Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:31])[CH3:35])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[Mg]Br
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(C)=O)cc1OC
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 537 mg (1.15 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 63A) in 10 ml of tetrahydrofuran was cooled to -78° C., and 4.1 ml (3.9 mmol) of a 0.95 M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise thereto over a period of 5 minutes. The reaction mixture was stirred at the same temperature for 1 hour and then at 0° C. for 90 minutes, after which a saturated aqueous solution of ammonium chloride was added to the mixture to terminate the reaction. The mixture was then extracting with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 25 g of silica gel, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 3:2 by volume, to give 479 mg (yield 86%) of the title compound as a foam-like substance.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:25]1([S:31](OC)=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C[O:38]CC1>>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:32])[C:8]2=[O:38])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CN2CCCCC2)cc1
Reactant: COS(=O)c1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1C(S(=O)c2ccccc2)CCCN1Cc1ccc(F)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of 1-(4-fluorobenzyl)piperidine (17 g, 82 mmol) in anhydrous THF (200 mL) was added LiHMDS (1.0M in THF, 180 mL, 180 mmol) over a period of 15 min. The reaction mixture was stirred for 30 min at −20° C., then methyl phenylsulfinate (15 g, 98 mmol) was added over a period of 5 min. After being stirred at −20° C. for 1 hour, the reaction was quenched by the addition of water (100 mL). EtOAc (200 mL) was added and the organic layer was separated and washed with water (3×100 mL) and brine. The organic layer was dried over Mg2SO4, filtered, concentrated under vacuum. The crude product was used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:39][CH2:40][CH:41]1[CH2:43][CH2:42]1>>[CH:41]1([CH2:40][NH:39][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:43][CH2:42]1
Reactant: NCC1CC1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCC6CC6)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and (aminomethyl)cyclopropane in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ8.55 (1H, d, J=5.1 Hz), 8.20 (1H, s), 8.05 (1H, s), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, s), 7.22 (1H, d, J=8.3 Hz), 6.69 (1H, d, J=5.3 Hz), 4.10-3.80 (3H, m), 3.70-3.50 (2H, m), 3.26 (3H, d, J=12.6 Hz), 3.15 (2H, m), 2.63 (3H, s), 2.20-1.95 (2H, m), 1.08 (1H, m), 0.45 (2H, d, J=7.1 Hz), 0.25 (2H, d, J=4.3 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:13]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH:8]=[CH:7][C:6]2[CH:20]=[C:2]([C:29]3[CH:34]=[N:33][C:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[CH:31][CH:30]=3)[N:3]=[CH:4][C:5]=2[CH2:12]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cnc(-c3ccc(N4CCOCC4)nc3)cc2C=Cc2ccccc21
Yield: 12.1 %

Procedure:
The title compound (3.5 mg, 12%) was prepared from 41D (20 mg, 0.07 mmol) and 5A (30.5 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.153 min; LCMS Found: (M+H)+=413.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[CH2:15])C(O)=O.C(Cl)(=O)[C:17](Cl)=[O:18].[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[NH:23][NH2:24]>O1CCCC1.CN(C)C=O>[C:27]([O:26][C:22]([N:23]([C:17](=[O:18])[CH:15]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[NH2:24])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: C=C(C(=O)O)c1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)C(=O)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2-naphthyl acrylic acid (5.0 g, 25.0 mmol) in dry tetrahydrofuran (100 ml) and N,N-dimethylformamide (0.2 ml) was added dropwise at 0° C. oxalyl chloride (4.8 g, 38.0 mmol). The mixture was stirred for 1 h at room temperature and the solvent was evaporated in vacuo affording crude acid chloride. To a solution of tert-butyl carbazate (6.7 g, 50.0 mmol) in dry tetrahydrofuran (80 ml) was added dropwise a solution of the acid chloride in dry tetrahydrofuran (50 ml) at 0° C. The resulting reaction mixture was stirred at 17 h at room temperature and the solvent was evaporated in vacuo. To the residue was added water (200 ml) and ethyl acetate (200 ml) and the phases were separated. The organic phase was washed with 0.1 N sodium hydroxide (2×100 ml), dried (MgSO4), filtered and evaporated in vacuo. The solid residue was suspended in heptane (50 ml), filtered off and dried in vacuo at 50° C. which afforded 4.7 g (59%) of N-(3-naphthalen-2-yl-acryloyl)hydrazine carboxylic acid tert butyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH2:9])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26].[CH:28](OC(=O)C)=[O:29].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH:9][CH:28]=[O:29])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(=O)OC=O
Reactant: CC(C)Oc1cc(C(N)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)Oc1cc(C(NC=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine (2.8 g, 7.1 mmol) in CH2Cl2 (30 mL) at 0° C. was added acetic formic anhydride (2.8 mL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ISCO (120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient) to give N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (2.56 g, 85% yield) as a colorless oil. LCMS: RT=1.99 min [M+H] 422.0 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). To a solution of N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (225 mg, 0.53 mmol) in THF (2 mL) at 0° C. was added Et3N (0.4 mL, 2.9 mmol) followed by phosphorous oxychloride (74 μL, 0.80 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with ice water (15 mL) and extracted with Et2O (3×15 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield 1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene (143 mg, 67% yield) as a pale yellow oil. LCMS: RT=2.13 min [M-NC] 377 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0. % TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.07-7.13 (1H, m), 6.91-7.03 (4H, m), 6.84-6.86 (1H, m), 5.78-6.04 (1H, m), 5.82 (1H, s), 4.54 (1H, ddd, J=11.97, 6.15, 6.04 Hz), 1.35 (6H, t, J=5.05 Hz).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C[CH:15]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(O)=O.[C:36](O)(=[O:38])C.O>ClCCl>[OH:38][CH2:36][CH:22]1[C:27]2[C:26]3[CH:25]=[CH:31][CH:30]=[CH:29][C:28]=3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:35]2[C:23]1=[CH:24][CH:32]=[CH:33][CH:34]=2
Reactant: O=C(O)CC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 3 h
Yield: 10 %

Procedure:
Diisobutylaluminum hydride (4.6 ml, 4.62 mmol; 1 M in CH2Cl2) was added at −65° C. to a solution of 13-carboxymethyl-dibenzo(a,c)fluorene (0.5 g, 1.54 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 3 h and the temperature maintained between −50° C. and −40° C. A white precipitate was obtained. The reaction mixture was treated with a mixture of acetic acid and water (1:1; 30 ml) and extracted with dichloromethane (3×60 ml). The organic layer was washed with saturated bicarbonate (50 ml), water (30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a crude solid. This crude solid was purified by flash chromatography using chloroform as the eluent. Compound (21) was obtained as a white solid which was washed with petrol (0.217 g, 48%); m.p. 167-168° C.; (Found: C, 89.0; H, 5.39; C22H16O requires: C, 89.2; H, 5.41%); t.l.c. Rf(D) 0.26; Rf(E) 0.64; νmax (CH2Cl2) 3610 (free OH), 3490 (H bonded OH), 3060 (CH stretching), 2940, 2890 (CH stretching, alkyl), 1610, 1600, 1580 (aromatic rings) cm−1; λmax 366 (888), 338 (12728), 322 (14504), 266 (27232), 246 (31968) nm; δH (CDCl3, 200 MHz), 8.88-8.68 (3H, m, aromatic), 8.38 (1H, d, 3J=7.9 Hz, aromatic), 8.14-8.08 (1H, m, aromatic), 7.81-7.33 (7H, m, aromatic), 4.45 (2H, m, Ha CH2 and Hc), 3.85 (1H, m, Hb, CH2), 1.64 (1H, s, OH), δC (CDCl3, 50 MHz), 146.7, 142.5, 139.4, 134.9, 130.9, 130.1, 128.7 (quaternary aromatic C's), 127.5, 126.8, 126.1, 125.9, 125.8, 124.7, 124.2, 124.1, 123.8, 123.4, 122.9 (aromatic CH's), 65.7 (CH), 50.0 (CH); m/z (EI) 296, 265.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>C(OCC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:17][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1
