Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>CN(C=O)C.[Cu]I>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])=[N:3][N:4]=[CH:5]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C=C(OCC)c1nncc2cc(Cl)ccc12
Temperature: 100 °C

Procedure:
In a glass tube, a mixture of 1,6-dichlorophthalazine (1.18 g, 5.93 mmol) in 7.0 mL of DMF was treated with copper(I) iodide (113 mg, 0.59 mmol), tetrakistriphenylphosphine palladium (343 mg, 0.29 mmol) followed by tributyl(1-ethoxyvinyl)stannane (2.10 mL, 6.23 mmol). The glass tube was sealed and heated at 100° C. for 25 min in a microwave. The mixture was loaded on a silica gel column, eluting with 50-100% EtOAc in Hexanes, to provide 6-chloro-1-(1-ethoxyvinyl) phthalazine as a brown oil. MS (ESI, pos. ion) m/z: 235.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:27]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CN(C)[C@@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (R)—N,N-dimethylpyrrolidin-3-amine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 10-35% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 2.22-2.35 (m, 2H) 2.90 (d, J=3.79 Hz, 6H) 3.78-3.91 (m, 1H) 4.01-4.16 (m, 2H) 4.35 (d, J=6.57 Hz, 2H) 6.26 (d, J=2.27 Hz, 1H) 7.15 (s, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.99 (d, J=8.34 Hz, 2H) 8.04 (d, J=2.27 Hz, 1H) 9.88 (br. s., 1H) 10.77 (s, 1H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)=[O:28])[CH:21]=2)=[CH:17][CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:36]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([O:19][C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:40][CH:39]=3)[CH:25]=[CH:24][N:23]=2)=[O:28])[CH2:34][CH2:33]1)[CH3:37]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 30 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.0 ml) to a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (79 mg) and (+)-10-camphorsulfonic acid (49.7 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=4:1) to provide the title compound (36.5 mg, 30%) as white powder.
Reaction SMILES: [O:1]=[C:2]([CH3:7])[CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[Cl-].[C:11]1([N+:17]#[N:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([NH:17][N:18]=[C:3]([C:2](=[O:1])[CH3:7])[C:4]([NH2:6])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(N)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(N)=O

Procedure:
5.0 g (0.049 mol) of 3-oxobutyramide, a solution of 6.9 g (0.171 mol) of NaOH in 75 ml of water and 0.051 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel(EtOAc) obtaining 3 g of the title compound which was used as such in the subsequent step. M.p.=146°-147° C.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.C1COCC1.Cl.[OH-].[Na+]>ClCCl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 32.5 °C

Procedure:
4-(N—BOC amino)-CBz piperidine (24.4 kg 73.42 mol), THF (65 kg) and 5 M HCl (23.0 kg, 110.13 mol) were combined and heated to 30-35° C. for ˜2 hours, and then at 55° C. overnight. After cooling the reaction mixture to 10° C., dichloromethane (97 kg) and 10M NaOH (7.97 kg, 145.12 mol) were added, while keeping the temperature at <25° C. The phases were separated and the organic phase was washed with 25 wt % NaCl solution (27.5 kg). The washed organic phase was distilled at atmospheric pressure to a volume of 70 L. Dichloromethane (162 kg) was then added, and the mixture was concentrated by distillation to a volume of 120 L to give the title product as a solution in DCM (17.2 kg. 100%.). 1H NMR (CDCl3) 7.33 (5H, m), 5.14 (2H, s), 4.14 (2H, br s), 2.87 (3H, m), 1.83 (2H, m), 1.66 (3H, m) and 1.28 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[O:7][C@H:8]1[C@H:13]2[CH2:14][C@H:10]([C@@H:11]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([N:12]1[C@H:11]([C:22]([OH:24])=[O:23])[C@H:10]2[CH2:14][C@@H:13]1[C@H:8]([O:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[CH2:9]2)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)/C=C/O[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)O
Yield: 82.8 %

Procedure:
To a solution of 3-benzyl 2-tert-butyl (1R,3S,4S,6R)-6-{[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]oxy}-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 30-2 (316 mg) in ethanol (8 mL), was added 10% palladium on carbon (60 mg). The mixture was stirred under 4 atm of hydrogen for 1 hr at room temperature. The resulting mixture was filtered through celite and washed with ethanol. The filtrate and washings were evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (210 mg).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[CH2:15][N:14]=2)=[CH:9][C:8]=1[Cl:30])CCC.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:30][C:8]1[CH:9]=[C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:19])([F:21])[F:20])[CH2:15][N:14]=2)[CH:11]=[CH:12][C:7]=1[C:6]([OH:31])=[O:5]
Reactant: CCCCOC(=O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 50 °C
Reaction time: 20 h
Yield: 107.9 %

