Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20]([NH:22][C:23](=[N:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])SC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCOCC1.CCOCC>[CH2:30]([O:29][C:27]([NH:26][C:23](=[N:22][C:20]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(N=C(NC(=O)OCc1ccccc1)N1CCCC(C(=O)O)C1)OCc1ccccc1
Reaction time: 48 h
Yield: 71.1 %

Procedure:
To a solution of nipecotic acid (1.66 g, 12.8 mmol) in 2 N NaOH (12.8 mL, 25.6 mmol) and dioxane (30 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (4.6 g, 12.8 mmol). After 48 h, the reaction mixture was added to H2O (200 mL) and Et2O (200 mL). The aqueous layer was separated and extracted with Et2O (2×200 mL). The aqueous layer was acidified to pH, 2.0 with 3 N HCl and extracted with EtOAc (500 mL). The organic layer was MgSO4 dried and concentrated to give the title compound (4.0 g, 71%): TLC Rf=0.65 (1:15:135 Acetic Acid:Methanol:Chloroform); NMR (CDCl3) δ1.55-1.92 (m, 6H), 2.00-2.15 (m, 1H), 2.70-2.80 (m, 1H), 3.20-3.35 (q, 1H), 3.38-3.45 (m, 1H), 3.75-4.10 (m, 1H), 5.10 (s, 2H), 5.22 (s, 2H), 7.30-7.40 (m, 10H); FD-MS 440 (NH+).
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][N:19]3[C:27](=[O:28])C4C(=CC=CC=4)C3=O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=C=O)=[CH:40][CH:39]=1>C(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH:19][C:27]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=3)=[O:28])[CH2:14][CH2:13]2)=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: O=C(NOC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 131.7 %

Procedure:
Hydrazine monohydrate (0.059 ml, 1.2 mmol) was added to a solution of 2-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)isoindoline-1,3-dione (193 mg, 0.406 mmol) in CH2Cl2 (5 ml) and stirred at room temperature for 15 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), 4-fluorophenyl isocyanate (0.023 ml, 0.20 mmol) was added and the whole was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (ethyl acetate/hexane: 25/75 to 45/55) and the resulting solid was recrystallized from ethyl acetate/hexane to give 1-(1-(bis(4-fluorophenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (120 mg, 65%) as a white solid: LCMS: 456 [M+1]+. 1H NMR (DMSO-d6) δ: 1.68 (m, 2H), 1.90-2.02 (m, 4H), 2.62 (m, 2H), 3.70 (m, 1H), 4.40 (s, 1H), 7.10 (m, 6H), 7.43 (m, 4H), 7.55 (m, 2H), 8.61 (s, 1H), 9.38 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH2:16][CH2:17][N:8]([CH2:7][C:6]([OH:41])=[O:5])[CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1

