Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH3:19][S-:20].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:20][CH3:19])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: C[S-]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (1.54 g) in THF (50 mL) was added sodium methanethiolate (0.39 g). The mixture was allowed to warm to room temperature and stirring continued for 2 h. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a pale yellow solid. Yield: 1.51 g.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:34])([C:11]([O:13][C:14]1[C:15]([O:30][C:31](=[O:33])[CH3:32])=[C:16]2[C:21](=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=13)[O:20][C:19]([CH3:29])([CH3:28])[CH2:18][CH2:17]2)=[O:12])[CH3:10])=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[CH3:34][C:9]([C:11]([O:13][C:14]1[C:15]([O:30][C:31](=[O:33])[CH3:32])=[C:16]2[C:21](=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=13)[O:20][C:19]([CH3:28])([CH3:29])[CH2:18][CH2:17]2)=[O:12])([CH3:10])[NH2:8]
Reactant: CC(=O)Oc1c2c(c3ccccc3c1OC(=O)C(C)(C)NC(=O)OC(C)(C)C)OC(C)(C)CC2
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Oc1c2c(c3ccccc3c1OC(=O)C(C)(C)N)OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 5-(acetyloxy)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl N-(tert-butoxycarbonyl)-2-methylalaninate (27) (0.4 g, 0.85 mmol) in 1,4-dioxane (5 mL) is added a solution of hydrogen chloride gas in anhydrous 1,4-dioxane (4.0 M, 10 mL). The reaction is stirred at room temperature for 2 hours. The reaction is dried under reduced pressure and the resulting solid is triturated with Et2O to afford the desired product as a white solid (0.388 g, 97%). M.p.=283-284° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.93 (br. s, 3H), 8.15 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.65-7.50 (m, 2H), 2.63 (t, J=6.6 Hz, 2H), 2.38 (s, 3H), 1.89 (t, J=6.6 Hz, 2H), 1.78 (s, 6H), 1.39 (s, 6H); LCMS: 372 [M+H]; Calc. for C21H25NO5.1.15 HCl: C, 60.96; H, 6.38; N, 3.39; Found C, 61.01; H, 6.06; N, 3.30.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:18]([C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=1)=[O:20]
Reactant: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Reactant: CNC
Product: CCCOc1ccccc1-c1ncc(C(=O)N(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-propoxyphenyl)pyrimidine-5-carboxylate (1.5 g, U.S. Pat. No. 4,031,093) was treated with dimethylamine (33% in industrial methylated spirit, 50 ml) in a pressure vessel (414 kPa) at 120° C. for 15 hours. Solvent was removed under reduced pressure affording a yellow oily residue which was washed several times with ether. The volume of the combined ethereal washings was reduced by evaporation to afford on standing overnight a white precipitate (540 mg). This was recrystallised from ether to afford the title compound, 310 mg, m.p. 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([NH:42][CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[Cl:33])=[O:6]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: NCCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1Cl)c1cc(Br)ccc1Cl
Yield: 90.2 %

Procedure:
To a stirred solution of 2-chloro-5-bromobenzoic acid (1.5 g, 6.3 mmol), EDCI (1.63 g, 8.5 mmol), and HOBT (1.15 g, 8.5 mmol) in DMF (20 ml) was added 2-(2-chlorophenyl)ethylamine (1.06 ml, 7.5 mmol). After 15 minutes triethylamine (1.18 ml, 8.5 mmol) and DMF (5 ml) was added. After 2 hours at ambient temperature the mixture was diluted with ethyl acetate (50 ml) and washed with 1 N HCl followed by a saturated solution of sodium bicarbonate, followed by water, and then brine. The organic layer was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.12 g of an amorphous solid. Mass Spectrum (ES+) 374.6, (ES−) 372.2.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C@H:14]1[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17](=[O:24])[CH2:16][CH2:15]1>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C@H:14]3[N:18]([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)CCN1C(=O)CC[C@H]1CN
