Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[S:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[CH3:19]I>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[S:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([F:11])[C:6]=1[Si:12]([CH3:13])([CH3:15])[CH3:14])[CH3:18]
Reactant: CCN(CC)C(=S)c1cccc(F)c1[Si](C)(C)C
Reactant: CI
Product: CCN(CC)C(=S)c1ccc(C)c(F)c1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 74 and 3.0 eq MeI according to General Method A and recrystallized from cold hexanes/ethyl acetate to give 2.5 g of the title compound, an 82% yield. m.p. 96°-97° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:19]=[CH:20][N:21]=[C:3]12.[CH3:22][NH2:23]>C(O)C.CO.CC(C)=O>[CH3:22][NH:23][C:16](=[O:18])[CH2:15][C:12]1[C:13]2[CH2:14][C:5]3[N:4]4[CH:19]=[CH:20][N:21]=[C:3]4[C:2](=[O:1])[NH:7][C:6]=3[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: O=C(O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Solvent: CO
Solvent: CC(C)=O
Solvent: CCO
Product: CNC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 0.25 h

Procedure:
A solution of 0.93 g of the ethyl ester of (4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetic acid, 20 ml of methylamine as a 33% solution in ethanol and 20 ml of methanol under an argon atmosphere is stirred at a temperature in the region of 20° C. for 18 hours. The reaction mixture is filtered. The precipitate obtained is washed successively with three times 40 ml of ethanol and three times 40 ml of methyl-tert-butyl ether and dried under reduced pressure (15 mm Hg; 2 kPa) at 20° C. The solid obtained is suspended in a mixture of acetone (25 ml) and methanol (5 ml) and stirred for 15 minutes and then filtered, washed with 10 ml of acetone and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 0.32 g of N-methyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl) acetamide is obtained in the form of a white solid, the melting point of which is greater than 260° C. (Analysis C16H14N4O2; % Calculated C: 65.30, H: 4.79, N: 19.04; % Found C: 65.00, H: 4.50, N: 18.80).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[C:35]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:28]=[CH:27][C:26]=3[N:25]=[C:24]2[CH2:36][CH2:37][CH3:38])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:12]1([C:18](=[O:39])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[C:35]3[C:34]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:28]=[C:27]([NH2:41])[C:26]=3[N:25]=[C:24]2[CH2:36][CH2:37][CH3:38])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
mCPBA (6.56 g, 28.5 mmol) was added to a solution of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinoline (6.2 g, 16 mmol) in chloroform (100 mL); the reaction was stirred for three hours at ambient temperature. Ammonium hydroxide (50 mL) was added. p-Toluenesulfonyl chloride (6.056 g, 31.76 mmol) was added over a period of five minutes, and the reaction was stirred for one hour. The work-up procedure and chromatographic purification was carried out as described in Part D of Example 8. The resulting oil was triturated with acetone, isolated by filtration, and dried to provide 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan powder, mp 178-179° C.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH3:18]>C(O)C>[CH2:15]([O:19][C:20]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:25][CH:26]=1)=[O:28])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCCCOC(=O)c1ccc(Nc2ncc(C(=O)OCC)c(=O)[nH]2)cc1
Reaction time: 48 h
Yield: 41.7 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and butyl -4-aminobenzoate (10.8 g) are added to ethanol (100 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(4-butoxycarbonylanilino)-6-oxo-5-pyrimidinecarboxylate (7.0 g). M.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][NH:31][CH3:30])=[CH:17][CH:18]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: CN
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Product: CNCc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1

Procedure:
4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155° C.; 1H NMR (300 MHz, d6-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, J=9.0, 2.4 Hz, 1H), 7.44 (m, 3H), 7.57 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.67 (br s, 1H). HRMS (MALDI MH+) Calcd for C19H18N3OF: 324,1512. Found: 325.1524. Anal. (C19H18N3OF.0.3 H2O) C, H, N.
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH:37][C:11]3[N:12]=[CH:13][C:8]4[CH:7]=[CH:6][C:5](=[O:17])[N:4]([CH:1]5[CH2:3][CH2:2]5)[C:9]=4[N:10]=3)=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CS(=O)c1ncc2ccc(=O)n(C3CC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CC5)c4n3)nc2)CC1
Temperature: 100 °C
Yield: 13.3 %

