Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C1COCC1.C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([NH:1][C:22]([N:19]3[CH:18]=[CH:17][N:21]=[CH:20]3)=[O:23])=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(-c2sc(N)nc2C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1
Temperature: 50 °C

Procedure:
A solution of 1-[4-(2-amino-4-methyl-thiazol-5-yl)-phenyl]-ethanone (0.57 g, 2.45 mmol) is dissolved in a mixture of THF (10 ml) and DCM (20 ml) and heated in an oil bath set to 50° C. CDI is added (0.64 g, 3.92 mmol) and the reaction mixture heated at 50° C. for a further 2 hours in which a pale yellow precipitate forms. After cooling to room temperature the precipitate is filtered, washed with DCM and dried under high vacuum to yield the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(C)(=O)=O)C3)cnc21

Procedure:
1-[(1-Methane sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[C:5]([C:18]2[S:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[N:23]=2)[N:4]=1
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CSc1cc(CCC(=O)O)cc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
tert-Butyl 3-[2-(methylthio)-6-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propanoate (0.12 g, 0.29 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 0.5 hr. Diisopropyl ether was combined with the reaction mixture to give precipitates, which were recrystallized from ethanol to give the titled compound (0.09 g, 87%) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:19])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COC(CC)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1 g., 50% w/w suspension in mineral oil) was added gradually to a stirred solution of 1-[4-(4-chlorophenyl)phenyl]propanol (4.9 g.) in dry dimethylformamide (20 ml.), keeping the temperature below 40° C. After 2 hours stirring ethyl bromoacetate (2.3 ml.) was then added, keeping the temperature below 30° C. After stirring for 16 hours at room temperature, the mixture was poured into water (150 ml.), and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-{1-[4-(4-chlorophenyl)-phenyl]propoxy}acetate as an oil (5 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[O:63][C:64]([F:67])([F:66])[F:65])[CH2:58][NH2:59]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:59][CH2:58][C:57]2[CH:60]=[CH:61][C:62]([O:63][C:64]([F:65])([F:66])[F:67])=[C:55]([F:54])[CH:56]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 78.4 %

Procedure:
To a solution of the compound (1.35 g) obtained in Example 783, Step 2 in chloroform (15 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (625 mg), 1-hydroxybenzotriazole hydrate (499 mg) and 3-fluoro-4-trifluoromethoxybenzylamine (620 mg) with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and chloroform, and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:l) to give the title compound (1.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH:15]([CH3:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:18]#[C:17][CH2:16][CH:15]([O:14][CH3:13])[CH3:19])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCC(C)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COC(C)CC#Cc1cc(Cl)c(N)c2c1OCO2
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
5-chloro-7-iodo-1,3-benzodioxol-4-amine (600 mg, 2.02 mmol) and 4-methoxypent-1-yne (500 mg, 5.10 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine)palladium(II) dichloride (141 mg, 10 mol %) followed by copper(I) iodide (38 mg, 10 mol %) and diisopropylamine (407 mg, 5.69 mmol). The reaction was allowed to warn to room temperature and stirred 90 min then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxol-4-amine (495 mg, 92%) as a dark brown oil;
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)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>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:14][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:30])=[O:20]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)C(=O)Nc1cnc(N2CCOCC2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 3.50 g (9.0 mmol) N-(4-iodo-6-morpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, (0.27 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.34 g (9.9 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.23 g (quantitative) of the title compound as a white foam.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH3:7][C:4]1[C:3]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([S:17]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:2]([NH2:1])[NH:6][N:5]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2s1
Yield: 19.6 %