Product: CC(C)CCN1C(=O)CC[C@H]1CNc1ccc2ncc(Br)n2n1
Yield: 60 %

Procedure:
The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with (S)-5-(aminomethyl)-1-isopentylpyrrolidin-2-one under the amine displacement conditions described in example 5.6.42, Part A to afford 60% titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (d, J=6.32 Hz, 6H) 1.39-1.66 (m, 3H) 1.95-2.08 (m, 1H) 2.13-2.26 (m, 1H) 2.31-2.53 (m, 2H) 3.02 (ddd, J=13.89, 9.22, 4.93 Hz, 1H) 3.48 (dt, J=14.15, 5.18 Hz, 1H) 3.79 (ddd, J=13.77, 9.35, 6.95 Hz, 1H) 3.91 (ddd, J=14.08, 7.01, 2.91 Hz, 1H) 4.00-4.11 (m, 1H) 5.42 (t, J=5.31 Hz, 1H) 6.67 (d, J=9.60 Hz, 1H) 7.52 (s, 1H) 7.66 (d, J=9.85 Hz, 1H); LRMS (ESI) m/380.0 doublet [(M+H)+, calcd for C16H22BrN5O 379.0].
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][N:12]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccsn1
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isothiazolylmethylthio)ethylamino]ethylene (see Example 72(ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([N:18]([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.O1CCC[CH2:22]1.[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([N:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][C:14]([CH3:22])([OH:17])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(C)(O)CC1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 10 ml. of 3 M methyl magnesium bromide in Et2O is added a solution of 1.25 g. (0.005 mole) of 4-(p-chlorophenyl)-4-(dimethylamino)cyclohexanone in 25 ml. of tetrahydrofuran. The mixture is stirred under nitrogen in the cold for one-half hour and then at room temperature for forty-eight hours. Following ice bath cooling there is added 20 ml. of saturated aqueous ammonium chloride, 10 ml. of water, 10 ml. diethyl ether and 25 ml. benzene. The organic layer is washed with 10 ml. water and 10 ml. brine and taken to dryness. The residue is chromatographed on a 1"×48" high pressure liquid chromatography column (elution with 3% MeOH in chloroform). Starting ketone is first eluted followed by a second material. Those fractions containing the second material are combined, concentrated to dryness and crystallized from CH3CN:H2O to yield 0.20 g. of the tertiary alcohol, melting point 119°-120°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To an ice-cooled solution 3,3-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 7.2 mmol) in THF (20 mL) was added 4-chlorophenylmagnesium bromide (1 M in ether, 15 mL, 15 mmol). The solution was allowed to warm to about room temperature, then stirred at room temperature for about 22 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, then purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[N:28])[CH:26]=3)[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:26]=3)[C:27]#[N:28])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(-c3cncc(C#N)c3)c2)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2cccc(-c3cncc(C#N)c3)c2)COCC(N)=N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (RS)-{5-[3-(5-cyano-pyridin-3-yl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl}-carbamic acid tert-butyl ester (49 mg, 0.13 mmol) in dichloromethane (1.5 ml) was treated with trifluoroacetic acid (1.03 ml, 13.3 mmol). The orange colored solution was stirred at room temperature for 30 minutes. For the workup, the solution was evaporated at high vacuum. Heptane was added to the oily residue, and the resulting suspension was evaporated at reduced pressure. After drying at high vacuum the title compound was obtained as a brown solid (49 mg, 98% of theory). MS (ISP): m/z=293.