Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH:12]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[OH:13]>ClCCl.O=[Mn]=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[O:13]
Reactant: COCOc1cc(C)ccc1C(O)c1nccs1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COCOc1cc(C)ccc1C(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [2-(methoxymethoxy)-4-methylphenyl](1,3-thiazol-2-yl)methanol from step 1 (3.6 g, 13.7 mmol) and MnO2 (8.28 g, 95.2 mmol) in dichloromethane was stirred at room temperature overnight, filtered, and the insoluble material washed well with boiling EtOAc. The filtrates were combined and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.07-8.03 (m, 2H), 7.50 (d, 1H), 7.10 (s, 1H), 6.95 (d, 1H), 5.11 (s, 2H), 3.34 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[C:5]([C:15]([NH2:17])=O)[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].COC(OC)[N:29]([CH3:31])C.C(O)(=O)C.O.[NH2:39]N>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)[S:6][C:5]=1[C:15]1[NH:29][CH:31]=[N:39][N:17]=1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(-c2ccnc(F)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide (0.90 g, 0.0022 mol) in 1,1-dimethoxy-N,N-dimethylmethanamine (5.50 g, 0.045 mol) was stirred at 85° C. overnight. The mixture was evaporated to dryness and the residue was dissolved in acetic acid (14 mL, 0.2 mol) and hydrazine hydrate (1.4 mL, 0.02 mol) was added. The mixture was stirred at 85° C. for 5 hours. The solvent was removed and the residue was suspended in water. The precipitate was collected and dried in an oven to afford the product (0.86 g, 90%). LCMS: (FA) ES+, 416, 418. 1H NMR (400 MHz, d4-Methanol) 8.42 (s, 1H), 8.41 (d, J=5.21 Hz, 1H), 7.81 (td, J=5.33, 1.58, 1.58 Hz, 1H), 7.63 (t, J=1.18, 1.18 Hz, 1H), 7.60 (s, 1H), 7.48-7.46 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH:31]([CH2:32][CH2:33][CH3:34])[C:25]=2[C:24]=1[Cl:36].Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH:31]([CH2:32][CH2:33][CH3:34])[C:25]=2[C:24]=1[Cl:36]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCCC1OC(=O)c2cnc(Cl)c(Cl)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (2.88 g, 19.1 mmol.) in THF (20 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (38 mL of a 1 M solution in THF, 38.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 6,7-dichloro-1-propyl-1H-furo[3,4-c]pyridin-3-one, (3.13 g, 12.72 mmol) in THF (20 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (350 mL). The resulting mixture is heated to 90° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and washed with small volumes of ethyl acetate (10×3 mL) to give the title compound as a yellow solid (1.75 g, 36%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:7]=[CH:8][CH:9]=1>CCO>[F:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Temperature: 60 °C

Procedure:
A 5 N aqueous solution of NaOH (5.0 mL, 25 mmol) was added into a solution of methyl 3′-fluoro-2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (4.85 g, 16.8 mmol) in EtOH (50 mL). The reaction mixture was heated at 60° C. for 1 hour, and then was concentrated under reduced pressure. The residue was taken up with MTBE (100 mL), water (50 mL) and a 5N aqueous solution of HCl (6 mL). The layers were separated and the organic layer was washed with water (50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. After purification by crystallization from a mixture of MTBE and pentane, the title compound was obtained as a white powder (3.85 g, 83%). HPLC (Method A), Rt 4.2 min (purity: 99.8%). LC/MS (Method B) 273.0. (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1cnc(-c2ccccc2)c1C=O
Temperature: 80 °C
Yield: 86.1 %