Procedure:
the title compound (30 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (128 mg, 0.39 mmol), 4-methylpiperazine (39 mg, 0.43 mmol) and triethylamine (0.1 mL). MS (m/z, ES+): 393.1 (M+1, 100%). Yield=20%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@@H:23]1[CH2:28][O:27][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@@H:23]1[CH2:24][O:25][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane to obtain the desired compound having a melting point of 73 to 75° C. in a yield of 70%.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:18][CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Nc1ncc(Br)nc1Br
Solvent: C1COCCO1
Product: CC(Nc1nc(Br)cnc1N)c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5-dibromopyrazin-2-ylamine (1.0 g; 3.95 mmol) in anhydrous dioxane (10 mL) was added (S)-(−)-1-phenylethylamine (0.51 mL; 3.95 mmol) at room temperature. The solution was heated to 100° C. and stirred for 20 h. After concentration under reduced pressure, the resultant residue was purified by flash chromatography [silica gel, hexanes/ethyl acetate (2:1)] to afford 5-bromo-N3-(1-phenylethyl)pyrazine-2,3-diamine as a brown solid (0.69 g; 60%). 1H NMR (300 MHz, DMSO): δ 7.37-7.29 (m, 5H), 7.14 (s, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.29 (s, 2H), 5.10-5.05 (m, 1H), 1.47 (d, J=6.9 Hz, 3H).
Reaction SMILES: COCCOC.Br[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: CCOC(=O)c1cccc(Br)n1
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+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1cccc(-c2ccccc2CNC(=O)OC(C)(C)C)n1
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
83 ml of 1,2-dimethoxyethane were aerated with argon, and 481 mg (0.41 mmol) of Pd(PPh3)4 and 1.9 g (8.3 mmol) of ethyl 6-bromopicolinate were added. After 10 min, 3.16 g (12.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 8.3 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux under argon for 18 h, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 2.12 g (72%) of a viscous orange oil were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=2[C:27]([N:29]([CH3:33])[CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=2[C:27]([N:29]([CH3:33])[CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: C#CCN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN(C)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (40 mg, 22%). LCMS (m/e) 519 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.94 (bs, 1H), 8.38 (d, 1H, J=8.3 Hz), 8.08 (s, 1H), 7.60-7.37 (m, 2H), 7.33 (s, 1H), 7.24 (d, 1H, J=8.1 Hz), 7.21-7.12 (m, 1H), 7.02 (d, 1H, J=8.1 Hz), 6.90 (s, 1H), 4.50-4.00 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 3.17 (bs, 3H), 2.95-2.84 (m, 4H), 2.79-2.68 (m, 6H), 2.40-2.28 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:31][NH:32][C:33]([CH:35]1[CH2:37][CH2:36]1)=[O:34].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:41][C:40]1[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33]([CH:35]2[CH2:36][CH2:37]2)=[O:34])=[CH:29][C:28]=1[NH:27][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([N:11]2[C:12](=[O:14])[NH:13][C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:10]2)=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 13.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-36, 0.085 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) and dry toluene (5.0 mL) to afford 0.020 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.1 Hz, 4H), 1.61 (m, 1H), 4.11 (s, 3H), 4.28 (d, J=5.4 Hz, 2H), 7.04 (d, J=6.9 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.71-7.79 (m, 4H), 7.88 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.44 (s, 1H), 8.67 (m, 1H), 10.53 (s, 1H), 12.82 (br s, 1H); MS (m/z): 587.96 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,4-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.80 (dt, J=10.5, 8.3 Hz, 1 H), 8.08-8.19 (m, 1 H), 8.29 (dd, J=5.4, 2.4 Hz, 1 H), 8.31-8.38 (m, 1 H), 9.55 (dd, J=5.4, 1.4 Hz, 1 H), 9.82 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z 261 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:7]2[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:3][C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: C1COCCN1
Solvent: CC#N
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(N2CCOCC2)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.7 %

