Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[C:18](O)(=[O:22])[C@H:19]([CH3:21])[OH:20].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:20][C@@H:19]([CH3:21])[C:18]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:22]
Reactant: C[C@H](O)C(=O)O
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 0.20 g (0.9 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one in 8 ml tetrahydrofurane was treated at 0° C. with 0.09 g (0.99 mmol) L-lactic acid, 0.14 g (0.9 mmol) 1-hydroxybenzotriazole hydrate, 314 μl (1.8 mmol) N-ethyldiisopropylamine and 0.18 g (0.9 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.19 g (70%) (S)-2-hydroxy-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide as white solid; MS: m/e: 297.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:29]3[CH2:31][CH2:30]3)[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[CH2:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:28]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO>[CH:29]1([C:17]2[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[CH2:21][C:20]([CH3:26])([CH3:27])[C:19]=3[CH:28]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[CH:12][CH:11]=3)[CH:16]=2)[CH2:30][CH2:31]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc21
Temperature: 55 °C

Procedure:
A solution of 2-{4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}2-methyl-propionic acid methyl ester (Intermediate 2, 0.046 g, 0.107 mmol) in methanol (5 mL) was treated with a 1M solution of sodium hydroxide (1.2 mL, 1.2 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was cooled to ambient temperature and the volatiles were evaporated in vacuo to a residue that was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid after flash column chromatography over silica gel (230–400 mesh) (0.067 g, 89%).
Reaction SMILES: CN1CCCC1=O.Br[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2=[O:18])=[CH:11][CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC.[F-].[K+]>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:24]1([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCc2ccc(-c3ccccc3)cc21
Temperature: 85 °C
Reaction time: 4 h
Yield: 51.3 %

Procedure:
To a three-necked flask of 500 ml, fitted with a condenser, was added 150 ml N-methylpyrrolidon (NMP), 10.45 g (49.5 mmol) 6-bromoindan-1-one and 19.9 g (54.2 mmol) of tributylphenyltin. To this mixture was added 1.05 g (1.50 mmol) of bis(triphenyl-phosphine)palladium(II)chloride. The reaction mixture was heated to 85° C. for 4 h, followed by stirring for 4 hours at ambient temperature. A solution of 23 g of potassiumfluoride in 50 ml of water was added. The solids were filtered off and the filtrate was diluted with diethylether, washed once with water and once with saturated sodiumchloride solution. The ether layer was evaporated under reduced pressure and the solid material was crystallised from toluene, petroleum ether. A total of 5.29 g of 6-phenylindan-1-one was obtained, yield 51.4%.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:13]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][N:13]1[S:26]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CN(Cc3ccccc3)C(=O)C[C@@H]2C(=O)NO)cc1
Reaction time: 3 h

Procedure:
A mixture of N-benzyloxy 1-benzyl-3-[(4-Methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)carboxamide (213 mg, 0.4 mmol) and 10% Pd/C (50 mg) in methanol (25 mL) is stirred under hydrogen atmosphere for 3 hours. The mixture is filtered over celite and the filtrate is collected and concentrated under reduced pressure to give an oil. The crude product is purified by flash silica gel chromatography (200:1 ethyl acetate-formic acid) to give N-hydroxy 1-benzyl-3-[(4-methoxyphenyl)sulfonyl]-6-oxo-hexahydro-pyrimidine-4(R)carboxamide as a white solid. MS (ESI): 420 (M+H+), 437 (M+NH4+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[N:21]1(C(OCC)=O)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CC(CCCCl)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(CC(CCCN2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
50 g (0.17 mol) of 4,5-bis(4-fluorophenyl)pentyl chloride, 32.5 g (0.21 mol) of ethyl piperazine-1-carboxylate, 46.9 g (0.34 mol) of powdered potassium carbonate and 2.8 g of potassium iodide were reacted in 580 ml of methyl isobutyl ketone and the mixture was worked up, by a process analogous to that described in Example 3d).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.O.NN>C(O)C>[F:1][C:2]([F:22])([C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cccc(COCC(F)(F)C(F)(F)C(F)(F)F)c1

