Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+].O1CCCC1>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(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(F)cc4)nc23)CC1
Temperature: 75 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.412 mmol), 4-fluorophenylboronic acid (87 mg, 0.619 mmol), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.041 mmol), 4 mL of 2M aqueous sodium bicarbonate, and 30 mL of tetrahydrofuran were placed in a round bottom flask. The mixture was heated to reflux (about 75° C.) and allowed to stir for about 18 hours. The reaction was poured into 3:1 chloroform:isopropyl alcohol, extracted three times each with 1N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 0-10% methanol/dichloromethane) to give 87.9 mg of the title compound. (79%). MS(FD) m/e 309.6 (M+). EA calculated for C19H20FN3: C, 73.79; H, 6.47; N, 13.59. Found: C, 73.69; H, 6.73; N, 13.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate (0.43 g, 1.462 mmol) in MeOH (12 mL) and THF (3 mL) was added 3 M NaOH (1.949 mL, 5.85 mmol). The reaction was stirred for 18 h at RT, at which time the volatiles were removed in vacuo. The residue was diluted with water and slowly acidified with 1 N HCl to pH 4-5, then extracted with EtOAc (2×). The combine organics were wash with brine, dried over magnesium sulfate, filtered, and concentrated to give 6-bromo-1-cyclopropyl-1H-indole-4-carboxylic acid (0.376 g, 1.315 mmol, 90% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.01 (m, 2H) 1.05-1.12 (m, 2H) 3.51 (tt, J=7.07, 3.66 Hz, 1H) 6.89 (d, J=2.53 Hz, 1H) 7.52 (d, J=3.03 Hz, 1H) 7.80 (d, J=1.77 Hz, 1H) 7.99 (d, J=1.01 Hz, 1H) 13.05 (br. s., 1H). MS(ES) [M+H]+ 280.1.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:16][CH3:17])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 1 g (5.06 mmol) of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% in mineral oil) at 0° C. This mixture was stirred for 30 min at RT and then 1.18 ml (7.59 mmol) of ethyl iodide were added. Stirring was continued for 16 h at RT, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The remaining residue was purified by crystallization from heptane to obtain 682 mg (60%) of 6-chloro-1-ethyl-1H-benzo[d][1,3]oxazine-2,4-dione as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 1.21 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.88 (dd, J=9.1 and 2.5 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]4=[N:18][CH:19]=[CH:20][C:21](Br)=[C:16]4[CH:15]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Br[C:34]1[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=1>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]4=[N:18][CH:19]=[CH:20][C:21]([C:34]5[C:35]([C:41]6[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=6)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=5)=[C:16]4[CH:15]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CC(=O)N1CCc2ccc(-c3cc4c(Br)ccnc4n3S(=O)(=O)c3ccccc3)cc2C1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc4c(c2)CN(C(C)=O)CC4)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 with 2-acetyl-7-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 688.6.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:35]/[O:36]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2\[C:25](=[O:34])[N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27]\2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:35]/[OH:36])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2\[C:25](=[O:34])[N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27]\2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4/CN(c5ccccc5)C4=O)CS[C@H]23)cs1
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4/CN(c5ccccc5)C4=O)CS[C@H]23)cs1
Reaction time: 1 h

Procedure:
384 mg (0.5 mmol) (6R,7R)-7-[(Z)-2-(2-Amino-thiazol-4-yl)-2-trityloxyimino-acetylamino]-8-oxo-3-[(Z)-2-oxo-1-phenyl-azetidin-3-ylidenemethyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid were stirred for 75 min in 4 ml of 90% formic acid. The suspension is concentrated in vacuo and the residue triturated with 50 ml of ethyl acetate. The solid was filtered off, dried and stirred for 1 hour with 20 ml of 90% ethanol. The product was isolated by filtration, washed with n-hexane and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.606 g, 3.537 mmol), 2-methoxy-phenyl-boronic acid (575 mg, 3.78 mmol) and of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (145 mg, 0.178 mmol) in acetonitrile (8 mL) and aqueous solution of sodium carbonate (2M, 8 mL) was stirred in a closed vial at 85° C. for 100 min. The resulting mixture was then distributed between a saturated aqueous solution of sodium bicarbonate and dichloromethane and the aqueous phase extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.002 g, 65% yield) as an off-white oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.70 (d, 1H), 8.40 (d, 1H), 7.61 (d, 1H), 7.50 (ddd, 1H), 7.23 (dd, 1H), 7.10 (ddd, 1H), 5.81 (s, 2H), 3.85 (s, 3H), 3.66 (t, 2H), 0.84 (t, 2H), −0.10 (s, 9H). MS: m/z 456, 458 [MNa+].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[SH:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([OH:50])=[O:49].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:43]=[CH:42][CH:41]=3)[CH2:2][S:44][C:45]3[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=3)[C:48]([OH:50])=[O:49])=[O:7])=[C:10]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)[CH:38]=[CH:39][N:40]=3)[CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 16 h
Yield: 37.9 %