Procedure:
Manganese dioxide (11.5 g) was added to a suspension of (1-methyl-4-phenyl-1H-imidazol-5-yl)methanol (intermediate 1) (5.75 g) in dioxane (100 mL), and the resulting mixture heated to 80° C. for 8 hours, and allowed to cool to ambient temperature overnight. The mixture was reheated to 80° C., filtered through diatomaceous earth and the cake washed well with acetone. Purification by flash chromatography on silica eluting with EtOAc:hexane (50:50 to 100:0) gave the title compound (4.90 g, 86%) as a pale solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1.[C:18](Cl)(=O)C(Cl)=O.[Si](C=[N+]=[N-])(C)(C)C.[BrH:31].C(O)(=O)C>C(Cl)Cl.CN(C=O)C>[Br:31][CH2:18][C:15]([CH:13]1[CH2:12][CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:14]1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br
Reactant: O=C(O)C1CC(c2ccc3ccccc3n2)C1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CBr)C1CC(c2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(quinolin-2-yl)cyclobutanecarboxylic acid (200 mg, 0.800 mmol) in DCM was cooled to 0° C. and treated with 10 μL of DMF followed by addition of oxalyl chloride (154 μL, 1.76 mmol). The resulting mixture was stirred at rt for 30 min and concentrated. The resultant residue was dried in vacuo for 15 min, dissolved in CH3CN (5 mL), and treated with a 2 M solution of TMSCHN2 in hexanes (0.88 mL, 1.76 mmol). The resulting mixture was stirred for 1 h, cooled to 0° C. and treated with 33 wt % HBr in acetic acid (0.35 mL, 1.76 mmol), dropwise. After stirring for 30 min, the reaction mixture was diluted with DCM (25 mL) and washed with saturated NaHCO3 (2×25 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue obtained was dried in vacuo for 15 min to obtain 2-bromo-1-(3-(quinolin-2-yl)cyclobutyl)ethanone as a viscous oil which was used without further purification in the next step.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1
Reactant: NCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 1.00 g (3.53 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml of acetonitrile, 0.54 g (3.5 mmole) 1,8-diazobicyclo[5.4.0] undec-7-ene, and 0.37 g (3.7 mmole) of 3-pyrrolidinemethanamine is refluxed one hour, then stirred at room temperature overnight. The reaction mixture is then filtered and the precipitate washed with ethyl ether until dry to yield 1.21 g (94.5%) of the title compound, mp 232°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:34][C:35]([F:47])([F:46])[C:36]1[CH:45]=[C:44]2[C:39]([CH2:40][CH2:41][CH2:42][NH:43]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)[CH:12]=[C:13]([N:43]2[C:44]3[C:39](=[CH:38][CH:37]=[C:36]([C:35]([F:34])([F:46])[F:47])[CH:45]=3)[CH2:40][CH2:41][CH2:42]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCc3ccc(C(F)(F)F)cc32)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline under the conditions described in Example 24, step (a).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[CH2:7][N:6]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH2:26]([N:6]1[CH2:7][CH:8]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reaction time: 8 h

Procedure:
Benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester (124 mg, 0.269 mmol) and LiOH (53.9 mg, 1.5 mmol) were dissolved in THF/H2O (4 mL), and then stirred overnight. After removal of solvent, the residue was neutralized to PH=6-7, and then extracted by EA twice. The organic layer was washed with water and brine, dried, and concentrated to afford the title product 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid, 65 mg (54.2%) as a yellow solid. MS m/e=447.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-5 using tert-butyl 4-hydroxypiperidine-1-carboxylate and 4-bromophenol (0.65 g, 36%); MS: 256 (M−100).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N:15]([CH2:25][CH:26]=[CH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:13]=[CH2:14].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH2:25]([N:15]([CH2:12][CH:13]=[CH2:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:26]=[CH2:27]
Reactant: C=CCN(CC=C)CCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CCN(CC=C)CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 24 h
Yield: 40.1 %

