Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[CH:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[C:14]=2[CH:13]=[CH:12][N:11]=1.CCO.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:9][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]=[CH:10]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: OB(O)c1cccc2cnccc12
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc3cnccc23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
4-Bromo-3-fluorobenzenamine (2.51 g, 13 mmol) and 5-isoquinolineboronic acid (4.23 g, 24 mmol) were suspended in toluene (35 ml) and EtOH (35 ml) and tetrakis(triphenylphosphine)palladium (812 mg, 0.70 mmol) was added, followed by 10% aqueous sodium carbonate (40 ml). The flask was fitted with a reflux condenser and placed in a preheated oil bath (110 C) and stirred under nitrogen for 4 hours. The reaction was then cooled to room temperature, partially concentrated, and diluted with water. The aqueous phase was extracted with DCM, and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on silica gel (50:1->30:1->20:1 DCM/MeOH). The fractions with product were collected, concentrated, and washed with DCM and hexanes. The remaining solid was dried under high vacuum to afford the desired 3-fluoro-4-(isoquinolin-5-yl)benzenamine (2.568 g, 10.78 mmol, 94% purity, 82% yield). MS (ESI pos. ion) m/z: 497 (MH+). Calc'd exact mass for C15H11FN2: 239. 1H NMR (400 MHz, CDCl3): 9.30 (s, 1H), 8.50 (dd, J=6.0 Hz, 2.0 Hz, 1H), 8.02-7.96 (m, 1H), 7.68-7.63 (m, 2H), 7.58-7.54 (m, 1H), 7.16 (dt, J=8.0 Hz, 2.0 Hz, 1H), 6.61 (dt, J=8.0 Hz, 2.0 Hz, 1H), 6.56 (dt, J=11.5 Hz, 2.0 Hz, 1H), 3.93 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1.[OH:17]O>CC(O)=O>[Br:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][C:3]=1[S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1)=[O:17]
Reactant: N#Cc1cc(Sc2cccc(Br)c2)c(Br)s1
Reactant: OO
Solvent: CC(=O)O
Product: N#Cc1cc(S(=O)c2cccc(Br)c2)c(Br)s1
Temperature: 50 °C

Procedure:
To a solution of 5-Bromo-4-(3-bromo-phenylsulfanyl)-thiophene-2-carbonitrile (Example 25: step g; 292 mg, 0.78 mmol) in AcOH (3 mL), 30% H2O2 (85 μL, 0.94 mmol) was added slowly and warmed to 50° C. for 2 hours. The reaction was concentrated and then dissolved in EtOAc and washed with water. The organic layer was dried (MgSO4) and concentrated. The compound was used without further purification. 1H-NMR (CDCl3): δ 7.87-7.85 (1H, m), 7.64 (2H, t, J=10.1, Hz), 7.57 (1H, s), 7.41 (1H, t, 7.91 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(/C=C/c2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1
Reaction time: 1 h

Procedure:
781.8 mg (1.34 mmol) of methyl 4-({(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenyl-ethenyl]benzyl}oxy)phenethyl]amino}methyl)benzoate from Ex. 6 and 80.0 mg of 10% palladium on activated carbon in 10 ml of ethyl acetate are hydrogenated under atmospheric pressure. After 1 hour, the calculated amount of hydrogen has been taken up. The solution is filtered and the solvent distilled off under reduced pressure. The crude product is purified by chromatography over silica gel using the mobile phase cyclohexane/ethyl acetate=10:1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+].C(OCC)(=O)C>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>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(I)cc1Cl
Reactant: CC(C)(C)OC(=O)C[Zn+]
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: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(=O)OC(C)(C)C)cc1Cl
Reaction time: 0.17 h

