Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[NH:33][C:29]3[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(F)cc5)nc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.15 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compound (28 mg) which was characterized by its mass spectrum: MS m/z (%): 492 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCCCC2)cn1
Temperature: 80 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (578 mg, 3.57 mmole) in 7 mL of dry acetonitrile is added 0.71 mL (7.14 mmol) of piperdine followed by 493 mg (3.57 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 581 mg (77% yield) of 2-Chloro-5-piperidin-1-ylmethyl-pyridine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.65 (m, 6H), 2.20–2.39 (s, 4H), 3.47 (s, 2H), 7.28 (d, 1H, J=7.9 Hz), 8.60–8.69 (m, 1H), 8.28 (d, 1H, J=2.1 Hz); MS 211.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][NH2:14])[CH:8]=2)[N:3]=1.[CH:15](OC)=[O:16]>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][NH:14][CH:15]=[O:16])[CH:8]=2)[N:3]=1
Reactant: CC1=Nc2ccc(CN)cc2C1(C)C
Reactant: COC=O
Product: CC1=Nc2ccc(CNC=O)cc2C1(C)C
Yield: 95 %

Procedure:
Aminomethylindole 36 (1.29 g, 6.86 mmol) was dissolved in methyl formate (40 mL) and the mixture was heated at reflux for 2 days. The volatile components were evaporated in vacuo to afford the protected amine 37 as a pale yellow oil (1.40 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=1[O:35][CH3:36]>ClCCl.CO>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:30][C:29]=1[O:35][CH3:36]
Reactant: COc1cc(N)ccc1OCCN1C(C)CCCC1C
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.663 mmol) of 4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]-3-methoxyphenylamine. Yield: 150 mg (49% of theory); melting point: 225° C.-227° C.; C26H28ClF3N2O3 (M=508.96); calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [O:1]([C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH2:22][CH3:23])[CH3:21]>C1(C)C=CC=CC=1.CO>[CH2:22]([N:20]([CH3:21])[CH:19]=[N:12][C:11]1[CH:13]=[C:14]([CH3:15])[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH3:16])[CH3:23]
Reactant: Cc1cc(Oc2ccccc2)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2ccccc2)cc1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
0.18 g (0.8 mmol) of 4-phenoxy-2,5-dimethylaniline was dissolved in 2.5 ml of toluene and this solution was then admixed with 0.18 ml of a solution of N-ethyl-N-methylformamide dimethyl acetal in methanol (60%). After 12 h of stirring of the reaction mixture at 50° C., subsequent filtration and removal of the solvent under reduced pressure, 240 mg (94.8% purity, 96.6% yield) of the product were obtained; log P(HCOOH)=1.87.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>CCCCCCC>[CH3:18][C:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][C:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:35]([C:34]3[CH:36]=[CH:37][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)=[O:19]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)CCC(C)(C)C)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)(C)CCC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Yield: 40.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(4,4-dimethyl-pentanoyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.115 g), dimethylaluminium chloride in heptane (0.9 molar, 0.78 ml) and 4-trifluoromethoxyanilin (0.068 g) to give the desired 8-(4,4-dimethyl-pentanoyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.06 g) as an off-white solid. MS (ESI): 427.2 (MH+).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17](=[O:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:20][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([OH:19])([CH3:20])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: C[Al](C)C
Reactant: CC(=O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)ethanone (171 mg, 0.67 mmol) in CH2Cl2 (5.6 mL) was treated dropwise at 0° C. with trimethylaluminium (0.56 mL of a 2.0 M solution in toluene, 1.12 mmol) and the resulting yellow solution was stirred for 90 min at 0° C. Sat. aq. NH4Cl was added to the reaction mixture which was extracted with CH2Cl2 (3×25 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.88 min, [M+H]+=272.20.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:8]=2)=[CH:12][N:13]=[C:14]1[C:17]([OH:20])([CH3:19])[CH3:18]
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(C(C)(C)O)n5C)sc34)ccc2[nH]1
Yield: 64.1 %

