Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:21][C:22]([F:35])([F:34])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[O:24]>CN(C)C=O>[F:21][C:22]([F:34])([F:35])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:32])=[O:24]
Reactant: O=C(Cl)CCCCCNC(=O)C(F)(F)F
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(NC(=O)CCCCCNC(=O)C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
To 0.57 g (3 mmol) of para-amino-benzenesulfonyl azide dissolved in 5 mL dimethylformamide was added 0.9 mL (6 mmol) triethylamine, then the (2,2,2-trifluro-acetylamino)-hexanoyl chloride dissolved in 10 mL dimethylformamide was added dropwise. The mixture turned brown and was stirred under argon for 24 hrs. Solvent was evaporated, and the remaining oil was dissolved in 10 mL dichloromethane and left at room temperature for 1 hr. The precipitate was filtrated and the solution was evaporated to yield 1.10 g crude oil. The obtained compound was directly used in oligonucleotide synthesis.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([OH:21])=O)#[N:2].F[P-](F)(F)(F)(F)F.[N:29]1([O:38][C:39](N(C)C)=[N+](C)C)[C:33]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CNOC>CN(C)C=O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]=1[C:19]([N:29]([O:38][CH3:39])[CH3:33])=[O:21])#[N:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1c(C(=O)O)n(-c2cccc(F)c2)c2ccccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
A mixture of 3-cyano-1-(3-fluorophenyl)-1H-indole-2-carboxylic acid (0.12 g, 0.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.32 g, 0.86 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (63 mg, 0.64 mmol) was added and the resulting suspension was stirred at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-25% EtOAc/hexane) to give the desired product (90 mg, 65%). LCMS calculated for C18H15FN3O2(M+H)+: m/z=324.1. Found: 324.0.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:29](=[O:30])[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)Cc3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (8 mL) was added phenylacetyl chloride (0.47 mL, 3.0 mmol), and triethylamine (0.41 mL, 3.0 mmol) was added to the obtained mixture. The reaction mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 20:1–4:1) and crystallized from isopropyl ether to give the title compound (0.75 g, yield 67%).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>CN(C=O)C>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: BrCc1ccncc1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccncc1
Temperature: 60 °C
Yield: 21.6 %

Procedure:
To a solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (375 mg, 1 mmol) in DMF (16 ml ) were added at ambient temperature potassium carbonate (415 mg, 3 mmol) and 4-(bromomethyl)pyridine hydrobromide (J.Org.Chem. 1958, 23, 575, 278 mg, 1.1 mmol). The reaction mixture was heated at 60° C. for 2 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column flash chromatography, eluting with methylene chloride/methanol (95/5) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline (93 mg, 22%). m.p. 201-202° C. 1H NMR Spectrum: (DMSOd6) 2.12(s, 3H); 2.34(s, 3H); 4.02(s, 3H); 5.40(s, 2H); 7.27(s, 1H); 7.30(d, 1H); 7.51(d, 2H); 7.62(s, 1H); 7.65(d, 1H); 7.91(s, 1H); 8.47(s, 1H); 8.63(d, 2H); 9.53(s, 1H) MS−ESI: 453 [MNa]+, 431 [MH]+
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N:11]1([S:17](Cl)(=[O:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([C:4]1[N:9]=[C:8]([NH:10][S:17]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:19])=[O:18])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cccc(N)n1
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1cccc(NS(=O)(=O)N2CCCCC2)n1
Yield: 32 %

