Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]=[O:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>CN(C)C=O.C(Cl)Cl>[CH:16]1([CH2:15][N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=[C:4]2[CH:12]=[O:13])[CH2:18][CH2:17]1
Reactant: O=Cc1cc2cccnc2[nH]1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cc2cccnc2n1CC1CC1
Temperature: 0 °C
Reaction time: 21 h
Yield: 73.3 %

Procedure:
A solution of sodium hydride (60.2 mg, 1.51 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 10 min. 1H-Pyrrolo[2,3-b]pyridine-2-carbaldehyde (200 mg, 1.37 mmol) was added and the mixture was stirred at 0° C. for 30 min and at it for 30 min. (Bromomethyl)cyclopropane (0.16 mL, 1.64 mmol available, for example, from Alfa Aesar) was added and the resulting mixture was stirred at 0° C. for 30 min and at it for 21 h. Reaction mixture was quenched by the addition of water (50 mL). After addition of Et2O (50 mL), the layers were separated. The aqueous layer was further extracted with Et2O (2×50 mL) and the combined organic layers were washed with H2O (2×35 mL). The organic phase was dried through a hydrophobic frit and concentrated under reduced pressure to give a brown oil which was loaded in DCM on a 50 g SNAP silica cartridge and purified by SP4, eluting with a gradient of 0-20% ethyl acetate/cyclohexane (15CV). The appropriate fractions were combined and evaporated under reduced pressure to give the required product 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (201 mg, 73.4%) as a colourless oil.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1B(O)O.[O:21]=[S:22]1(=[O:39])[CH2:27][CH2:26][N:25]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:24]2=[N:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([C@H:31]2[C:24]3=[N:23][S:22](=[O:39])(=[O:21])[CH2:27][CH2:26][N:25]3[CH2:28][CH2:29][CH2:30]2)=[CH:37][CH:36]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cc(C(F)(F)F)ccc4Cl)cc3)C2=N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.6 %

Procedure:
Diacetoxycopper (907 mg) was added to a mixture of pyridine (0.606 mL), 2-chloro-5-(trifluoromethyl)phenylboronic acid (459 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (700 mg) and cesium carbonate (814 mg) in MeCN (25 mL). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give the title compound (5.9 mg) as pale yellow gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([O:16][C:22]2[CH:23]=[C:18]([Cl:17])[N:19]=[CH:20][N:21]=2)[CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1cc(Cl)c2[nH]c(C3CCOC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOC4)nc3c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80 mg (0.34 mmol) 7-chloro-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazol-5-ol and 51 mg (0.34 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 55 mg (0.40 mmol) potassium carbonate were added and the mixture was stirred overnight at RT. The reaction mixture was filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Cl)[CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-3-{[(2S)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])[O-:16].[Cs+].[Cs+].CO.Cl>CN(C=O)C.C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:16][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: Cl
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
2,5-Difluoro-4-nitrobenzoic acid (Fluorochem; 100 mg, 0.43 mmol) and caesium carbonate (708 mg, 2.17 mmol) were taken up in dry DMF (2 mL) and dry methanol (120 uL, 2.88 mmol) was added and the reaction stirred at room temperature for 2 hrs. The reaction mixture was diluted with Ethyl Acetate (50 mL) and water (50 mL) and acidified to pH1 with 2N HCl solution. The organics were removed and the aqueous further extracted with Ethyl Acetate (2×50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give the title compound as a yellow solid (91 mg, 0.42 mmol, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:33])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:20][C:21]=1[Cl:22])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[3-chloro-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.30 g, 0.59 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.34 g of crude product which was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O.[NH2:13][NH2:14]>C(O)CCC>[N:5]1([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCOCC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)CN1CCOCC1
Yield: 68 %

Procedure:
As described for example 112a, morpholin-4-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 1 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.40 (m, 4H), 2.90 (s, 2H), 3.57 (m, 4H), 4.24 (s, 2H), 8.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:23][C:22](C(OCC)=O)=[N:21][N:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[S:23][CH:22]=[N:21][N:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1nnc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)Nc2nncs2)nnn1Cc1ccc(Cl)c(Cl)c1
Yield: 49.4 %

