Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:6][C:5](=[O:7])[CH2:4][CH2:3]1.C[Al](C)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:42][C:40]([F:41])([F:43])[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:5](=[O:7])[CH2:4][CH2:3][C:2]([OH:6])([CH3:8])[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:34][CH:33]=1)([OH:44])[C:36]([F:39])([F:38])[F:37]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: CC1(C)CCC(=O)O1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(O)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.4 %

Procedure:
5,5-Dimethyldihydrofuran-2(3H)-one (0.433 mmol, 0.049 g) was stirred in toluene (5 mL). Trimethylaluminium (0.867 mmol, 0.867 mL, 1 M in heptane) was added and the reaction stirred for 10 minutes at room temperature. (4-Aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.433 mmol, 0.2 g) was added and the reaction heated to reflux for 1 hour then a drop of N,N-dimethylformamide was added. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was quenched with water. Ethyl acetate was added and the layers separated. The organic phase was concentrated under vacuum and the resulting residue purified by acidic preparative HPLC to afford the desired compound (1 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNCc1ccc(OC)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccc(CN(C)c2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methyl-4-methoxybenzylamine (45 mg, 0.302 mmol) by a procedure similar to example 1b and was isolated as white powder (30 mg, 60%). 1H NMR (CDCl3): 7.93 (dd, J=8.4 and 1.2 Hz, 1H), 7.78 (dd, J=8.4 and 1.5 Hz, 1H), 7.68 (ddd, J=8.4, 7.5 and 1.5 Hz, 1H), 7.34-7.26 (m, 3H), 6.96-6.92 (m, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[C:3]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Product: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NS(C)(=O)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 33 from ethyl 3-amino-6-chloro-2-(3-methylbenzoyl)-1H-indole-1-carboxylate (step 1 of Example 3) and methanesulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:21][CH2:22][C:23](=[O:25])[NH2:24])[C:14]([O:16]C(C)(C)C)=[O:15])[C:7]2=[O:12])#[N:2].FC(F)(F)C(O)=O>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:21][CH2:22][C:23](=[O:25])[NH2:24])[C:14]([OH:16])=[O:15])[C:7]2=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(C#N)cccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc2c1CN(C(CCC(N)=O)C(=O)O)C2=O
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of tert-butyl 2-(4-cyano-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (1.0 g, 2.91 mmol) and trifluoroacetic acid (5 mL) was stirred for 2 hours. The mixture was concentrated and the residue was crystallized from ether (15 mL) to give 2-(4-cyano-1-oxoisoindolin-2-yl)-4-carbamoylbutanoic acid (0.74 g, 89%) as a white solid: 1H NMR (DMSO-d6) δ 13.12 (b, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 4.80–4.62 (m, 3H), 2.32–2.09 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1cc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3,4,5-trimethoxybenzaldehyde (124 mg, 0.633 mmol) similar to Example 6 and isolated as a bright yellow solid (120 mg, 38%), 1H NMR (CDCl3): 7.65 (d, J=15.6 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.34 (d, J=3.3 Hz, 1H), 7.12 (dd, J=3.3, 9.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 6.85 (s, 2H), 4.48-4.34 (m, 4H), 3.90 (d, J=1.8 Hz, 9H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>O>[CH:7](=[CH:3][C:4](=[O:5])[CH3:6])[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)=O
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 2 h

Procedure:
o-Anisalacetone is prepared by adding 70 ml of 10% aqueous sodium hydroxide to 7.7 moles of acetone, 280 ml of water, and 2.8 moles of o-anisaldehyde, slowly with cooling to maintain the temperature in the range of 25°-31° C. Another 2 hours stirring followed by acidification, separation of layers, dehydration with acid in benzene at reflux, and finally distillation at reduced pressure gives the crude o-anisalacetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][C@H:20]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][O:22]2)(=O)=O>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:20]1[CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[O:22][CH2:21]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: Fc1cc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)ccn1
Yield: 68 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 68% yield, starting from 2-fluoro-4-pyridinylboronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate. The reaction was irradiated in a microwave at 150° C. for 3 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (d, 1 H), 7.33-7.37 (m, 1 H), 7.24-7.33 (m, 8 H), 7.15-7.22 (m, 4 H), 6.79-6.87 (m, 2 H), 4.32-4.38 (m, 1 H), 4.04-4.10 (m, 1 H), 3.61-3.74 (m, 4 H), 2.93-3.10 (m, 2 H), 2.42-2.48 (m, 1 H); MS (ESI) m/z 425[M+H+].
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6]1)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:5]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(CN2CCOCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1cc(CN2CCOCC2)c[nH]1
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step A (75 mmoles) in THF (100 ml) there is added, dropwise, at 0° C., Bu4NF 1.0M in THF (75.0 mmoles). After stiffing at 0° C. for one hour, the solution is poured onto ice and is then extracted with DCM. The organic phases are combined and then washed with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.Br>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Temperature: 25 °C