Procedure:
A solution of 6-propyl-pyridin-2-ylamine (0.2 g) and piperidine-1-sulfonyl chloride (0.296 g, Bull. Soc. Chim. Fr.; 1936, 2143) in pyridine (7 mL) was heated to reflux for 15 h. After concentration of the reaction mixture in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9:1 to 1:1) as eluent. Combination of the purified fractions and concentration in vacuo gave the desired piperidine-1-sulfonic acid (6-propyl-pyridin-2-yl)-amide (0.133 g) as a colorless amorphous solid. MS (ESI−): 282.0 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH2:37]>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: NCCc1ccccn1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCc3ccccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(pyridin-2-yl)ethanamine were reacted to give 322. [M+H]+ 484.6.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([N:29]2[CH2:35][CH:34]3[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:28])=[CH:25][N:24]=1>>[CH3:14][N:13]([CH3:15])[C:11]([C:9]1[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:6]2[N:7]=[C:2]([NH:22][C:23]3[CH:45]=[CH:44][C:26]([C:27]([N:29]4[CH2:30][CH:31]5[N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH:34]([CH2:33][CH2:32]5)[CH2:35]4)=[O:28])=[CH:25][N:24]=3)[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCOC1
Yield: 25.4 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (80 mg, 0.26 mmole) was combined with tert-butyl 3-(6-aminonicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82 mg, 0.26 mmole) which gave tert-butyl 3-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg) in 25% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.84 (s, 1H), 8.72-8.65 (m, 1H), 8.42 (m, 1H), 7.89-7.82 (m, 1H), 6.56 (s, 1H), 4.63-4.52 (m, 1H), 4.52-4.41 (m, 1H), 4.26 (br, 2H), 4.08-3.96 (m, 2H), 3.70-3.49 (m, 3H), 3.16 (S, 6H), 3.23-3.02 (m, 1H), 3.03-2.88 (m, 1H), 2.18-2.07 (m, 1H), 2.02-1.57 (m, 7H), 1.51 (s, 9H). HR-MS m/z 605.3201 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[OH:28][NH3+:29].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[N:29][OH:28])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [NH3+]O
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of crude 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (35 g), hydroxylammonium chloride (10.4 g) and anhydrous sodium acetate (12.3 g) in ethanol (400 ml) was stirred at room temperature for a day. Then the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (500 ml), an 8 N aqueous solution (30 ml) of sodium hydroxide and water (100 ml) and the layers were separated. The organic layer was washed with brine and dried over magnesium sulfate. After removing the solvent, the residue was dissolved in a hot toluene (100 ml)-isopropyl ether (100 ml) mixtures and allowed to cool at room temperature. The resulting crystals were collected by filtration and dried at 50° C. to give the title compound (31 g) as a pale yellow powder (yield: 85%).
Reaction SMILES: OC1C=C(C[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])C=C(O)C=1.C[O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31]C)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[OH:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([CH3:30])[C:22]=1[OH:21]
Reactant: COc1ccc(C=O)c(OC)c1C
Reactant: Oc1cc(O)cc(CCCc2ccc(O)cc2O)c1
Product: Cc1c(O)ccc(CCCc2ccc(O)cc2O)c1O

Procedure:
Compound 32 was synthesized following a similar procedure as described for compound 30 using as starting materials 2,4-dibenzyloxyacetophenone and 2,4-dimethoxy-3-methylbenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.879 (d, 1H, J=8.5 Hz), 6.747 (d, 1H, J=8.0 Hz), 6.352 (d, 1H, J=1.5 Hz), 6.341 (d, 1H, J=4.0 Hz), 6.285 (dd, 1H, J=8.0 Hz & 2.5 Hz), 2.567 (dd, 4H, J=8.0 & 7.5 Hz), 2.133 (s, 3H), 1.786-1.817 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 155.486 (C), 155.316 (C), 153.428 (C), 152.906 (C), 130.295 (CH), 126.523 (CH), 120.933 (C), 120.518 (C), 111.556 (C), 106.788 (CH), 106.377 (CH), 102.283 (CH), 30.767 (CH2), 29.649 (CH2), 29.127 (CH2), 7.833 (CH3).
Reaction SMILES: CN(C)C=O.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].CS[C:13]1[S:17][CH:16]=[CH:15][S+:14]=1.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH2:19]1.C(OCC)(=O)C>CC(C)=O.C(OCC)C>[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[S:14]1[CH:15]=[CH:16][S:17][C:13]1=[N+:18]1[CH2:26][CH2:25][CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCNCC1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)C1CC[N+](=c2sccs2)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To 5 ml of dimethylformamide, 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was suspended, and 1.2 g of isonipecotic acid was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and after an addition of 60 ml of ethyl acetate, the precipitated crystals were collected by filtration and recrystallized from acetone-ethyl ether, whereby 1.6 g (yield: 61%) of 1-(1,3-dithiol-2-ylidene)-4-carboxypiperidinium perchlorate (Compound No. 57) was obtained as crystals having a melting point of from 170° to 172° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][CH2:7]1)=O)C.Cl>>[CH2:12]([N:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCN1CCN(C(=O)OCC)CC1
Agent: Cl
Product: CCCCCCCCCCCCCCCN1CCNCC1
Temperature: 0 °C

