Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH:9]([C:11]([OH:13])=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(=O)(O)[O-].[Na+]>[C:14]([NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:9]([C:11]([OH:13])=[O:12])[OH:10])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(c1ccccc1)C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1

Procedure:
reacting said 3-phenyl-isoserine with said benzoyl chloride in sodium bicarbonate to form N-benzoyl-3-phenyl-isoserine;
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]([F:43])([F:42])[C:27]1[CH:28]=[C:29]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:30]=[CH:31][C:32](O)=[O:33].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]([F:42])([F:43])[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 45.6 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3,5-bis(trifluoromethyl)cinnamic acid (4.0 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.6 g, 64%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:12])=O)[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:22])[NH2:12])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 58.7 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carboxamide (10.4 g, 46 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, 22.0 g, 54 mmol) in toluene (150 mL) was heated under reflux for two hours. The reaction mixture was cooled, diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexanes) to give 4, 5, 6-trichloropyridine-2-carbothioamide (6.5 g, 27 mmol): mp 168-169° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
(7-Fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (0.50 g, 2.41 mmol) (for a preparation see Example 88(a)) was combined with 1,1-dimethylethyl 4-piperidinylcarbamate (0.48 g, 2.41 mmol) in 1:1 MeOH/DCM (20 mL). Excess Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature for 16 h. NaBH(OAc)3 (1.53 g, 7.23 mmol) was added and the reaction was stirred an additional 2 h. The solution was concentrated onto silica gel under vacuum and the crude residue purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired product as a yellow solid (0.678 g, 72%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:25]3[CH:24]([CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:29][CH2:28][CH2:27][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(phenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1.[Cl:16]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[C:5]([Cl:16])=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1
Reactant: CCCNc1cc(N(C)C)nc(N)[n+]1[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCNc1c(Cl)c(N(C)C)nc(N)[n+]1[O-]
Reaction time: 4 h
Yield: 60.2 %

Procedure:
1 g of 2-amino-4-propylamino-6-dimethylamino-pyrimidine 3-oxide of Example 1 is dissolved in 15 ml of ethanol. 0.75 g of N-chlorosuccinimide are added as solution in 35 ml of ethanol, dropwise at room temperature. After 4 hours' stirring the reaction mixture is evaporated to dryness. The oil obtained is taken up in 10 ml of water. The pH is adjusted to 8 by adding sodium hydroxide and the mixture is then extracted with 3×20 ml of butanol. The butanol phase is evaporated to dryness. The residue is recrystallized from 5 ml of acetonitrile. 0.7 g of 2-amino-4-propylamino-5-chloro-6-dimethylaminopyrimidine 3-oxide are obtained.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]1)=[O:5].[C:37]([C:39]1[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=1)#[CH:38].C(N(CC)CC)C>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:37]#[C:38][C:33]2[CH:34]=[CH:35][C:2]([F:1])=[C:3]([CH:32]=2)[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[O:5])=[CH:40][N:41]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Reaction time: 0.5 h

