Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:12])=O.[Br:15][C:16]1[C:17]([O:28][CH:29]([CH3:31])[CH3:30])=[C:18]([C:23]2[NH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[C:20]([Br:22])[CH:21]=1.[BH4-].[Na+]>ClCCCl.CO.O>[OH2:3].[ClH:12].[Br:15][C:16]1[C:17]([O:28][CH:29]([CH3:31])[CH3:30])=[C:18]([C:23]2[NH:24][C:25]([CH:1]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH3:2])=[CH:26][CH:27]=2)[CH:19]=[C:20]([Br:22])[CH:21]=1.[Br:15][C:16]1[C:17]([O:28][CH:29]([CH3:31])[CH3:30])=[C:18]([C:23]2[NH:24][C:25]([CH:1]([N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH3:2])=[CH:26][CH:27]=2)[CH:19]=[C:20]([Br:22])[CH:21]=1.[ClH:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)N1CCCCC1
Reactant: CC(C)Oc1c(Br)cc(Br)cc1-c1ccc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CO
Product: CC(C)Oc1c(Br)cc(Br)cc1-c1ccc(C(C)N2CCCCC2)[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To 1-acetylpiperidine (0.36 ml) under argon was added phosphorous oxychloride (0.26 ml) at room temperature. The mixture was stirred at room temperature for 50 minutes and 1,2-dichloroethane (5 ml) was added. The solution was cooled to 5° C. and 2-(3,5-dibromo-2-isopropoxyphenyl)-1H-pyrrole (D7) (0.52 g) in 1,2-dichloroethane (5 ml) was added in one portion. The mixture was stirred at 5°-10° C. for 20 minutes and was then stirred at room temperature for 22 hrs. The mixture was cooled in an ice bath and sodium borohydride (0.50 g) was added in one portion. After stirring for a further 2 hrs, water (7.2 ml) was added dropwise over 6 minutes. After a further 4 minutes, MeOH (6 ml) was added over 6 minutes. After stirring for a further 10 minutes, the mixture was partitioned between water (100 ml) and dichloromethane (50 ml). The aqueous layer was re-extracted with dichloromethane (2×40 ml) and the combined organic layers were dried over sodium sulphate. The residue was dissolved in MeOH (7 ml), dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs. The mixture was partitioned between dichloromethane (100 ml) and water (60 ml). The aqueous layer was brought to pH 12 with 10% NaOH and was extracted with dichloromethane (2×40 ml). The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was chromatographed on neutral alumina to give the free base of the title compound. This material was dissolved in diethyl ether (100 ml) and was washed with water and was extracted with 0.4M HCl (4×25ml). The combined HCl layers were extracted with dichloromethane (4×50 ml). The ether layer was then diluted with pentane and re-extracted with the HCl layer. The acid layer was extracted with dichloromethane and the combined dichloromethane extracts were dried over sodium sulphate and evaporated in vacuo to give the title compound (E20).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][C:11]=1[Cl:20])=[O:8].[CH2:24](O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:6][C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][C:11]=3[Cl:20])[CH2:24]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCO
Reactant: Cc1cccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c1
Solvent: O
Product: Cc1cccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)c1

Procedure:
2-(3-Methylanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide 3.5 g dissolved in ethanol (100 ml) was reacted with p-formaldehyde (0.6 g) in water (200 ml) as in Example 15 (b) to yield 2.8 g product, m.p. 198°-202°C
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:29]=[N:28][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]=2[CH:16]=1
Reactant: COc1ccccc1C(=O)CP(=O)(OC)OC
Reactant: O=C1CCCCCC1=O
Reactant: NN
Solvent: O
Product: COc1ccccc1-c1cc2c(nn1)CCCCC2

Procedure:
light yellow gum. MS (ESI): 255.2 (MH+). Prepared from cycloheptane-1,2-dione, [2-(2-Methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained ethyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 109°-110° C.;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Sn](C)(C)C)[N:10]=1.[Br:15]C1SC=C(Br)N=1.C1(S)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Br:15])[N:10]=1
Reactant: Brc1csc(Br)n1
Reactant: C[Sn](C)(C)c1csc(-c2cccs2)n1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1csc(-c2cccs2)n1
Temperature: 45 °C
Yield: 84 %