Procedure:
A solution of {4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid tert-butyl ester (250 mg, 0.44 mmol), DCM (5 mL), and TFA (5 mL) is stirred at rt for 1 h. The solution is concentrated in vacuo and separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 512.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.41 (s, 1H), 8.33 (d, J=9.1 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J=3.5 Hz, 1H), 7.89 (s, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.38-7.47 (m, 2H), 7.12 (dd, J=9.0, 2.4 Hz, 1H), 6.74 (d, J=3.5 Hz, 1H), 4.08 (s, 2H), 3.56 (s, 2H), 3.26 (t, J=6.1 Hz, 2H), 3.07 (t, J=5.7 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][N:7]=1>O1CCCC1.O>[CH3:1][CH:2]([CH3:37])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:8][N:7]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate (0.40 g, 0.77 mmol) in tetrahydrofuran (5 mL) was added a solution of LiOH monohydrate (326 mg, 7.77 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. Tetrahydrofuran was removed under reduced pressure and the aqueous residue was acidified to pH=3 by addition of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Phenomenex Gemini 200×21.2 mm, 10 μm; modifier: ammonium hydroxide (to pH 10); gradient: 28 to 50% acetonitrile in water) gave (+/−)-3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoic acid (30 mg) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.49-8.53 (m, 1H), 8.0-8.05 (m, 1H), 7.77 (d, 2H), 7.72 (d, 2H), 7.61 (d, 2H), 7.49 (d, 2H), 6.88 (d, 1H), 6.25-6.20 (m, 1H), 3.50-3.55 (m, 2H), 2.50-2.40 (m, 2H), 2.08-2.02 (m, 1H), 1.80-1.63 (m, 2H), 1.01-0.96 (m, 6H). MS (M+Na): 523.5.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.I[CH:24]([CH3:26])[CH3:25].Cl>C1COCC1.O>[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH:24]([CH3:26])[CH3:25])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)I
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOC(C)C)cs1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 129 mg, 5.39 mmol) was added to a stirred solution of EXAMPLE 181A (359 mg, 1.08 mmol) in THF (10 mL) at room temperature. After stirring for 15 min, the mixture was treated with 2-iodopropane (917 mg, 5.39 mmol). After two days at 50° C., additional sodium hydride (26 mg, 1.08 mmol) and 2-iodopropane (366 mg, 2.16 mmol) were added. After stirring for 1 h the reaction mixture was acidified with 2M HCl and water was added. The product was extracted with DCM and dried (sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 4% acetone in DCM giving (15 mg, 4%) of an oil which solidified on standing: MS (Ionspray, [M+H]+) m/z 374.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.C1(C)C=CC=CC=1.N1C=CC=CC=1.P(Br)(Br)[Br:29]>CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Br:29]
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(CBr)c(OC)c1OC
Temperature: 4 °C

Procedure:
2.04 g (10 mmol) of 2,3,4-trimethoxybenzyl alcohol in 30 ml of abs. toluene are treated with 0.258 ml (0.32 equivalents) of pyridine, and the solution is cooled down to approximately 4° C. using ice-water. 0.951 ml of phosphorus tribromide in 5 ml of abs. toluene is added dropwise, at this temperature and over the period of 30 min, to this solution, which is left to stir at this temperature for a further 45 ml. The reaction mixture is diluted with ether and the whole is poured onto ice-water, with this mixture then being stirred for 5 min. After the phases have been separated, the organic phase is washed, in succession, with water, saline, sat. sodium bicarbonate solution and once again with saline (all being cold). After the organic phase has been dried over sodium sulfate, it is concentrated, and residual solvents are removed from the residue under high vacuum for 1 h. The resulting title compound is subjected, without purification, to further processing. 1H-NMR (200 MHz; CDCl3) =7.05/d (1H); 6.65/d (1H); 4.55/s (2H); 4.07, 3.88 and 3.85/each s (each 3H).
Reaction SMILES: C[C:2]1[C:3]([OH:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]1[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[O:14][CH:7]21.[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].Cl>CN(C=O)C.O>[CH:23]([O:19][C:3]1[CH:2]=[C:11]2[C:6]([CH:7]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:8]3[CH2:9][O:10]2)=[CH:5][CH:4]=1)([CH3:24])[CH3:22]
Reactant: C=CCBr
Reactant: Cc1c(O)ccc2c1OCC1c3ccccc3OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 60.4 %