Procedure:
The 1-(4-bromo-phenyl)-6-methoxy-isoquinoline obtained is boiled under reflux in 53 ml of acetic acid and 37 ml of 62% aqueous hydrobromic acid. Subsequently, after cooling to room temperature and addition of 150 ml of ethyl acetate the separated precipitate is filtered off. The crystals are washed with ethyl acetate and dried. There are obtained 7.6 g of 1-(4-bromo-phenyl)-isoquinolin-6-ol, MS: m/e 300 (M+H+, 1 Br).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16][CH2:15]1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]-amide (AMR01038, 80 mg, 0.219 mmol) in dry DCM (6 mL) were added triethylamine (0.3 mL, 2.19 mmol) and methanesulphonyl chloride (0.034 mL, 0.438 mmol). The reaction mixture was stirred at room temperature for 24 h, and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-methanesulfonyl-piperidine-4-carboxylic acid [2-(2,4-dichloro-phenoxy)-phenyl]-amide (47.6 mg, 49%) as an oil. Rf: 0.25 (hexane/EtOAc 4:6). 1H NMR (300 MHz, CDCl3) δ 1.88 (2H, m, CH2), 2.37 (1H, m, CH), 2.72 (3H, s, CH3), 2.78 (2H, m, CH2), 3.71 (2H, td, J=12.5, 3.6 Hz, CH2), 6.67 (1H, dd, J=8.1, 1.3 Hz, ArH), 6.89 (1H, d, J=8.8 Hz, ArH), 6.95 (1H, td, J=8.1, 1.6 Hz, ArH), 7.07 (1H, td, J=8.0, 1.3 Hz, ArH), 7.16 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.43 (1H, d, J=2.5 Hz, ArH), 7.72 (1H, br s, NH) and 8.31 (1H, br d, J=8.1 Hz, ArH). Further purification by flash chromatography on silica gel using hexane/EtOAc 4:6 as eluent gave AMR01051 as a white solid, mp 150-151° C. LC/MS (APCI) tr=4.63 min, m/z 443.37 (M++H, 100), 445.39 (55). HPLC tr=2.52 min (100%)
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.ClC(OCC(C)C)=O>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
Condensation of ZPheOH (11.7 g.) and HPheOMe (9.0 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-PheOMe in 82% yield. Debenzyloxycarbonylation of ZPhe-PheOMe (13.0 g.) by hydrogenation with palladium catalyst gave HPhe-PheOMe in 86% yield. Condensation of BocProOH (5.04 g.) and HPhe-PheOMe (8.5 g.) by the mixed anhydride method using isobutyl chloroformate gave BocPro-Phe-PheOMe in 63% yield. Hydrazinolysis of BocPro-Phe-PheOMe (4.5 g.) gave BocPro-Phe-PheNHNH2 in 93% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([Cl:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:15][C:14]=2[CH:24]=1>CN(C)C=O>[Cl:18][C:17]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:24][C:14]=2[S:15][C:16]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1sc2cc(CBr)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Cl
Reaction time: 0.67 h
Yield: 63 %

Procedure:
Imidazole (2.0 g, 30 mmol) was added in portions to a stirred suspension of sodium hydride (0.48 g of 60% dispersion in mineral oil, 12 mmol) in anhydrous dimethylformamide (15 ml) at 0° C., under a nitrogen atmosphere. After 40 minutes, ethyl 6-bromomethyl-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 10, 3.33 g, 10 mmol) was added. After 2 hours the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with more water, dried (magnesium sulfate), and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant, and the isolated product was crystallised from diethyl ether to give the title compound as a colourless solid (2.02 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9]OCCCC)=[C:4]([O:15][CH2:16][O:17][CH3:18])[C:3]=1[C@H:19]1[CH2:21][C@H:20]1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24].[OH2:33]>O1CCOCC1.Cl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@H:19]2[CH2:21][C@H:20]2[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])[C:4]=1[O:15][CH2:16][O:17][CH3:18])(=[O:33])[CH3:9]
Reactant: CCCCOC=Cc1ccc(F)c([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1OCOC
Reactant: O
Agent: Cl
Solvent: C1COCCO1
Product: COCOc1c(C(C)=O)ccc(F)c1[C@H]1C[C@H]1NC(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
(+,-)-N-(cis-2-(2-fluoro-5-butoxyvinyl-6-methoxymethoxy)-cyclopropyl)-N'-(5-chloropyrid-2-yl)-urea (Example 55) was dissolved in dioxane and a few drops of dilute hydrochloric acid was added. The solution was stirred for 15 minutes, was diluted water and evaporated. The residue was co-evaporated with water to yield the title product as a solid. 1 H-NMR CDCl3 1.3 (q, 1H) 1.5 (q, 1H) 2.1 (q, 1H) 2.5 (s, 3H) 3.4 (m, 1H) 3.5 (s, 3H) 5.1 (m, 2H) 6.8 (m, 2H) 7.4-7.6 (m, 2H) 7.8 (d, 1H) 9.1 (bs, 1H) 9.8 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C(O)(=O)C.[CH:13](=O)[C:14]([CH3:16])=[O:15].C([O-])(O)=O.[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(=O)C=O
Reactant: NNc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C=NNc1ccccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.9 %

