Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: COc1ccc(O)c(Cc2cccc(C(F)(F)F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:18]1[N:17]=[C:16]([CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2cccc(Nc3nccs3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OC1(Cc2cccc(Nc3nccs3)n2)CCNCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.9 mg of tert-butyl 4-hydroxy-4-((6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-1-carboxylate in 1 ml of chloroform was added 0.5 ml of trifluoroacetic acid at 0° C., followed by stirring the reaction mixture at 0° C. for 2 hours. The reaction mixture was concentrated in vacuo, basified with saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-aminobenzoate (0.500 g; 3.31 mmol), 3-fluorobenzeneboronic acid (0.925 g; 6.62 mmol), copper acetate (1.20 g; 6.62 mmol) and pyridine (0.535 mL; 6.62 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH2:17])[C:6]([O:8]CC)=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38](O)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][C:38](=[O:39])[CH2:37][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[O:28])=[C:20]([O:19][CH3:18])[CH:21]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCN)c(OC)c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-aminoethoxy)benzoate (250 mg, 1.04 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (500 mg, 1.04 mmol) was added Et3 N (210 μl, 3.01 mmol), and the resulting mixture was stirred for 2 days. 0.25 N NaOH (20 mL) and THF (20 mL) was added to the mixture and the resulting mixture was heated under reflux overnight. After cooling, the mixture was evaporated and the residue was acidified by the addition of 1 N HCl. The mixture was extracted with CHCl3, and the extract was washed with brine, dried over Na2SO4, and evaporated. The obtained crude solid was recrystallized from CHCl3 to give 110 mg (20% for 2 steps ) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 255 as a white crystalline powder. mp 180–181° C.; IR (KBr) 1687 cm−1; 1H-NMR (DMSO-d6) δ 2.24 (s, 3 H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.41–3.50 (m, 2 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.06–4.08 (m, 2 H), 6.76–8.55 (series of m, total 12 H); MS (FAB) m/z 508 (M++1); Anal. Calcd for C27H29N3O7.1/2H2O: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.46; H, 5.69; N, 8.03.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:54])[F:53])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2C[C@@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-[(7S,9aR)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D25) (87 mg, 0.111 mmol) was dissolved 4 mL of methanol. To this solution was added concentrated HCl (0.2 mL) at 0° C., and stirred at room temperature for 1 h (complete conversion). The reaction mixture was loaded on a SCX cartridge and washed with MeOH. The product was eluted with 0.5 M methanolic ammonia. The UV-active basic fractions were evaporated, leaving the target compound as a white solid: 69 mg, 0.103 mmol, 93%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: Oc1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-bromo-4-chlorophenol (25.0 g, 120.5 mmol) in dichloromethane at 0° C. was added imidazole (9.0 g, 132.5 mmol) and t-butyldimethylchlorosilane (TBSC1) (19.0 g, 126.5 mmol). The solution was stirred at 0° C. for 30 min, then at room temperature for 14 h. The reaction mixture was diluted with deionized water, extracted with dichloromethane (2×200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% ethyl acetate in hexanes) to afford (3-bromo-4-chlorophenoxy)-t-butyldimethylsilane as colorless oil (37.0 g, 115.0 mmol, 98%). MS: (ES) m/z calculated for C12H19BrClOSi [M+H]+ 321.0. found 321.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>O1CCOCC1.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:27]#[C:26][CH2:25][OH:28])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: C#CCO