Procedure:
Synthesis of 2-Thiophenyl-4-(trimethylstannyl)thiazole 381 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in ethanol (0.1 M) and treated with thiophenol (3.0 equiv) and solid sodium hydroxide (3.0 equiv). The reaction mixture was heated at 45° C. for 4 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-thiophenyl-4-bromothiazole 380, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 84% yield.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:5])=[O:4].Cl[CH2:20][C:21]1[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][O:27][C:22]1[C:21]([CH2:20][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][C:7]3[S:8][CH:9]=[CH:10][C:6]=3[S:3]([CH3:2])(=[O:4])=[O:5])[CH2:14][CH2:15]2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COc1ncccc1CCl
Reactant: CS(=O)(=O)c1ccsc1CCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1CN1CCC(CCc2sccc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
4.41 g of 4-[2-(3-methylsulfonyl-2-thienyl)ethyl]piperidine hydrochloride, 2.36 g of 3-(chloromethyl)-2-methoxypyridine and 5.90 g of potassium carbonate were suspended in 30 ml of N,N-dimethylformamide, and the mixture was stirred for 12 hours at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 809 mg of the title compound as a colorless oil (quantitatively).
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](N(CC)CC)(O)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.CCCCCC[O:36][C:37]([C:39]1[C:44]([C:45](C2C=CC(N(CC)CC)=CC=2O)=O)=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH3:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:37][O:36][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:23])=[C:10]([OH:9])[CH:11]=1
Reactant: CCCCCCOC(=O)c1ccccc1C(=O)c1ccc(N(CC)CC)cc1O
Reactant: CCN(CC)C(O)(CCCCCOC(=O)c1ccccc1)C(=O)c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
Diethylaminohydroxybenzoylhexyl benzoate sold under the trade name “Uvinul A Plus” by BASF,
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[N+:14]=[N-:15]
Reactant: O=C(O)CCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
9-Bromo-nonanoic acid (3.82 g, 17 mmol) was dissolved in DMF (30 mL) and sodium azide (1.11 g, 17 mmol) was added. The solution was heated to 80° C. and stirred overnight. The reaction was poured onto ice and extracted with DCM (3×200 mL). The combined extracts were washed with water (3×200 mL), brine (200 mL), and dried over MgSO4. The solvent was removed in vacuo to give a clear oil 2.83 g (84% yield);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.O.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(C)(C)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC(C(=O)O)(C(C)(C)O)C1
Temperature: 110 °C
Yield: 49.6 %

Procedure:
To a solution of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopentanecarboxylate (1.0 g, 3.3 mmol) in a mixture of THF (30 mL), methanol (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.22 g, 5.3 mmol) and the mixture refluxed overnight (110° C.). The organic solvents were evaporated and the aqueous layer was washed with ether one time. The aqueous layer was then acidified with 6N HCl to about pH 4 and extracted with methylene chloride three times. The combined extracts were dried, filtered, and concentrated to provide the desired product (0.47 g, 49%).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([P:7]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[CH2:23]([I:25])[CH3:24].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[I-:25].[CH2:23]([P+:7]([C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([C:3]1[CH:2]=[C:1]([CH3:22])[CH:6]=[CH:5][CH:4]=1)[C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[CH3:24]
Reactant: Cc1cccc(P(c2cccc(C)c2)c2cccc(C)c2)c1
Reactant: CCI
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC[P+](c1cccc(C)c1)(c1cccc(C)c1)c1cccc(C)c1
Product: [I-]
Temperature: 40 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5.49 gms (0.0181 mole) of tri-m-tolyl phosphine and 25 gms of toluene. The slurry is heated to 40° C., then 3.38 gms (0.0217 mole) of ethyl iodide is added. This reaction mass is heated to 40° C. and maintained for 16 hours, then heated to 70° C. and maintained for 4 hours, then cooled to 30° C. and the resulting phosphonium salt collected by filtration. After vacuum drying, there is obtained 5.8 gms of catalyst which has a melting point of >250° C. and a chemcial shift of 25.7 ppm (phosphoric acid reference).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10][C:11]1[S:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1.Cl[Pd]Cl>[Br:10][C:11]1[S:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CSc1nccc(I)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2ccc(Br)s2)n1