Procedure:
To 30.0 grams of 1-ethoxycarbonyl-4-pentadecylpiperazine is added 200 ml. of concentrated hydrochloric acid and the mixture refluxed for 48 hours. The mixture is cooled to approximately 0° C. and the resultant solid filtered and suction-dried. The solid is suspended in water and 10 ml. of 50% sodium hydroxide added. The solution is then extracted with ethyl ether. Removal of the ethyl ether leaves, as an oil, 1-pentadecylpiperazine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17]>C(Cl)Cl.C(O)(C)C>[C:16]([C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)#[CH:17]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 4-chloro-7-fluoro-6-nitroquinazoline (12 g, 0.052 mol) in 120 mL DCM in an ice bath was added slowly a solution of 3-ethynylaniline (7 g, 0.060 mol) in 200 mL isopropanol. The reaction solution was stirred for 1 hour, then TEA (7 g, 0.069 mol) was added and stirred for another 0.5 hour at room temperature. The resulting solid precipitate was filtered and washed with 20 mL isopropanol twice, 20 mL H2O for twice, and dried to give N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine as yellow solid 8.2 g (50.3% yield).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[C:14]([NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCNC(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
After dissolving 5 g of homoveratrylamine in 20 ml of pyridine, 5.6 g of acetic anhydride was added and reacted at 65°-70° C. with stirring for 2 hours. The reaction mixture was poured into 150 ml of ice water and then made weakly acidic by adding 50 ml of a 6N aqueous hydrochloric acid solution. The resultant solution was extracted three times with 50 ml of chloroform. The extracted solution was combined, washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Ether was added to the residue and precipitated crystals were filtered. N-acetylhomoveratrylamine having a melting point of 101°-102° C. was obtained as colorless crystals. The yield was 5.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[C:30](=O)[C:31](=[O:35])[C:32]=1[O:33]C>CO>[CH3:27][O:28][C:29]1[C:32](=[O:33])[C:31](=[O:35])[C:30]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 70.8 %

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(2-phenylpropylamino)methyl]phenylamine (2.52 g) [prepared as described in step (b) above] in methanol (25 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione (1.09 g) were reacted, to afford the title compound (2.35 g) as a pink foamy solid.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[C:3]1=[C:12]1[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]4)[CH2:18]3)[CH2:9]2.[Cl:22][CH2:23][CH2:24][OH:25]>O1CCOCC1>[Cl:22][CH2:23][CH2:24][O:25][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[C:3]1=[C:12]1[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]4)[CH2:18]3)[CH2:9]2
Reactant: OCCCl
Reactant: BrC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Solvent: C1COCCO1
Product: ClCCOC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2
Yield: 89.7 %