Procedure:
To methyl 2-chloro-4-iodobenzoate (296 mg) was added a solution (4.5 mL) of 2-tert-butoxy-2-oxoethylzinc bromide in THF, then, bis(tri-tert-butylphosphine)palladium (51 mg) was added, and a reaction was performed at 50 W and 80° C. for 10 minutes using a microwave synthesis apparatus manufactured by CEM Co. The reaction solution was poured into an aqueous saturated ammonium chloride solution, and ethyl acetate was added. Insolubles were filtered off with Celite, and layers were separated. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by medium pressure preparative liquid chromatography W-prep 2XY (column: main column M, inject column S; automatic condition setting: n-hexane:ethyl acetate=4:1, Rf=0.60) to obtain the title compound (94 mg) having following physical property values.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])(=O)=O.[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:16]=12.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[N:15]1[S:19][N:18]=[C:17]2[CH:20]=[C:21]([C:24]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:14])=[C:11]([F:13])[F:12])=[O:25])[CH:22]=[CH:23][C:16]=12
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1ccc2nsnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1ccc2nsnc2c1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To 30 ml of ethanol was dissolved 2.0 g (10 mmol) of methyl benzo[1,2,5]thiadiazole-5-carboxylate, followed by the addition of 3.3 g of a 25% aqueous solution of sodium hydroxide and stirring at room temperature for 3 hours. To the reaction liquid was added 50 ml of water and a dilute hydrochloric acid to make pH of 2. Crystal precipitated was filtered off and dried under reduced pressure to obtain 1.7 g (yield: 92%) of benzo[1,2, 5]thiadiazole-5-carboxylic acid. In a separate reactor, 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.43 g (2.4 mmol) of benzo[1,2,5]thiadiazole-5-carboxylic acid were dissolved in 7 ml of N,N-dimethylformamide, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.44 g (yield: 64%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[1,2,5]thiadiazole-5-carboxylate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]=[C:10]([CH3:25])[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:28][Si:27]([CH3:30])([CH3:29])[O:9][C:10](=[CH2:25])[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(CC1CCN(C(=O)OC(C)(C)C)CC1)O[Si](C)(C)C
Reaction time: 0.42 h
Yield: 108.1 %

Procedure:
To a cooled (−78° C.) solution of LDA (12.3 mL, 24.6 mmol) in THF (50 mL) was added dropwise over 40 minutes a solution of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate (4.95 g, 20.5 mmol) in THF (20 mL). After an additional 25 minutes, chlorotrimethylsilane (5.21 mL, 41.0 mmol) was added dropwise over 20 minutes. After stirring for an hour, the reaction was poured into saturated NaHCO3 and extracted with ether (2×400 mL). The combined ether layers were washed with brine, dried, filtered and concentrated to afford the title compound (6.95 g, 108% yield) which was used as is in the next step.
Reaction SMILES: [OH:1][CH2:2][C@:3]([C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH3:22])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C(=O)N([Cl:32])C(=O)C1>CN(C=O)C>[Cl:32][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH3:22])[CH:20]=1
Reactant: Cn1ccc2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc([C@](C)(O)CO)cc3)cc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
(S)-4-(1,2-dihydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (650 mg, 2.0 mmol) was dissolved in DMF (25 ml) and NCS (270 mg, 2.0 mmol) was added to the mixture, which was stirred at 50° C. for 16 hours. The mixture was then poured into 50 ml ice water and was extracted into ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparatory HPLC (TFA mode, 15-50% ACN in water). Fractions containing the desired mono chlorinated product were combined, concentrated, washed with saturated NaHCO3 and brine, and then extracted into ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (S)-N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (120 mg, 0.32 mmol, 16%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 2 H) 2.43-2.64 (m, 1 H) 3.46 (dd, J=5.56, 2.53 Hz, 2 H) 3.69-3.84 (m, 2 H) 4.76 (t, J=5.81 Hz, 1 H) 5.04 (s, 1 H) 7.40-7.67 (m, 2 H) 8.02 (d, J=8.59 Hz, 1 H) 8.21-8.40 (m, 1 H) 8.59 (s, 1 H) 10.65 (s, 1 H); ESI-MS: m/z 360 (M+H)+; m.p. 210-212° C.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:19][C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
30 g of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione, 20.6 g of phenacyl bromide and 25.4 g of potassium carbonate are introduced into 400 ml of DMF and heated at an internal temperature of 80° C. for 3 hours. The solution is cooled to about 50° C., and 400 ml of water are slowly added. The mixture is then stirred overnight, and the precipitated solid is filtered off with suction. After washing with water, the pale brown solid is recrystallized from 300 ml of isopropanol.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][C@@H:47]2[CH2:49][O:48]2)=[CH:41][C:40]=1[NH:50][S:51]([CH3:54])(=[O:53])=[O:52])C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:49][C@H:47]([OH:48])[CH2:46][O:45][C:42]3[CH:43]=[CH:44][C:39]([OH:38])=[C:40]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:41]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1
Yield: 19 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.516 g, 1.2 mmol) was reacted with N-{2-(benzyloxy)-5-[(2S)oxiranylmethoxy]phenyl) methanesulfonamide (prepared according to patent WO9604233) (0.38 g, 1.09 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.15 g, 0.207 mmol).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: C[Si](C)(C)C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (27.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.37 g). To the solution was added 60% sodium hydride (0.27 g) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3-bromo-1-(trimethylsilyl)-1-propyne (1.48 ml), and the mixture was stirred at 65° C. for 90 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(O)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: NC(=O)c1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C