Procedure:
2-[5-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol (190 mg, 0.62 mmol) and 2-methyl-5-aminoindole (108 mg, 0.714 mmol) were dissolved in 3 mL of t-butyl alcohol and 3 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 45 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (66%) of 2-{1-methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.40 (d, 1H), 7.02 (d, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 3.33 (s, 3H), 2.44 (s, 3H), 1.64 (s, 6H). LC-MS: 418, 419 (MH+); HPLC RT: 3.98 min.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C>[N:20]1([CH2:19][CH2:18][O:3][C:4]2[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCCN2CCOCC2)c1
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
A suspension of 97% NaH (1.75 g, 0.07 mol) in DMF (50 mL) was stirred for 15 minutes then ethyl 3-hydoxyphenylacetate (5.4 g, 0.03 mol) in DMF (25 mL) was added. The reaction mixture was stirred for 0.5 hours, then was cooled in an ice bath and N-(2-chloroethyl)morpholine hydrochloride (5.6 g, 0.03 mol) was added. The reaction mixture was at room temperature overnight, then was heated on a steam bath for four hours. The solvent was stripped, the residue was partitioned between cold water and ether, the organic layer was separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried over MgSO4, filtered and stripped to afford crude product which was purified by column chromatography on silica gel eluting with ethyl acetate to afford 4.64 g of ethyl 3-[2-(4-morpholinyl)ethoxy]phenylacetate.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=O)[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:14]2[C:5]3[N:6]([C:2]([CH3:1])=[CH:3][N:4]=3)[C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Cc1cnc2c(=O)[nH]c3ccccc3n12
Product: Cc1cnc2c(NC3CCCCC3)nc3ccccc3n12

Procedure:
By reaction of 1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (example 2) with cyclohexylamine, according to a procedure that is similar to that followed in example 9, there is obtained 4-cyclohexylamino-1-methyl imidazo [1,2-a]quinoxaline. m.p. (DSC)=126.5° C. (onset); IR (KBr): 3345, 2938, 1546 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7 (1H,dd), 7.5÷7.1 (3H,m), 6.0 (1H,d), 4.2 (1H,m), 2.85 (3H,s), 2.3÷1.95 (4H,m), 1.95÷0.9 (6H,m); UV (EtOH): λmax =225, 243, 272, 301, 316, 329 nm. Elementary analysis for C17H20N4 (m.w.280.37): calcd. C 72.83, H 7.19, N 19.98%; found C 72.21, H 7.54, N 20.14%.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([Cl:16])[CH:5]=[CH:4][N:3]=1.CC1C=CN=C(C=C)C=1[CH2:26][O:27]C1CCCCO1.CC1C=CN=C(CO)C=1COC1CCCCO1>[Pd]>[Cl:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:26][OH:27])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: Clc1ccnc(Cl)c1COC1CCCCO1
Reactant: C=Cc1nccc(C)c1COC1CCCCO1
Agent: [Pd]
Agent: Cc1ccnc(CO)c1COC1CCCCO1
Product: OCc1nccc(Cl)c1COC1CCCCO1

Procedure:
Pd catalyzed vinylation of 2,4-dichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (1.71 g. 6.52 mmol) according to the synthesis of 4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine subsequent ozonolysis and reduction according to the synthesis of [4-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol and flash chromatographic purification yielded the title compound. MS (m/z): 257.8 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](Cl)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.4 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added dropwise 4-tert-butylphenoxyacetyl chloride (0.32 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a colorless syrup that was triturated with diethyl ether to afford the title compound (0.280 g, 58%) as a white solid, m.p. 85° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:21]([C:33]([F:35])([F:34])[F:36])[CH:20]=2)=[O:17])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: C#Cc1cnc2cccnn12
Reactant: CN1CCN(Cc2ccc(NC(=O)c3cccc(I)c3)cc2C(F)(F)F)CC1
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc(C#Cc4cnc5cccnn45)c3)cc2C(F)(F)F)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 519 m/z (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>CO>[ClH:38].[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reactant: O=C=NC(=O)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetyl isocyanate (83 mg, 0.62 mmoL) [J. Hill et al. JACS, 62: 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc. A white solid was obtained, which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et2O) to form a clear solution. The solution was concentrated to form a precipitate which was collected by filtration, to afford the title compound 305a (48 mg, 33% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.05(s, 1H), 10.62(s, 1H), 8.57(d, 1H), 8.02(s, 1H), 7.81(d, 1H), 7.48-7.43(m, 2H), 7.33-7.25(m, 5H), 6.74(d, 1H), 3.85(t, 2H), 3.78(s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2(M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:20](=[O:21])[N:19]([CH3:23])[CH3:18])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc(SCc2nc(Cl)ccc2Cl)cc1
Reaction time: 15 h