Procedure:
4-Toluene-sulphonyl chloride (12.5 g, 0.066 mol) was added slowly to a stirred solution of 8-diallylaminooctan-1-ol (10.0 g, 0.044 mol) and pyridine (7.0 g, 0.088 mol) in chloroform (100 cm3) at 0° C. After 24 h, water (100 cm3) was added and the solution washed with dilute hydrochloric acid (20%, 100 cm3), sodium carbonate solution (100 cm3), water (100 cm3), dried (MgSO4) and concentrated to a yellow oil which was purified by column chromatography [silica gel, 4% diethyl ether in hexane eluting to DCM:ethanol 10:1] to yield the desired product (6.7 g, yield 40%).
Reaction SMILES: O=[Si]=O.C(O)C.[C:7]([O:12][CH2:13][CH2:14][CH2:15][Si](OC)(OC)OC)(=[O:11])[C:8]([CH3:10])=[CH2:9]>O>[C:7]([O:12][CH2:13][CH2:14][CH3:15])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: O=[Si]=O
Solvent: O
Solvent: CCO
Product: C=C(C)C(=O)OCCC
Temperature: 50 °C
Reaction time: 20 h

Procedure:
100 g of Ludox TMA® [available from Helm AG; 34% nanosilica dispersion in water] is mixed with 100 ml of ethanol. To this mixture is added 11.7 g (25.6 mmol) of a photoinitiator [see reaction scheme] and 12.7 g (51 mmol) of 3-(trimethoxysilyl)propyl methacrylate at room temperature. The mixture is stirred at 50° C. for 20 hours. The amount of solvent is halved by evaporation in the rotary evaporator. By adding 150 ml of cyclohexane the product precipitates and is separated by centrifugation. After re-dispersing the product in butylacetate (BuOAc) a dispersion with 18.6 wt. % solid content is obtained. The ratio of photoinitiator to methacrylic groups is calculated based on analytical data to be 1 to 1.54. Thermographimetric analysis (TGA; heating rate: 10° C./min from 25° C. to 600° C.): Weight loss: 28.6%, corresponding to the organic material. Elemental analysis: found: C, 18.68%, H, 2.64%, O, 9.52%, S, 1.72: corresponding to an organic content of 32.6%. DLS: Average diameter d=54 nm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.CN(C)C=O.[I:20]N1C(=O)CCC1=O.O>ClCCl>[I:20][C:14]1[C:7]2[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:11][CH:10]=[N:9][C:8]=2[NH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COCCOc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COCCOc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (24, 5.70 g, 29.5 mmol) in 150.0 mL of dichloromethane, N,N-dimethylformamide (6.0 mL, 78 mmol) and N-iodosuccinimide (7.22 g, 32.1 mmol) are added and the reaction stirred at room temperature for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is washed with ethyl acetate and hexane to provide the desired compound (25, 6.75 g).
Reaction SMILES: [C:1]1([CH:11]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:12][O:13][CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH2:14][O:13][CH2:12][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCN(CCOCC(OC2CCCCO2)c2cccc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 7.5 g of 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane, 2.65 ml of N-methylpiperazine, 3.96 g of potassium carbonate and 38 ml of N,N-dimethylformamide was stirred for 2 hours at 90°-100° C. The reaction mixture was cooled and added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice each with 25 ml of diethyl ether. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain 3.36 g of colorless, oily 2-[2-(4-methylpiperazin-1-yl)ethoxy]-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy) ethane (compound No. 258).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[CH3:15][CH:16]([CH3:24])[C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:4][C:3]1[NH:5][CH:17]([CH:16]([CH3:24])[CH3:15])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)[N:2]=1
Reactant: N=C(N)N
Reactant: COC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(c2ccc(F)cc2)N=C(N)NC1C(C)C
Temperature: 70 °C
Yield: 55 %