Procedure:
A solution containing 44 g (0.32 m) of 3-aminobenzamide, 71.6 g (0.32 m) of p-nitrobenzenesulfonyl chloride and 700 ml of pyridine was stirred and heated on a steam bath for 2.5 hours, then poured into ice water. Acetic acid was added to a pH 5.0-6.0 and the resulting solid collected by filtration, washed with water and air-dried to give 105 g, m.p. 240°-244°.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl:27][C:28]1[C:29]2[C:36](I)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:27][C:28]1[C:29]2[C:36]([C:8]3[CH:7]=[CH:6][C:5]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[C:4]([O:3][CH3:2])[CH:9]=3)=[CH:35][N:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:30]=2[N:31]=[CH:32][N:33]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 81.3 %

Procedure:
A mixture of water (25 ml) and tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (65% pure) (4.25 g, 7.92 mmol) was frozen and subjected to vacuum followed by filling with nitrogen while defreezing. 4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.83 g, 5.28 mmol), tetrakis (triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol), sodium carbonate (1.40 g, 13.20 mmol) and ethylene glycol dimethyl ether (50 ml) were added and the resulting mixture was heated at 80° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate twice. The combined ethyl acetate extracts were dried over magnesium sulfate and evaporated to give a dark oil which was purified by flash column chromatography on silica using n-heptane/ethyl acetate (3:1) with 2% triethylamine as the mobile phase. Appropriate fractions were collected, combined and concentrated to give tert-butyl N-[4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate as white solids (1.90 g, 4.29 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 7.94 (s, 2H), 7.74 (d, 1H), 7.19 (d, 1H), 7.07 (dd, 1H), 5.22 (m, 1H), 3.87 (s, 3H), 2.19 (m, 2H), 1.99 (m, 2H), 1.91 (m, 2H), 1.73 (m, 2H), 1.48 (s, 9H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: Oc1ccccn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
A mixture of 2-hydroxypyridine (6.0 g), N-(4-bromobutyl)phthalimide (17.8 g), potassium carbonate (8.7 g) and N,N-dimethylformamide (DMF) (80 ml) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The oily residue was subjected to a silica gel column chromatography. From the fraction eluted with chloroform-ethyl acetate (4:1 v/v), N-[4-(2-pyridyloxy)butyl]phthalimide (4.4 g, 23%) was obtained Recrystallization of the product from ether gave colorless prisms, m.p. 77° C. to 78° C.
Reaction SMILES: [I-].[I-].[I-].[In+3:4].[CH2:5]([Mg]Cl)[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C>[CH2:5]([In:4]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: [In+3]
Agent: [I-]
Solvent: CCOCC
Product: CC(C)(C)C[In](CC(C)(C)C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask, charged with 29.13 g (58.3 mmol) of indium triiodide dissolved in 100 ml. of dry diethyl ether (from sodium/benzophenone), was fitted with a condenser, magnetic stir bar and a pressure equalizing addition funnel. Under a cover of argon, 100 ml., 2.32 M neopentyl magnesium chloride in diethyl ether solutin (previously prepared from purified neopentyl chloride and magnesium turnings) was transferred to the addition funnel. The Grignard reagent was then added to the indium triiodide solution over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The condenser and addition funnel were then replaced by a stopper and a Teflon valve adapter and the diethyl ether was removed by vacuum distillation at room temperature. The crude product, a trisneopentyl indium etherate mixture, was isolated by vacuum distillation at 110° C. into a side-arm flask (cooled to -196° C.) attached to the reaction flask by means of an 85° elbow. The distillation must be continued for approximately 8 hours. The diethyl ether was then removed from the crude trisneopentyl indium by simple vacuum distillation at room temperature for 12 hours. The product, a crystalline solid, is finally purified by vacuum sublimation at 30° C. with the receiving flask at -10° C. The yield of purified trisneopentyl indium was 17.7 g (53.9 mmol, 92.4% based on indium triiodide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18](O)[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.CN(C)C.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CN(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-{[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}-4-(5-chloropyridin-3-yl)butan-2-ol (111 mg, 0.25 mmol) in dry CH2Cl2 (2.5 mL) at RT was added under an atmosphere of argon, trimethylamine hydrochloride (2 mg, 0.02 mmol), triethylamine (52 μl, 0.25 mmol), then methanesulfonyl chloride (21 μl, 0.25 mmol). The reaction was stirred for 30 mins at RT, then quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×6 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then dissolved in CH2Cl2 (2.5 mL) and treated with triethylamine (100 μl, 1.36 mmol). After 30 minutes, the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×6 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The crude material was used in the next step.