Procedure:
The bromo-substituted compound having formula 16 (220 mg, 0.58 mmol) was dissolved in dry dioxane (10 cm3) and 2-chloroethanol (5 cm3) was added. The mixture was refluxed for 18 hours, cooled, and concentrated at a reduced pressure. Water (50 cm3) was added and the product was twice extracted with n-hexane, with the combined extracts being washed with brine. The hexane solution was dried with MgSO4, filtered and concentrated at a reduced pressure. Columnchromatography over Al2O3 (act. II/III), using hexane as the eluent, produced 180 mg (0.52 mmol, 89.7%) of pure compound having formula 23 in the form of a colourless oil. IR (neat) 2950 (s), 1455 (m), 1100 (s) and 785 cm-1 (s) 1H-NMR (CCl4, TMS): δ 3.6 (double triplet, 4H), 3.25 (m, 1H), 2.85 (m, 5H), δ 2.4-1.1 (m, 22H), 13C-NMR (CBCl3): δ 135.8; 130.8; 82.6 (d); 67.9 (t); 43.2 (t); 39.7; 39.6; 39.5; 39.1; 37.1; 36.8; 35.7; 33.0; 32.4; 32.1; 31.8; 31.0; 30.1; 28.4 and 27.6. Mass: M+ at m/e 346 (100%). Exact mass: calculated for C22H31ClO: 346.206. Found 346.205.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[C:20](=[C:28]([C:32]([OH:34])=O)[CH:29]=[CH:30][CH:31]=2)[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1[N:39]=[CH:38][N:37]([C:40](N2C=NC=C2)=O)[CH:36]=1.CN(C)CCN>CN(C=O)C.O>[CH3:38][N:37]([CH3:40])[CH2:36][CH2:35][NH:39][C:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:19]2[C:18]3[C:23](=[N:24][CH:25]=[CH:26][C:17]=3[NH:16][C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:15][CH:14]=3)[NH:22][C:21](=[O:27])[C:20]=12)=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(C(=O)O)cccc4c23)cc1)c1ccccc1
Agent: CN(C)CCN
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNC(=O)c1cccc2c1c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reaction time: 2 h

Procedure:
434 (20 mg, 0.04 mmol), and CDI (14 mg, 0.09 mmol) were suspended in DMF (1 mL), and stirred for 2 h. N,N-dimethylethane-1,2-diamine (8 mg, 0.09 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with H2O. The resulting precipitate was filtered, washed with MeOH, and dried under vacuum to provide 435. LC-MS (M+H=521, obsd.=521). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 6H), 2.49 (4H), 6.93 (d, 1H), 7.20 (d, 2H), 7.54 (m, 3H), 7.76 (m, 3H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 9.18 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: C(N1[C:8](=[O:9])[C:7]2=[C:10]([F:17])[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5]1=[O:18])(C)C.S(=O)(=O)(O)[OH:20].C(O)(=O)C>O>[F:17][C:10]1[C:11]([F:16])=[C:12]([F:15])[C:13]([F:14])=[C:6]2[C:5](=[O:18])[O:9][C:8](=[O:20])[C:7]=12
Reactant: CC(C)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 66.4 %

Procedure:
In a 500 ml three neck distillation flask were placed 47 g (0.18 mol) of N-isopropyl-tetrafluorophthalimide, 71 ml of concentrated sulfuric acid, 43 ml of acetic acid, and 13 ml of water, and the mixture was reacted for 5 hours at 140° to 150° C. with stirring. After cooling, the reaction mixture was extracted three times with 200 ml of toluene, and the toluene layers thus formed were collected and concentrated by distillation under a reduced pressure to provide 26.3 g (yield 66.4%) of tetrafluorophthalic anhydride as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][CH3:14])[CH:8]=2)[N:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:26]=2)[CH:19]=[CH:20][C:21]=1[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:26]=2)=[CH:17][C:16]=1[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([NH:13][CH3:14])[N:10]=[CH:11][N:12]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CNc1cc(-n2nccc2N)ncn1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(C(F)(F)F)c2)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNc1cc(-n2nccc2Nc2cc(NC(=O)c3cc(N4CCN(C)CC4)cc(C(F)(F)F)c3)ccc2C)ncn1

Procedure:
[6-(5-Amino-pyrazol-1-yl)-pyrimidin-4-yl]-methyl-amine (200 mg, 1.05 mmol) is mixed with N-(3-bromo-4-methyl-phenyl)-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide (640 mg, 1.40 mmol), palladium acetate (60 mg, 0.27 mmol), Xantophos (235 mg, 0.41 mmol) and cesium carbonate (1.03 g, 3.15 mmol). 10 mL of anhydrous 1,4-dioxane is added under nitrogen environment and the mixture is subjected to microwave irradiation to 160° C. for 25 minutes. The reaction mixture is treated with 150 mL THF, passed through a celite column and condensed. The crude product is purified by ISCO chromatography eluting with THF and methanol (v/v=1:1) in methylene chloride from 0% to 10% to afford N-{4-Methyl-3-[2-(6-methylamino-pyrimidin-4-yl)-2H-pyrazol-3-ylamino]-phenyl}-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide.