Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5].O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[C:22]([CH3:29])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=[CH:8][CH:9]=2)=[O:25])[CH3:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCCCOc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCCCOc3ccccc3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3-phenoxypropoxy)benzonitrile (Example 33b) and ethyl 3-oxobutanoate as a yellow solid (47%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=8.0 Hz, 3H), 2.34 (m, 2H), 2.57 (s, 3H), 4.19 (t, J=4.0 Hz, 2H), 4.33 (q, J=8.0 Hz, 2H), 4.37 (t, J=4.0 Hz, 2H), 6.91-6.97 (m, 4H), 7.24-7.29 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 8.17 (s, 2H). MS 381 (MH+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[F:44])=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(F)cc1F
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(F)cc2F)CC1
Yield: 40.1 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 6-bromo-1-(2,4-difluorophenyl)-1-hexanone (0.9 g) were reacted and treated in the same manner as in Example 172 to give 0.55 g of 4-amino-5-chloro-N-((1-(6-(2,4-difluorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:18])=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)ccc2c1cnn2Cc1ccccc1
Reaction time: 4 h
Yield: 37.7 %

Procedure:
A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature and stirred for 4 hours. The mixture was diluted with water, extracted with EtOAc, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-5-chloro-1H-indazol-4-amine (0.035 g, 38% yield).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:13][CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:26]C(=O)OCC1C=CC=CC=1)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3]>COCCOC.O>[CH2:1]([O:4][CH2:5][C@H:6]([NH:13][CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH2:26])[CH2:17][C:18]1[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: O
Product: C=CCOC[C@H](NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)c1ccccc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
Step Q (5): A mixture of benzyl (2S,3R)-4-((R)-2-(allyloxy)-1-phenylethylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate (1.1 g, 2.15 mmol) from step Q (4), Ba(OH)2.H2O (1.23 g, 6.47 mmol), and DME/H2O (12 mL/8 mL) was heated at 110° C. in a sealed tube. After 18 h, the vessel was cooled to rt and the precipitate was removed by filtration. The vessel and filtercake were rinsed with fresh DME and the combined filtrates were concentrated in vacuo. The crude product was purified by silica gel chromatography to give 550 mg (68% yield) of the title compound as a yellow viscous oil. LC-MS (M+H)+=377.4; 1H NMR (300 MHz, CDCl3) δ ppm 2.46-3.01 (m, 3H) 3.13-3.72 (m, 7H) 3.89-4.04 (m, 2H) 5.10-5.28 (m, 2H) 5.77-5.96 (m, 1H) 6.52-6.78 (m, 3H) 7.24-7.41 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][CH:4]([OH:25])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)=O)[N:17]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:31][CH2:30]1>CN1C(=O)CCC1>[F:26][C:2]([F:1])([F:27])[CH2:3][CH:4]([OH:25])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:28][CH:29]2[CH2:34][CH2:33][CH:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:31][CH2:30]2)[N:17]=1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCC(O)CC(F)(F)F)cccc32)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-n3ccc4c(OCC(O)CC(F)(F)F)cccc43)n2)CC1
Yield: 57.3 %

Procedure:
4,4,4-Trifluoro-1-[1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-butan-2-ol (0.3 g), N-(4-aminocyclohexyl)-methanesulfonamide (0.514 g) and TEA (0.523 mL) were stirred in NMP (3 mL) at 110° C. for 3 h. After cooling, the resulting solid was filtered washed with H2O and dried. The product was purified on a column using 70% EtOH/hexane to 100% EtOAc, the fractions collected, concentrated in vacuo at 50° C. overnight to yield N-(4-{4-[4-(4,4,4-trifluoro-2-hydroxy-butoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide (Compound 314, 0.227 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]=1[CH3:8].[F:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1B(O)O.[F-].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][C:7]1[N:6]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:5](=[O:14])[CH:4]=[CH:3][C:2]=1[C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:16]=1[F:15]
Reactant: Cc1c(Br)ccc(=O)n1CC(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(-c2cc(F)cc(F)c2F)ccc(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Argon was bubbled through a stirred solution of 5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (9.43 g, 34.9 mmol) in THF (280 mL) for 15 min. To this solution were added 2,3,5-trifluorophenylboronic acid (12.3 g, 69.8 mmol), then cesium fluoride (10.6 g, 69.8 mmol), and finally bis(tri-tert-butylphosphine)palladium(0) (892 mg, 1.75 mmol), and argon was bubbled through the mixture for 5 min after each addition. The reaction mixture was stirred at ambient temperature for 90 min and was then partitioned between saturated aqueous sodium bicarbonate (500 mL) and EtOAc (600 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (300 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=322.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.B.C1COCC1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH:10]2[CH:5]([CH:6]=[C:7]([OH:11])[CH:8]=[CH:9]2)[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:3]12
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1C2C=CC(O)=CC2C2CCC(NCc3ccccc3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (14.0 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A solution of 1M borane/THF in THF (145 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back to 0° C. and trifluoroacetic acid was added in a dropwise manner. The solution was stirred for 15 minutes, neutralized with 10% NaOH (Aq), extracted with CH2Cl2, dried (Na2SO4) and concentrated to give 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][CH-:21][CH2:20][CH2:19]1.[Mg+2].[Cl-]>O1CCCC1>[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([C:10]2([OH:11])[C:4]3[CH:3]=[C:2]([Br:1])[CH:16]=[CH:15][C:5]=3[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]23)[CH2:20][CH2:19]1
Reactant: O=c1c2cc(Br)ccc2ccn2cccc12
Reactant: CN1CC[CH-]CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3cc(Br)ccc3C=Cn3cccc32)CC1
Yield: 65 %