Procedure:
A mixture of 250 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide 8.1a, 70 mg of 3-mercaptobenzoic acid, 10 mL of acetone, and 171 mg of K2CO3 was stirred for 16 h and then filtered. The solvent was removed by evaporation. The residue was dissolved in dichloromethane and the resulting solution was washed with aqueous hydrochloric acid. The solution was dried, and the solvent was evaporated. The residue was purified by silica gel chromatography to give 113 mg of product. MS (ES, m/z) 725 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[C:5]([B:22]([OH:27])[OH:23])=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(-n2cccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nccc2B(O)O)cc1
Reaction time: 1 h

Procedure:
4-(1H-Pyrazol-1-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5 g, 8.87 mmol) in dry THF (50 ml) under argon was stirred at −78° C. whilst lithium diisopropylamide (1.8M solution in THF/hexane/ethyl benzene; 5.2 ml, 9.32 mmol) was added dropwise during 20 min. Stirring and cooling were continued for 1 h, triisopropyl borate (8 ml, 34.5 mmol) was added dropwise during 30 min and then the temperature was allowed to rise overnight to RT. The pH of the reaction mixture was adjusted to 5 with 1M HCl and the mixture was then concentrated to a minimum volume and extracted with ethyl acetate (200 ml) and brine (3×100 ml). The organic phase was collected, dried (Na2SO4), filtered and evaporated to a brown solid (1.32 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Br:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCBr
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)CCBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
(-)-6-(4-Aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (0.195 g) suspended in dichloromethane (15 ml) was cooled to 0° C. Aqueous saturated sodium bicarbonate (15 ml) was added to form a two phase system. To the organic phase was added with stirring 3-bromopropionyl chloride (0.248 g) in dichloromethane (5 ml). The mixture was allowed to warm to room temperature and vigorously stirred for 3 hours to give a fine suspension. This was filtered to give the title compound (0.279 g); [α]D25 =-333° [concentration 0.91% in dimethylformamide]: nuclear magnetic resonance spectrum consistent with racemic material. Material from another run gave C, 49.41%; H, 4.73%; H, 12.22%; Br, 23.14%: theory C, 49.72%, H, 4.77%; N, 12.43%; Br, 23.63%.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]>C1C=CC=CC=1>[CH3:3][C:4]1[S:5][C:6]([I:1])=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: Cc1csc(C)c1CO
Reactant: II
Solvent: c1ccccc1
Product: Cc1sc(I)c(C)c1CO
Temperature: -50 °C

Procedure:
10.0 G. (46 mmol) of mercuric oxide and 14.7 g. (58 mmol) of iodine were added alternately over a period of 11/4 hrs. to a vigorously stirred solution of 8.2 g. (57.7 mmol) of 2,4-dimethyl-3-hydroxymethylthiophene in 300 ml. of benzene. The reaction mixture was kept at room temperature by cooling with and ice bath and stirring was continued for an additional hour. The mercuric iodide which precipitated was filtered and washed well with warm ethyl ether. The combined organic solutions were washed with 10% sodium thiosulfate and saturated sodium chloride solution, dried and evaporated. The resulting residue was dissolved in a minimum amount of hot ether, an equal amount of hexane was added and the solution cooled to -50° C. The crystals which precipitated were filtered and washed with cold hexane to yield after drying 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene, m.p. 118.5°-120.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine following General Procedure B-3 (500 mg), cyclopropanesulfonyl chloride (0.24 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([CH2:13][C:14](=[O:31])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)[CH:9]=1)=[O:7])(C)(C)C>ClCCl.C(OCC)C>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14](=[O:31])[CH2:13][N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[CH:18][CH:19]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
0.049 g (0.115 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylate is dissolved in 10 ml absolute dichloromethane and mixed with 0.988 g (8.67 mmol) tifluoroacetic acid. Having stirred at room temperature for 3½ hours, the batch is concentrated to dryness on the rotary evaporator. Two dissolution steps in toluene and respective concentrations on the rotary evaporator leave as a crude product a greenish solid which is solved in diethyl ether and precipitated with petroleum ether. Twenty minutes of centrifugation at 3000 rpm, decantation of the supernatant, displacement of the solvent residues in the nitrogen flow and drying in a vacuum desiccator yield the product as a beige solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=O)[CH3:11])=[CH:6][CH:5]=1.B>C1COCC1.C(OCC)C>[CH2:10]([NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CC(=O)NCc1ccc(OC(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNCc1ccc(OC(F)(F)F)cc1
Temperature: -10 °C
Yield: 19.4 %

