Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC([O-])(C)C.[K+]>COCCOC>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[O:10][CH3:11])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1ccc(Br)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 1-bromo-2,4-dimethoxybenzene (433 mg, 1.99 mmol, 1 equiv), [1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg, 1.99 mmol, 1 equiv), t-BuOK (313.7 mg, 2.79 mmol, 1.4 equiv) and allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (Nolan's catalyst, 11.4 mg, 0.02 mmol, 0.01 equiv) in 4 mL of DME was degassed with compressed nitrogen gas for 5 min. The resulting mixture was stirred at 60° C. overnight and cooled down to room temperature. EtOAc (˜30 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) sequentially and then dried over magnesium sulfate. The residue was purified by flash column chromatograph using 30 to 100% EtOAc in hexane to afford the title compound as yellowish liquid (300 mg) after evaporation and dried in vacuo. MS (ES) m/z 337.2 (M+H+).
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.NC1C=CC=C([Cl:24])C=1C(O)=O>>[Cl:24][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: Nc1cccc(Cl)c1C(=O)O
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-chlorobenzoic acid. 1H NMR (DMSO-d6, 400 MHz) δ=7.07 (dd, J=0.8, 8 Hz, 1H), 7.24-7.27 (m, 1H), 7.58-7.63 (m, 1H), 11.81 (brs, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[CH:28](N=NNC1C=CC(C)=CC=1)([CH3:30])[CH3:29]>CC(C)=O>[CH:28]([O:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C@@H:5]1/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:30])[CH3:29]
Reactant: Cc1ccc(NN=NC(C)C)cc1
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)OC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (9.7 mg, 0.026 mmol), 1-isopropyl-3-p-tolyltriazene (5 mg, 0.028 mmol) and acetone (0.5 mL) was stirred at rt for 18 h. The reaction was quenched with saturated aqueous NH4Cl (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (50% CH2Cl2/Hexane→CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 5.1 mg (47%) of the title compound.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH2:5]([NH:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C1(C)C(C)=CC=CC=1>[CH2:5]([N:8]([CH2:9][CH2:10][CH3:11])[C:2]([NH2:1])=[O:3])[CH2:6][CH3:7]
Reactant: NC(N)=O
Reactant: CCCNCCC
Solvent: Cc1ccccc1C
Product: CCCN(CCC)C(N)=O
Temperature: 25 °C

Procedure:
180 g (3 mols) of urea are suspended in 500 ml of dry xylene. This is heated to an internal temperature of from 130° to 135° C. and a mixture of 303 g (3 mols) of dipropylamine and 250 ml of xylene is slowly introduced. When the reaction temperature has been reached, more dipropylamine mixture is added, with stirring. When all of the amine solution has been added, the reaction mixture is concentrated to half its volume. It is then left to cool to room temperature and the crystallized reaction product is separated by suction filtration. 345 g (80% of the theoretical yield) of N,N-dipropyl-urea having a melting point of 69° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C(N(CC)CC)C>ClCCl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCCC#Cc1cccnc1

Procedure:
A dry 250 ml B 3-neck flask was fitted with a gas inlet tube extending nearly to the bottom of the flask and was charged with 9.81 ml of 3-bromopyridine, 11.8 g of 5-hexyn-1-ol, 40 ml of distilled triethylamine and 60 ml of dichloromethane. The mixture was degassed with argon for 15 minutes and 0.70 g of bis(triphenylphosphine)palladium dichloride and 0.13 g of cuprous iodide were added. The flask was evacuated and filled three times with argon and the reaction was heated to reflux for 2 hours. The cooled mixture was diluted with dichloromethane and was washed with water and brine, dried (potassium carbonate) and concentrated to 20 g of a dark red oil which was used directly in the next step. A portion was chromatographed over 70 g of silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine to yield a colorless oil which was evaporatively distilled, bp 145°-150° C./0.1 mm to give an analytical sample of 6-(3-pyridinyl)-5-hexyn-1-ol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH:13](N(C)C)N(C)C)[CH3:12]>C1C=CC=CC=1>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccnc1
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
A mixture of 0.02 mole of 3-acetylpyridine and 0.022 mole of tris(dimethylamino)methane in benzene was refluxed for 5 hours, giving 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=1[O:38][CH3:39]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][CH2:25][OH:24])=[C:30]([O:38][CH3:39])[CH:31]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc(OCCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as brown solid (41%). MS 526 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([N+:18]([O-])=O)[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[CH2:30][CH:29]([NH:35][C@@H:36]([CH2:40][CH2:41][CH3:42])[C:37](O)=[O:38])[CH2:28][CH2:27]2>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([NH:18][C:37](=[O:38])[C@@H:36]([NH:35][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:40][CH2:41][CH3:42])[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)CNC[C@H](c1ccccc1)n1cnc([N+](=O)[O-])c1
Reactant: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn([C@H](CNCC(C)(C)C)c2ccccc2)cn1

Procedure:
(S)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)propan-1-amine was reduced and coupled with (S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 538 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27]>C1COCC1>[CH2:16]([O:15][C:13]([C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])=[O:27])=[CH:7][CH:6]=2)[CH:12]=1)=[O:14])[CH3:17]
Reactant: O=C=Nc1ccccc1F
Reactant: CCOC(=O)c1cc(-c2ccc(N)cc2)no1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Ethyl 3-(4-aminophenyl)isoxazole-5-carboxylate (4 g) was dissolved in THF (80 ml). 2-Fluorophenyl isocyanate (2.83 g) was added and stirred at RT overnight. Reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography in 1:9 EtOAc: CHCl3 to get off white solid which was crystallized from CH2Cl2/Pet ether to yield 5 gm (78%) white solid. MS (ES+): m/z 370 (M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 9.32 (s, 1H), 8.62 (s, 1H), 8.12 (m, 1H), 7.89 (d, 2H), 7.81 (s, 1H), 7.59 (d, 2H), 7.24 (m, 1H), 7.12 (m, 1H), 7.05 (m, 1H), 4.38 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:11]([F:16])[F:15])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cccnc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
As shown in step 3-i of Scheme 3, 2-chloro-3-hydroxypyridine (Compound 1005, 2.0 g, 15.4 mmol, obtained from Aldrich Chemical Co.) was dissolved in 40 mL of DMF and 5.0 mL of water along with sodium chlorodifluoroacetate (4.71 g, 30.9 mmol, obtained from Lancaster Synthesis, Inc.) and anhydrous potassium carbonate (2.56 g; 18.5 mmol). The reaction mixture was heated in an oil bath at 100° C. for 2 hours. Another equivalent of sodium chlorodifluoroacetate and 1.2 equiv. of potassium carbonate were added and heating continued for an additional 2.0 hours. After this time, the reaction was cooled and the volatiles removed under reduced pressure. The residue was partitioned between brine and ethyl acetate and the organics washed once more with brine, dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography, eluting with a hexanes/DCM to DCM gradient, to produce 2-chloro-3-(difluoromethoxy)pyridine as a white solid (Compound 1006, 2.0 g, 72% yield): ESMS (M+H) 180; 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.45 (m, 1H), 6.90 (m, 1H), 6.60 (t, 1H; J=75 Hz), 4.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]([CH2:28][CH2:29]Cl)[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH2:28][CH2:29][N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:6][CH:7]=3)[CH2:18][CH2:19]2)=[CH:22][CH:23]=1
Reactant: ClCCN(CCCl)c1ccc(Cl)cc1
Reactant: CCCCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)CCc1ccc(N2CCN(c3ccc(Cl)cc3)CC2)cc1

Procedure:
A mixture of 12.3 g. (55 mmole) n-butyl 3-(4-aminophenyl)-propionate, 16.0 g. (55 mmole) N,N-bis-(2-chloroethyl)-4-chloroaniline and 50 ml. n-butanol is maintained at reflux temperature for 48 hours, then 3.8 g. (27 mmole) pulverised anhydrous potassium carbonate are added thereto and stirring continued for 1 week at reflux temperature. Thereafter, it is suction filtered hot, the filtrate is evaporated in a vacuum and the residue is stirred with ligroin and suction filtered. The product is now taken up in diethyl ether, filtered and mixed with hydrogen chloride-containing diethyl ether. Since the hydrochloride is difficult to suction filter, the ether phase is evaporated in a vacuum and the residue recrystallised from n-butanol. Yield 9.5 g. (39% of theory) of hydrochloride; m.p. 179°-183° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:8]([CH3:20])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:23][N:24]1[C:28]([NH2:29])=[N:27][N:26]=[C:25]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CCO>[CH3:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:8]([CH3:20])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:29][C:28]2=[N:27][N:26]=[C:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:24]2[N:23]=1
Reactant: Cc1cc(OCCN2CCOCC2)c(C)c2c1NC(=O)C2=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Solvent: CCO
Product: Cc1cc(OCCN2CCOCC2)c(C)c2c1[nH]c1nc3nnc(Cc4ccc(O)cc4)n3nc12
Temperature: 120 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
A mixture of 4,7-dimethyl-5-(2-morpholin-4-yl-ethoxy)-1H-indole-2,3-dione (121.6 mg, 0.4 mmol) and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (82 mg, 0.4 mmol) in EtOH (15 mL) was heated with stirring in a pressure tube at 120° C. for 72 h. The solvent was removed and the residue was purified with a flash silica gel chromatography (CH2Cl2:MeOH:NH4OH=100:7:0.7) to give the title compound as a pink solid (50 mg, 27%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[N:27]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=4[F:20])[CH2:7][C@@H:6]3[CH3:21])=[O:4])[C:28](=[O:30])[O:29][C:25]=2[CH:24]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)[C@@H](C)C2)c(F)cc1Cl

Procedure:
Compound 7 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (6), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.87 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A, 0.1% formic acid/5% acetonitrile/94.9% water, B, 0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 468.3, found, 468.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(CN2CCN(c3ccc(Cl)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 41.2 %

Procedure:
A solution of 0.97 g (0.00493 mol) of 1-(4-chloro-phenyl)-piperazine in 35 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.0016 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 60 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent, digested in dichloromethane/water 1:1 and subsequently filtered off under suction. 0.21 g (40%) of 5-[4-(4-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 296°-298°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1ncccn1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)CC1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using benzyl 4-(aminomethyl)-1-piperidinecarboxylate (6.50 g, 26.19 mmol) and 2-chloropyrimidine (990 mg, 8.64 mmol) as starting materials without a solvent to give the title compound as a yellow oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH2:35][CH:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH2:35][CH:36]([NH:43][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CCNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and compound (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (322 mg, 1.29 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (3-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 51 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([CH2:19][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(c2nc3ccc(C=O)cc3s2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(CN4CCOCC4)cc3s2)CC1
Temperature: 63 °C
Yield: 20.8 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxaldehyde (0.5 g, 1.73 mmol) and AcOH (11 mg, 0.173 mmol) in THF (5 mL), morpholine (0.31 mL, 3.46 mmol) and NaCNBH3 (132 mg, 2.08 mmol) were added in turn. The reaction mixture was heated at 63° C. for 12 hours. The solvent was removed and the residue was extracted with ethyl acetate, washed with water and brine and dried (MgSO4). The volatiles were evaporated and the residue was purified by preparative HPLC to yield 130 mg (21%) of 2-(4-isopropylpiperazin-1-yl)-6-(morpholin-4-ylmethyl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2nccnc2Cl)cc1
Reaction time: 17.5 h
Yield: 43.6 %

Procedure:
Couple 2,3-dichloropyrazine (0.302 g, 2.03 mmol) and 4-chlorophenylboronic acid (0.320 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.107 mmol), and potassium fluoride (0.355 g, 6.11 mmol) in toluene (19 mL) and water (5 mL), at 100° C. for 17.5 hr. Cool the reaction, partition the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 35:65 ethyl acetate:hexanes), to give 2-chloro-3-(4-chlorophenyl)-pyrazine (0.199 g, 44%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([N:2]([CH3:1])[C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:23])=[CH:24][CH:25]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)COc1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[NH2:35][CH2:36][CH:37]([OH:39])[CH3:38]>>[OH:39][CH:37]([CH3:38])[CH2:36][NH:35][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: CC(O)CN
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCC(C)O)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19 60 mg, 0.105 mmol) and 1-amino-propan-2-ol using a similar method to that employed in Example 48 (16 mg).