Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][CH:18]3OCC[O:19]3)[C:14]3[CH:23]=[C:24]([C:27]([N:29]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH:25]=[CH:26][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:14]3[CH:23]=[C:24]([C:27]([N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:28])[CH:25]=[CH:26][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC2OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC=O)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of 2-[(4-acetylphenyl)amino]-1-[2-(1,3-dioxolan-2-yl)ethyl]-N,N-bis(3-methylbutyl)-1H-benzimidazole-6-carboxamide (900 mg) in a mixture of tetrahydrofuran (30 ml) and aqueous hydrochloric acid (3N, 40 ml) is stirred for 18 hours at a temperature of approximately 20° C. then concentrated under reduced pressure at 40° C. Dichloromethane (100 ml) is added to the remaining aqueous phase. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of a beige foam (820 mg, 99% yield).
Reaction SMILES: [Cl-:1].[Cr+3:2].N1C2C=CC=CC=2N=C1CNCC1NC2C=CC=CC=2N=1.[Cl-].[Cl-].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C@H:35]1[NH:40][C@@H:39]([C:41]2[NH:45][C:44]3[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=3[N:42]=2)[CH2:38][CH2:37][CH2:36]1.[K+].[Br-]>>[Cl-:1].[Cr+3:2].[NH:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[CH:35]1[NH:40][CH:39]([C:41]2[NH:42][C:43]3[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=3[N:45]=2)[CH2:38][CH2:37][CH2:36]1.[Cl-:1].[Cl-:1]
Reactant: c1ccc2[nH]c([C@@H]3CCC[C@H](c4nc5ccccc5[nH]4)N3)nc2c1
Agent: [Cr+3]
Agent: [Br-]
Agent: [Cl-]
Product: c1ccc2[nH]c(C3CCCC(c4nc5ccccc5[nH]4)N3)nc2c1

Procedure:
3k was synthesised by an analogous procedure to that described for 3a using 2k (0.30 g, 0.95 mmol) and CrCl3(THF)3 (0.38 g, 1.0 mmol). Yield 0.34 g (765%). Anal. Calc. for C19H19Cl3CrN6 (in %): C, 47.97; H, 4.03; N, 14.72. Found C, 47.89; H, 4.13; N, 14.62. +FAB-MS: (m/z): 439 ([M-Cl]+), 403 ([M-2Cl]+), 368 ([M-3Cl]+). IR (KBr, cm−1), υ 3398 (NH, s), υ 3152, 3112 (Ar—H, s), υ 1637-1540 (ArC═C, C═N, m), δ 1454 (N—H, s), υ 1278 (CN, s), δ 749 (CH, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH2:20][C:21]1([C:34](OCC)=[O:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[CH:15][C:14]([O:39][CH3:40])=[CH:13][CH:12]=2.O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH2:20][C:21]1([CH2:34][OH:35])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:25][CH2:26]1)=[CH:15][C:14]([O:39][CH3:40])=[CH:13][CH:12]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(CCCC3(CO)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
1.05 g of lithium aluminum hydride was added portionwise, with stirring and under an inert atmosphere, to a solution of 12.3 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate in 250 cm3 of tetrahydrofuran, at a temperature in the region of −20° C. After stirring for 2 hours at a temperature in the region of 20° C., 0.5 g of lithium aluminum hydride was added to the reaction mixture at a temperature in the region of −20° C. After 1 and a half hours, the reaction mixture was cooled to 0° C. and was then hydrolyzed by successive addition of 1.8 cm3 of water, 1.3 cm3 of 5N sodium hydroxide and 5.7 cm3 of water. After stirring for 30 minutes at a temperature in the region of 20° C., the reaction mixture was filtered and then washed with 400 cm3 of ethyl acetate. The filtrate was washed with 200 cm3 of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 10.9 g of tert-butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethylpiperidine-1-carboxylate were obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([Cl:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28](O)=[O:29])[CH:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[O:27][N:26]=[C:25]([C:28]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([Cl:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:29])[CH:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Yield: 19.6 %