Procedure:
A mixture of ethyl 5-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3,4-thiadiazole-2-carboxylate (Example 3) (0.302 g, 0.68 mmol) and a 1N NaOH solution (7 mL, 7 mmol) in ethanol (20 mL) was stirred at 50° C. for 1 hour. The solvent was evaporated and the residue was acidified with a 1N HCl solution. The precipitate formed was filtered and the solid was recrystallised from acetonitrile to give the title compound as a white solid (124 mg, 49%). HRMS calculated for C13H10Cl2N6OS (M+H)+369.0092, found: 369.0107, Rt: 2.64 min. MP: 215.6° C.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.C(OC(=O)C)(=O)C.CP(C)C1C=CC=CC=1.CCCCCCCCCC>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[ClH+][Rh-][ClH+].[Rh]>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC(=O)O
Agent: [ClH+][Rh-][ClH+]
Agent: [Rh]
Agent: CP(C)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCCCCCC
Product: C=CCCCCCCC
Temperature: 255 °C
Yield: 5903.6 %

Procedure:
A mixture of decanoic acid (10.0 g, 0.0581 mol), acetic anhydride (5.93 g, 0.0581 mol), chlorodicarbonylrhodium (I) dimer (0.113 g, 2.9×10-4 mol), and dimethylphenylphosphine (0.16 g, 0.0012 mol) was heated under a slow stream of nitrogen using an oil bath maintained at 255° C. As product distilled from the reactor, it was continuously replaced with an equimolar mixture of decanoic acid and acetic anhydride, which also contained 0.6 mol % of dimethylphenylphosphine (relative to the decanoic acid content of the feed), in a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The olefin product was removed as rapidly as possible from the reactor. The formation of product ceased after ca. 90 hours of reaction time. Examination of the combined distillate product by GC (using n-decane as an internal standard) showed the presence of 433 g of 1-nonene (isolated yield of 94% based on decanoic acid employed), which was found to be 99.2% of the α-olefin. TON=5915.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](O)[CH:8]=[C:7]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:18].O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([Cl:18])[CH:8]=[C:7]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(O)cc(C2CCC2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
2-tert-butyl-6-cyclobutyl-pyrimdin-4-ol (3.15 g, 15.27 mmol) was dissolved in toluene (25 ml)/DMF (0.3 ml). POCl3 (3.5 mL, 38 mmol) was added dropwise at 10° C. The resulted solution was stirred at room temperature for 3 h then poured into water, extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (3.28 g, 97%). The crude material was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:26][C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][C@H:23]([C:33]([O:35]C)=[O:34])[CH2:22]2)[N:10]=1.[OH-].[Na+]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[NH:20][N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([N:21]2[CH2:26][C@H:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][C@H:23]([C:33]([OH:35])=[O:34])[CH2:22]2)[N:10]=1
Reactant: COC(=O)[C@H]1C[C@@H](c2ccccc2)CN(c2nc(C)cc(Nc3ccn[nH]3)n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ccn[nH]2)nc(N2C[C@@H](C(=O)O)C[C@@H](c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
To the solution of methyl cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-phenylpiperidine-3-carboxylate trifluoroacetate (34.9 mg) in MeOH (3 ml) was added 2 M aqueous solution of NaOH (1 ml). And the mixture was stirred at room temperature for 1 hour. The mixture was concentrated followed by addition of TFA for neutralization. The residue was purified with preparative RP-HPLC to give cis-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]-5-phenylpiperidine-3-carboxylic acid trifluoroacetate (34.9 mg) as a colorless solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ncn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)pyrimidin-4-yl)propanoate (201 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered with silica gel and the solvent was evaporated under reduced pressure to give the title compound (184 mg) as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Product: O=C(Cl)c1cc(F)c(Br)cc1F
Temperature: 90 °C
Yield: 91 %

Procedure:
A total of 2075 g (8.79 moles) of crude 4-bromo-2,5-difluorobenzoic acid from step (b) was treated with thionyl chloride (2.0 L), and the resulting slurry was slowly heated to reflux (90° C. internal) to obtain a solution. After removal of excess thionyl chloride, the product was collected at 85°-95° C. (oil pump, vacuum not measured), leaving a solid residue. The distillate afforded 2045 g (91%) of a liquid which was used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[N:9][C:8](OC)=[CH:7][CH:6]=2)[CH3:2].[H][H]>C(O)(=O)C.[Pt]=O>[CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1cc(=O)c2nc(OC)ccc2[nH]1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCc1cc(=O)c2c([nH]1)CCCN2
Yield: 73.3 %

Procedure:
Compound E5 (5.0 g) was dissolved in glacial acetic acid (50 ml) and catalytically hydrogenated at atmospheric pressure over platinum oxide (0.5 g). When hydrogen uptake ceased, the catalyst was removed by filtration through diatomaceous earth. The solvent was removed by evaporation and the residue purified by flash chromatography eluting with ethyl acetate/methanol/aqueous ammonia (17:2:1 v/v), to give 2-ethyl-5,6,7,8-tetrahydro-1,5-naphthyridin-4(1H)-one (D5) (3.2 g), m.p. 206°-209° C. (after trituration with ethyl acetate); NMR (d6 -DMSO): 1.15(t,3H), 1.7-1.9(m,2H), 2.35(q,2H), 2.55(t,2H), 3.1(t,2H), 5.75(s,1H), 10.6-11.1(br s,1H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].CN1C=CN=C1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ccc(O)cc1
Agent: Cn1ccnc1
Product: CSc1ccc(OP(=O)(Cl)Cl)cc1
Yield: 42.8 %

