Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.10 g, 0.52 mmol), 4-(pyridin-2-ylamino)phenol (0.29 g, 1.55 mmol), and cesium carbonate (0.51 g, 1.55 mmol) were mixed in NMP (1.5 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 360.1 (M+1). IC50 (uM) 0.002.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[N:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperidine-1-carboxylate (0.0518 g, 0.143 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0220 g, 0.151 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0525 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 69-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.10-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.67 (t, 2H), 2.10-3.00 (m, 5H), 3.70-4.10 (m, 5H), 6.55 (d, 3H), 6.62 (d, 1H), 6.83 (t, 1H), 7.00 (d, 2H), 7.52 (d, 2H), 10.45-10.80 (m, 2H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5S (MH+): 518.2437. Found: 518.2446.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:16](=O)(O)[O-:17].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([N:7]=[C:16]=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of L-phenylalanine ethyl ester hydrochloride (25.0 g, 109 mmol) in methylene chloride (800 mL) a saturated solution of sodium bicarbonate (800 mL) was added and the mixture was vigorously stirred at 0° C. for 30 minutes. Stirring was stopped to allow the separation of the two layers and a solution of phosgene in toluene (20%, 100 mL, 190 mmol) was added directly into the organic layer. Stirring was resumed while keeping the mixture at 0° C. for one hour and at room temperature for one additional hour. The organic layer was separated, and washed sequentially with water and a saturated solution of sodium chloride, dried with sodium sulphate, filtered and evaporated to yield a colorless oil that slowly solidifies (22.7 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(O)C>[CH:39]1([NH:45][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCCC1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(NC3CCCCC3)ncc12
Yield: 15.3 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), cyclohexylamine (0.02 mL, 0.17 mmol) and ethanol (2.5 mL) to afford N-cyclohexyl-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (8 mg) as a yellow solid. MS m/z 308 (M+1).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.C([O:15][P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)([O:18]CC)=[O:17])C>CN(C=O)C>[P:16]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])([OH:18])([OH:17])=[O:15]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCOP(=O)(COCCCCBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCCCOCP(=O)(O)O
Reaction time: 2 h

Procedure:
To a slurry of 0.962 g (22.8 mmol) of 57% NaH in 150 ml of distilled DMF was added in one portion 3.363 gm (24.9 mmol) of adenine. The mixture was heated at 80° for 1 hr. and then cooled to 300 and 6.30 g (20.7 mmol) of 4-(diethylphosphonomethoxy)-1-bromobutane was added and the mixture was warmed to 60° and stirred for 2 hrs. The solvent was then removed under high vacuum and the residue was triturated three times with 100 ml of CH2Cl2 and filtered. The combined filtrates were evaporated and purified by SiO2 chromatography to give 4.9 g (66%) of Ia product as a white crystalline material mp 67°.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 150 °C
Yield: 44.4 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (50 mg, 0.27 mmol), Acetic acid 2,6-dibromo-benzyl ester (164 mg, 532 mmol), cuprous iodide (10 mg, 0.053 mmol), and potassium carbonate (37 mg, 0.27 mmol) were deposited in sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 30 to 40% ethylacetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-benzyl ester (48 mg, 0.12 mmol). MS (ESI) 417.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC(C1N=C[N:34]2[C:40]3[CH:41]=[CH:42][C:43](F)=[CH:44]C=3C(=O)N(C)CC=12)=O)C#C.IN1C(=O)CCC1=O.N1CCCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20][N:34]5[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]5)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1Cc2c(-c3ncc(CN4CCCCC4)o3)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 10.7 ml (0.109 mol) of piperidine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the beige-brown product was chromatographed over silica gel with ethyl acetate/methanol 4:1 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.85 g (17%) of 8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 191-193°.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:33]1[CH2:37][CH:36]([CH2:38][O:39][NH2:40])[O:35][N:34]=1)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([C:33]1[CH2:37][CH:36]([CH2:38][O:39][NH:40][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:35][N:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: CCCCC1=NOC(CON)C1
Product: CCCCC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-butyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 91).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH3:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:19]([CH:17]([C:14]2[CH:15]=[N:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[CH3:18])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1ccc(C(C)N)cn1
Solvent: O
Product: Cc1ccc(C(C)n2c(C)cc(O)cc2=O)cn1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A stirred mixture of 4-Hydroxy-6-methyl-2-pyrone (1.394 g, 11.1 mmol) and 1-(6-Methyl-pyridin-3-yl)-ethylamine (1.806 g, 13.3 mmol) in water (18 ml) was boiled under reflux for 65 h. The mixture was cooled to ambient temperature and the supernatant liquid was decanted off to leave a dark semi-solid residue. This was triturated with ethyl acetate to give 4-Hydroxy-6-methyl-1-[1-(6-methyl-pyridin-3-yl)-ethyl]-1H-pyridin-2-one as a grey solid (475 mg) which was used in the next step without further purification. LC-MS m/z 245 [M+H]+ Rt=1.21 min.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCCCCCCCO1

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of toluene, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of toluene over a period of 8 hours at a continuous and uniform rate and the reaction mixture was refluxed for and additonal 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15 -pentadecanolide was obtained in 63%. yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3].[S:27](Cl)([Cl:30])(=[O:29])=[O:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:27]([Cl:30])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.7 g (2 mmol) of 2-(2-propoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][12,4]triazin-4-one (Example 17A). This gives 0.8 g (89.3%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1ccc(C=O)cc1C1CCCC1
Product: COc1ccc(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C1CCCC1