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C#CCO)ccc12
Temperature: 90 °C
Yield: 75.8 %

Procedure:
To a solution of 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (500 mg, 1.24 mmol, 1.00 eq) in degassed 1,4-dioxane (2.50 mL, 5.00 V), prop-2-yn-1-ol (0.09 mL, 1.49 mmol, 1.20 eq) Et3N (0.52 mL, 3.71 mmol, 3.00 eq), Bis(triphenylphosphine)palladium (II) dichloride (34.86 mg, 0.05 mmol, 0.04 eq) and copper (I) iodide (4.81 mg, 0.02 mmol, 0.02 eq) were added. The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and subjected to column chromatography to afford the title compound (0.38 g, 0.94 mmol, 75.7%) as a off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.87 (t, J=5.92 Hz, 1H), 8.09 (d, J=8.61 Hz, 1H), 8.01 (d, J=9.01 Hz, 1H), 7.86 (d, J=9.11 Hz, 1H), 7.68 (d, J=8.72 Hz, 1H), 5.53 (t, J=6.13 Hz, 1H), 4.39 (d, J=6.01 Hz, 2H), 3.27 (t, J=6.32 Hz, 2H), 1.98-2.04 (m, 2H), 1.74-1.86 (m, 5H), 1.24-1.33 (m, 2H). m/z: 393.2 [M+H]+
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2nc(Br)sc2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Bromo-6-benzothiazolecarboxylic acid (0.500 g, 1.94 mmol) was suspended in dichloromethane/methanol (12 ml, 6:1) and cooled to 0° C. with an ice-water bath. Then, 2M (trimethylsilyl)diazomethane (2.91 ml, 5.81 mmol) was added dropwise over 5 min. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 hrs. The resulting mixture was concentrated in vacuo to yield methyl 2-bromobenzo[d]thiazole-6-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.F[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]3[CH:37]=[CH:36][NH:35][C:29]=3[N:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39]>CN1CCCC1=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]4[CH:37]=[CH:36][NH:35][C:29]=4[N:30]=[C:31]([C:33]#[N:34])[N:32]=3)=[CH:23][C:22]=2[C:38]([F:39])([F:40])[F:41])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCN)CC1
Reactant: N#Cc1nc(-c2ccc(F)c(C(F)(F)F)c2)c2cc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCC(CCNc2ccc(-c3nc(C#N)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
2-(1-Methylpiperidin-4-yl)ethanamine (93 mg) and N,N-diisopropylethylamine (0.22 mL) were added to a mixture of 4-[4-fluoro-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) and N-methylpyrrolidone (2 mL), and the mixture was stirred at 140° C. for 1 hour under microwave irradiation. After the reaction mixture was cooled to room temperature, the reaction mixture was purified by silica gel column chromatography (CHCl3:MeOH=98:2 to 85:15), whereby 4-[4-{[2-(1-methylpiperidin-4-yl)ethyl]amino}-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (66 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[C:14]([SH:23])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)=O)=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:2].CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:9]=1[C:10]1[S:23][C:14]2[C:13]([N:12]=1)=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)[CH3:2]
Reactant: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 150 °C
Reaction time: 10 h
Yield: 31.1 %

Procedure:
A mixture of 494 mg of 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide, 1.05 g of p-toluenesolufonic acid-hydrate, 3 ml of DMF and 1 ml of toluene was heated and stirred at 150° C. for 10 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was applied to a silica gel column chromatography to obtain 146 mg of 2-(4-ethylsulfanylpyridin-3-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as Compound of Present Invention 42).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.O[N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:32][C:14]([F:13])([F:31])[C:15]1[CH:16]=[C:17]([S:21]([N:24]2[CH2:25][CH2:26][CH:27]([O:30][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])[CH2:28][CH2:29]2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A solution of diethyl azodicarboxylate (1.10 g, 6.32 mmol) in tetrahydrofuran (5 ml) was added dropwise to a mixture of 1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-ol (0.94 g, 3.04 mmol), 2-hydroxyisoindoline-1,3-dione (0.50 g, 3.07 mmol) and triphenylphosphine (1.65 g, 6.30 mmol) in tetrahydrofuran (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 25/75) to give 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (1.02 g, 74%) as a white solid: LCMS: 455 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[C:5](/[N:7]=[C:8]1/[N:9]([C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[N:13]=[CH:12][C:11]=2[NH:29]/1)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[F:55][C:56]1([F:60])[CH2:59][NH:58][CH2:57]1>CN(C=O)C.C(Cl)Cl>[F:55][C:56]1([F:60])[CH2:59][N:58]([C:36]([C@@H:33]2[CH2:34][CH2:35][C@H:30]([N:9]3[C:10]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:20][CH2:21][CH:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH2:23][CH2:24]5)[N:13]=[CH:12][C:11]=4[NH:29]/[C:8]/3=[N:7]\[C:5](=[O:6])[C:4]3[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[CH:3]=3)[CH2:31][CH2:32]2)=[O:37])[CH2:57]1
Reactant: FC1(F)CNC1
Reactant: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)O)CC2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)N3CC(F)(F)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylic acid (0.05 g, 0.088 mmol) in DMF (1 mL) was added CDI (0.029 g, 0.176 mmol), and the resulting mixture was stirred at RT for 1 hour. To this mixture was added 3,3-difluoroazetidine hydrochloride (0.057 g, 0.440 mmol), and the mixture was stirred at RT for 1 hour. The mixture was diluted with DCM (10 mL) and washed with aqueous NH4Cl (5 mL) and brine (5 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (5-75% ACN/H2O; 0.1% TFA) to afford (E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide (35 mg, 61.8% yield). MS m/z=643.2 [M+H]. Calc'd for C33H41F3N6O4: 642.3.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[F:12]C1C=C(C=CC=1C)N>>[ClH:1].[F:12][C:8]1[CH:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][C:7]=1[CH3:9]
Reactant: Cc1ccc(NN)c(Br)c1
Reactant: Cc1ccc(N)cc1F
Agent: Cl
Product: Cc1ccc(NN)cc1F

Procedure:
3-Fluoro-4-methylphenylhydrazine hydrochloride (21.4 g) was prepared as described for 2-bromo-4 methylphenylhydrazine hydrochloride in Example 4, except using 3-fluoro-4-methylaniline as starting material.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)N1CCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.24 g of 5-amino-2-methoxy-4-nitrobenzoic acid in 30 ml of N,N-dimethylformamide was added 3.24 g of N,N'-carbonyldiimidazole at room temperature. After 30 minutes, 5 ml of pyrrolidine was added, and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound, m.p. 159°-162° C., yield of 4.16 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1)#[N:2].[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:15]([NH:14][CH2:13][CH2:12][Cl:11])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=NCCCl
Reactant: N#Cc1ccc(CN)cc1
Product: N#Cc1ccc(CNC(=O)NCCCl)cc1

Procedure:
The 4-cyanobenzenemethanamine obtainable by modified Gabriel synthesis, when reacted with chloroethylisocyanate, yields 1-[(4-cyanophenyl)methyl]-3-(2-chloroethyl)urea which when treated with potassium tert.butoxide in dimethylformamide is easily cyclised into the 1-[(4-cyanophenyl)methyl]-2-imidazo-lidinone; catalytic hydrogenation then leads to the desired 4-[(2-oxo-1-imidazolidinyl)methyl]benzenemethanamine.
