Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1([C:43]2[CH:48]=[CH:47]C(O)=[CH:45][CH:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:45]=[CH:44][C:43]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:48][CH:47]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccc(-c5ccccc5)cc4)cc3C)c2cc1OC
Yield: 68.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-phenylphenol (39 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 66%).
Reaction SMILES: [Br:1]C1C(C#N)=NC=CC=1.C(O/N=C(\C1C=CC=CN=1)/[C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[OH:24])(C)(C)C.[C:31]([O:35]/[N:36]=[C:37](\[C:46]1[C:51]([Br:52])=[CH:50][CH:49]=[CH:48][N:47]=1)/[C:38]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:39]=1[OH:45])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35]/[N:36]=[C:37](\[C:46]1[C:51]([Br:52])=[CH:50][CH:49]=[CH:48][N:47]=1)/[C:38]1[CH:43]=[C:42]([Br:44])[CH:41]=[CH:40][C:39]=1[OH:45])([CH3:34])([CH3:32])[CH3:33].[Br:1][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=1[OH:24]
Reactant: CC(C)(C)O/N=C(\c1ccccn1)c1cc(Br)ccc1O
Reactant: N#Cc1ncccc1Br
Agent: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1ncccc1Br
Product: Oc1ccc(Br)cc1Br

Procedure:
Employing 3-bromo-2-cyanopyridine (5.88 g) in place of 2-cyanopyridine in the production of Compound 75 in Example 9, substantially the same reaction as in Example 9 was conducted to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-bromopyridine O-t-butyloxime (3.74 g) (Compound 81) from 2,4-dibromophenol (8.01 g).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].NCC1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][C:24]3[N:32]([CH3:35])[N:33]=[CH:34][C:23]=3[CH2:22]2)=[O:20])=[CH:17][C:16]=1[CH3:38].CN1[CH2:46][CH2:45][CH2:44]NCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:32]1[C:24]2[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:21]([C:19](=[O:20])[C:18]3[CH:36]=[CH:37][C:11]([CH2:12][NH:8][C:1]([N:3]4[CH2:46][CH2:45][CH2:44][N:5]([CH3:4])[CH2:6][CH2:7]4)=[O:2])=[C:16]([CH3:38])[CH:17]=3)[CH2:22][C:23]=2[CH:34]=[N:33]1
Reactant: CN1CCCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)N1CCCN(C)CC1
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (37 mg, 0.23 mmol) was added to a solution of 5-(4-(aminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo-[5,4-b][1,5]benzodiazepine (75 mg, 0.22 mmol) in DMF (2 ml). The solution was stirred for 1 h, a solution of 1-methylhomopiperazine (27 mg, 0.24 mmol) and DIEA (31 mg, 0.24 mmol) in DMF (1 ml) was added and stirring was continued for 24 h. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (eluant 30/2/1-1/1/1 chloroform/methanol/concentrated ammonia) to give a white solid identified as 1-methyl-5-(3-methyl-4-(4-methylperhydro-1,4-diazepine-1-carbonylaminomethyl)benzoyl)-4,10-dihydropyrazolo[5,4-b][1,5](38 mg, 36%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:42])=[C:27]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:28]=1)=[O:21])=[O:14])(C)(C)C>C(Cl)Cl>[C:13]([CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:43]=[CH:44][CH:45]=1)[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:42])=[C:27]([NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH:28]=1)=[O:21])([OH:14])=[O:12]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(OCC(=O)OC(C)(C)C)c3)ccc2C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(OCC(=O)O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of N-[5-(3-tert-butoxycarbonylmethoxybenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.455 g) in methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was azeotroped with toluene. The resultant solid was dried under vacuum at 60° C. There was thus obtained the title compound (0.375 g), m.p. 206-207° C.; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.83 (s, 6H). 4.74 (s, 2H), 7.06 (d, 1H), 7.11 (m, 1H), 7.23 (d, 1H), 7.43 (t, 1H), 7.48 (d, 1H), 7.55 (br m, 1H), 7.63 (m, 1H), 7.8 (d, 1H), 9.75 (br s, 1H), 10.17 (br s, 1H); Mass Spectrum: M+H+ 465.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28].[C:41]([O-])(=[O:43])C.[Na+]>>[CH:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:43])=[S:39])([CH3:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Agent: [Na+]
Product: Cc1ccc(NC(=S)NC(=O)NCCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(2-isopropyl-4-methylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.101 g, 32%): 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.04 (s, 1H), 9.39 (s, 1H), 8.14-7.99 (m, 4H), 7.71-7.55 (m, 2H), 7.46-7.33 (m, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.08 (t, J=5.6 Hz, 1H), 7.04-6.95 (m, 1H), 3.17 (d, J=5.2 Hz, 2H), 2.96 (p, J=6.8 Hz, 1H), 2.70 (dd, J=8.6, 6.6 Hz, 2H), 2.31 (s, 3H), 1.81 (p, J=7.3 Hz, 2H), 1.16 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 597 ([M+H]+), 595 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])[O:31][C:32](Cl)(Cl)Cl)Cl.[Cl:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:31][CH2:32][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[Cl:38])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: OCc1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c([N+](=O)[O-])c3)c2cc1OC
Yield: 49.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (74 mg, yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:22]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:33][S:34]([O-:36])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([S:34]([CH3:22])(=[O:36])=[O:33])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc(C)sc2-c2ccc(Br)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Br)cc2)s1
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 5-(4-bromophenyl)-2-methyl-4-[4-(methylthio)phenyl]-1,3-thiazole from step 3 (3.8 g, 0.010 mol) in CH2Cl2 (40 mL), m-CPBA (6.2 g, 0.025 mol) was added at 0° C. The mixture was allowed to warm to room temperrature and stirred for 12 hours. The mixture was poured into aqueous saturated Na2SO3 (40 mL) and diluted with CH2Cl2 (50 mL). Organic later was separated and washed with aqueous saturated NaHCO3 (50 mL), dried over MgSO4, and concentarted in vacuo. The mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (3.1 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C@@H:5]([NH:17]C(OC(C)(C)C)=O)[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Cl.O1CCOCC1>ClCCl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C@@H:5]([NH2:17])[CH2:6][S:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COC(=O)C[C@H](CSCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C[C@@H](N)CSCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(R)-3-t-butoxycarbonylamino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl ester (30 g, 81.3 mmol) prepared in Step D was dissolved in dichloromethane (70 mL). 4N hydrochloric acid/1,4-dioxane solution (71 mL) was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the residue were added dichloromethane (30 mL) and diethylether (150 mL). The resulting solid was filtered and dried to give the title compound (19.2 g, Yield 87%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[C:12]1([C:18]([CH2:20][CH2:21][C:22]#[CH:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[OH:19][C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: C1CSCSC1
Reactant: C#CCCC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCCC(O)(c1ccccc1)C1SCCCS1
Reaction time: 1.25 h
Yield: 75 %