Reactant: OCc1cccc(Cl)c1
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(CCC(=O)OCc2cccc(Cl)c2)N1
Temperature: 100 °C

Procedure:
Two hundred and eighty eight milligrams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 600 mg of m-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 40 hours. The mixture is cooled and is dissolved in 50 ml of anhydrous diethylether. The filtrate is cooled to induce crystallization and the resulting crystals are isolated by filtration. Recrystallization from toluene-petroleum ether yields 5-oxo-2-pyrrolidinepropanoic acid m-chlorobenzyl ester with a melting point of 90°-91° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([OH:40])=O)=[C:32]2[S:41]([C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[CH:45]=1)(=[O:43])=[O:42].[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(N(CC)CC)C>CN(C=O)C.O>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([N:56]1[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]1)=[O:40])=[C:32]2[S:41]([C:44]1[CH:45]=[C:46]([CH3:51])[CH:47]=[C:48]([CH3:50])[CH:49]=1)(=[O:42])=[O:43]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)O)[nH]c3ccc(Cl)cc23)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(S(=O)(=O)c2c(C(=O)N3CCN(C)CC3)[nH]c3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.8 %

Procedure:
Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) (1.22 g, 0.00275 g) was added to a solution of 5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indole-2-carboxylic acid (12) (1.00 g, 0.00275 mol), N-methylpiperazine (0.55 g, 0.0055 mol), triethylamine (0.55 g, 0.0055 mol) in anhydrous DMF (50 mL). Reaction was stirred at room temperature for 72 hours, then diluted with water and extracted with ethyl acetate. Organic extracts were washed with brine, dried and the solvent evaporated to give 1.20 g (98%) of pure title compound, mp 281-283° C. (from aqueous ethanol).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].[O:13]=[CH:14][C:15]([OH:17])=[O:16].Cl.C(N(CCCC)CCCC)CCC>O.COC(C)(C)C>[OH:13][CH:14]([C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[C:9]([OH:10])=[CH:8][CH:7]=1)[C:15]([OH:17])=[O:16]
Reactant: Oc1cccc2sccc12
Reactant: O=CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(O)C(O)c1ccc(O)c2ccsc12
Reaction time: 3 h
Yield: 111.5 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-benzothiophen-4-ol (1.0 g, 6.32 mmol, 1.00 equiv, 95%), potassium hydroxide (821 mg, 1.46 mmol, 2.20 equiv, 10%). This was followed by the addition of 2-oxoacetic acid (592 mg, 4.00 mmol, 1.20 equiv) at 0-5° C. with 30 min. If necessary, more 2-oxoacetic acid is added such that the pH of the solution at the end of the addition was 11.5. After stirring for 3 h at 0-5 degree C. 20 mL of tert-butyl methyl ether were added to the reaction mixture followed by HCl(25%) solution in water such that the pH was 7. The biphasic mixture was filtered through Speedex, then HCl (25%) solution in water were added to the aqueous phase such that the pH was 2.0. After addition of tert-butyl methyl ether (3*20 mL), the organic phase was separated at 25° C., and 50 mL acetonitrile was added to organic phase. To the resulting clear solution was added portions wise at 20-30° C., a solution of tributylamine (1.23 g, 1.00 equiv) in 20 mL of tert-butyl methyl ether under seeding with crystals of the product. The resulting suspension was stirred over night at 20-30 degree C., and then filtered off. The filter cake was dried oven at 60° C. The result afford (1.0 g, 63%) of 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid as gray solid.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C(O)=O)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:22].C1(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(C)(C)C>C(N(CC)CC)C>[NH2:37][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][C:10](=[O:22])[N:9]2[CH3:8])=[CH:14][CH:15]=1
Reactant: CN1C(=O)CCc2ccc(C(=O)O)cc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CN1C(=O)CCc2ccc(N)cc21
Reaction time: 14 h
Yield: 46.6 %

Procedure:
Into 10 ml of toluene was suspended 200 mg of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid, and then 268 mg of diphenylphosphoryl azide (DPPA), 722 mg of tert-butyl alcohol, and 0.135 ml of triethylamine were added thereto, followed by 14 hours of stirring under reflux with heating. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the organic layer was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. To the residue was added 5 ml of a 4M ethyl acetate solution of hydrochloric acid, followed by 7 hours of stirring at room temperature. Then, the reaction solution was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 80 mg of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Reactant: NCc1ccccc1
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: C(=O)([O-])OCC[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[O:13])=[CH:7][CH:6]=1.[OH-:33].[Na+]>C(O)(=O)C>[ClH:30].[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:14]([CH:15]2[CH2:16][CH2:17][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][CH2:20]2)[C:12](=[O:13])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([OH:33])=[CH:6][CH:7]=2)=[CH:25][CH:26]=1
Reactant: CC(C)N1CCC(N(C(=O)Cc2ccc(CCOC(=O)[O-])cc2)c2ccc(Cl)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N1CCC(N(C(=O)Cc2ccc(O)cc2)c2ccc(Cl)cc2)CC1
Product: Cl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.5 parts of {4-[2-{(4-chlorophenyl)[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl}ethyl carbonate and 50 parts of a sodium hydroxide solution 10% is stirred for 90 minutes at 45° C. The reaction mixture is cooled to room temperature and acidified with acetic acid to pH 5.5-6. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60° C., yielding 1.9 parts of N-(4-chlorophenyl)-4-hydroxy-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide monohydrochloride; mp. 242.9° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:21]([CH2:24][OH:25])[CH2:22][NH2:23].CCN(C(C)C)C(C)C>CCCCO>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH2:22][CH2:21][CH2:24][OH:25])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: Clc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: NCCCO
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 200 °C
Yield: 40 %

Procedure:
165 mg of 6-chloro-N-(4-morpholinophenyl)pyrimidin-4-amine, 86 mg of propanolamine and 147 mg of DIPEA were dissolved in 2 mL of n-BuOH, The mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. n-BuOH was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH-EtOH solvent mixture. 3-(6-(4-Morpholinophenylamino)pyrimidin-4-ylamino)propan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]([C@H:5]1[CH2:9][O:8][C:7](=[O:10])[NH:6]1)[CH3:4].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1.[H-].[Na+]>CN(C=O)C.C(OC(=O)C)C.[Cl-].[Na+].O.O>[Cl:12][C:13]1[N:18]=[C:17]([N:6]2[C@@H:5]([C@@H:3]([CH3:4])[CH:2]([F:1])[F:11])[CH2:9][O:8][C:7]2=[O:10])[C:16]([F:20])=[CH:15][N:14]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[C@@H](C(F)F)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(F)F)[C@H]1COC(=O)N1c1nc(Cl)ncc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (S)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (114 mg, 069 mmol) and 2,4-dichloro-5-fluoropyrimidine (115 mg, 0.690 mmol) in DMF (2.26 mL) was added sodium hydride (60% wt.; 35.9 mg) in three portions at <0° C. (sodium chloride/ice). After the first portion of sodium hydride the mixture was stirred for ˜5 min. The remaining two portions of sodium hydride were added over ˜5 min and stirring was continued for 30 min. The mixture was diluted with ethylacetate (10 mL), stirred for 5 min and further slowly diluted with brine/water (1/1; 10 mL). The mixture was allowed to warm to 5° C. and poured into a mixture of brine/water (1/1; 10 mL) and ethylacetate (10 mL). The aqueous layer was separated and extracted with ethylacetate (25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane] to provide (S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-4-((R)-1,1-difluoropropan-2-yl)oxazolidin-2-one (134 mg) as a white solid. MS m/z 296.1 (M+H)+; Rt-0.75 min. 1H NMR (400 Mhz, CD3OD) δ ppm 8.69 (d, J=2.6 Hz, 1H), 5.99 (q, J=1.0 Hz, 1H), 5.17 (ddd, J=3.5, 7.4, 8.6 Hz, 1H), 4.69-4.50 (m, 2H), 2.88-2.70 (m, 1H), 1.04 (d, J=7.1 Hz, 3H).