Procedure:
N-[4-(Trifluoromethoxy)benzyl]acetamide (10.4 g, 44.6 mmol) was dissolved in THF (100 mL) and cooled to −10° C. Borane (56 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the reaction mixture was stirred at −10° C. for 15 minuters and was then allowed to warm to room temperature. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched by careful addition of 10% HCl (30 mL) at 0° C. and the mixture was stirred at room temperature overnight and then concentrated in, vacuo. The residue was taken up in water (200 mL) and diethyl ether (200 mL) and the phases were separated. Concentration in vacuo of the diethyl ether phase afforded 1.9 g (21%) of the title compound as a colourless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:3][CH:2]=1.CN(C)C=O>[Pd].C(O)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccncc3)c2n2ccnc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccncc1)c1ccccc1-2
Yield: 24.8 %

Procedure:
The procedure is performed as in Example 13, but starting with 0.8 g of 10-(4-pyridylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide and 80 mg of 10% palladium on charcoal, with addition also of 10 ml of acetic acid. 0.2 g of 10-(4-pyridylmethyl)-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one is obtained, in the form of a pale yellow solid melting above 260° C. (Analysis % calculated C: 72.60, H: 4.49, N: 17.82, O: 5.09, % found C: 72.3, H: 4.3, N: 17.8).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[NH:14][C:15](=[O:28])[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=4)[C:7]=3[C:6]=2[CH:5]=1.[C:29](Br)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([N:14]1[C:8]2[CH:9]=[N:10][C:11]3[CH:12]=[CH:13][C:4]([Cl:3])=[CH:5][C:6]=3[C:7]=2[N:16]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:27])[C:24]#[N:25])=[CH:19][CH:18]=2)[C:15]1=[O:28])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Reactant: O=C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)c3ccccc3)c3cnc4ccc(Cl)cc4c32)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (22 mg, 0.557 mmol) was added to dry DMF (5 mL) in a nitrogen atmosphere. The reaction flask was cooled in an ice-bath to 0° C., and 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 100 mg, 0.27 mmol) was added. After 15 minutes benzoyl bromide (61 mg, 0.33 mmol) was added, and the reaction mixture was heated at 50° C. for 24 hours. The reaction mixture was concentrated in vacuum. The crude product was purified by column chromatography (silica gel, 2.5% acetone in chloroform) to obtain the title compound. Yield: 30 mg (23%); 1H NMR (DMSO-d6, 300 MHz): δ 9.372 (s, 1H), 8.048-8.078 (d, 1H, J=9 Hz), 7.905-7.929 (d, 2H, J=7.2 Hz), 7.810-7.839 (d, 2H, J=8.7 Hz), 7.730-7.759 (d, 2H, J=8.7 Hz), 7.611-7.666 (m, 2H), 7.449-7.523 (m, 2H), 6.698-6.705 (d, 1H, J=2.1 Hz), 1.752 (s, 6H); MS: m/z 467 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([S:52](Cl)(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>C(#N)C>[C:42]1([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:54])=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc4ccccc34)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 61.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0358 g, 0.0776 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0650 mL, 0.465 mmol) and 1-naphthalenesulfonyl chloride (0.0530 g, 0.233 mmol) to obtain 4-(1-naphthalenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0309 g, yield 61%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:18](=[N:22][NH:21][C:23]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[S:24])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: CC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Yield: 68.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(3-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (0.229 mmol, 65.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.229 mmol, 48.3 mg) were stirred with dimethylformamide (2.5 mL) and three drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and is the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a yellow solid (74.7 mg, yield 68%).