g, 51%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:49]([CH2:51][NH2:52])[OH:50]>CN(C=O)C.CC(=O)OCC>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:52][CH2:51][CH2:49][OH:50])=[O:22])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(C(=O)NCCO)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid ethyl ester (1.42 g) is prepared starting from 4-(N-hydroxycarbamimidoyl)-benzoic acid ethyl ester (1.01 g, 4.84 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (1.00 g, 4.40 mmol) according to Method A; LC-MS: tR=0.63 min; [M+1]+=400.12; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 1.45 (t, J=7.0 Hz, 3H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 4.44 (q, J=7.3 Hz, 2H), 7.69 (s, 1H), 8.16-8.20 (m, 2H), 8.22-8.25 (m, 2H). This material (1.42 g, 3.58 mmol) is dissolved in 2 M LiOH in methanol (50 mL) and the mixture is stirred at rt for 20 h before it is acidified by adding aq. HCl. The mixture is extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (710 mg) as a white solid; LC-MS: tR=0.52 min; [M+1]+=372.14. b) To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid (400 mg, 1.08 mmol) in DMF (5 mL), HOBt (160 mg, 1.19 mmol) followed by EDC HCl (227 mg, 1.19 mmol) is added. The mixture is stirred at rt for 5 min before ethanolamine (72 mg, 1.19 mmol) is added. The reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3. The washing is extracted back twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 4% of methanol to give the title compound (290 mg) as a white solid; LC-MS: tR=0.47 min; [M+1]+=415.14; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.67-3.72 (m, 2H), 3.73 (s, 2H), 3.90 (t, J=4.8 Hz, 2H), 6.69 (t br, J=5.3 Hz, 1H), 7.68 (s, 1H), 7.91-7.95 (m, 2H), 8.22-8.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CN1CCNCC1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Methyl piperazine (0.072 mmol). The mixture can be microwaved at 120 degrees. The reaction mixture can then be filtered through a syringe filter and can be purified by prep-HPLC.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH:21]([NH2:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:29][CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:2]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NC(Cc1ccccc1)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 1,2-diphenylethylamine (0.69 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 45 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide (0.60 g, 1.8 mmol, yield: 58%) as colorless syrup. Next, to this syrup was added a 5% hydrogen chloride solution in methanol (2.5 ml). The solution was crystallized from a methanol-diethyl ether to give N-cyano-N'-(1,2-diphenylethyl)-3-pyridinecarboximidamide hydrochloride as colorless powder.
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12].C(N(CC)CC)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][C:21]([N:8]3[CH2:9][CH2:10][C:6]4([O:5][CH2:4][CH2:3][CH2:2][O:1]4)[CH2:7]3)=[C:22]([F:27])[CH:23]=2)[N:18]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[CH:17]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: C1COC2(CCNC2)OC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(N3CCC4(C3)OCCCO4)c(F)cc2c1=O
Temperature: 45 °C

Procedure:
Into oven-dried glassware under a N2 atmosphere were placed 0.176 g (1.23 mmol) of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2, then 0.300 g (0.82 mmol) of 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by H. Narita, et al., Yakugaku Zasshi, 106(9), 795-801, 1986; CA106:196218) dissolved in 10 mL of pyridine, and 0.46 mL (3.28 mmol) of triethylamine. The solution was then heated at 45° C. for 24 hours. The solvent was removed by evaporation to afford the title product which was purified by column chromatography over silica gel (0.5% methanol/chloroform increasing to 2.0% methanol/chloroform). The ester was not further purified, but was taken directly to the next step.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].[CH3:16][Mg]Br>C1COCC1>[OH:2][CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:16]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: C1CCOC1
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Yield: 90.2 %

Procedure:
Placed tert-butyl 4-formylpiperidine-1-carboxylate (2.00 g, 9.38 mmol) in THF (40 mL) and cooled to −78° C. Slowly added methylmagnesium bromide (3.44 mL, 10.3 mmol) stirred for 1 hour. Slowly added saturated ammonium chloride and extracted with CH2Cl2. Concentrated and redisolved in 5% MeOH in CH2Cl2. Added ether and filtered off solids. Concentrate filtrate to give the title compound (1.94 g, 90.2% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[C@@H:11]([OH:28])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:36]N(C)C=O.CI>C(#N)C.[Ag]=O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:13][C@@H:12]([NH:14][C:15](=[O:27])[C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=3)[C@@H:11]([O:28][CH3:36])[CH2:10]2)=[CH:34][CH:33]=1
Reactant: O=C(N[C@@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@@H]1O)c1ccc(OC(F)(F)F)cc1
Reactant: CN(C)C=O
Agent: O=[Ag]
Solvent: CI
Solvent: CC#N
Product: CO[C@H]1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C[C@H]1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 51 %

Procedure:
To a solution of (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (75.6 mg, an optical isomer of the compound obtained in Example 2) in acetonitrile (8 mL)/dimethylformamide (2 mL) was added successively methyl iodide (233 μL) and silver oxide (216.8 mg) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered through Cerite, washed with acetonitrile and evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→2:1) to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine (39.5 mg; yield: 51%) as an amorphous powder.