Procedure:
3-Cyclopentyl-4-methoxybenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-chloro-3-(3-cyclopentyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[N:3]=1
Reactant: [H][H]
Reactant: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: [Pd]
Solvent: CO
Product: CC1Cc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (Example 43, Step 1) (0.20 g, 0.38 mmol) in methanol (5 mL) was added palladium on carbon 10% wt. (20 mg) under an atmosphere of nitrogen. The mixture was vacuumed and re-charged with hydrogen three times, and stirred at r.t. for 48 h. The mixture was filtered. The filtrate was concentrated to afford the desired product which was directly used in next step reaction without further purification (200 mg, 99.61%). LCMS (M+H)+: m/z=522.3.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C1COCC1>[C:29]([O:28][C:26]([CH2:25][C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([N:3]1[C@H:2]([CH3:1])[C@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the resultant compound from Example 65 (12.9 g, 41.7 mmol) in dry THF (100 ml) under nitrogen was added at -78° C. a solution of sodium hexamethyldisilylamide 45.9 ml (1M in THF). After 30 min, t-butyl bromoacetate (13.6 ml, 83.4 mmol) was added as a solution in THF. The resulting reaction mixture was stirred for 1 h at -78° C., quenched with sat. NH4Cl solution (50 ml) and the entire reaction mixture partitioned between diethyl ether and water. The organic layer was separated and the aqueous layer extracted once with ether. The combined organic solutions were washed with 10% HCl, sat. NaHC3O, brine, dried (Na2SO4). filtered, and concentrated. The resulting yellow oil was submitted to silica gel chromatography (flash): yield 12.4 g (70%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([Cl:10])=[C:4]([O:11][CH3:12])[CH:3]=1.ClCCCl.[C:17](Cl)(Cl)=[S:18].C(=O)([O-])[O-].[Ca+2]>O>[Cl:10][C:5]1[CH:6]=[C:7]([C:2]([N:1]=[C:17]=[S:18])=[CH:3][C:4]=1[O:11][CH3:12])[C:8]#[N:9]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(N)c(C#N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCCl
Solvent: O
Product: COc1cc(N=C=S)c(C#N)cc1Cl
Temperature: 20 °C

Procedure:
To a solution of 27.4 g. (0.15 mole) of 6-amino-3-chloro-4-methoxybenzonitrile in 150 ml. of 1,2-dichloro-ethane at 0°-5° C. is added with stirring a mixture of 23 g. (0.2 mole) thiophosgene, 100 ml. 1,2-dichloroethane, 20 g. (0.2 mole) calcium carbonate and 200 ml. of water. After the addition the mixture is stirred for one hour at 0°-5° C., warmed to 20° C. and stirred for 6 hours at this temperature and finally at 35° C. for an hour. The reaction mixture is filtered and the organic layer separated, washed with dilute hydrochloric acid, water and dried (MgSO4). The solvent is removed by evaporation and the residue used without purification in the next step.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCO[C:29]2[CH:37]=[C:36]3[C:32]([C:33](C4C=CC=CC=4)=C(Br)C3=O)=[CH:31][CH:30]=2)CC1.B(O)(O)C1C=CC(C)=CC=1>>[CH3:18][O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:19])[C:2]([C:29]1[CH:37]=[CH:36][C:32]([CH3:33])=[CH:31][CH:30]=1)=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Agent: Cc1ccc(B(O)O)cc1
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)cc1)C2=O
Reaction time: 0.17 h
Yield: 70 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, p-tolylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (70%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][NH:39][O:40][CH3:41]>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([N:39]([O:40][CH3:41])[CH3:38])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (3R)-3-[(tert-butoxycarbonyl)amino]butanoic acid (1 g, 5 mmol) in acetonitrile (40 mL) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 1.05 g, 5.5 mmol), 1-hydroxybenzotriazole (HOBt; 810 mg, 6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) and triethylamine (1.4 mL) and stirred at room temperature for 2 d. The solution was evaporated and the residue purified by flash chromatography on a Biotage® system (silica gel, 40-90% ethyl acetate/hexane gradient) to yield the desired product as a colorless viscous oil. MS 269.1 (M+Na).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH:15](OCC)=[O:16]>>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH2:9][NH:10][CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: CCOC=O
Reactant: NCCOc1ccc(C(F)(F)F)cc1
Product: O=CNCCOc1ccc(C(F)(F)F)cc1
Yield: 97 %

Procedure:
A mixture of 2-(4-trifluoromethylphenoxy)ethylamine (1.38 g, 6.72 mmol) prepared in Reference Example 159 and ethyl formate (10 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford N-[2-(4-trifluoromethylphenoxy)ethyl]formamide (1.51 g, yield 97%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=1)=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>CO.[Pd].N1C=CC=CC=1>[CH3:28][S:29]([NH:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:31])=[O:30]
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 86 %

Procedure:
A suspension of 3-methoxy-4-nitro-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.4 g) in methanol (20 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (5 ml) and cooled to 0° C. when methanesulfonyl chloride (0.5 ml) was added, the mixture was kept at 0° C. for a further 2 hours then brought to R.T. for 1 h. The mixture was poured onto ice (50 g) and hydrochloric acid (3M, 50 g), the resultant brown solid filtered and washed with water to give 4-methanesulfonylamino-3-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (1.26 g, 86%) as a brown solid.