Procedure:
To a solution of freshly distilled phosphoryl chloride (45 ml, 0.5 mol) and 1-methylimidazole (0.15 ml), is added 4-(methylthio)phenol (14, 0.1 mol) and the solution is heated under reflux for 20 h. The excess of phosphoryl chloride is removed by distillation and the residue distilled under reduced pressure to give the product (11 g, 42% yield); bp 135°-142° C. (2 mm Hg) 1H NMR (CDCl3) δ 2.39 (3H, S, SCH3), 7.22 (4 H, s, phenyl).
Reaction SMILES: [N:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.NN>C(O)COCCO>[N:1]1[C:13]2[CH2:12][C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2cccnc2-c2cccnc21
Agent: NN
Solvent: OCCOCCO
Product: c1cnc2c(c1)Cc1ncccc1-2
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Following the procedure described in Example 608, Part C, 6.0 g (33 mmole) of 1,5-diazafluoren-9-one and 11.8 g (0.37 mole) of hydrazine were combined with 100 ml of diethyleneglycol and heated rapidly to 200°. The reaction was kept at this temperature for 30 minutes, then for 3 hours at 180°. Following the described workup, the crude yield was 4.69 g, m.p. 85°. Recrystallization from cyclohexane yields 4.0 g, m.p. 99°-100° of pure 1,5-diazafluorene.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]3[NH:11][C:12](=[O:23])[C:13]4[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=4[N:15]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:24][S:25](O)(=[O:27])=[O:26]>>[Cl:24][S:25]([C:8]1[CH:7]=[C:6]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:27])=[O:26]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cccc4c3OCC4)nc12
Reactant: O=S(=O)(O)Cl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)cc4c3OCC4)nc12
Temperature: 0 °C

Procedure:
Compound 5a (0.95 g, 0.003 mole) was added in portions to chlorosulfonic acid (2 ml) cooled to 0° C. (ice-bath) under stirring. The resulting yellow solution was then allowed to attain room temperature and was subsequently slowly heated to 65-70° C. (oil bath) for 1 h. The reaction mixture was then slowly poured onto crushed ice (25 g), whereby a white solid precipitated immediately. The white solid was filtered, dried and recrystallized from THF/petroleum ether (b.p. 40-60° C.), thereby yielding 6a.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37]CC)=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:40])[CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]4[C:30]5[C:25](=[C:26](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=5)[CH:24]=[CH:23][C:22]4=[O:40])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C=C/C(=O)O)c2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To 2 mL of an ethanol solution containing 0.10 g of ethyl (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate, 0.22 mL of 20% aqueous sodium hydroxide solution was added and stirred at room temperature for 3 hours. Ethanol was removed under reduced pressure, water was added, and adjusted to pH 6.0 with 1 mol/L hydrochloric acid under ice-cooling. The resulting solid was filtered to afford 85 mg of (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylic acid as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].C(OCCC)CC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCCOCCC
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 20 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in absolute ethanol (5 ml) with stirring at room temperature followed by adding 10 ml of dipropyl ether. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 127.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[N:17]=[C:16]3[C:19]([F:25])=[C:20](F)[C:21]([F:23])=[CH:22][C:15]3=[CH:14][C:13]=2[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1.O>CS(C)=O>[F:23][C:21]1[C:20]([N:42]2[CH2:41][CH2:40][N:39]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=3)[CH2:44][CH2:43]2)=[C:19]([F:25])[C:16]2=[N:17][C:18]3[N:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[CH:10]=[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:26])[C:13]=3[CH:14]=[C:15]2[CH:22]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A suspension of 1.5 g of ethyl 1-(2,4-difluorophenyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate and 1.8 g of 4-(4-fluorophenyl)piperazine in 20 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature around 100° C. for approximately 1 hour. After cooling to approximately 20° C., the reaction mixture was poured into 100 cm3 of water and extracted 3 times with 50 cm3 of trichloromethane. The combined organic extracts were washed 1 time with 50 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 1.7 g of ethyl 7,9-difluoro-1-(2,4-difluorophenyl)-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 298-299° C., which solid was used without additional purification in the subsequent stages.