Procedure:
To a solution of 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-benzoic acid butyl ester (Example I16) (0.48 g) in THF (16 ml) and water (8 ml) was added lithium hydroxide monohydrate (103 mg). The reaction mixture was stirred at 50° C. for 20 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (1M) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-benzoic acid (459 mg). 1H-NMR (400 MHz, CDCl3): 8.15-7.40 (m, 6H), 4.95 (d, 1H), 4.30 (d, 1H), 3.85 (d, 1H), 3.35 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Reactant: CC(C)C(=O)Cl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(=O)C(C)C
Yield: 64.1 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 19, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described for the starting material in Example 13), was reacted with isobutyryl chloride (48 μl, 0.45 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]7-{[(2R)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline (120 mg, 64%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:41].CO.C1COCC1.NN.O>O>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:41]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN4C(=O)c5ccccc5C4=O)c3=O)nc12
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN)c3=O)nc12
Temperature: 50 °C
Yield: 71.3 %

Procedure:
To a solution of (R)-ethyl 5-(2-(1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.20 g, 0.36 mmol) in 1:1 MeOH/THF (12 mL) was added hydrazine-H2O (0.18 g, 3.6 mmol). The reaction mixture was heated at 50° C. for 24 hours. After cooling, the reaction mixture was poured into water and extracted with DCM (3×20 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the desired product (0.11 g, 72% yield). MS (apci) m/z=429.0 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])([O-:17])=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1cccc([N+](=O)[O-])c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (368 mg, 1.89 mmol) in ClCH2CH2Cl (8 mL), 3-nitrobenzoic acid (393 mg, 2.35 mmol) and P2O5 (3.2 g) as a yellow oil (500 mg, 1.46 mmol, 77%). 1H NMR (CDCl3) 8.60 (s, 1H), 8.43 (d, J=7.8, 1H), 8.13 (d, J=7.8, 1H), 7.68 (t, J=7.8, 1H), 6.86 (s, 1H), 6.82 (s, 1H), 6.07 (s, 2H), 3.87 (s, 2H), 3.63 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:16])[S:10][CH2:11][CH2:12][C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1.[BH4-].[K+]>CO.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:16])[S:10][CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 62.4 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 3-oxobutyl 5-chloropyrid-2-yldithiocarbamate (17.5 g) in methanol (220 cc) and a solution of potassium borohydride (3.44 g) in distilled water (55 cc) are used as the starting materials at a maximum of 30° C. The reaction is allowed to proceed for 1 hour at between 20° and 30° C. The resulting product (14.2 g; m.p.=115° C.) is dissolved in chloroform (500 cc). The solution is chromatographed on silica (0.2-0.5 mm) (140 g) contained in a column of diameter 3.4 cm. Elution is carried out with chloroform (1,500 cc), this eluate being discarded, and then with chloroform (4 liters). The eluate which is collected is evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The chromatographed product (11.4 g) is recrystallised from acetonitrile (85 cc). 3-Hydroxybutyl 5-chloropyrid-2-yldithiocarbamate (11.0 g), which melts at 122° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[N:36][OH:37])[NH2:35]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:37][N:36]=[C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: NC(=NO)c1ccccc1F
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine -3-carboxylic acid (Example 59A) and 51 mg (0.33 mmol) of 2-fluoro-N′-hydroxybenzene-carboximidamide were reacted according to the General Method 2. Yield: 71 mg (67% of theory)
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[C:12]([CH3:31])[CH:11]=2)[CH2:6][CH2:5]1.[N:32]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45]I)=[N+:33]=[N-:34].O>CN(C=O)C>[N:32]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)=[C:12]([CH3:31])[CH:11]=2)[CH2:6][CH2:5]1)=[N+:33]=[N-:34]
Reactant: Cc1cc(N2CCC(O)CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: [N-]=[N+]=NCCOCCOCCOCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCC(OCCOCCOCCOCCN=[N+]=[N-])CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 21.3 %