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@@H:11]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[C:23]([N:27]=[C:28]=[S:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([NH:27][C:28]([NH:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C@@H:19]([OH:22])[CH2:20][CH3:21])=[S:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC[C@H](O)[C@H](N)Cc1ccncc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](O)[C@@H](Cc1ccncc1)NC(=S)NC(C)(C)C
Temperature: 50 °C

Procedure:
4.3 cm3 of triethylamine are added to a solution of 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60 cm3 of ethanol, followed by addition of 2.6 cm3 of tert-butyl isothiocyanate. The mixture is heated at a temperature in the region of 50° C. for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and the residue is taken up in 50 cm3 of water and 100 cm3 of dichloromethane. The organic phase is washed with 30 cm3 of water, dried over sodium sulfate, filtered and concentrated under the above conditions. 4.3 g of N-tert-butyl-N′-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea are obtained in the form of a thick colorless oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.80 (t, J=7.5 Hz: 3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9 Hz: 1H); 2.93 (dd, J=14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt: 1H); 4.88 (unresolved complex: 1H); 7.11 (s: 1H); 7.16 (d, J=8.5 Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:21][CH3:22])[N:9]([C:10](=[O:20])[NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH2:8][CH2:7][S:6]1)=O>C[O-].[Na+].CO>[CH2:21]([C:5]12[C:3](=[O:2])[N:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=3)[C:10](=[O:20])[N:9]1[CH2:8][CH2:7][S:6]2)[CH3:22]
Reactant: CCC1(C(=O)OC)SCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC12SCCN1C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O
Temperature: 50 °C
Yield: 25.1 %

Procedure:
0.70 g of 2-ethyl-3-(3,5-dichlorophenylcarbamoyl)thiazolidine-2-carboxylic acid methyl ester was added to 20 ml of 0.1 N sodium methylate-methanol solution, heated at 50° C. for 20 minutes. The reaction mixture was cooled and filtered. The resulting filtrate was 0.16 g (yield 25%) of 7a-ethyl-6-(3,5-dichlorophenyl)perhydroimidazo[5,1-b]thiazole-5,7-dion (compound No. 7). The results of elementary analysis and a melting point were given in table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:25][CH2:26][OH:27])[N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.I[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]([CH2:25][CH2:26][O:27][CH3:34])[N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccnn4CCO)ccc3n(C)c21
Product: COCCn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 101 above, with compound A, 3-(2,4-dichlorophenyl)-6-[2-(2-hydroxyethyl)-2H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH:34](O)[C:35]4([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.S(Cl)([Cl:44])=O>C1COCC1>[Cl:44][CH:34]([C:35]1([CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:21]1[CH:20]=[C:19]([O:18][CH2:17][C:13]2[CH:12]=[C:11]([CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:16]=[CH:15][CH:14]=2)[CH:24]=[CH:23][C:22]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)C3(C)CCCC3)c2)c1)C1CC1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C(Cl)C3(C)CCCC3)c2)c1)C1CC1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-(hydroxy(1-methylcyclopentyl)methyl)-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (99 mg) in THF (3 mL) was added thionyl chloride (64 μL) and the mixture was stirred at 50° C. for 15 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (95 mg) as a colorless oil.
