Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].C(N(C(C)C)CC)(C)C.[F:43][C:44]1[CH:67]=[CH:66][C:47]([CH2:48][N:49]2[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[N:51]=[C:50]2[C:58]([CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[O:59])=[CH:46][CH:45]=1.O1CCOCC1>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:63]2[CH2:64][CH2:65][CH:60]([C:58]([C:50]3[N:49]([CH2:48][C:47]4[CH:46]=[CH:45][C:44]([F:43])=[CH:67][CH:66]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=4[N:51]=3)=[O:59])[CH2:61][CH2:62]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 14 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.50 g, 0.94 mmol), diisopropylethylamine (0.24 g, 1.9 mmol), 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.47 g, 1.91 mmol), and dioxane (7 mL). Heat to reflux. After 14 hours, cool and partition the reaction mixture between ethyl acetate and water. Extract the organic layer with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 12% methanol/ethyl acetate containing 0.1% a concentrated aqueous ammonia solution to give the title compound: Rf=0.35 (silica gel, 12% methanol/ethyl acetate containing 0.1% concentrated aqueous ammonia solution).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=2[O:23]1>>[O:23]1[C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[C:4]([F:21])[CH:3]=3)=[CH:28][C:29]=2[O:30][CH2:22]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(c1ccc(-c2ccc3c(c2)OCO3)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3,4-Methylenedioxybenzene boronic acid. MS (M+H) 397.2
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:22]([O:30][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCO
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 20 g (72.4 mmol) of 2-fluorotetracene-5,12-dione, 94.3 g of octan-1-ol, 30.01 g (217.2 mmol) of anhydrous potassium carbonate and 200 ml of dimethyl sulfoxide is stirred for 20 hours at 100° C. The reaction mixture is cooled, and extracted with toluene/dilute hydrochloric acid. The organic phase is separated, washed with water, dried over sodium sulfate, and concentrated by evaporation. The residue is washed with pentane and recrystallised from cyclohexane. Yield: 22.9 g (82%), m.p. 127°-129° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[CH2:15][C:16]([O:18]CC)=[O:17])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1cc(C(=O)OC)ccc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(NC(C)=O)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a mixture of ethyl α-(2-acetylamino-5-methoxycarbonylphenyl)acetate (4.18 g, 0.015 mol) in methanol (60 mL), 1N sodium hydroxide (15.0 mL, 0.015 mol) was added over a period of 10 min. The mixture was stirred at room temperature for 1 h. After dilution with water (50 mL), the mixture was filtered and the filtrate neutralized with concentrated hydrochloric acid. The precipitate obtained was collected by filtration and washed with water. The cake was recrystallized from ethyl acetate and dried to give 2.3 g (61%) of α-(2-acetylamino-5-methoxycarbonylphenyl)acetic acid as a white solid, mp 194° C.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:8]=[C:9]([Cl:14])[C:10]=1[CH:11]([OH:13])[CH3:12].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCOCC>[C:11]([C:10]1[C:9]([Cl:14])=[CH:8][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:6][C:5]=1[Cl:4])(=[O:13])[CH3:12]
Reactant: CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 80.2 %

Procedure:
An anhydrous methylene chloride solution (50 ml) of 23.5 g of 3,5-dichloro-4-(1-hydroxyethyl)benzotrifluoride (9) was added at a time to 100 ml of an anhydrous methylene chloride suspension of 30.0 g of pyridinium chlorochromate and 20 g of Celite at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with 100 ml of ether and thereafter applied to a column packed with 100 g of silica gel. Ether was used for elution, and the eluent was concentrated under reduced pressure to obtain 18.7 g of the desired compound in the form of a yellow oil (crude yield 72.8%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCS(C)(=O)=O)CC1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of methanesulfonyl chloride 0.374 g, 3.3 mmol in ethyl acetate (3ml was added to a mixture of 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido) piperidine (1.0 g, 3 mmol) and triethylamine. The resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oily residue. The residue was chromatographed on silica gel (290 g; ethyl acetate/hexane: 1:4) to yield 1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenyl-propionamido)piperidine (0.53 g, 43%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.[OH:12][CH2:13][CH:14]([CH2:17]O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([CH:7]2[O:12][CH2:13][CH:14]([CH2:15][OH:16])[CH2:17][O:8]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1
Reactant: OCC(CO)CO
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc([N+](=O)[O-])c1C1OCC(CO)CO1
Temperature: 25 °C

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (718 mg, 4.63 mmol, intermediate 3) in toluene (100 mL) was added 2-(hydroxymethyl)propane-1,3-diol (700 mg, 6.73 mmol) followed by p-toluenesulfonic acid (88 mg, 0.463 mmol). The reaction mixture was heated at reflux for 18 hr whilst azeotropically removing the water. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with a saturated aqueous NaHCO3 (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methanol (trans isomer) as the first eluting isomer as a colourless solid (220 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 6.42 (s, 1H), 4.34 (dd, J=11.6, 4.7 Hz, 2H), 4.12 (s, 3H), 3.81 (t, J=11.5 Hz, 2H), 3.56 (t, J=5.1 Hz, 2H), 2.53-2.38 (m, 1H), 1.67 (t, J=4.6 Hz, 1H).