Procedure:
180 g (0.54 mol) of 1-(2,2,3,3,4,4,4-heptafluorobutoxy)methyl-3-nitrobenzene (Compound No. 11) obtained in Example 2 was dissolved in 500 ml of ethanol, and the mixture was refluxed for 30 minuted after adding 7.9 g of FeCl3.6H2O and 12.5 g of activated carbon thereto. While the mixture was being stirred, 100 g (2.00 mol) of hydrazine hydrate was added dropwise thereto so as not to cause violent foaming. The mixture was refluxed for 2 hours after the completion of the dropping, thereby completing the reaction. After the reaction mixture was left to cool, the reaction mixture was filtered through a Celite layer and washed with ethanol. The filtrate was concentrated and dissolved in 500 ml of benzene. The solution was successively washed with water and saturated saline solution and was dried by anhydrous sodium sulfate.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[Br:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:14][CH2:15][CH2:16][C:17]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:18]
Reactant: OCC(F)(F)F
Reactant: O=C(Cl)CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCBr)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
2,2,2-Trifluoroethanol (15 ml, 0.15 mol) and triethylamine (4.5 ml, 32.12 mmol) were added to 30 ml of dichloromethane, and cooled to 0° C. After 10 min, 2.94 ml of 3-bromopropionyl chloride (29.2 mmol) was added dropwise thereto. The mixture was warmed to room temperature and stirred for 5 hrs. After the reaction was terminated by addition of water, the mixture was extracted with ethyl acetate, and the solvent was evaporated under a reduced pressure. The solid impurities were removed by filtration to obtain the title compound as a liquid (3.53 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.CCN(C(C)C)C(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl.CC(O)=O.C1COCC1>[CH3:1][N:2]([CH3:22])[CH:3]([CH2:20][CH3:21])[CH:4]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([NH:17][C:33](=[O:34])[O:35][CH2:36][CH3:37])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccc(C(C(CC)N(C)C)n3ccnc3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (52 mg, 0.16 mmol) and Hunig's base (31.6 μL, 0.18 mmol) in DCM (1 mL) was treated with ethyl chloroformate (17.3 μL, 0.0.18 mmol) in 2 mL 10% AcOH THF. The mixture was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue was purified using PTLC on a 1 mm silica plate eluting with 5% MeOH (2N NH3)/DCM to provide Ethyl (6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamate. MS (ESI+) m/z 388.17 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[C:17]([C:20]4[CH:21]=[N:22][N:23]([C:25]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:24]=4)[CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:44][C:45]1[S:46][CH:47]=[C:48]([CH3:50])[N:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:50][C:48]1[N:49]=[C:45]([NH:44][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([C:25]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:10][C:2]=2[F:1])[S:46][CH:47]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cn23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cn34)cc2F)n1
Yield: 84.9 %

Procedure:
170 mg 2-fluoro-4-[6-(1-trityl-1H-4-pyrazolyl)imidazo-[1,2-a]pyridin-3-yl]benzoic acid (compound in Example 472) and 34.4 mg 2-amino-4-methyl-1,3-thiazole were allowed to react overnight with 146 mg benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 50 μL triethylamine in 6 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 169 mg of the title compound as colorless crystals (recrystallization solvent: ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4](Cl)[N:3]=1.[Cl:15][C:16]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:17]=1[CH2:18][N:19]1[CH:23]=[CH:22][C:21](=[O:24])[NH:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([O:24][C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C:17]3[C:16]([Cl:15])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[N:20]=2)[N:3]=1
Reactant: O=c1ccn(Cc2c(Cl)cccc2Cl)[nH]1
Reactant: COC(=O)Cc1c(C)nc(C)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1c(C)nc(C)nc1Oc1ccn(Cc2c(Cl)cccc2Cl)n1

Procedure:
A mixture of methyl (2,4-dimethyl-6-chloro-5-pyrimidinyl)-acetate (0.5 g, 23 mmol), 1-(2,6-dichlorobenzyl)-1H-pyrazol-3-on (5.80 g, 23 mmol) and potassium carbonate (10.0 g, 70 mmol) in dimethylformamide (30 ml) is heated at +130° C. for 2 hours. Addition of water, extraction with ether and drying gives the intermediate methyl 2-[2,4-dimethyl-6-(1-(2,6-dichlorobenzyl)-1H-pyrazol-3-yloxy)-pyrimidin-5-yl]-acetate as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N1CCCCC1>C(O)C>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccc(NC(C)=O)cc1
Yield: 41.3 %