Reaction SMILES: C([O:9][CH:10]([C:18]([F:21])([F:20])[F:19])[C:11]([F:17])([F:16])[S:12]([O-:15])(=[O:14])=[O:13])(=O)C1C=CC=CC=1.[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CO>[OH:9][CH:10]([C:18]([F:21])([F:19])[F:20])[C:11]([F:16])([F:17])[S:12]([O-:15])(=[O:14])=[O:13].[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reaction time: 4 h
Yield: 85 %

Procedure:
In 72 g of methanol was dissolved 34.4 g of triphenylsulfonium 2-benzoyloxy-1,1,3,3,3-pentafluoropropane-1-sulfonate synthesized in Synthesis Example 10. While the solution was stirred under ice cooling, 54.0 g of 5% sodium hydroxide solution was added dropwise at a temperature below 10° C. It was aged at the temperature for 4 hours. At a temperature below 10° C., 6.8 g of 12N hydrochloric acid was added to quench the reaction. The methanol was distilled off in vacuum, after which 270 g of dichloromethane was added to the residue. The organic layer was washed with 40 g of water three times. The organic layer was concentrated, after which 60 g of diethyl ether was added to the residue for crystallization. The crystals were filtered and dried, obtaining the target compound. White crystals, 24.3 g (yield 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([NH:36][CH2:37][C:38]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:39]=1[O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](O)=[O:46])=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:45](=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][O:40][C:39]3[CH:48]=[C:49]([F:52])[CH:50]=[CH:51][C:38]=3[CH2:37][NH:36][C:34]([O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:35])[CH2:21][CH2:20]2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(N2CCNCC2)c2cccnc2c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(N2CCN(C(=O)CCCCOc3cc(F)ccc3CNC(=O)OC(C)(C)C)CC2)c2cccnc2c1OCc1ccccc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of methyl 8-(benzyloxy)-5-(piperazin-1-yl)-1,6-naphthyridine-7-carboxylate (Example 13; 1.3 mmol), 5-(2-((tert-butoxycarbonylamino)methyl)-5-fluorophenoxy)pentanoic acid (Example 17; 1.6 mmol) and diisopropyl ethylamine (3.9 mmol) in dichloromethane (10 ml) was added HBTU (2.0 mmol). The mixture was stirred overnight. The mixture was washed with saturated NaHCO3, 10% citric acid and brine and dried over Na2SO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography over SiO2 (eluent: methanol/CH2Cl2, 1:100) to afford the title compound (800 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH3:29])[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=2[CH3:29])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Cc1cc(F)ccc1B(O)O
Product: Cc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-fluoro-2-methylbenzene boronic acid [CAS-no. 139911-29-8; prepared from 2-bromo-5-fluorotoluene by reaction with n-BuLi at −78° C. followed by treatment with B(OMe)3 and subsequent hydrolysis] according to the general procedure B. Obtained as a yellow solid (1.71 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:18](O)C>[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6](/[C:9](=[CH:14]\[CH:13]=[CH2:18])/[CH:10]=[N:11]/[CH2:12][NH2:15])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCO
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Product: C=C/C=C(/C=N/CN)N1CCN(CC)CC1
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 1-ethyl-4-(6-nitropyridin-3-yl)piperazine (500 mg, 2.12 mmol) in ethanol (20 mL) was added 10% Pd/C (113 mg, 0.11 mmol) and the resulting mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was filtered through celite, washed with ethanol and concentrated to give N-[(E)-2-(4-ethyl-piperazin-1-yl)-penta-2,4-dien-(Z)-ylidene]-methanediamine (377 mg, 86%) as a grey solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:3]1.[H][H]>CO.[Pt](=O)=O>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([CH3:1])([CH3:20])[CH2:3][CH:4]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: [H][H]
Reactant: CC1(C)CC(Oc2ccc([N+](=O)[O-])cc2)CC(C)(C)C1
Agent: O=[Pt]=O
Solvent: CO
Product: CC1(C)CC(Oc2ccc(N)cc2)CC(C)(C)C1

Procedure:
Under atmospheric pressure, 8.3 g of 4-(3,3,5,5-tetramethylcyclohexyloxy) nitrobenzene in 500 ml of methanol are hydrogenated in the presence of 400 mg of platinum dioxide until the uptake of hydrogen has ended. The catalyst is filtered off, the solution is then concentrated using a rotary evaporator and the residue, a brownish oil which slowly solidifies, is used for the further reactions without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C(OCC)C.O>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 15.8 mg (0.022 mmol) of [(t-Bu)2P(Cl)PdC2]2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.92 g (6.67 mmol) of K2CO3 in 3 mL of EtOH. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[O:29][CH:30]=1>>[F:39][C:36]1[CH:37]=[CH:38][C:33](/[CH:32]=[CH:31]/[C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=3)[N:27]=2)=[CH:34][CH:35]=1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3)n2)cc1
Yield: 70.4 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (291 mg), 65% oily sodium hydride (39 mg) and 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg), the same reaction as Example 2 was carried out to yield the titled compound (347 mg).