Reaction SMILES: [Zn](C)[CH3:2].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]>O.O=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][C:6]([N+:19]([O-:21])=[O:20])=[C:5]2[CH3:2]
Reactant: C[Zn]C
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=O
Solvent: O
Product: COc1cc2ncc([N+](=O)[O-])c(C)c2cc1OC
Temperature: 80 °C
Yield: 127.2 %

Procedure:
Zn(CH3)2 (1.2 M in toluene, 15.35 ml, 18.43 mmol) and Pd(dppf)Cl2 (2.28 g, 2.92 mmol) are added to a solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (7.5 g, 27.92 mmol) in water- and oxygen-free dioxane (200 ml, pre-treatment: nitrogen gas passed through for 30 min). The reaction mixture is heated at 80° C. for 8 h, giving a solution. After cooling to room temperature, water (65 ml) is slowly added, and the mixture is extracted with ethyl acetate (60 ml). After separation, the organic phase is washed with a little hydrochloric acid (1.0 M, 5 ml). The aqueous phase is extracted three times with ethyl acetate (60 ml each time). The combined organic phases are dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified by chromatography over flash silica gel (solvent cyclohexane/ethyl acetate 2:1, parts by volume), giving 6,7-dimethoxy-4-methyl-3-nitroquinoline (5.82 g, 23.44 mmol) as a solid. MS: 249.0 (M+H+), TLC (HPTLC): Rf=0.45 (cyclohexane/ethyl acetate 1:1, parts by volume).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:24](OC)([O:27]C)[O:25]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:24]([OH:27])[OH:25])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran (1.2 g, 5 mmol), 12 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (6.17 mL, 10.5 mmol) and trimethyl borate (1.2 mL, 10.5 mmol) the title compound was obtained as a foam that was used as such for the next step without purification and characterization. 5-Bromo-3,3,7-trimethyl-2,3-dihydro-benzofuran can be prepared as described in U.S. Pat. No. 6,093,838, incorporated herein by reference.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH:15]=[CH:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.C(O)(=[O:23])C.OO>O>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH:15]=[CH:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11](=[O:23])[C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1
Reactant: C1=Cc2ccc(-c3nnn[nH]3)cc2Sc2ccccc21
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: O=S1c2ccccc2C=Cc2ccc(-c3nnn[nH]3)cc21
Temperature: 65 °C

Procedure:
To a solution of 2.03 g. (7.3 millimoles) of 3-(5-tetrazolyl)dibenzo[b,f]thiepin in 100 cc. glacial acetic acid is added 15 cc. 30% aqueous hydrogen peroxide. The mixture is heated to 65° C. for 10 minutes; the sulfoxide separates from the hot solution. After cooling and diluting with water, the crystalline product is filtered and washed with water. It is then heated on a steam bath in 25 cc. DMF and filtered hot. The solid is washed with methanol and dried. The yield of sulfoxide is 1.55 g. (72%) as a white solid decomposing at 277° C.-279° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:7]#[N:8])([O-])=O.Cl[Sn]Cl.[OH-].[Na+]>Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH2:12])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: N#Cc1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To 3,5-dinitrobenzonitrile (5.0 g, 25.89 mmol) in 20 mL of HCl 1M, was added SnCl2 (34.4 g, 7 eq). The reaction mixture was stirred at room temperature for 2 h and then cooled to 0° C. The mixture was made alkaline with a 50% aqueous solution of NaOH and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate and the combined organic layers were evaporated. The residue and the precipitate were purified by flash chromatography on silica gel (DCM/MeOH//95/5) to yield expected compound as an orange solid (1.95 g, 57% yield). m/z (ESI) 134.0 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][N:8]2C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.CO.[Pd]>[C:13]1([N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccc2)CC1c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C2CN(c3ccccc3)CCN2)cc1
Yield: 93.2 %

Procedure:
A solution of benzyl 2,4-diphenylpiperazine-1-carboxylate (0.17 g, 0.45 mmol) and 5% Pd on carbon (0.1 g) in tetrahydrofuran/methanol 5:1 (10 mL) was stirred under hydrogen (1 atm) for 4.5 hours. The reaction was filtered through celite and concentrated to give the title compound 1,3-diphenylpiperizine (0.10 g, 93% yield) as an oil. MS (EI) for C16H18N2: 239 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C.[Pd]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(O)C(Oc1ccccc1N)c1ccccc1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of erythro ethyl 2-hydroxy-3-(2-nitrophenoxy)-3-phenylpropanoate (6a) (3.956 g, 11.940 mmol) in ethanol (150 mL) was added 5% palladium on carbon (500 mg) and the mixture was hydrogenated at 35 psi on a Parr shaker for 30 min. The reaction mixture was filtered through diatomaceous earth and the resulting solution concentrated in-vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound (3.585 g, 99%) as a red oil. 1H NMR (300 MHz, CDCl3) δ1.18 (t, 3H), 3.34 (m, 1H), 3.99 (br, 2H), 4.17 (m, 2H), 4.60 (m, 1H), 5.42 (d, 1H, J=3 Hz), 6.51-6.65 (m, 2H), 6.69-6.82 (m, 2H), 7.20-7.40 (m, 5H). MS APCI, m/z=324 (M+Na). LC/MS: 1.70 min.
Reaction SMILES: FCC1(NC(=O)CC2C(C(F)(F)F)=CC=CC=2C(N)=O)CCNC1.[F:25][CH2:26][C:27]1([NH:39][C:40](=[O:55])[CH2:41][NH:42][C:43](=[O:54])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.O1CCOCC1.[ClH:62]>C1COCC1>[ClH:62].[F:25][CH2:26][C:27]1([NH:39][C:40](=[O:55])[CH2:41][NH:42][C:43](=[O:54])[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:51])[F:52])[CH:45]=2)[CH2:31][CH2:30][NH:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(CF)(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: NC(=O)c1cccc(C(F)(F)F)c1CC(=O)NC1(CF)CCNC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-{[(3-(Fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide. To a solution of 578 mg (1.29 mmol) of tert-butyl 3-(fluoromethyl)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate in 5 mL of THF was added 2 mL of 4 N HCl dioxane solution. The reaction mixture was stirred at room temperature for 1 h and evaporated to give the yellow solid, N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide HCl salt: MS (m/e): 347 (M+1)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(C)C=CC(S(O[CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.Cl>O.C(OCC)C>[CH3:28][O:27][CH2:26][CH2:25][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COCCc1ccc(-c2ccccc2)cc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
Metallic magnesium (14.6 g, 0.6 mol) was placed in a completely dried 2 l three-neck flask and dry nitrogen gas was passed through the inside of the vessel to completely dry it, followed by adding anhydrous ethyl ether (45 ml) and a trace of iodine. A dry ethyl ether solution (500 ml) of p-bromobiphenyl (140 g, 0.6 mol) was gradually added with stirring while maintaining the reaction temperature at 30° to 35° C., and after the addition, the reaction was further carried out at the same temperature for 3 hours. At an inner temperature of 35° C., an anhydrous ethyl ether solution (300 ml) of β-methyloxyethyl p-toluenesulfonate (276 g, 1.2 mol) obtained in step A was gradually added. During the addition, reflux began to occur due to the reaction heat. After the addition, the mixture was placed under reflux for 2 hours while maintaining it on a water bath at an inner temperature of 35° C. After completion of the reaction, the reaction liquid was cooled and 500 ml of water was added and then 6 N--HCl (1.5 l) was added. The reaction liquid was transferred into a separating funnel and subjected to extraction with toluene (500 ml). The resulting toluene layer was separated from the resulting aqueous layer, and this aqueous layer was further subjected to extraction with toluene (100 ml). The toluene layers were combined together, and insoluble matters therein were removed by suction filtration. The resulting toluene layer was washed once with 2 N--NaOH aqueous solution (200 ml) and filtered through a pleated filter paper, followed by distilling off toluene under reduced pressure. To the residue were added NaOH (10 g), water (20 ml) and ethanol (500 ml), and the mixture was placed under reflux on a water bath for 30 minutes. The mixture liquid was cooled and poured in 1 l of water, and toluene (300 ml) was added, followed by transferring the mixture into a separating funnel, washing the upper toluene layer 3 times with 300 ml of water and distilling off toluene under reduced pressure. The residue was then distilled under reduced pressure and fractions of b.p. 137°~140° C./1.5 mmHg were collected to obtain 4-(β-methyloxyethyl)-biphenyl (IV) (34 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Product: COc1cc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2cc1OC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile with 3-chloro-4-(phenylthio)aniline gave the title compound as a tan solid, mp 124-130° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[P:11]([O:16]C)([O:14][CH3:15])[O:12][CH3:13]>>[CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][P:11](=[O:16])([O:14][CH3:15])[O:12][CH3:13])=[O:7]
Reactant: COP(OC)OC
Reactant: O=Cc1cccc(CBr)c1
Product: COP(=O)(Cc1cccc(C=O)c1)OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.60 g of 3-(bromomethyl)benzaldehyde and 0.45 ml of trimethyl phosphite was stirred at 100° C. for 3 hours. The reaction mixture was subjected to silica gel column chromatography to obtain 0.62 g of oily dimethyl (3-formylbenzyl)phosphonate [Compound No. (x)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:16][O:15][CH2:13][CH3:14])[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOc1ccc(C#N)cc1Br
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 3-bromo-4-hydroxybenzonitrile (25 g, 125 mmol) in THF (375 mL) at room temperature was treated with 95% NaH (4.3 g, 170 mmol) in a few portions. The resulting slurry was heated to 60° C. for 30 minutes, treated with chloromethyl ethyl ether (25 g, 260 mmol), and the mixture was stirred at 60° C. for another 2 hours. The reaction was cooled to room temperature, concentrated to a slush, treated with water (200 mL), and filtered. The solid was dried for about 16 hours under vacuum in the presence of P2O5 to provide 30 g (95%) of the desired product. MS (DCI/NH3) m/z 273, 275 (M+H+NH3)+; 1H NMR (CDCl3) δ 7.84 (d, 1H), 7.56 (dd, 1H), 7.25 (d, 1H), 5.35 (s, 2H), 3.76 (q, 2H), 1.23 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:10][CH:9]=1)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([N:40]1[C:47]([NH2:48])=[C:46]([NH2:49])[C:44](=[O:45])[N:43]([CH2:50][CH2:51][CH3:52])[C:41]1=[O:42])[CH2:38][CH3:39]>O1CCCC1.CN(C)C=O.C(OCC)C>[NH2:48][C:47]1[N:40]([CH2:37][CH2:38][CH3:39])[C:41](=[O:42])[N:43]([CH2:50][CH2:51][CH3:52])[C:44](=[O:45])[C:46]=1[NH:49][C:16](=[O:18])[CH:15]([CH3:19])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][CH2:6][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CC(Cc1ccc(SCC(=O)OC(C)(C)C)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(SCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]thio]-alpha-methyl-benzenepropanoic acid (1.13 g, 3.64 mmol) in tetrahydrofuran (15 mL) and treat with N-methylmorpholine (0.4 mL, 3.64 mmol). Cool to -20° C. and treat with isobutyl chloroformate (0.47 mL, 3.64 mmol). Stir for 30 minutes and add a solution of 1,3-dipropyl-5,6-diaminouracil (0.82 g, 3.64 mmol) in dimethylformamide (5 mL). Stir for 3 hours at -20° C., warm to room temperature and dilute with ethyl ether (200 mL). Separate the organic phase, wash with water (200 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to yield the title compound.
Reaction SMILES: BrC1C=C(Cl)C=CC=1O.C(O[CH:13](OCC)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Br:23])C>>[Cl:22][C:19]1[CH:18]=[C:17]([Br:23])[C:16]2[O:15][CH:14]=[CH:13][C:21]=2[CH:20]=1
Reactant: CCOC(COc1ccc(Cl)cc1Br)OCC
Agent: Oc1ccc(Cl)cc1Br
Product: Clc1cc(Br)c2occc2c1

Procedure:
Beginning with 25 gm (120.5 mMol) 2-bromo-4-chlorophenol, 41.16 gm crude 2-(2-bromo-4-chlorophenoxy)-acetaldehyde diethyl acetal was prepared essentially as described in Preparation IV. A sample of this crude material was subjected to silica gel chromatography to provide an analytical sample.