Procedure:
Guanidine hydrochloride (12.1 g), 4-Fluorobenzaldehyde (7.0 g), methyl 4-methyl-3-oxo-pentanoate (8.9 g) and DMF (150 ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture was stirred until a clear solution was obtained. Potassium carbonate (17.5 g) is charged and the mixture heated to 70° C. for 3 hours. The reaction mixture was cooled to ambient temperature and filtered. It contained methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate in 55% yield. An analytical sample was prepared by removing the reaction solvents by evaporation under reduced pressure, precipitating the product from the resultant oil in acetonitrlie and recrystallisation from acetonitrile.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1O)([O-])=O.[NH2:14][N:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33][C:34]([CH3:36])=O>C(O)C>[CH3:36][C:34]1[C:33]([C:32]([O:38][CH2:39][CH3:40])=[O:37])=[C:25]2[CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=[CH:16][N:15]2[N:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)C1=CCN(N)C=C1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccn2nc(C)c(C(=O)OCC)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-aminoisonicotinate 2,4-dinitrophenol salt (10.2 g) was suspended in ethanol (147 ml), and potassium carbonate (3.77 g) was added, which was followed by stirring at room temperature for 30 min. To the mixture was added ethyl acetoacetate (3.69 ml), and the mixture was stirred at 60° C. for 5 hr with heating. The insoluble matter was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/1) to give the objective compound (2.70 g) as an amber-colored solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:20][CH:19]=2)[CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[C:29](=[O:30])[C:28]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:36][CH:37]=4)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]=[C:25]3[CH3:49])=[CH:22][CH:23]=2)[CH2:15][CH2:14]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OCC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(cyclopropylmethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.93 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.84 g, 81%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH+]1C=CC=CC=1>O>[C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]([OH:2])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:9]
Reactant: COc1cccc(OC)c1-c1ccccc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1cccc(O)c1-c1ccccc1
Temperature: 25 °C

Procedure:
2,6-Dimethoxybiphenyl (5.00 g) and 15 g of pyridinium hydrochloride were placed in the round-bottom flask and immersed in the oil bath (210° C., 1.5 hours). Then the reaction was cooled down to room temperature, diluted with 200 ml of water and extracted with ethyl acetate (4×50 ml). Organic fractions were combined, dried over sodium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent hexane/ethyl acetate 1/1 mixture), providing 3.3 of biphenyl-2,6-diol as yellow solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[C:9]([CH:10]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[NH:14][C:12](=O)[CH2:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH2:2]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]1[C:20]2[CH:19]=[C:18]3[O:21][CH2:22][O:23][C:17]3=[CH:16][C:15]=2[NH:14][C:12](=[S:33])[CH2:11]1)[CH3:1]
Reactant: CCOc1ccccc1C1CC(=O)Nc2cc3c(cc21)OCO3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccccc1C1CC(=S)Nc2cc3c(cc21)OCO3
Yield: 57.1 %

Procedure:
FQI-1 (200 mg, 1.0 equiv) was weighed into a dry reaction vial under an atmosphere of nitrogen. Dry toluene (4.3 mL) was added, followed by Lawesson's reagent (416 mg, 1.6 equiv). The vial was tightly sealed and the reaction was heated to reflux overnight. After cooling, the solvent was removed in vacuo and the residue was purified by flash column chromatography (gradient of 20% to 70% ethyl acetate in hexanes). Fractions which contained product were pooled to give 120 mg of an impure red oil which was recrystallized from dichloromethane/hexanes to give Compound X as white needles (40 mg, 19%). 1H NMR (400 MHz, CDCl3) δ=9.69 (br. s., 1 H), 7.20 (ddd, J=2.9, 6.0, 8.3 Hz, 1 H), 6.89-6.82 (m, 3 H), 6.46 (d, J=3.1 Hz, 2 H), 5.93 (d, J=1.2 Hz, 2 H), 4.54 (dd, J=6.4, 7.8 Hz, 1 H), 4.10-4.02 (m, 2 H), 3.42 (dd, J=7.8, 17.0 Hz, 1 H), 3.23 (dd, J=6.4, 17.0 Hz, 1 H), 1.40 (t, J=7.0 Hz, 3 H). ESI-MS (M+H+) m/z=328.