Procedure:
To a solution of 2-pyridylhydrazine (10.0 g, 91.6 mmol) in water (30 mL) was added acetic acid (8.7 mL). This mixture was then added to a solution of pyruvaldehyde (16.5 g, 14.9 mL, 91.6 mmol) in water (400 mL). The mixture was stirred at room temperature for 3 days. The mixture was neutralized with NaHCO3 (solid) whereupon a yellow precipitate forms. The solid was isolated by filtration and then washed with water (30 mL). The solids were dried under high vacuum to afford 2-oxopropanal pyridin-2-ylhydrazone as a yellow solid (6.12 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[C:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH2:13][N:6]1[CH2:7][CH2:8]2.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH2:13][N:6]1[CH2:7][CH2:8]2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1C(=Cc2ccccc2Cl)N2CCC1CC2
Solvent: Cc1ccccc1
Product: O=C1C2CCN(CC2)C1C(c1ccccc1)c1ccccc1Cl

Procedure:
2-(2-Chlorobenzylidene)-1-azabicyclo[2.2.2]octan-3-one (3 g) was dissolved in toluene (30 ml) and placed in a dropping funnel. Phenylmagnesium bromide was dissolved in toluene (15 ml) and stirred under nitrogen. This was cooled in an ice/water bath and the benzylidene solution was added dropwise. After 3 hrs the reaction was quenched with ammonium chloride solution and the aqueous layer extracted with dichloromethane (×4); this was combined with the original toluene layer and dried (MgSO4). The solvent was removed in vacuo and the residue purified by chromatography on silica eluting with 1:1 hexane:diethyl ether which afforded the title compound as a 2:1 mixture of its diastereoisomers:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C1CCN2C(=NCCC2)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:59]([CH2:66][CH2:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:71]2[CH2:70][CH2:69][N:68]([CH2:67][CH2:66][O:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH2:73][CH2:72]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: c1ccc(OCCN2CCNCC2)cc1
Reactant: Nc1nc2sc(CCc3ccc(F)cc3)nc2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(CCOc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-6H-thiazolo[5,4-d]pyrimidin-7-one (133 mg, 0.46 mmol) in DMF (5 ml) was added DBU (0.69 mmol), BOP (0.59 mmol) and 1-(2-phenoxyethyl)piperazine (1.37 mmol). The reaction mixture was stirred at room temperature for 3 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (56 mg) which was characterized by its mass spectrum: MS m/z (%): 479 ([M+H]+, 100).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:25]1([CH2:24][N:11]2[C:12]3[C:7](=[C:6]([OH:38])[C:5]([C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:4])=[N:14][C:13]=3[C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[CH:8]=[C:9]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:10]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(CC4CCCCC4)c23)cn1
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(CC4CCCCC4)c23)cn1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A mixture of 1-cyclohexylmethyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.068 mmol), β-alanine (607 mg, 6.8 mmol) and NaOMe solution (11 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 572.36 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17]([O:28][CH3:29])(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-])=O)=[CH:20][CH:19]=1>>[CH3:29][O:28][C:17](=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COC(=O)c1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)cc1
Yield: 60 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.21 mmol) was converted using mono-methyl terephthalate instead of o-toluic acid to the title compound (1.98 mg, 60%) which was obtained as a colorless liquid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([OH:40])=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].O[C@H:42]1[CH2:46][CH2:45][O:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:40][C@@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCc1ccccc1
Reactant: O[C@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Nc2ncnc3cc(O[C@@H]4CCOC4)c(OCc4ccccc4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.03 ml Diethyl azodicarboxylate are added dropwise to a solution of 8.00 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 A1) and 2.42 ml (S)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g triphenylphosphine in 160 ml tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and subsequently concentrated by evaporation in the rotary evaporator. The flask residue is purified chromatographically on a silica gel column with methylene chloride/ethyl acetate (gradient from 2:1 to 1:2) as eluant.