Reaction SMILES: C=C[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]1[O:21][C@H:20]([C@H:22]2[O:27][O:26][C@H:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]2)[CH2:19][CH2:18]1.[CH2:32]=CCCC/C=C/C=C\CCCCCCCC[C@@H]1O[C@H]([C@@H]2OO[C@H](CC(O)=O)CC2)CC1>CCOCC>[CH3:32][O:31][C:29]([CH2:28][C@H:25]1[O:26][O:27][C@H:22]([C@H:20]2[O:21][C@H:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH:8]=[CH:7]/[CH2:6][CH2:5][CH:4]=[CH2:3])[CH2:18][CH2:19]2)[CH2:23][CH2:24]1)=[O:30]
Reactant: C=CCC/C=C\C=C/CCCCCCCC[C@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)O)OO2)O1
Reactant: C=CCCC/C=C/C=C\CCCCCCCC[C@H]1CC[C@@H]([C@H]2CC[C@@H](CC(=O)O)OO2)O1
Solvent: CCOCC
Product: C=CCC/C=C\C=C/CCCCCC[C@@H]1CC[C@@H]([C@@H]2CC[C@@H](CC(=O)OC)OO2)O1
Reaction time: 1 h

Procedure:
Methylation of the mixture of stolonoxides A (1) and B (2): Excess of CH2N2 was added to a solution of the mixture of stolonoxide A (1) and B (2) (22 mg) in Et2O (2 mL) at room temperature. After 1 h, the solvent was removed under reduced pressure and the reaction crude subjected to HPLC chromatography yielding stolonoxide A methyl ester (1b, 18 mg) and stolonoxide B methyl ester (2b, 2 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](NC(OC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NC1CCC[N:22]([C:26]([O:28][C:29](C)(C)C)=[O:27])C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH:12]([NH:22][C:26]([O:28][CH3:29])=[O:27])[CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Product: COC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
In analogy to the procedure described for intermediate 38A, (rac)-3-amino-1-BOC-piperidine gave the title compound as off-white gum. MS: 258.9 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl.O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[O:13][CH:11]([CH3:12])[CH2:10]2
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC(C)O)cc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1Br)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
18.04 g (132.4 mmol) of freshly melted zinc chloride is added to a solution of 32.46 g (132.4 mmol) of 1-(3-bromo-4-methoxyphenyl)-propan-2-ol and 20.01 g (132.4 mmol) of 4-nitrobenzaldehyde in 166 ml of dry benzene, and then dry hydrogen chloride gas is introduced for 3 hours. The reaction mixture is then heated to boiling for 1 hour and stirred with 150 ml of water. The organic phase is separated and washed in succession with water (2×50 ml), 20% sodium hydrogen sulfite solution (100 ml), 8% sodium bicarbonate solution (50 ml) and water (2×50 ml) and dried. After concentration by evaporation, a thick oil, which during treatment with hot ethanol (450 ml) yields crystalline 6-bromo-3-methyl-7-methoxy-1-(4-nitrophenyl)-isochroman, is obtained: 20.39 g (41%), melting point 128-129° C.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([O:23]CC)=O)[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([NH2:1])=[O:23])[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Reactant: N
Solvent: CCO
Product: COc1cc2cc3c(=O)[nH]c(C(N)=O)nc3nc2cc1OC
Temperature: 95 °C

Procedure:
Anhydrous ammonia is bubbled into a mixture of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 9.00 millimoles) in absolute ethanol (75 ml.) for 15 minutes. A clear solution formed followed after a few minutes by formation of a precipitate. The reaction mixture is transferred to a pressure bomb (Monel) and heated in a 95° C. oil bath overnight. The bomb is then cooled to room temperature and the contents removed. The bomb is washed with ethanol and the combined reaction mixture plus wash filtered to recover the product. The filter cake is washed with ethanol and then dried in air. Yield = 260 mg. (95%) M.P. 310° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[NH:16][C:15]([CH3:20])=[CH:14][C:13]=3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].C(OCC)(OCC)O[CH2:33][CH3:34]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[N:16][C:17]=3[O:19][CH2:33][CH3:34])[NH:12][C:11]([CH3:21])=[C:10]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2cc(C)[nH]c(=O)c21
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
1.52 g (3.76 mmol) of the compound from Example 25A are suspended in 40 ml of triethyl orthoformate and heated to 130° C. Then, over a total period of 8 hours, 10 drops of concentrated sulfuric acid are added each hour to the reaction mixture. It is then stirred at the same temperature overnight. After cooling, excess orthoester is removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). The product fractions are combined, the solvent is removed, and the residue is taken up in a little methanol. The crystallizing product is filtered off. Drying under high vacuum results in 1.09 g (67% of theory) of the title compound.