Procedure:
1,3-Dithiane (3.8 g, 31.6 mmol) was stirred in 120 mL of tetrahydrofuran at -40° C. under argon and 13.2 g (33 mmol) of 2.5M n-BuLi in hexane was added. After 10 minutes the temperature was adjusted to -20° C. and 1.25 hours later 2.27 g (14.36 mmol) of but-3-ynyl phenyl ketone was added as a solid. Stirring was continued for 20 minutes before placing in a freezer at -20° C. for 20 hours. The mixture was then poured onto water, the layers were separated, and the aqueous portion extracted with methylene chloride (3×30 mL). The combined organics were washed with brine, dried (MgSO4) and solvents evaporated at reduced pressure. The residue was chromatographed on 75 g silica (98:2, hexane:EtAc, then 4%, 10%, and 20% EtAc) to give 3.0 g (75%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:32][CH:33]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 15.5 g of m-aminobenzyl alcohol and 36.21 g of pyridine in 250 ml of tetrahydrofuran, cooled to 0° C. is added over 40 minutes a solution of 42 g of p-tetradecyloxyphenylacetyl chloride in 250 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and the solvent is evaporated. The residue is partitioned between water and chloroform with some heating to afford a complete solution. The hot chloroform solution is washed with warm water and warm dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride to give 40 g of the desired product as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Na].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=O>CN(C=O)C.C(OC)(C)(C)C.O.N>[CH2:17]([O:16][C:10]([C:11]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:12]=1[CH3:14])=[O:15])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1I
Agent: N
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
A mixture of 2-iodo-phenylamine (44.30 g, 202 mmol), sodium salt of ethyl acetoacetate (42.1 g, 263 mmol), and Cu(I)I (50.1 g, 263 mmol) in DMF (200 mL) was stirred at 120° C. overnight. Then the reaction mixture was cooled to room temperature, then diluted with methyl tert-butyl ether (MTBE) and water, and concentrated ammonia was added to dissolve the solid, the two layers were separated, the water layer was back extracted with MTBE; all MTBEs were combined and washed with sat. NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated sequentially. The residue was crystallized in hexanes/EtOAc, giving the desired product (10.84 g), the mother liquor was concentrated and purified on column to give an additional batch of product (4.76 g). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.32 (1H), 8.09 (m, 1H), 7.31-7.13 (m, 3H), 4.39 (q, 2H, J=6.8 Hz), 2.74 (s, 3H), 1.45 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)Cl)[CH3:2].[OH2:19].[Cl:20]Cl>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([Cl:20])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(Cl)c1ccc(-n2cccn2)cc1
Reactant: ClCl
Reactant: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=O)c1ccc(-n2cc(Cl)cn2)cc1