Procedure:
(S)-5-acetyl-N-(2-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (500 mg, 1.794 mmol) and 5-acetylisoxazole-3-carboxylic acid (417 mg, 2.69 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 19.6%. 1H-NMR (400 MHz; DMSO): δ 1.51 (d, 3H), 2.57 (s, 3H), 3.56-3.77 (m, 2H), 4.65-4.77 (m, 1H), 7.01 (d, 1H), 7.56 (s, 1H), 7.89 (dd, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 9.03 (t, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][CH:8]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[C:9](O)=[O:10].C1(C)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.O>[NH2:7][CH:8]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)c1ccc(OCC(N)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(OCC(N)CO)cc1
Yield: 89.6 %

Procedure:
To a mixture of 4.00 g (105 mmol.) of lithium aluminum hydride and 50 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 2.50 g (10.5 mmol.) of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propionic acid obtained in Production Example 13 in 50 ml of anhydrous tetrahydrofuran with stirring under reflux by heating for 30 minutes. Then the reaction mixture was further refluxed by heating with stirring for 2 hours. After the reaction was completed, the resultant mixture was cooled to a temperature of from 5° C. to 10° C. To the resultant mixture, there was added 100 ml of toluene and further added slowly, 10 ml of water and a 5N aqueous solution of sodium hydroxide. The above mixture was dried over anhydrous magnesium sulfate, filtrated with a filter agent (Celite®) and concentrated under reduced pressure to give 2.10 g of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propanol as a light-yellowish solid (m.p. 101.7° C.).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:39])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([NH:24][C@H:25]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=3[O:27][B:26]2[OH:38])=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C.Cl>>[NH2:8][C@@H:9]([CH3:39])[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]([NH:24][C@H:25]2[CH2:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([OH:37])=[O:36])[C:28]=3[O:27][B:26]2[OH:38])=[O:23])[CH2:17][CH2:16]1
Reactant: C[C@@H](CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H](N)CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
To the compound from step 1 was added 3N HCl (2 ml) and the resultant reaction mixture was heated at reflux for 1 hr. The solvents were then removed in vacuo and the residue purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 447 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[OH:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13](=[O:15])[CH3:14])[CH:2]([CH3:1])[CH2:11]1
Reactant: CC1CC(O)c2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2C(O)CC1C
Yield: 92 %

Procedure:
A solution of 1,2,3,4-tetrahydro-2-methyl-4-quinolinol (5.9 g, 36.4 mmol) and acetic anhydride (37.1 g, 364 mmol) in dichloromethane (100 ml) was stirred for one hour. The solvents were evaporated and the crude product was purified on silica (ethyl acetate:heptane 1:1) to obtain the sub-titled product (33.5 mmol).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[CH3:14][NH:15][C:16]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:17]
Reactant: CN=C=O
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
0.5 moles of diphenylamine was taken in 150 ml of toluene. 0.53 mole of methyl isocyanate and 1 g of acid compound (see Table 1) were added. The mixture was heated at 100° C. for 8 hours, with stirring, and allowed to cool to room temperature, and the N-methyl-N', N'-dipenylurea formed was filtered off. The urea was washed with 100 ml of cold toluene. For the yield, see Table 1.
Reaction SMILES: FC1C=C(C=CC=1F)C[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[N:8]([CH3:18])[C:7]1=[O:19].C(N(C(C)C)CC)(C)C.C1(CC#C)C=CC=CC=1.O>CN(C=O)C.[Cu]I>[I:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[C:7](=[O:19])[NH:6][C:15]2=[O:16]
Reactant: Cn1c(=O)n(Cc2ccc(F)c(F)c2)c(=O)c2cc(I)ccc21
Agent: [Cu]I
Agent: C#CCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2cc(I)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 0.45 g (1.1 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.56 g (4.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.18 g (1.3 mmol) 3-phenyl-propyne is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stirred overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent).
Reaction SMILES: [ClH:1].Cl.C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:17]=[N:18][C:19]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1)C.[Li+].[OH-].Cl.[CH3:43][NH:44][CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C1COCC1.CO.O.O.CCOC(C)=O.C(O)(=O)C.CN(C=O)C.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:35]([C:19]1[N:18]=[N:17][C:16]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([N:44]([CH3:45])[CH3:43])=[O:5])[CH2:14][CH2:13]2)=[CH:21][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:26][CH:27]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CNC
Reactant: CCCCc1nnc(OC2CCN(CCC(=O)OCC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCCCc1nnc(OC2CCN(CCC(=O)N(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of 3-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionic acid ethyl ester dihydrochloride (Example 15, 1.0 mmol, 583 mg) in THF-MeOH—H2O (1:1:1, 3 mL) was added LiOH (20 mmol, 480 mg). The mixture was stirred at 100° C. for 10 min. The mixture was then diluted with water/EtOAc and neutralized with acetic acid. The organic layers combined, dried, and condensed in vacuo, and the residue was dissolved in DMF (2 mL). Dimethylamine hydrochloride (3.0 mmol, 245 mg), HBTU (3.0 mmol, 1.14 g), DIEA (3.0 mmol, 0.53 mL) were added to the mixture, and the mixture was stirred at 100° C. for 2 hours. It was then diluted with water/EtOAc and neutralized with acetic acid. The organic layers were combined, dried, and condensed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 2N HCl in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (279 mg). LCMS: m/z 510 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.31-7.35 (2H, m), 7.01-7.07 (3H, m), 5.46-5.52 (1H, m), 4.37-4.43 (1H, m), 3.35-3.50 (5H, m), 3.03 (6H, s), 2.87-2.95 (5H, m), 2.20-2.35 (4H, m), 1.96-2.03 (2H, m), 1.78-1.84 (2H, m), 1.27-1.63 (8H, m), 1.20-1.24 (2H, m), 0.80 (3H, t).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Cc3ccccc3O4)nn2)n1

