Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Oc1ccccc1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,8-dichloroquinoline-3-carbaldehyde (1 eq) in DMF (0.25 M) was added phenol (1.5 eq) and K2CO3 (2.0 eq) at rt and the mixture was stirred for 3 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on a Redi-Sep™ column using 0 to 40% gradient of EtOAc in hexane to provide 8-chloro-2-phenoxyquinoline-3-carbaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:21][C:31](=[O:32])[CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(NC(=O)Cc2cccc(C(F)(F)F)c2)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3-methyl-4-(3-pyrimidin-4-yl-pyridin-2-yloxy)-phenylamine (30 mg, 0.11 mmol), (3-trifluoromethyl-phenyl)-acetic acid (27 mg, 0.13 mmol), and EDC (41 mg, 0.22 mmol) was added CH2Cl2 (2.0 mL). The mixture was stirred for 6 h at RT, concentrated, diluted with EtOAc, and extracted with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to yield N-(3-Methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide. MS m/z=465 [M+1]+. Calc'd for C25H19F3N4O2: 464.45.
Reaction SMILES: Br.[Br:2][C:3]1[N:4]=[C:5]([CH3:11])[NH:6][C:7]=1[C:8](=O)[CH3:9].C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:2].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:7]2[N:6]=[C:5]([CH3:11])[NH:4][CH:3]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: CC(=O)c1[nH]c(C)nc1Br
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 4-bromo-acetyl-2-methylimidazole hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After one hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of the title compound, M.P. 158° (dec.); nmr (DMSO-d6) (delta): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH:22]=O)=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:4][C:3]=1[F:24]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](C=O)C1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (150 mg) and pyridin-2-amine (79 mg) in THF (1.3 mL) and methanol (0.1 ml) was added borane-2-picoline complex (90 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was stirred in 1 M aqueous hydrochloric acid solution, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (112 mg).
Reaction SMILES: [F:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[C:9]2[CH:10]=[N:11][C:2]([F:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)ncc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc2ncnc(Cl)c2cn1

Procedure:
A suspension of 7-fluoro-4-oxo-3H-pyrido[4,3-d]pyrimidine (0.23 g, 1.39 mmol) in POCl3 (10 mL) is stirred under reflux for 3.5 h, and is then concentrated under vacuum. The resulting oil is ice-cooled, diluted with CH2Cl2 (100 mL), saturated aqueous Na2CO3 (40 mL) and ice, and stirred at 20° C. for 2 h. The CH2Cl2 extract is separated and the aqueous portion further extracted with CH2Cl2 (2×100 mL), and then the combined extracts are dried (Na2SO4) and filtered to give crude 4-chloro-7-fluoropyrido[4,3-d]pyrimidine. 3-Bromoaniline (1.26 g, 7.35 mmole), 3-bromoaniline hydrochloride (20 mg) and dry isopropanol (5 mL) are added, then the resulting solution is concentrated under vacuum to remove the CH2Cl2 and stirred at 20° C. for 1 h. Upon addition of dilute NaHCO3 and water, the product crystallises. Filtration, washing with water and CH2Cl2, gives pure 4-(3-bromoanilino)-7-fluoropyrido[4,3-d]pyrimidine (297 mg, 67%) as a cream solid. 1H NMR (DMSO) δ 10.38 (1H, brs), 9.59 (1H, s), 8.72 (1H, s), 8.17 (1H, s), 7.85 (1H, m), 7.38 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(CNCc2cccnc2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A 3.2 g. portion of 3-(2,4-dichlorobenzylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and to it was added 2 g. of potassium carbonate and 1.16 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and was then extracted twice with 15 ml. portions of water, dried, filtered, and evaporated under vacuum to an oil. The residue was dissolved in chloroform and purified over silica gel, eluting first with chloroform and then with 9:1 chloroform:acetone. The product-containing fractions were combined and evaporated under vacuum to obtain 2.9 g. of impure product, which was triturated with petroleum ether to obtain 2.1 g. of the desired product, m.p. 78°-80°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][NH2:8].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([O:17][CH3:18])=[CH:12][N:11]=1>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][NH2:8])[C:13]([O:17][CH3:18])=[CH:12][N:11]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnc(Cl)nc1NN
Temperature: 43 °C
Reaction time: 4.5 h
Yield: 95.7 %

Procedure:
Anhydrous sodium carbonate (29.15 g, 0.275 mole), methanol (300 mL), and 35% aqueous hydrazine (54.9 g, 0.60 mole) were loaded into a 1 L glass jacketed reactor equipped with a thermocouple temperature probe, overhead stirrer with glass agitator, condenser, and a programmable circulating bath. 2,4-Dichloro-5-methoxypyrimidine (89.50 g, 0.50 mole) was added as a solid in small increments over 70 min. During the addition, the reactor jacket was kept at 20° C., and the reaction temperature rose from 21° C. to 28° C. Upon completion of the addition, the reaction mixture was heated to 43° C. over 60 min, then held at 43° C. for 4.5 h. Water (300 mL) was then added, and a distillation head was attached to the reactor. Vacuum was applied to lower the pressure to 140 mmHg, and methanol was removed by distillation. Distillation continued for 1.5 h, at which point the rate of distillation had slowed greatly. The pressure as further decreased to 85 mmHg until water started to distill over, then vacuum was broken under a nitrogen flow. The reaction mixture was cooled from 43° C. to 25° C. over 60 min. The resulting slurry was stirred overnight at 25° C. The product was recovered by filtration through Whatman #52 filter paper using a Buchner funnel and aspirator vacuum. After washing the filter cake with water (221 g), the product was dried overnight in vacuo at 42° C., to give 83.5 g of white 2-chloro-4-hydrazino-5-methoxypyrimidine (purity 96.8%, yield=92.7%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16](Cl)(=[O:18])=[O:17])[CH:10]=[CH:9]2.[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(Cl)Cl.O>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([C:23]1[CH:24]=[CH:25][C:20]([O:26][CH3:27])=[CH:21][CH:22]=1)(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)c2ccc3cc(Br)ccc3c2)cc1
Temperature: 4 °C
Yield: 23.1 %

Procedure:
Aluminium chloride (3.33 g) was added portionwise over 30 minutes to a stirred mixture of 6-bromonaphth-2-ylsulphonyl chloride (6.11 g) and anisole (3.33 g) in dry methylene chloride (35 ml). The resultant mixture was stirred for 24 hours. Methylene chloride (75 ml) was added. the mixture cooled to 4° C. and water (100 ml) added cautiously. The mixture was acidified with 2M hydrochloric acid, separated and the aqueous phase extracted with methylene chloride (30 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated. Recrystallisation of the residue from an ethyl acetate/ethanol mixture gave 4-(6-bromonaphth-2-ylsulphonyl)anisole (1.74 g), m.p. 180-181° C.;
Reaction SMILES: C1(S(CC2C=[CH:19][C:18]([C:21]3[O:25][CH:24]=NC=3)=CC=2C(OC)=O)(=O)=O)C=CC=CC=1.Br[C:27]1[C:28]([O:51][CH3:52])=[C:29]([C:34]([CH2:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH:47]=[CH:48][CH2:49][OH:50])(=[O:40])=[O:39])=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C1(S(CC2C(C(OCC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.O1C=CC(B(O)O)=C1>>[O:25]1[CH:21]=[CH:18][C:19]([C:27]2[C:28]([O:51][CH3:52])=[C:29]([C:34]([CH2:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH:47]=[CH:48][CH2:49][OH:50])(=[O:39])=[O:40])=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])=[CH:24]1
Reactant: COC(=O)c1cc(-c2cnco2)ccc1CS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(Br)c1OC
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2C=CCO)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 42, starting from methyl 3-bromo-6-((2-(3-hydroxyprop-1-enyl)benzenesulfonyl)methyl)-2-methoxybenzoate (mixture of E and Z isomers, Intermediate 60) and furan-3-yl boronic acid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=1>C1COCC1.C(=O)=O>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[N:13]=1
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Reactant: OCCCCCCS
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCSc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-Mercapto-1-hexanol (1.4 mL, 10.2 mmol) was added to a suspension of NaH (60% in mineral oil, 0.42 g, 10.5 mmol) in THF (20 mL) and stirred at room temperature for 10 min then cooled down to −78° C. in dry ice bath. A suspension of the product Example 46a (1.74 g, 9.03 mmol) was added to the above mixture and stirred at −78° C. for 2.5 hours. The reaction was quenched with water (20 mL) and extracted with Et2O (100 mL). The extract was washed with water (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography eluting with 1:2 EtOAc:Hex to obtained the title compound as a viscous oil, 1.8 g (81%). 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=5.3 Hz, 1H), 7.00 (d, J=5.3 Hz, 1H), 3.63 (t, J=6.6 Hz, 2H), 3.14 (t, J=7.4 Hz, 2H), 2.60 (S, 1H), 1.8-1.4(mult, 8H); 13C NMR (75 MHz, CDCl3) δ 173.4, 160.7, 157.8, 116.2, 62.3, 32.3, 30.8, 28.6, 28.3, 25.1; mass spectrum (API-TIS) m/z 247 (M+H).