Procedure:
2.65 g of α-chloro-4-(pyrazol-1-yl) phenylacetic acid ethyl ester are dissolved in 50 ml of carbon tetrachloride, and 2 ml of water are added. Chlorine is introduced for 30 minutes and the reaction mixture is washed with sodium carbonate solution; concentration is effected, followed by purification through column chromatography on silica gel. (cyclohexane/diethyl ether 4:1). 4-(4-chloropyrazol-1-yl) phenylglyoxylic acid ethyl ester is obtained which, through saponification analogously to Example 10 is converted into 4-(4-chloropyrazol-1-yl) phenylglyoxylic acid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:45]=[CH:44][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32]4[N:37]=[C:36]([C:38]5[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][N:33]=4)[CH:25]=3)=[O:22])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.O>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32]4[N:37]=[C:36]([C:38]5[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][N:33]=4)[CH:25]=3)=[O:22])=[CH:44][CH:45]=2)[CH2:12][CH2:11]1.[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: O
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 90 °C

Procedure:
(Trans)-butenedioic acid (fumaric acid; Fluka, Buchs, Switzerland; 1.16 g, 10 mmol) is added to a solution of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide (4.94 g, 10 mmol) in ethanol (25 mL). The mixture is heated to 90° C., treated with water (18 g) and filtered. Upon cooling, the product crystallizes and is filtered and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, fumarate a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 63.91; H, 5.99; N, 15.74%; H2O, 1.27%. Calculated for C33H35N7O5-0.44 H2O: C, 64.18; H, 5.86; N, 15.88%; H2O, 1.28%.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](Cl)=[O:12].[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[CH:19]1([CH2:25][NH:26][C:11](=[O:12])[C:10]2[CH:9]=[C:8]([F:7])[C:16]([F:17])=[C:15]([F:18])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCC1CCCCC1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCC1CCCCC1)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To 10 ml of ethyl acetate were added 0.50 g of 3,4,5-trifluorobenzoyl chloride, 0.32 g of cyclohexylmethylamine and 0.50 g of triethylamine and the mixture obtained was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Crystals obtained were washed with a mixture of hexane and MTBE to obtain 0.70 g of N-cyclohexylmethyl-3,4,5-trifluorobenzamide. N-cyclohexylmethyl-3,4,5-trifluorobenzamide:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:61][CH:60]([NH2:62])[CH2:59]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1>CN(C=O)C.C(Cl)Cl>[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:59][CH:60]([NH:62][C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)=[O:8])[CH2:61]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a stirred solution of 6-methylnicotinic acid (5.5 mg, 40 μmol) in 1:1 DCM:DMF (1 ml) was added HOBt (12 mg, 87 μmol) followed by HBTU (30 mg, 80 μmol) at room temperature. After 15 minutes 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (10 mg, 40 μmol) was added and the reaction was stirred for 16 hours. The reaction was concentrated at reduced pressure and purified directly via preparative HPLC to give the title compound (5 mg, 34%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][CH:19]=O)[CH:13]=[C:14]([Cl:16])[CH:15]=1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][C@H:19]2[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: CCCC(CO)CO
Reactant: O=CCCc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H](CCc2cc(Cl)cc(Cl)c2)OC1
Yield: 72.1 %

Procedure:
A solution comprising 18.3 g (155.1 mmol) of 2-propyl-1,3-propanediol, 30.0 g (147.7 mmol) of 3-(3,5-dichlorophenyl)-propionaldehyde, 1.5 g of p-toluenesulfonic acid, and 300 ml of toluene was heated to reflux while taking out the distilled water for 3 hours. After termination of the reaction, the organic layer was washed with a diluted aqueous sodium bicarbonate solution once and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: toluene) to obtain 32.3 g of a crude trans-2-(2-(3,5-dichlorophenyl)ethyl)-5-propyl-1,3-dioxane. (Yield: 72.1%)
Reaction SMILES: [OH-].[Na+].C1COCC1.CO.C[O:11][C:12]([C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=[CH:18][CH:19]=1)=[O:13]>CCOC(C)=O>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([OH:13])=[O:11])[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1cccc(CCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCc2cccc(C(=O)O)c2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Aqueous 1 M sodium hydroxide solution (196 ml) was added to a THF (200 ml)/methanol (50 ml) mixed solution of tert-butyl 4-{2-[3-(methoxycarbonyl)phenyl]ethyl}-1-piperidinecarboxylate (45.4 g), followed by stirring at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure, and under ice cooling, 0.5 M hydrochloric acid (400 ml) was added to the residue. The reaction liquid was diluted with EtOAc, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}benzoic acid (43.5 g) was obtained.
Reaction SMILES: C1(=O)CCCC=C1.[CH2:8]([O:10][C:11](=[O:28])[CH:12]([CH:18]1[CH2:23][CH2:22][CH:21](CCC)[C:20](=[O:27])[CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([CH:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:27])[CH2:19]1)[C:11]([O:10][CH2:8][CH3:9])=[O:28])[CH3:17]
Reactant: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1=O
Agent: O=C1C=CCCC1
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Yield: 88 %

Procedure:
Step 1 (3-Oxo-cyclohexyl)-malonic acid diethyl ester was prepared in 88% yield from cyclohexenone by the method described above for the synthesis of 2-(3-oxo-4-propyl-cyclohexyl)-malonic acid diethyl ester: 1H NMR (300 MHz, CDCl3) δ 4.44–4.12 (m, 4H), 2.88–1.22 (m, 16H).