Procedure:
Compound 4-methyl-6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.34 mmol) was dissolved in DMF (5 ml) and NaH (8.1 mg, 0.34 mmol) was added to the solution at room temperature, followed by allyl bromide (0.06 ml, 0.68 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (58 mg, 50%) as white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])[CH2:23][O:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:26])=[O:19].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCC>>[CH3:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]/[CH:35]=[CH:34]\[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([O:24][CH2:23][CH:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:19])[O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
The stearin part of transesterified oil can be obtained by transesterifying a raw oil-and-fat containing 10 to 40% by mass of oleic acid, 10 to 40% by mass of stearic acid and 30 to 70% by mass of palmitic acid, and then fractionating it so as to obtain an olein part, and further fractionating the olein part. It is preferable to use a raw oil-and-fat containing 10 to 35% by mass of oleic acid, 15 to 40% by mass of stearic acid and 35 to 65% by mass of palmitic acid, and it is more preferable to use a raw oil-and-fat containing 10 to 30% by mass of oleic acid, 15 to 35% by mass of stearic acid and 35 to 55% by mass of palmitic acid.
Reaction SMILES: N[C:2]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1.CN1C2C(=CC=CC=2)C(C2C=CC=C(CCC)C=2)=CC1=O>>[ClH:36].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:2]([C:24]2[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]3[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=2)=[CH:31][CH:32]=1
Reactant: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(N)(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Agent: CCCc1cccc(-c2cc(=O)n(C)c3ccccc23)c1
Product: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Product: Cl

Procedure:
6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethoxyphenyl)-1-methyl-2(1H)-quinolinone, 6-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-4-(3-propylphenyl)-2(1H)-quinolinone; a stereoisomeric form thereof or a pharmaceutically acceptable acid or base addition salt; and
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34]C1C=CC=CC=1N1CCNCC1.O1CCCC1>Cl>[ClH:34].[Cl:34][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Clc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccccc2Cl)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-diethylethylenediamine, and 5.9 g (0.03 mole) of 1-(2-chlorophenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-ethyl ether to yield 3.4 g (33%) of title compound as a white solid, m.p. 185°-188° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([CH:6]1[O:8][CH2:7]1)[Cl:5].[CH3:9][NH2:10]>CO>[ClH:5].[CH3:1][N:2]([CH3:3])[CH2:4][CH:6]([OH:8])[CH2:7][NH:10][CH3:9]
Reactant: CNC
Reactant: CN
Reactant: ClCC1CO1
Solvent: CO
Product: CNCC(O)CN(C)C
Product: Cl
Reaction time: 1.5 h
Yield: 84 %

Procedure:
Dimethylamine 22.6 g, 40% solution (0.2 mole) was added dropwise to a solution of 16 ml of epichlorohydrin (0.2 mole) in 100 ml of methanol at 5° C. stirring in an ice bath. After two hours at 5° C. a chilled solution of 86 ml methylamine of 40% solution (1 mole) was poured into the reaction mixture. Stirring was continued in ice bath for one hour and then room temperature overnight. The solvents were evaporated and the clear oil was pumped under vacuum at 75° C. for 1.5 hr to give 28.23 g (~84% yield) of 1-dimethylamino-3-methylamino-2-propanol hydrochloride (I) as the main product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1.[I-].[Na+]>ClCCl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:13][CH:12]=2)[N:15]2[CH2:18][C:17](=[C:19]([C:24]3[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=3)[S:20]([CH3:23])(=[O:21])=[O:22])[CH2:16]2)=[CH:37][CH:36]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(Cn3ccnc3)cc2)C1)c1cc(F)cc(F)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
0.055 g of imidazole is added to solution of 0.24 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, in 5 cm3 of dichloromethane. After heating for 3 hours under reflux, the mixture is supplemented with 5 mg of sodium iodide. After stirring for 20 hours under reflux, the reaction mixture is cooled to 20° C. and then chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 cm3 of dichloromethane without fractionating, and then with a dichloromethane and methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm3 fractions. Fractions 12 to 14 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.039 g of 1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:36]=[CH:35][S:34][C:33]=1[C:37](O)=[O:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[S:34][CH:35]=[CH:36][C:32]=4[O:31][CH3:30])=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccsc1C(=O)O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2sccc2OC)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 3-methoxythiophene-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: [CH:1]1([C:4]2[C:23]([F:24])=[C:22](F)[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]([CH3:21])[CH2:19][OH:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:26])[C:5]=2[F:27])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([C:4]2[C:23]([F:24])=[C:22]3[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]3[CH:18]([CH3:21])[CH2:19][OH:20])=[C:6]([F:26])[C:5]=2[F:27])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1c(F)c(F)c(C2CC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)CO)c2c(F)c(C3CC3)c(F)c(F)c2c1=O
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In 3 ml of N,N-dimethylformamide was dissolved 300 mg of ethyl 2-(4-cyclopropyl-2,3,5,6-tetrafluorobenzoyl)-3-(2-hydroxy-1-methylethylamino)acrylate. To the resulting solution was added 130 mg of potassium carbonate. The resulting mixture was stirred at 80°-90° C. for 30 minutes, and 20 ml of water was added to the reaction mixture. The resulting crystals were collected by filtration to obtain 240 mg (yield: 84.5%) of ethyl 7-cyclopropyl-5,6,8-trifluoro-1-(2-hydroxy-1-methylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[ClH:22].[Cl:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][C:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]
Reactant: OC(Cc1c(Cl)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cl
Product: OC(Cc1c(Cl)cccc1Cl)(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To a solution of 1-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-1-phenyl-ethanol (450 mg, 1 equiv.) in ethyl acetate (15 mL) at room temperature under nitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.) followed by addition of palladium on charcoal (10%, 45 mg.). The reaction mixture was heated to reflux for 3 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum, and the resulting solid was purified via preparative HPLC. The isolated white solid was taken up in ethanol. Hydrogen chloride was added (large excess of 2M solution in diethyl ether) and the mixture was stirred until it became a clear solution. Then all the volatiles were evaporated “in vacuo”, to give 60 mg of the title compound as white solid. 1H NMR (300M1, CD3OD D4) δ: 2.52-2.61 (d, 1H), 2.79-2.96 (t, 1H), 2.98-3.13 (t, 1H), 3.15-3.19 (s, 1H), 3.56-3.71 (q, 2H), 3.88-4.02 (t, 1H), 4.10-4.21 (d, 1H), 4.29-4.39 (d, 1H), 6.97-7.08 (m, 1H), 7.10-7.21 (m, 7H). LCMS (12 minutes method) [M+H]+=352 @ Rt 4.63 min. single major peak.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][N:8]=[C:9]([NH2:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>C(OCC)(=O)C>[NH2:11][C:9]1[N:8]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(-c2ccco2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-Furan-2-yl-2H-pyrazol-5-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using 100% ethyl acetate afforded the title compound as a white solid. 1H NMR (400 MHz, CD6CO); 7.48-7.52 (m, 1H), 6.98-7.06 (m, 2H), 6.52-6.56 (m, 2H), 6.44-6.48 (m, 2H), 5.74 (s, 1H), 4.98 (s, 2H), 3.68-3.88 (m, 4H), 3.12-3.24 (m, 4H). MS (ES) M+H) expected=369.4, found 370.1.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[NH:11]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12]1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[N:17]1([CH2:16][C:13]2[CH:14]=[CH:15][NH:11][C:12]=2[CH:4]=[O:5])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: c1cc(CN2CCOCC2)c[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]ccc1CN1CCOCC1
Reaction time: 0.08 h

Procedure:
To a solution of DMF (66 mmoles) in DCM there is added, dropwise, at 0° C., POCl3. After stirring for 5 minutes, a solution of the compound obtained in Step B (33 mmoles) in DCM (60 ml) is added dropwise. After stirring for 4 hours at 0° C. and for 30 minutes at reflux, an aqueous solution of sodium acetate (110 mmoles) is added. After a further 30 minutes at reflux, aqueous 2M sodium hydroxide solution is added at ambient temperature until the pH is alkaline (9-10). The solution is stirred for 2 hours at ambient temperature, and then 300 ml of DCM are added. After extracting with DCM, the organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel (SiO2; gradient DCM/AcOEt) to yield the title product.