Procedure:
A suspension of 9-bromo-11H-pyrrolo[2,1-b][3]benzazepine-11-one (10.0 g., 0.036 mole) in 100 ml dry tetrahydrofuran, under a nitrogen atmosphere, is stirred in an ice bath. A solution of 1-methylpiperidine-4-magnesium chloride in tetrahydrofuran (76 ml, 0.51 M, 0.039 mole) is added dropwise. Upon completion of addition the solution is allowed to stir at room temperature for one hour after which time the solvent is removed on a film evaporator. The residue is dissolved in 300 ml benzene, the solution stirred and treated with a solution containing one gram of ammonium chloride in 10 ml H2O. After one hour the mixture is filtered and the filter cake washed three times with 100 ml portions of boiling benzene. Upon evaporation of the combined filtrates in vacuo, the residue is chromatographed over a column of 400 g of silica gel packed with chloroform. A non-polar impurity is eluted with chloroform and thereafter the eluant is changed to 2%, then 5% methanol in chloroform. A second contaminant is eluted prior to the product fractions. The product fractions are combined and evaporated to give crude 1-methyl-4-(9-bromo-11-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-yl)piperidine (8.8 g, 65%). The crude product is used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2nc(Nc3cccc(N)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2-(3-aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.82 min.; purity: 85.8%; MS (m/e): 369.11 (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.[ClH:30]>C(O)C>[ClH:30].[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:10]2[O:9][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NC2CCCCC2)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(NC2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of ethyl 2-(cyclohexylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.019 g, 0.075 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.011 g, 0.075 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.079 mL, 0.16 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.0070 g, y. 22%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:25])[CH:22]([OH:24])[CH3:23])[CH3:2]>Cl.CO.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@:4]2([OH:25])[CH:22]([OH:24])[CH3:23])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@]2(O)C(C)O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@]2(O)C(C)O
Yield: 53.6 %

Procedure:
Hydrolyze dl-13-ethyl-17β-hydroxy-17-(1-hydroxyethyl)-3-methoxygona-2,5(10)-diene (0.70 g) in hydrochloric acid-methanol-water. Recrystallize from ethyl acetate to obtain the title compound (0.36 g), m.p. 159°-164°; ultraviolet absorption peak at 240 mμ (ε15,230), infrared absorption peaks at 3.0 μ (strong), 6.05 μ.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])C.[OH-].[Na+]>CCO.O>[CH3:14][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[N:9]([CH:8]=1)[CH:13]=[CH:12][S:11]2
Reactant: CCOC(=O)c1c(C)cn2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn2ccsc2c1C(=O)O
Temperature: 75 °C

Procedure:
A mixture of 6-methyl-pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (7.29 mmol) and NaOH (10.9 mmol) in EtOH (11.8 mL) and water (11.8 mL) is heated to 75° C. for 3 d. The mixture is concentrated in vacuo and made acidic by addition of aq. HCl (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. LC-MS: tR=0.73 min; [M+H]+=182.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: C=CC#N
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was dissolved in ethanol. The solution was cooled and filtered to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)- 1-benzopyran-3-carbonitrile (5A), a solid. A mixture of 5A with 250 ml of methanol containing 2 ml of sulfuric acid, was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (5B), as light yellow needles, m.p.: 106°-109°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH:19]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[Cl:11][C:4]1[C:5]([S:9][CH3:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][O:22][CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)OCCCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1c(Cl)nc(NCCCOC(C)C)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
68.5 g (0.3 mole) of 2,4,6-trichloro-5-methylthiopyrimidine are dissolved in 300 ml of toluene. 30.3 g (0.3 mole) of triethylamine and 35.1 g (0.3 mole) of isopropoxypropylamine are added dropwise at 0° C. After the mixture had been subsequently stirred at room temperature for 1 hour, it is diluted with 500 ml of toluene and the organic phase is washed with water. After drying over sodium sulphate and removal of the solvent in vacuo, the resulting residue is stirred with 100 ml of petroleum ether, filtered off with suction, rinsed with petroleum ether and dried. 25.3 g (27.2% of theory) of the above-mentioned pyrimidine, melting point: 88° C., are thus obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:4]2[N:3]=[C:2]([NH:33][C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[C:7]([C:8]#[N:9])=[CH:6][N:5]=2)=[N:11]1
Reactant: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Cl
Reactant: Nc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1