Procedure:
A mixture of 8-cyclopropyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (388 mg, 1.56 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (462 mg, 2.0 mmol) in toluene (5 mL) was heated at 100° C. for 18 hours. It was cooled to room temperature and the solid was collected by filtration and washed with toluene and dried to give 4-[6-(8-cyclopropyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (96 mg, 13%). 1H NMR δ (400 MHz, DMSO) 9.97 (s, 1H), 8.67 (s, 1H), 8.39 (d, J=9.3 Hz, 1H), 8.0 (d, J=2.95 Hz, 1H), 7.71 (d, J=9.3 Hz, 1H), 6.28 (d, J=9.3 Hz, 1H), 3.42 (br, 4H), 3.05 (br, 4H0, 2.80 (m, 1H), 1.37 (s, 9H), 1.20 (d, J=6.1 Hz, 2H), 0.76 (br, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(OCC)C.C(OCCCC)CCC.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [Li]c1ccccc1
Reactant: COc1cnccn1
Solvent: CCCCOCCCC
Solvent: CCOCC
Solvent: O
Product: COc1nccnc1-c1ccccc1
Yield: 12 %

Procedure:
First, in a three-neck flask, 11.30 g of 2-methoxypyrazine and 200 mL of diethylether were put, and a dibutyl ether solution (2.1 mol/L) of phenyl lithium was dropped thereto while the mixture was cooled down with ices and stirred under a nitrogen atmosphere, and stirred to be reacted for 20 hours. After the reaction, water was added to the reaction solution, and an organic layer was extracted with ethyl acetate. The obtained organic layer was washed with water, and dried with magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was distilled off. The obtained residue was refined with a column chromatography using dichloromethane as a development solvent, so that 2-phenyl-3-methoxypyrazine was obtained (light yellow powder, yield: 12%). A synthesis scheme of Step 1 is shown by the following (a2-1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Brc1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2cccnc2)cnc1F

Procedure:
By carrying out the operation analogously to example 49, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII and 3-bromopyridine, the desired product is obtained in the form of a gray solid (yield=26%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:41][CH2:42][N:43]([CH2:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[CH2:44][CH2:45]1
Reactant: O=C(O)C1CCC(c2c[nH]c3ccccc23)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(N2CCN(C[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1H-3-indolyl)-cyclohexanecarboxylic acid (1.60 g, 6.57 mmol) and methylene chloride (30 mL) is treated with triethylamine (1.53 mL, 10.97 mmol) and the resulting solution is cooled to 0° C. Isobutyl chloroformate (0.93 mL, 7.15 mmol) is added and the reaction is stirred at 0° C. for 10 minutes. A solution of 1-(2-pyridinyl)piperazine (1.18 g, 7.23 mmol) in methylene chloride is added and the reaction is then stirred at ambient temperature for 18 hours. A saturated solution of sodium bicarbonate (20 mL) is added and the organic phase is separated. The aqueous phase is extracted with two 40 mL portions of methylene chloride and the combined organic extracts are dried with sodium sulfate, and evaporated. The residue is chromatographed on silica gel (2% methanol in chloroform) and 2 main fractions are isolated. The first fraction consisted of trans 1-({4-[1H-3-indolyl]cyclohexyl}carboxyl)-4-(2-pyridinyl)piperazine and the second fraction consisted of the corresponding cis isomer. The resulting trans amide is reduced by the method described in Example 1 to give trans 3-[4-[4-(2-pyridinyl)-1-piperazinylmethyl]cyclohexyl]-1H-indole (Example 15); m/e 374.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C>>[CH3:1][C:2]1([CH3:21])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: CCc1cc(C#N)cc(C)c1O
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a beige oil (0.86 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.67 min, [M+H]+=308.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][NH:17][CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:17]1[CH2:16][CH2:15][C:14]2[NH:13][CH:12]=[C:11]3[C:20](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]3[C:19]=2[CH2:18]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CNCC3
Product: CC(=O)N1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
2-p-Chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one is treated with an excess of acetic anhydride with heating to obtain 8-acetyl-2-p-chlorophenyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c][1,6]naphthyridin-3(5H)-one, mp above 350°; IR: 1640, 1670 cm-1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[F:1][C:2]1[C:3]([C:33]([F:34])([F:35])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a mixture of tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (35, 41.2 g, 80.0 mmol) and CH2Cl2 (150 mL) was added TFA (70 mL). The mixture was stirred at ambient temperature for 16 h and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-20% CH3OH in CH2Cl2) to give (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone (36) as a white solid (0.052 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m, 1H), 7.14 (m, 1H), 4.92 (m, 2H), 4.04 (s, 2H), 3.27-2.69 (m, 7H), 1.89-1.65 (m, 4H); MS (ESI+) m/z 415 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F
Yield: 69 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 69% yield. MS: M=417.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Sn](C)(C)C)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:21])[CH3:20]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: CC(=O)c1ccccc1Br
Product: CC(=O)c1ccccc1-c1ccc(C)cc1