Procedure:
The object product (200 mg, 87%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,4′-piperidine] (150 mg) and potassium carbonate (110 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[NH:8][CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3].[CH2:19](I)[CH2:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[N:8]([CH2:19][CH2:20][CH3:21])[CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3]
Reactant: CCCI
Reactant: C=CCn1c(-c2cccs2)nc2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(-c2cccs2)nc2c(=O)n(CCC)cnc21
Temperature: 27 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
A mixture of 9-Allyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 0.39 mmol), n-propyl iodide (0.04 ml, 0.4 mmol) and Cs2CO3 (0.192 g, 0.59 mmol) were taken in DMF (1 ml) and stirred for 20 hours at 27° C. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml), dried over Na2SO4. Solvent was removed to get 9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 86%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[C:26]([O:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=2[O:44][CH3:45])=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:41]=[C:40]([C:39]2[CH:42]=[CH:43][C:36]([O:35][C:26]3[C:25]([Cl:24])=[CH:30][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:28][N:27]=3)=[C:37]([O:44][CH3:45])[CH:38]=2)[N:2]([CH3:1])[N:3]=1
Reactant: COc1cc(C#N)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(-c2nc(-c3c(F)cccc3Cl)nn2C)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)-3methoxybenzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[F:26][C:17]1[C:16]([O:15][CH2:14][C:9]2[S:10][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=3[N:8]=2)=[CH:21][CH:20]=[C:19]([F:22])[C:18]=1[C:23]([NH2:25])=[O:24]
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: Cc1cccc2sc(N)nc12
Product: Cc1cccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc12
Yield: 36 %

Procedure:
Synthesised from 4-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 36% (second step), mp 201-202° C., HPLC-MS (method 1): m/z 335 [M+H]+, Rt=3.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=4[S:19][C:18]3=[N:30]C(=O)C(F)(F)F)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH:30]=[C:18]1[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:29])[F:28])=[CH:25][C:20]=2[S:19]1
Reactant: COc1ccc(N2CCN(CCn3c(=NC(=O)C(F)(F)F)sc4cc(C(F)(F)F)ccc43)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(N2CCN(CCn3c(=N)sc4cc(C(F)(F)F)ccc43)CC2)cc1
Yield: 115.9 %