Procedure:
4-Iodo-2-methylsulfanyl-pyrimidine (2.5 g, 10 mmol), (5-Bromo-thiophen-2-yl)-tributyl-stannane (4.9 g, 11 mmol) and PdCl2 (702 mg, 1 mmol) were heated to 105° C. in toluene (30 ml) for 2 hours. The reaction mixture was poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via chromatography on silicagel (acetone/hexanes:0/100 to 3/97) to give the title compound as colourless foam. Yield: 1.6 g (55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:2]1([NH:1][S:18]([CH:17]=[CH2:16])(=[O:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Aniline (0.98 mL, 10.7 mmol) and Et3N (1.8 mL, 12.9 mmol) in toluene (25 mL) were treated with 2-chloro-1-ethanesulfonylchloride (1.1 mL, 10.5 mmol). The exothermic reaction was stirred for 14 hours at room temperature. After stirring, the solution was diluted with EtOAc and washed with HCl (˜10% aq. soln.). The organic layer concentrated and purified via flash column chromatography (4:1 hexane/EtOAc) to afford two lots of phenyl(vinylsulfonyl)amine.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:16]=1[C:17]([N:19]([CH3:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1)=[O:18])C.C(=O)(O)[O-].[Na+].[S:47]([O-:51])([O-])(=[O:49])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:47]([C:15]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:16]=1[C:17]([N:19]([CH3:33])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1)=[O:18])(=[O:51])=[O:49])[CH3:3]
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.39 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.30 g of 2-ethylsulfanyl-N-methyl-N-(5-pentafluoroethyl-pyridin-2-yl)-4-trifluoromethyl-benzamide and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.31 g of 2-ethylsulfonyl-N-methyl-N-(5-pentafluoroethyl-pyridin-2-yl)-4-trifluoromethyl-benzamide (hereinafter, referred to as Compound of Present Invention 9).
Reaction SMILES: [CH3:1][CH:2]([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][CH:2]([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC#CCC(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
410 mg. of (5Z,13E)-(15S,16RS)-16-methyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated at 23° for 16 hours with 11 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the mixture is evaporated under vacuum, and the residue is purified by column chromatography on silica gel. With methylene chloride/5% methanol, 290 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:1]([N:8]1[C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Reactant: O=CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C(=CCc2ccccc2)c2cncn2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Titanium tetrachloride (0,03 mol) is added dropwise to a stirred suspension of zinc powder (0,06 mol) in tetrahydrofuran (30 ml) at -10° C. under dry nitrogen. The mixture is heated to reflux and refluxing is continued for 1 hour. The solution is cooled to 0° C. and 1-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-1H-imidazole (0,005 mol) in tetrahydrofuran (10 ml) and phenylacetaldehyde (0,006 mol) in tetrahydrofuran (10 ml) are added into the mixture, respectively. The mixture is refluxed with stirring for 1 hour. The dark mixture is poured into water (60 ml), tetrahydrofuran is evaporated and the mixture is extracted with methylene chloride (2×100 ml). The methylene chloride solution is washed with 2N sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography.
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].[CH3:6][CH:7]([CH3:15])[CH2:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12].[Cl-:16].[NH4+]>Cl.CO>[ClH:16].[CH3:12][C:11]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[C:9]([CH2:8][CH:7]([CH3:15])[CH3:6])[CH:10]=1
Reactant: [Cl-]
Reactant: CC(=O)CC(=O)CC(C)C
Reactant: NC(=O)NO
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(CC(C)C)[n+]([O-])c(O)n1
Temperature: -11 °C
Yield: 58 %