Procedure:
In a 25-mL RBF (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.496 g, 0.80 mmol), 5-ethynylpyrimidin-2-amine (0.19 g, 1.6 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.040 mmol), and Copper(I) iodide (0.0076 g, 0.040 mmol) were taken up in CH3CN and Triethylamine (1.7 ml, 12 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70 deg. C for 16 h. The reaction was cooled and transferred to a larger flask with EtOAc and concentrated in vacuo. The solid was adsorbed onto 4 g silica gel from 10% MeOH/MC purified by Isco {Redi-Sep® pre-packed silica gel column (80 g); eluent 0-75% EtOAc/hexanes over 30 min}. Product-containing fractions were concentrated to afford (S)-tert-butyl 1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate as a orange foam. MS m/z=613 [M+H]+. Calc'd for C31H32F4N6O3: 612.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1.ClCCl.CO.N>>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1
Reactant: NC(=O)C1CCNCC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.4 g (10.87 mmol) of piperidine-4-carboxylic acid amide. Yield: 1.05 g (90% of theory); C15H21N3O5 (M=323.34); calc.: molecular ion peak (M+H)+: 324; found: molecular ion peak (M+H)+: 324; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH:15]1([CH:20]=[CH:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1.N12CCCN=C1CCCCC2>C(#N)C>[CH:15]1([CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][C:22]#[N:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=CC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 0.0103 mol) in acetonitrile (30 mL) was added 3-cyclopentylacrylonitrile (1.25 g, 0.0103 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.54 mL, 0.0103 mol). The resulting mixture was stirred at 60° C. overnight, then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.36 g, 73%). LCMS (M+H) 316.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[S:4][N:3]=1.Cl[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[CH:26][C:25]([O:29][CH3:30])=[CH:24]2.CC(O)CC.N>CO>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:17][CH2:16][C:13]3[N:11]4[N:12]=[C:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[CH:6]=5)[CH:8]=[CH:9][C:10]4=[N:15][N:14]=3)=[CH:20][CH:21]=[N:22]2)=[N:27][CH:26]=1
Reactant: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: N
Solvent: CO
Solvent: CCC(C)O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cc(C)ns5)nn34)ccnc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
(6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (548 mg, 2225 μmol) and 8-chloro-3-methoxy-1,5-naphthyridine (576 mg, 2959 μmol) were charged in a microwave vial. 2-butanol (7 mL) was added and the reaction mixture was stirred at 120° C. under micro-waves irradiation for 8 h. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH: 100/0 to 90/10) afforded the title compound (720 mg, 80% yield). MS m/z=405.1 [M+H]+. Calc'd for C19H16N8OS: 404.46
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][NH:11][C:12]2=S)=[CH:7][CH:6]=1.O.[NH2:22][NH2:23]>>[OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[N:10][N:11]=[C:12]2[NH:22][NH2:23])=[CH:7][CH:6]=1
Reactant: NN
Reactant: CC(C)NCC(O)COc1ccc2cn[nH]c(=S)c2c1
Solvent: O
Product: CC(C)NCC(O)COc1ccc2cnnc(NN)c2c1

Procedure:
7-(2-Hydroxy-3-isopropylaminopropoxy)-1(2H)-phthalazinethione was reacted with hydrazine hydrate in a similar manner to that described in Example 1(viii) to give 7-(2-hydroxy-3-isopropylaminopropoxy)-1-hydrazinophthalazine which was isolated as its hydrochloride m.p. 249°-253° (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:20]([O:27][C:28]1[C:33](F)=[CH:32][C:31]([NH:35][C:36]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[C:30]([N+:44]([O-:46])=[O:45])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([O:27][C:28]1[C:33]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:32][C:31]([NH:35][C:36]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[C:30]([N+:44]([O-:46])=[O:45])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1F
Reactant: O=C(Nc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccccc2F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
0.54 ml of 2-fluorophenol and 2.53 g of potassium carbonate were added to a dimethylformamide (16 ml) solution of 2.14 g of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)pyrazinecarboxamide, and the reaction liquid was stirred at 90° C. for 5 hours, and then water was added to it. The resulting deposit was taken out through filtration to obtain the entitled compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:10]2[CH:11]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[NH:3]1.[Br:22]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:22][C:7]1[C:8]2[O:13][CH2:12][CH:11]([C:14]3[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][CH:19]=3)[N:10]3[C:2](=[O:1])[NH:3][C:4]([C:9]=23)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ncccc1C1COc2cccc3[nH]c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ncccc1C1COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A solution of 3-(2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile (709 mg, 2.548 mmol) in N,N-dimethylformamide (25.0 mL) was treated with N-bromosuccinimide (630 mg, 3.54 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (0.44 g, 48%) as a racemic mixture. LCMS calculated for C15H10BrN4O2 (M+H)+: m/z=357.0, 359.0. found: 356.8, 358.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc(F)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline were reacted to yield N2,N4-bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.79 (d, 2H, J=5.4 Hz), 7.40 (m, 2H), 7.30 (m, 2H), 6.90 (m, 4H); 19NMR (CDCl3): −32425 (s, 1F), −32940 (s, 1F), −45525 (s, 1F); LCMS: ret. time: 23.53 min.; purity: 100%; MS (m/e): 317 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:3]12.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.Cl>CN(C)C=O.O1CCOCC1>[CH:28]1([CH2:27][N:8]2[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]3[CH2:13][CH2:14][NH:15][CH2:16][CH:3]3[C:2]2=[O:1])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3CNC(=O)C2C1
Reactant: BrCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1C2CNCCN2c2ccccc2CN1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate (100 mg, 0.315 mmol, Example 1) in anhydrous N,N-dimethylformamide (2 mL) was added sodium hydride (13.86 mg, 0.347 mmol). After stirring for 1 hour at room temperature, (bromomethyl)cyclopropane (102 mg, 0.756 mmol) was added to the reaction mixture. The reaction was stirred for 20 hours. The reaction was then quenched carefully with water and extracted with ethyl acetate. The organic layer was separated, dried with MgSO4, and concentrated. The residue was purified via flash chromatography (0-40% ethyl acetate/hexanes). The material obtained was dissolved in 1,4-dioxane (0.8 mL) and 4 M HCl in 1,4-dioxane (0.8 mL). The mixture was stirred for 20 hours. at room temperature. The title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.07-6.94 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (s, 1H), 4.17 (d, J=16.1 Hz, 1H), 3.51-2.79 (m, 8H), 0.66 (m, 1H), 0.15-0.05 (m, 1H), 0.05-0.08 (m, J=4.1 Hz, 1H); MS (DCI) m/z 221.1 (M+H)+.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C