Procedure:
Using the procedure described in Example 19, but starting with 3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-2-trifluoroacetylimino-6-trifluoromethylbenzothiazoline (0.1 g), a 7% strength aqueous solution (0.5 cc) of potassium carbonate and methanol (5 cc). 2-imino-3-{2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl}-6-trifluoromethylbenzothiazoline (0.095 g) m.p. 270° C. is obtained.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.[C:54]([O:58][C:59](/[C:61](/[CH2:71][O:72][CH2:73][CH2:74][O:75][CH3:76])=[CH:62]/[C:63]1([C:68]([OH:70])=[O:69])[CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>CO.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.[C:54]([O:58][C:59]([C@H:61]([CH2:71][O:72][CH2:73][CH2:74][O:75][CH3:76])[CH2:62][C:63]1([C:68]([OH:70])=[O:69])[CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:60])([CH3:56])([CH3:55])[CH3:57]
Reactant: COCCOC/C(=C\C1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: CO
Solvent: C1=CCCC=CCC1
Solvent: NC1CCCCC1
Product: COCCOC[C@H](CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Chloro(1,5-cyclooctadiene)rhodium(I)dimer (15.2 mg, 0.03 mmole) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (42.2 mg, 0.06 mmole) were charged to a 50 mL three necked flask equiped with gas inlet and outlet lines and the third neck sealed with a rubber septum. The system was flushed with nitrogen, methanol (10 mL) was added and the mixture purged with nitrogen for 30 minutes. The reaction was hydrogenated at atmospheric hydrogen pressure and room temperature for 1 hour. At this point a solution of (E)-1-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)prop-1-enyl]-1-cyclopentanecarboxylic acid cyclohexylamine salt (0.5 g, 1.17 mmol) in methanol (10 mL) was added and the mixture hydrogenated at atmospheric pressure and room temperature for 5 days. The reaction mixture was purged with nitrogen and concentrated under reduced pressure to give a brown solid (Ratio S:R 89:11). The crude product was recrystallised from ethyl acetate (3.5 ml) and hexane (3.5 ml) to give the title compound (0.37 g, 74%). (Ratio S:R 92:8), Rf =0.29 (ethyl acetate/hexane, 1:1+1% acetic acid).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(O)cccc1OCCCCN

Procedure:
Methyl 2-{4-[(tert-butoxycarbonyl)amino]butoxy}-6-hydroxybenzoate (410 mg, 1.2 mmol) was treated with trifluoroacetic acid/dichloromethane (6 mL, 1:1/v:v) at ambient temperature for 3 hours, concentrated under reduced pressure and evaporated with acetonitrile twice to provide the titled amine as its trifluoroacetic acid salt (450 mg).
Reaction SMILES: [BH4-].[Na+].Cl.Cl.[C:5]1([C:11]2[CH:20]=[C:19]([C:21](=[O:29])[CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[C:5]1([C:11]2[CH:20]=[C:19]([CH:21]([OH:29])[CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CC1CCNCC1)c1cc(-c2ccccc2)nc2ccccc12
Yield: 68.2 %

Procedure:
6 g of sodium borohydride were added in 20 minutes, at the ambient temperature, to 16 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone dihydrochloride in 500 ml of methanol. After reacting for 2 hours at the ambient temperature, 350 ml of water were added and the methanol was removed by distillation under reduced pressure. The residual aqueous suspension was extracted with diethyl oxide, the organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue (13 g) was crystallized from petrol ether. 9 g of 1-(2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanol (racemic) were thus obtained, which melted at 147° C.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:24][C:21]1[CH:22]=[N:23][C:2]2[N:19]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:20]=1
Reactant: N=C(COCCc1cccc(Cl)c1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(3-chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as colorless crystals. MS: m/e=350.2 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([S:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: Clc1ccc(Cl)nc1
Product: Clc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2,5 Dichloropyridine (8.9 g, 60 mmol) and thiophenol (6.1 mL, 60 mmol) were heated to 150° C. for 41 h. The mixture then was removed from heat and cooled to room temperature. Column chromatography (silica gel, 200 mL) using hexanes as eluent gave 8.06 g of the title compound; IR (liq.) 1564, 1548, 1476, 1440, 1356, 1122, 1092, 1024, 1006, 821, 748, 727, 706, 691, 628 cm−1. 1H NMR (CDCl3) δ 6.8, 7.4, 7.6, 8.38.