Procedure:
Prepared from 4-methylphenyltrimethylstannane (Example 69, Step A) and 2'-bromoacetophenone by the procedure described in Example 69, Step B. 1H NMR (200 MHz,CDCl3): 1.98 (s,3H), 2.37 (s,3H), 7.20 (s,4H), 7.3-7.5 (m,4H). FAB-MS: calculated for C15H14O 210; found 211 (M+H,100%).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=O)#[N:2].Cl.[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28](C(OC4CCNCC4)=O)[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[C:18]([N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)[N:17]=1>>[NH2:15][C:16]1[N:21]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:5](=[O:7])[CH2:4][CH:3]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:1]#[N:2])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[C:18]([N:41]2[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]2)[N:17]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Reactant: N#CC(CC(=O)O)c1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC(C#N)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 4 starting from 3-cyano-3-phenylpropanoic acid and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=482.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6]2.[I:15]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(C(F)(F)F)=O>[I:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]#[N:14])=[CH:9]2
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc2cc(C#N)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(C#N)ccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-methoxynaphthalene-2-carbonitrile (1.0 g, 5.5 mmol), N-iodosuccinimide (1.4 g, 6.0 mmol) in ACN (10 ml) and TFA (125 μl) is stirred at RT for 4 h. A saturated aqueous solution of sodium hydrogencarbonate is added and the mixture extracted with DCM. The combined organic layers are extracted with an aqueous solution of sodium thiosulfate, dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 1.68 g (99%). HPLC-MS: tR=1.32 min (METHOD—1).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].Cl[C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][S:14][C:10]=2[N:11]=[CH:12][N:13]=1>O1CCCC1.[Cu]I>[CH2:1]([C:8]1[C:9]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][S:14][C:10]=2[N:11]=[CH:12][N:13]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Reactant: C=CCC[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCCc1ncnc2scc(-c3ccc(F)cc3)c12
Temperature: 25 °C
Yield: 67 %

Procedure:
3-Butenylmagnesium bromide (0.0040 mol) was added to a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (0.529 g, 0.00200 mol), copper (I) iodide (0.038 g, 0.00020 mol) and ferrous bromide (0.043 g, 0.00020 mol) in tetrahydrofuran (10 mL) and the resulting mixture was maintained at room temperature for 5 h, then quenched by the addition of water (10 mL). Ethyl acetate (50 mL) was added and the mixture was filtered. The filtrate was washed with a saturated solution of sodium bicarbonate (40 mL) and the organics were concentrated and purified by silica gel column chromatography (using 15% ethyl acetate/hexane as eluent) to afford 4-But-3-en-1-yl-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine as a white solid in 67% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3]/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)[CH:10]=1)=[O:7].O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:44][N:2]([CH3:1])[CH2:3]/[CH:4]=[CH:5]/[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)[CH:10]=1)=[O:7]
Reactant: COc1cc(F)c(C)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(C)cc1-c1c[nH]c2ncc(-c3cccc(NC(=O)/C=C/CN(C)C)c3)cc12
Temperature: 60 °C

Procedure:
A solution of (E)-4-(dimethylamino)-N-(3-(3-(4-fluoro-2-methoxy-5-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide 137 (60 mg, 0.098 mmol) was taken in methanol (7 mL) and water (3 mL) was added potassium carbonate (54.10 mg, 0.392 mmol). The reaction was heated to 60° C. for overnight. The methanol was completely distilled and diluted with water. The organic phase was extracted with ethyl acetate (50 mL) twice. The organic layer was dried over sodium sulphate and filtered and concentrated to get the crude. The crude was purified through flash chromatography by using neutral alumina. The compound was eluted in 2% methanol in chloroform as half white solid (E)-4-(dimethylamino)-N-(3-(3-(4-fluoro-2-methoxy-5-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)but-2-enamide 138. MS-ES+458.3, 1H NMR (400 MHz, DMSO): 11.89 (s, 1H), 10.14 (s, 1H), 8.48 (d, 1H), 8.05 (d, 2H), 7.63 (m, 2H), 7.40 (m, 3H), 6.98 (d, 1H), 6.73 (m, 1H), 6.26 (d, 1H), 3.80 (s, 3H), 3.06 (s, 3H), 2.23 (d, 3H), 2.18 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(N)CO
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NC(C)(C)CO)cnc21

Procedure:
Intermediate 49 was prepared from Intermediate 17 and 2-amino-2-methyl-1-propanol (commercially available from Aldrich) using an analogous method to that for Intermediate 42. LCMS showed MH+=362; TRET=2.28 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=NO)[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[O:41])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2cc(-c3oc(C4CCN(C(=O)CN5CCOCC5)CC4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A solution of the product of Step 1 (0.15 g, 0.35 mmol) in dry dichloromethane (3 ml) was treated with morpholine (0.060 ml, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.05 g, 29%); MS(ES+) m/e 486 [M+H]+.