Procedure:
A mixture of 33.9 g (0.3 mol) of ethyl cyanoacetate and 59.1 g (0.3 mol) of 4-acetamidobenzaldehyde in 300 ml of ethanol in the presence of 5 ml of piperidine is refluxed for 3 hours. The very viscous medium is diluted with 800 ml of hot ethanol. It is filtered while hot. The yellow solid obtained is washed with hot ethanol. After filtration and drying, 32 g (41% yield) of ethyl 3-(4-acetylaminophenyl)-2-cyanoacrylate are obtained in the form of a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl.CO>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[C:4]([CH:3]=1)[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
To a solution 2.00 g (10.7 mmol) of benzaldehyde 12 in 20 mL of dichloromethane under argon at 0° C. was added 1.20 mL (11.8 mmol) of boron tribromide. The solution was stirred at 0° C. for 0.3 h and 25° C. for 4 h, diluted with 40 mL of methanol, and the solvents were removed on a rotary evaporator (the trimethylborate was removed). To it was added 40 mL of methanol and methanol and trimethyl borate were removed by evaporation on a rotary evaporator, and this process was repeated three times. The residue was diluted with dichloromethane and filtered and washed with a small amount of dichloromethane to give 1.722 g (94% yield) of pure 5-chloro-3,4-dihydroxybenzaldehyde. This material was used in next step without purification. 1H NMR (CDCl3) δ 10.43 (s, 2H, OH), 9.70 (s, 1H, CHO), 7.42 (d, J=2.0Hz, 1H, C6-H), 7.22 (d, J=2.0Hz, 1H, C2-H); 13C NMR (DMSO-d6) δ 190.6 (C═O), 148.3 (s), 146.9 (s), 128.4 (d), 124.2 (d), 120.3 (s), 112.5 (s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:18]=[CH:19][CH:20]=2)[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1.[Cl:21]N1C2C=CC=CC=2N=N1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:21][C:20]1[CH:19]=[N:18][N:6]2[C:7]([C:8]3[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:12][CH:13]=3)=[C:2]([CH3:1])[CH:3]=[N:4][C:5]=12
Reactant: Cc1cnc2ccnn2c1-c1cccc(C(F)(F)F)c1
Reactant: Cln1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(Cl)cnn2c1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2.77 g. of 6-methyl-7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine, 100 ml. of chloroform and 1.68 g. of N-chlorobenzotriazole is refluxed for 20 minutes, allowed to stand at room temperature for 30 minutes and then poured into 1 N sodium hydroxide in an ice bath. The product is separated, dried over sodium sulfate and treated as described in Example 1, giving the desired product, m.p. 195°-197° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[C:13]1([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[CH:27]=[CH:31][CH:30]=[CH:29]3)[CH2:7][CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)N2CCN(CCCCn3cccc3)CC2)cc1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
Under reflux, for 20 minutes is heated a solution of 1.28 g (3.96 mmoles) of 1-(4-aminobutyl)-4-diphenylmethylpiperazine and 0.77 g (5.8 mmoles) of 2.5-dimethoxytetrahydrofurane in 25 ml of acetic acid. It is cooled, it is poured over ice water, neutralized with NaCHO3 and extracted with chloroform. It is dried with Na2SO4, and evaporated under vacuum to dryness. 1.7 g of crude oil is obtained which is purified on a silica chromatographic column (eluant: ethyl acetate). 0.95 g of 1-[4-(4-Diphenylmethyl-1-piperazinyl)butyl]pyrrole is obtained in solid form, with a melting point 80°-84° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 120 mg (0.37 mmol) 2 in 10 ml of ethyl acetate was added 43 mg (0.37 mmol) N-hydroxysuccinimide followed by addition of 85 mg (0.41 mmol) N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 24 hours. The N,N'-dicyclohexylurea which formed was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give an orange-red solid. It was purified by chromatography on silica gel with chloroform as eluant to give 118 mg (77%) of orange-red needles of 3. Succinimidyl esters 6 and 9 were prepared by similar procedures.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in a analogous manner to Example 61e. Product was isolated as a white solid (0.029 g, 27%). MP: 103-127° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.99 (s, 1H), 7.95 (s, 1H), 7.31 (s, 1H), 6.65 (s, 1H), 6.07-5.74 (m, 1H), 5.34 (d, 1H, J=8.1 Hz), 5.22 (d, 1H, J=7.1 Hz), 4.01-3.90 (m, 1H), 3.87 (s, 3H), 3.29-3.19 (m, 1H), 2.98-2.74 (m, 14H), 2.29-2.16 (m, 2H), 1.89-1.74 (m, 2H), 1.41-1.34 (m, 3H). MS: 559 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][NH:32][CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([CH2:2][C:3]3[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=3)[CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(COc2ccc3c(c2)CNCC3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccc(OCc4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A suspension of 0.23 g (0.0012 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.42 ml (0.0030 mol) of triethylamine and 0.29 g (0.0012 mol) of 7-benzyloxy-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.22 g (51%) of 5-(7-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a colourless solid; m.p. 151°-153°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([CH:14]=[O:15])[C:13]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH2:8][CH2:7]1.[C:16](OCC)(=[O:18])C.O>CN(C)C=O>[N:6]1([CH:14]=[O:15])[C:13]2[N:9]([N:10]=[CH:11][C:12]=2[CH:16]=[O:18])[CH2:8][CH2:7]1
Reactant: O=CN1CCn2nccc21
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c1N(C=O)CC2

Procedure:
To phosphoric trichloride (136 ml) was added N,N-dimethylformamide (339 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the mixture was added a solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carbaldehyde (100 g) in N,N-dimethylformamide (200 ml), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was carefully added to a mixture of ethyl acetate and water under ice-cooling, and the mixture was adjusted to pH 6. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1,7-dicarbaldehyde (102 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)C(C)C)(C)C>CCOC(C)=O>[Cl:11][C:12]1[C:13]([C:14]([NH:1][C:2]2[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:15])=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: COc1nccc(C)c1N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nccc(C)c1NC(=O)c1cccnc1Cl
Reaction time: 10 h
Yield: 86.9 %

Procedure:
To a solution of 0.4 g (2.9 mmol) of 3-amino-2-methoxy-4-methylpyridine and 0.5 g (2.9 mmol) of 2-chloronicotinoyl chloride in EtOAc at 0° C. was added 0.4 g (3.0 mmol) of N,N-diisopropylethylamine. Stirring was continued for 10 h at which point the mixture was washed with 0.1N HCl , dried (MgSO4), concentrated and purified by flash chromatography on silica gel (1:1 EtOAc:hexanes) to yield 0.7 g (88%) of the desired material. m.p.: 145°-146° C. (Recrystallized from ethyl acetate).