Procedure:
A mixture of 0.46 g of 4-chloro-2-diisopropylaminomethyleneamino-5-(4-chlorophenylethynyl)-pyrimidine, 40 mL of acetonitrile and 0.41 g of morpholine was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was washed once more with water, dried over sodium sulfate and filtered. The filtrate was loaded on a column of silica gel equilibrated in the same solvent. After elution of an unknown impurity, the product eluted as a yellow band. Additional material was obtained by a final elution with 1:1 dichloromethane and ethyl acetate. Like fractions of the two eluants were pooled and evaporated to give 0.63 g of a yellow oil, 5-(4-Chlorophenylethynyl)-2-diisopropylaminomethyleneamino-4-morpholinopyrimidine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].CN(C)C=O>O>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=4[O:39][CH3:40])[CH2:16][CH2:17]3)=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 75 °C
Yield: 35.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (5.0 g, 19 mmol), K2CO3 (5.8 g) and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) and dimethylformamide (80 ml) was heated at 75° C for 6 hours. The reaction was poured into water, and an off-white solid formed from solution. The solid was collected and dried to yield 4.5 g of crude product. The compound was recrystallized from ethanol (3 times) to afford 3.0 g of an off-white solid. The solid was chromatographed on a Waters Prep 500 utilizing silica gel columns and eluting with methylene chloride/methanol (7%). Concentration of the appropriate fractions afford 2.3 g of an off-white solid, which when recrystallized from ethanol yielded 1.9 g (26%) of analytically pure 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-]-piperazinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.: 156°-158° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:10].Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(=O)([O-])O.[Na+]>>[CH2:12]([O:14][C:15]([C:16]1[NH:17][C:2]2[C:3]([Cl:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:18])[CH3:13]
Reactant: CCOC(=O)CN
Reactant: N#Cc1cncc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c2c(Cl)cncc2c1N

Procedure:
A mixture of 4,5-dichloronicotinonitrile (3.0 g, 17.3 mmol), glycine ethyl ester hydrochloride (7.2 g, 52.0 mmol) and sodium hydrogen carbonate (9.06 g, 104 mmol) in IMS (50 ml) was heated at reflux for 16 hours. The cooled reaction mixture was then partitioned between ethyl acetate and water, the organic layer washed with water then brine, dried (MgSO4) filtered and concentrated in vacuo. The resultant residue was triturated in diethyl ether to give the title compound as a buff solid (3.58 g, 86%). 1H NMR (CDCl3) 8.80 (1H, s), 8.36 (1H, s), 4.97 (2H, s, br), 4.44 (2H, q, J=7.0 Hz), 1.44 (3H, t, J=7.0 Hz).
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][C:7]1[N:11]2[CH:12]=[C:13]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[CH3:35])C>>[C:19]([SiH2:18][O:17][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([CH2:6][C:5]([NH2:1])=[O:4])=[C:8]([CH3:35])[N:9]=2)[CH:12]=1)([CH3:21])([CH3:22])[CH3:20]
Reactant: CCOC(=O)Cc1c(C)nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Reactant: N
Product: Cc1nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1CC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
At −78° C., ammonia (25 ml) is added to [6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester (950 mg, 1.85 mmol) in a glass autoclave. The reaction mixture is stirred at room temperature for 48 hours. After removal of volatiles, the residue is recrystallized from diethylether to afford the title compound (800 mg, 90%). MS (ES+): 458 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[NH:7]2.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>CN(C=O)C.O.[Cu]=O>[C:21]1([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH:5]=[C:6]2[C:16]([O:18][CH3:19])=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2[nH]1
Agent: O=[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1-c1ccccc1
Reaction time: 6 h

Procedure:
Methyl 4,5,6-trimethoxyindole-2-carboxylate (533 mg), bromobenzene (0.22 mL), copper oxide (64 mg) and potassium hydroxide (336 mg) were suspended in dry DMF (10 mL), and the suspension was refluxed and stirred for 6 hours under an argon atmosphere. After cooling, the reaction mixture was dissolved in water (100 mL) and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and chloroform (20 mL), and water-soluble carbodiimide hydrochloride (192 mg) and N,N-dimethylaminopyridine (small amount) were added to the solution. The mixture was stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (ethyl acetate:hexane=1:3) to obtain the title compound.