Procedure:
NaH (13.2 mg, 60% in mineral oil, 0.330 mmol) was added to a 0° C. solution of N-(4-(4-(4-hydroxypiperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (14.8 mg, 0.0362 mmol) in dry DMF (0.5 mL); the mixture was then stirred at 50° C. for 20 min. After that, the mixture was cooled to 0° C., and a solution of 1-azido-2-(2-(2-(2-iodoethoxyl)ethoxy)ethoxy)ethane (14.3 mg, 0.0435 mmol)6 in DMF (0.15 mL) was added dropwise. The mixture was stirred at rt overnight. Water (2 mL) was added to quench the reaction, and the mixture was extracted with DCM (4×2 mL). The combined organic layer was washed with brine and concentrated. The residue was briefly purified on a short silica column (EtOAc) to furnish N-(4-(4-(4-(2-(2-(2-(2-azidoethoxyl)ethoxy)ethoxy)ethoxy)piperidin-1-yl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (4.7 mg, 21.3%). MS (ESI) m/z 632.4 (M+Na+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=2/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: NC(=O)c1ccc(Br)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1
Product: NC(=O)c1ccc(N2CCCC2)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-bromo-3-[(E)-2-(4-trifluoromethoxy-phenyl)-vinyl]-benzamide and pyrrolidine by the same procedure as in Example 2-5-2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[C:26]([OH:28])=[O:27])=[O:33])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)c3ccccc3C(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of 2.97 g (0.01 mole) of 4'-amino-3,5-di-t-butyl-4-hydroxy biphenyl in 200 ml of diethyl ester was added a solution of 1.48 g (0.01 mole) of phthalic anhydride, and the resulting solution was stirred for about 16 hours. The solvents were removed under vacuum and the residual solid was recrystallized from a mixture of ethyl acetate and hexane to give 2.4 g of 2-{N-[4-(3,5-di-t-butyl-4-hydroxyphenyl)phenyl]carbamoyl}benzoic acid, m.p. 196°-198° C. Analysis: Calculated for C28H31NO4 : % C, 75.5; % H, 7.0; % N, 3.1; Found: % C, 75.5; % H, 7.1; % N, 3.0.
Reaction SMILES: [C:1]1(O)[C:5](=[O:6])[C:3](=O)[C:2]=1[OH:7].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([CH3:23])=[O:22])[CH:15]=1)[CH2:11][CH2:12][OH:13].[CH3:24][CH2:25][CH2:26][CH2:27]O>C1(C)C=CC=CC=1>[NH:20]([C:16]1[CH:15]=[C:14]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])[CH:19]=[CH:18][C:17]=1[C:3]1[C:2]([OH:7])=[C:1]([C:27]2[CH:26]=[CH:25][C:24]([N:10]([CH2:11][CH2:12][OH:13])[CH3:9])=[CH:15][C:16]=2[NH:20][C:21]([CH3:23])=[O:22])[C:5]=1[OH:6])[C:21]([CH3:23])=[O:22]
Reactant: CCCCO
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC(=O)Nc1cccc(N(C)CCO)c1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(N(C)CCO)ccc1C1=C(O)C(c2ccc(N(C)CCO)cc2NC(C)=O)=C1O
Temperature: 120 °C

Procedure:
342 mg of squaric acid) and 2 g of 2-(methyl(3-acetaminophenyl)amino)ethan-1-ol were put in a 100 mL 3-neck rounded bottom flask, and 40 mL of n-BuOH and 20 mL of toluene were added thereto. The mixture was heated and refluxed at 120° C. for 10 hours. Then, a Dean-Stark trap set was used to remove water generated from the reactant during the reaction, and the reactant kept being reacted. When the reaction was complete, the reactant was cooled down, producing crystals. The crystals were filtered, several times cleaned with hexane, and once more recrystallized, obtaining a desired compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C[Si]([C:19]#[N:20])(C)C.[OH-].[NH4+]>C(O)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9]2([C:19]#[N:20])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)C#N
Reactant: Nc1ccc(I)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(I)cc2)CCCC1
Reaction time: 0.25 h
Yield: 94 %

Procedure:
3.5 g (16 mmol) of 4-iodo-aniline are added to a solution of 1.3 ml (14.7 mmol) of cyclopentanone in 20 ml of acetic acid at 0° C. The solution is stirred for 15 minutes and 2 ml (15 mmol) of trimethylsilyl cyanide are added. The reaction medium is stirred for one night at ambient temperature. It is then poured gently into a solution of ice-cooled ammonium hydroxide until the pH is basic and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. After evaporation of the solvents, 4.3 g of 1-(4-iodo-phenylamino)-cyclopentanecarbonitrile are obtained in the form of a brown oil. (Yield=94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>>[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:35]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)CN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1

Procedure:
Synthesis in analogy to Example 8 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 2-methoxy-benzoyl chloride to yield 2-methoxy-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-benzamide. LC/MS at 254 nm; [M+H] 518; Rt 3.772 min.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[C:10]([N:14]=[C:15]=[O:16])[CH:9]=1>>[CH3:17][C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCCC1=N
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)N=C2CCCN2C)c1

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred, and 6.66 g. (0.05 mole) of m-tolylisocyanate is added (solid forms). The reaction mixture is stirred at room temperature overnight. The solid is collected, m.p. = 148°-149° C. The benzene filtrate, after removal of solvent, yields a further crop of solid material, m.p. 137°-142° C. Recrystallizations of the combined solids from acetone gives the pure product, 1-m-methylphenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 149°-151° C.