Procedure:
A solution of 4-(((3,6-dichloro-2-pyridinyl)methyl)thio)benzenamine (10 grams; 0.035 mole) in 25 ml. of dry pyridine was prepared and dimethyl carbamoyl chloride (3.77 grams; 0.035 mole) added thereto while maintaining the temperature of the reaction mixture at 24°-45° C. The resulting reaction mixture was stirred at ambient temperatures for a period of about 15 hours and then mixed with ice and allowed to stand for a period of about two hours. The aqueous layer was decanted and the residue washed with water and recrystallized twice from ether. As a result of the above operations, the desired N'-(4-(((3,6-dichloro-2-pyridinyl)methyl)thio)phenyl)-N,N-dimethyl urea compound was recovered as a crystalline solid having a melting point of 112°-113.5° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: CC(C)(CO)CBr
Agent: Cl
Product: CC(C)(CO)CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1
Yield: 15.2 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (510 mg) and 3-bromo-2,2-dimethyl-1-propanol (474 mg), 3-[1-(3-hydroxy-2,2-dimethylpropyl)piperidin-4-yl]-2H-isoquinolin-1-one (92 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Br.[CH3:11][C:12]1([CH3:21])[CH2:17][CH2:16][C:15](B(O)O)=[CH:14][CH2:13]1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:15]1[CH2:16][CH2:17][C:12]([CH3:21])([CH3:11])[CH2:13][CH:14]=1
Reactant: N#Cc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(C)CC=C(c2cc(C#N)ccc2N)CC1

Procedure:
The title compound was prepared from 4-amino-3-bromo-benzonitrile (as prepared in the previous step, 1.0 g, 5.0 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (938 mg, 6.07 mmol), Pd(PPh3)4 (585 mg, 0.506 mmol) and 2M Na2CO3 (20.2 mL, 40.5 mmol) according to the procedure in Example 44, step (b) (284 mg, 25%). Mass spectrum (ESI, m/z): Calcd. for C15H18N2, 227.1, found 227.3.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.B([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(O)O>>[O:29]=[S:25]1(=[O:28])[CH2:26][CH2:27][N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:2]3[N:7]4[N:8]=[C:9]([NH2:11])[N:10]=[C:6]4[CH:5]=[CH:4][CH:3]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24]1
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Nc1nc2cccc(Br)n2n1
Product: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Yield: 79.2 %

Procedure:
5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (368 mg, 1.73 mmol) and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide (0.512 mg, 1.90 mmol), in a manner analogous to Step 73c. The residue was purified on a 12 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (490 mg, 79%) was isolated as a beige foam. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.93 (d, J=8.5 Hz, 2H), 7.50 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 6.02 (s, 2H), 3.78 (s, 2H), 3.15 (s, 4H), 2.91 (s, 4H). MS=358 (MH)+. 95b) 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 0.140 mmol) and 1-bromo-4-methoxy benzene (29 mg, 0.154 mmol) were combined in a manner analogous to Example 77 to yield 5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine (28 mg, 42%) as a beige solid. The material was purified via trituration with methanol. MP=241° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.37 (s, 1H), 8.03 (d, J=8.1 Hz, 2H), 7.51-7.67 (m, 6H), 7.17 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H), 3.80 (s, 2H), 3.69 (s, 3H), 3.15 (br s, 4H), 2.92 (br s, 4H). MS=464 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[CH:9][C:8]=2[O:16][CH3:17])[N:6]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[CH:19]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:28]([C:20]2[CH:19]=[N:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:29])[S:3][CH:4]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: COc1cc(C)cc(OC)c1-c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC)c1-c1csc(NC(=O)c2cnc3ccccc3c2)n1
Reaction time: 48 h
Yield: 97.5 %

Procedure:
1 g of 2-amino-4-(2,6-dimethoxy-4-methylphenyl)-thiazole, 0.76 g of 3-quinolinecarboxylic acid, 0.65 ml of triethylamine and 2.15 g of BOP are dissolved in 10 ml of DMF, and the reaction mixture is left at r.t. for 48 hours. It is then poured into pH 2 buffer solution, a precipitate is separated by filtration, and the yellow solid is successively washed with water, stirred in 5% sodium carbonate solution, filtered off and thereafter dissolved in DCM. The solution is washed with 5% sodium carbonate solution and then, successively, the organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is stirred in ether, filtered off and dried to yield 1.58 g of the expected compound, m.p.=245°246° C.