Reaction SMILES: [CH2:1]1[O:15][C:14]2[C:3](=[CH:4][C:5]3[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=3[CH:13]=2)[O:2]1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:26]1[C:27]2[C:22](=[C:21]([O:20][CH2:19][CH2:18][CH2:17][NH:12][CH2:11][CH:8]3[O:7][C:6]4[CH:13]=[C:14]5[O:15][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[O:10][CH2:9]3)[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: BrCCCOc1cccc2ncccc12
Reactant: NCC1COc2cc3c(cc2O1)OCO3
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1cc(OCCCNCC2COc3cc4c(cc3O2)OCO4)c2cccnc2c1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine (2.3 g, 11 mmole), 5-(3-bromopropoxy)quinoline (2.54 g, 9.2 mmole), and diisopropylethylamine (2.6 g, 20 mmole) were combined in 100 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 500 ml of dichloromethane. The mixture was washed with 250 ml each of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 250 g of silica gel using 2% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue (2.0 g) recrystallized from 50 ml of ethanol with the addition of 6 ml of 4N isopropanolic HCl to give 1.4 g of the title compound as an orange solid dihydrochloride, one-quarter hydrate, m.p. 140°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:22][O:23][C:24]1(OC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:24]3([O:23][CH3:22])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC1(OC)CCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: COC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCC1
Yield: 13.6 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-dimethoxycyclooctane (1.62 g, 10 mmol) in the same manner as the example 20 to give the compound 30 (66 mg, 13%). Mp 54-56° C.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([O:22]CC)=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=[O:21])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)OCC)ccc2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2

Procedure:
To ethyl 2-(4-carbomethoxy-2-propylphenoxy)-3,4-methylenedioxyphenylacetate (Step A of Example 56) (2.04 g, 5.10 mmol) in MeOH (40 mL) was added 5N NaOH (8 mL). The rapid reaction was followed immediately by TLC to monitor mono deesterification. The reaction was quenched with 9N HCl (4.5 mL) after loss of the ethyl ester and before methyl ester saponification. A saturated solution of NaHCO3 was added to the reaction until it was basic and the MeOH was removed in vacuo. The residue was partitioned between Et2O and water collecting the product in the aqueous phase and removing impurities with the organic phase. The aqueous phase was then acidified with 9N HCl (pH=1) and the product extracted into EtOAc. The solution was dried over MgSO4, filtered and the solvent removed. yield=1.78 g (4.78 mmol, 94%) rf=0.16 (80:10:1/CHCl3 :MeOH:NH4OH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:25]([O:26][CH3:27])=[CH:24][C:16]3[CH2:17][CH2:18][O:19][C:20](=[O:23])[N:21]([CH3:22])[C:15]=3[CH:14]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[CH:32][C:31]=1[NH2:42]>>[CH3:27][O:26][C:25]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:42][C:31]3[CH:32]=[CH:33][C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:35][C:30]=3[O:29][CH3:28])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[O:19][CH2:18][CH2:17][C:16]=2[CH:24]=1
Reactant: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Cl)n1)N(C)C(=O)OCC2
Reactant: COc1cc(N2CCOCC2)ccc1N
Product: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)N(C)C(=O)OCC2
Yield: 43 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 3-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-Methoxy-4-morpholin-4-yl-phenylamine. Product was isolated as a white solid (55 mg, 43%). mp: 221-223° C., MS (ESI+): 575 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.60 (br d, 1H), 7.03 (s, 1H), 6.63 (s, 1H), 6.32 (br d, 1H), 4.36 (t, J=6 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.75 (m, 4H), 3.11 (m, 4H), 3.01 (s, 3H), 2.93 (t, J=6 Hz, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH2:13][O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:34])[NH:19][C:18]=1[CH2:35][O:36][CH2:37][CH2:38][NH2:39])=[O:16]>CO>[CH3:12][CH2:13][O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([C:30]([O:32][CH3:33])=[O:31])=[C:20]([CH3:34])[NH:19][C:18]=1[CH2:35][O:36][CH2:37][CH2:38][NH2:39])=[O:16].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
In 100 ml of methanol was dissolved 20 g of para-toluenesulfonic acid. To the solution, 40 g of the amlodipine prepared in Reference Example 1 in 500 ml of methanol was added dropwise, followed by stirring at 23° C. for 3 hours.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCN(C)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 22.1 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 1-methylpiperidin-4-amine (195 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 56 mg, 22%) which was obtained as an off-white solid. MS: m/e=446.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=O)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[C:29]1(B(O)O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.2 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (0.20 g, 0.515 mmol) was dissolved in dichloromethane (1.0 mL) and HCl (4M dioxane, 1 mL) was added. The resultant suspension was stirred at room temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was combined with phenyl boronic acid (188 mg, 1.545 mmol) and DCM (15 mL) was added. Triethylamine (1.2 mL, 8.89 mmol) was added, followed by copper(II) acetate and molecular sieves 4 Å. The reaction was stirred at room temperature. After 24 hrs, the reaction was quenched with aqueous ammonium hydroxide solution (10%) and the organic layer was isolated. The organic layer was washed with aqueous HCl solution (0.5 M), brine, and was dried over sodium sulfate. Filtration and evaporation gave crude material. Purification via flash chromatography on silica gel (eluent: EtOAc/hexanes) yielded the desired product 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51.0 mg, 0.14 mmol): LCMS-ESI+: calc'd for C18H25N3O5: 363.4 (M+). Found: 364.4 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1>>[CH3:3][C:2]([CH3:5])([CH3:4])[CH:1]=[N:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: NC1CCNC1
Reactant: CC(C)(C)C=O
Product: CC(C)(C)C=NC1CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 g (0.1 mol) of 71% strength pivalaldehyde, initially introduced into the reaction vessel and 8.6 g (0.1 mol) of 3-aminopyrrolidine are added dropwise at 20° C. to 30° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for 1 hour and is then distilled. Yield: 13.5 g (85% of theory), boiling point: 63° C.-65° C./10 to 12 mbar; content: 97%.