Procedure:
0.20 mol (15.21 g) hydroxy urea were dissolved in 300 ml of M HCl, 300 ml of methanol were added, and 0.20 mol (28.44 g) 6-methyl-2,4-heptanedione were added dropwise while cooling at −12 to −10° C. The solution was allowed to warm slowly to room temperature and stirred over night, then evaporated to dryness. The residue was suspended with 200 ml of acetone, the mixture cooled to below 0° C. in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.23 g of a product was obtained, which contained 58% of the title compound and 42% of the by-product ammonium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1.C[O:27]C1C=CC(N2[C@@H](C)[C@@H](COC3C=CC(C#N)=CC=3)OC2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]([CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:27])=[CH:19][CH:18]=3)([CH3:14])[O:11][C:10]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C[C@](C)(COc3ccc(C#N)cc3)OC2=O)cc1
Reactant: COc1ccc(N2C(=O)O[C@H](COc3ccc(C#N)cc3)[C@@H]2C)cc1
Product: COc1ccc(N2C[C@](C)(COc3ccc(C=O)cc3)OC2=O)cc1
Yield: 85 %

Procedure:
The same procedure of Example 16 was repeated except that 4-[(R)-(-)-3-(4-methoxyphenyl)-5-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile obtained in Reference Example 15 was used in lieu of 4-[(4S, 5S)-(-)-3-(4-methoxyphenyl)-4-methyl-2-oxooxazolidin-5-yl]methoxybenzonitrile to give the title compound (compound 44) as an oil (yield 85%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>>[N:38]1[CH:43]=[CH:42][C:41]([O:20][C@@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[C@@H:23]([C:34]([O:36][CH3:37])=[O:35])[CH2:22]2)=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CC[C@@H]1C(=O)OC(C)(C)C
Reactant: Oc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CC[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (2.0E3 mg, 0.0077 mol) was added to a solution of 1-tert-butyl 2-methyl (1S,2S,4S)-4-hydroxycyclohexane-1,2-dicarboxylate (1.0 g, 0.0039 mol) and 4-pyridinol (730 mg, 0.0076 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) at rt. A solution of diethyl azodicarboxylate (1200 uL, 0.0077 mol) in tetrahydrofuran (10.0 mL, 0.123 mol) was added. The reaction mixture was stirred at rt overnight. The reaction was chromatographed by combiflash (ethyl acetate in hexanes: 80%) to give 1-tert-butyl 2-methyl(1S,2S,4R)-4-(pyridin-4-yloxy)cyclohexane-1,2-dicarboxylate, contaminated with a little Ph3PO, which was used in next step.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[C:21]([C:18]1[O:17][C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(NCc2ccc(C(=O)O)o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1

Procedure:
3-[(5-Carboxy-furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.90 g, 2.70 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:44])[C:38](=[O:43])[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[F:29][C:23]1[CH:24]=[C:25]([NH:26][C:40](=[O:41])[CH2:39][C:38]([N:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH3:44])=[O:43])[CH:27]=[CH:28][C:22]=1[O:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][N:10]=3)[S:20][C:19]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Reactant: CN(C(=O)CC(=O)O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CN(C(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(C=O)cn4)sc23)c(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To intermediate 38 (0.35 g, 0.86 mmol) in dry DMF (25 mL) was added 3-((4-fluorophenyl)(methyl)amino)-3-oxopropanoic acid (44) [US 2007/0004675 A1] (0.36 g, 1.7 mmol) [Met-036], and EDC.HCl (0.33 g, 1.7 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated. The crude product was dissolved in acetone (50 mL) to give a colorless solution. The solution was diluted with water (20 mL) and TFA (2 mL), and heated to reflux for 3 h. It was then cooled and concentrated. The residue was then partitioned between ethyl acetate and water, the organic phase was collected, washed with water, saturated NaHCO3, and brine, dried (anhydrous MgSO4), filtered and concentrated to produce intermediate 45 (0.27 g, 57% yield). MS (m/z): 559.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[C:12]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)#[N:13].[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[C:2]([C:3]1[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[C:12]#[N:13])[C:27]2[C:23](=[N:24][NH:25][CH:26]=2)[NH:22][C:9]=1[CH:9]1[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)#[N:1]
Reactant: N#Cc1ccccc1C=O
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1ccccc1C#N

Procedure:
The title compound was prepared from ethyl nipecotate, 2-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.