Procedure:
Sulfuric acid (0.53 ml, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Yield: 93 %

Procedure:
A solution (0.07 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (2 N solution, 15 eq.). The mixture was heated to reflux for 90 min then concentrated and acidified to pH 1 with aqueous HCl (6 N) and extracted with AcOEt. The combined organic phase was washed with brine then dried and concentrated to give the title compound (93%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:36][CH2:35][C@H:34]([C:37](OC)=[O:38])[CH2:33][CH2:32]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:32][CH2:33][C@H:34]([C:37]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:38])[CH2:35][CH2:36]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Reactant: Nc1cccnc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)Nc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of 3-aminopyridine (40 mg, 0.43 mmol) in toluene (1.3 mL) was treated with a 2M toluene solution of trimethylaluminum (0.3 mL, 0.60 mmol). After 25 min, the resulting solution was treated with methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (30 mg, 0.08 mol) and the mixture stirred at rt overnight. The mixture was then stirred with 2M NaOH (20 mL) and ethyl acetate (20 mL) for 10 min., then the organic phase was separated and the aqueous extracted EtOAc (3×15 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo to give crude product which was subjected to mass-directed preparative HPLC to afford pure desired product. 1H NMR (d6-DMSO, 400 MHz): δ 11.45 (br s, 1H), 10.12 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (m, 1H), 7.15-7.00 (m, 3H), 6.65 (s, 1H), 6.42 (br s, 2H), 3.22 (m, 1H), 2.47 (m, 1H), 2.15-1.95 (m, 4H), and 1.85-1.65 (m, 4H). MS (ES+): m/z 452.17 [MH+].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1N)[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])=[O:3].N([O-])=O.[Na+].[ClH:22]>O.[Cu]Cl>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:22])[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])=[O:3]
Reactant: Cl
Reactant: CC(=O)c1cc2c(cc1N)C(C)(C)CC2(C)C
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc2c(cc1Cl)C(C)(C)CC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
113.1 g of (6-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are suspended in 2260 ml of 20% hydrochloric acid and the suspension is cooled down to 0°-5° C. The cold mixture is treated dropwise within 10 minutes with a solution of 33.9 g of sodium nitrite in 115 ml of water and the resulting solution is stirred for 30 minutes. The cold solution is subsequently introduced dropwise over a period of 2 hours while stirring into a solution of 243.2 g of copper (I) chloride in 250 ml of water and 250 ml of concentrated hydrochloric acid, which is warmed to 40°-45° C. The mixture is then cooled down, introduced into ice-water and extracted three times with methylene chloride. The organic extract is washed with a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure. The residue is purified by adsorption on silica gel using hexane/acetone (19:1) for the elution. The (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts at 69°-71° C. after recrystallisation from hexane/ether.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Br[CH2:10][CH:11]=O>C(O)CCC>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=CCBr
Solvent: CCCCO
Product: Clc1ccc2nccn2n1
Temperature: 0 °C
Yield: 38.7 %

Procedure:
3-Amino-6-chloro pyridazine (1.5 g, 0.0116 mol) was dissolved in n-butanol (12 ml), cooled to 0° C. and bromoacetaldehyde (2.8 g, 0.023 mol) was added. The reaction was refluxed for 20 hrs and n-butanol was removed under reduced pressure. To the reaction mixture, water was added and extracted with EtOAc (5×20 ml). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to afford 6-Chloro-imidazo[1,2-b]pyridazine (4) (690 mg, yield=40%).