Procedure:
73 mg of 4-chloro-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidine-5-carbonitrile (1-14-1, 0.201 mmol, 1. eq.), 22.66 mg of pyridin-4-amine (0.241 mmol, 1.2 eq.), 42 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.241 mmol, 1.2 eq.) and 1 ml of N,N-dimethylformamide were stirred at room temperature for 24 hours. The reaction mixture was partitioned between half-saturated aqueous sodium hydrogen carbonate solution and dichloromethane/isopropanol 4:1. The aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 24.4 mg (0.06 mmol, 28.9%) of the analytically pure target compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:11]([NH:10][CH2:9][CH2:8][NH2:7])[S:12][C:13]=1[CH3:17]
Reactant: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(NCCN)sc1C
Yield: 24.6 %

Procedure:
A solution of [2-(4,5-dimethyl-thiazol-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (2.71 g) in methylene chloride (50 ml) was treated with TFA (5 ml) overnight at RT and 1 hour at 60° C. The solvent was evaporated. Ethyl acetate and 1N HCl were added. The separated aqueous layer was extracted under basic conditions with ethyl acetate. The obtained organic layer washed with brine, dried (MgSO4) and evaporated yielding 0.42 g of a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:30][C:31]([CH3:33])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:14][CH2:13]1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2cc[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using alkylation method A, N-[1-(2-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (135 mg, 0.34 mmol) and acetone (1 mL, 14 mmol) afforded, after purification (SiO2: 10:2:2:1 DCM:EtOAc:hexane:isopropylamine), 90 mg (60%) of the title compound.
Reaction SMILES: C[Mg]Br.CC([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:28]3[C:23](=[C:24]([C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=3)[C:22]([NH:32][S:33]([C:36]3[S:37][C:38]([Cl:41])=[CH:39][CH:40]=3)(=[O:35])=[O:34])=[N:21]2)[CH:14]=1)C(=O)[O-])(C)C.O1CCOC[CH2:43]1>C1COCC1.Cl>[NH2:8][CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[C:28]3[C:23](=[C:24]([C:29]([OH:31])([CH3:30])[CH3:43])[CH:25]=[CH:26][CH:27]=3)[C:22]([NH:32][S:33]([C:36]3[S:37][C:38]([Cl:41])=[CH:39][CH:40]=3)(=[O:35])=[O:34])=[N:21]2)[CH:16]=[CH:17][CH:18]=1
Reactant: C1COCCO1
Reactant: CC(=O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Methylmagnesium bromide (3M solution in diethyl ether) (0.730 mL, 2.191 mmol) was added slowly dropwise to a stirring solution of 1,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 76) (210 mg, 0.365 mmol) in THF (3 mL) at room temp. The reaction was stirred for 2 h and then more methylmagnesium bromide (3M solution in diethyl ether) (0.730 mL, 2.191 mmol) was added and stirred overnight. LCMS indicated molecular ion 592 [M+1] corresponding to the desired alcohol and that the starting material co-eluted with the product. 1N HCl (5 mL) was added and the product was extracted with EtOAc (15 mL×3). The combined organic layers were dried by passing through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in 4N HCl in Dioxane (2 mL, 8.00 mmol) and the reaction was stirred at room temp over 1 h. The reaction mixture was loaded on an SCX-2 ion-exchange 20 g cartridge eluting with methanol and 2M ammonia in methanol. The appropriate ammoniacal fractions were combined and evaporated in vacuo to give the title compound (168 mg, 76%) as a brown oil. LCMS (System A) RT=0.79 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]4[NH:53][N:52]=[N:51][N:20]=4)=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: N#Cc1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(-c4nnn[nH]4)cc32)cc1)N1CCCC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
30 mg (0.059 mmol) of 4-(4-chlorobenzoyl)-8-cyano-1-[4-(pyrrolidinylcarbonyl)benzyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 2 ml of toluene. 0.032 ml (0.11 mmol) of tributyltin azide was added to the obtained solution, and they were stirred at 120° C. for 6 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the solvent was evaporated and the obtained crude product was treated in the same manner as in Step 3 in Example 1 to obtain the title compound.