Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[NH:24][C:23]2[CH:25]=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[C:22]=2[N:21]=1>CCO>[F:17][C:15]([F:18])([F:16])[C:8]1[CH:9]=[C:10]([CH2:13][OH:14])[CH:11]=[N:12][C:7]=1[N:1]1[CH2:6][CH2:5][N:4]([C:20]2[NH:21][C:22]3[C:28]([C:29]4[CH:30]=[C:31]([F:37])[C:32]([F:36])=[C:33]([F:35])[CH:34]=4)=[CH:27][C:26]([C:38]([F:41])([F:39])[F:40])=[CH:25][C:23]=3[N:24]=2)[CH2:3][CH2:2]1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: OCc1cnc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: CCO
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)CC2)c(C(F)(F)F)c1

Procedure:
A mixture of (6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-methanol from step (e) above (131 mg, 0.5 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (175 mg, 0.5 mmol, Example 51b) in EtOH (2 mL) reacted under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 576 (M+1).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[C:17]([O:22][CH3:23])(=[O:21])/[CH:18]=[CH:19]/[CH3:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:20][C@@H:19]1[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][C@H:18]1[C:17]([O:22][CH3:23])=[O:21]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C/C=C/C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.8 %

Procedure:
To a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.8 mL, 7 mmol) and methyl crotonate (0.62 mL, 5.8 mmol) in DCM (25 mL) at 0° C. was added dropwise a solution of trifluoroacetic acid (0.045 mL, 0.58 mmol) in DCM (1 mL). The reaction was allowed to warm to room temperature and was stirred for 3 h. Saturated sodium bicarbonate solution was added and the phases were separated. The aqueous phase was extracted twice with DCM and the combined organics were dried over sodium sulfate and concentrated in vacuo. This yielded crude methyl rac-(trans)-4-methyl-1-(phenylmethyl)-3-pyrrolidinecarboxylate (1.58 g) which was used without further purification. LCMS: (M+H)+: 234.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([CH3:19])[C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:15]([C:16](=[O:17])[NH2:18])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(N[C@H]1CCN(C(=O)OC(C)(C)C)C1)C(N)=O
Temperature: 80 °C

Procedure:
To a solution of MeCN (3 mL) was added 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.186 g, 1 mmol), 2-Bromo-propionamide (0.15 g, 1 mmol) and potassium carbonate (0.153 g, 1.1 mmol). The resulting mixture was heated at 80° C. overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with MeOH/CH2Cl2 (20/80) to afford the title product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C([O-])=O.[Na+].[O:12]=[C:13]1[C:21]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][NH:26]2)=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)=O>[CH:1]([N:26]1[CH:25]([C:23]([NH:22][C:21]2([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:13]2=[O:12])=[O:24])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2)c2ccccc21
Agent: O=C([O-])O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CCC(=O)OCC)(NC(=O)C2Cc3ccccc3CN2C=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 0.66 g of formic acid and 1.35 g of acetic acid anhydride was heated at 50° C. for 15 minutes. After cooling by dilution with 15 ml of anhydrous methylene chloride, 0.68 g of sodium formate and 15 ml of a methylene chloride solution of 1.70 g of ethyl 3-[2,3-dihydro-2-oxo-1-pentyl-3-(1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-1H-indol-3-yl]propionate were added to this mixed anhydride solution. The whole was stirred at room temperature overnight. The reaction mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with chloroform. The extract was washed, dried, filtered and then evaporated in vacuo to afford 1.72 g of ethyl 3-[3-(2-formyl-1,2,3,4-tetrahydro-3-isoquinolinyl)carbonylamino-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3- yl]propionate as a pale yellow amorphous solid. IR (Nujol) (cm-1): 3280, 1720, 1655, 1610, FAB-MS (m/z): 506 (MH+) 160 (base).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([O-])=[O:18])[S:16][C:9]=12.[Li+]>>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:18])[S:16][C:9]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: C1COCCN1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1CCOCC1

Procedure:
The title compound was prepared from morpholine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 282/284 (MH+), HPLC Rf: 3.96 min.; HPLC purity 98%.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH2:33])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1.O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:21]3[N:22]([CH3:35])[C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH2:32][NH:33][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[CH:29]=[CH:28][C:27]=4[Cl:34])=[N:24][C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Solvent: ClCCl
Solvent: O
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of pivaloyl chloride (34 mg; 0.28 mmol) in DCM (1 mL) was added dropwise to a mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide ((see Example 72, step (d)) 150 mg; 0.27 mmol), TEA (41 mg; 0.41 mmol) and DCM (2 mL) at 0° C. The resulting mixture was stirred over night at rt, poured into water and extracted with DCM. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc/petroleum ether to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11]Br.[Li]CCCC>C1COCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[CH2:11][CH2:10][O:9][C:3]=2[CH:4]=1
Reactant: BrCCOc1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
1,4-dibromo-2-(2-bromoethoxy)benzene (136) (922 mg, 2.57 mmol) was dissolved in 25 ml dry THF. After cooled down to −78° C., a solution of 2.5M n-BuLi (1.23 ml, 1.2 q) in hexane was added dropwise. The reaction mixture was stirred at −78° C. for 4 h before poured into ice-water. After extracted twice with ethyl acetate, the org. phase was washed with brine, dried over sodium sulfate and then concentrated to give 504 mg (purity ca 80%) 6-bromo-2,3-dihydrobenzo[b]furan (137) as dark brow oil which was used directly for further reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)cc1
Yield: 78.7 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(4-methoxyphenyl)benzamide (556.9 mg, 1.17 mmol) and acetic anhydride (0.13 ml, 1.41 mmol), the procedure of Inventive Example 94 was repeated to obtain 476.8 mg (78.7%) of the title compound in the form of colorless powder.
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:25])[NH:13][C:14]([S:23][CH3:24])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH2:1]([N:13]1[C:12](=[O:25])[C:11]([C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=[C:14]1[S:23][CH3:24])[CH3:2]
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1c(SC)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 8 h

Procedure:
Ethyl bromide (600 ml, 8.03 mmol) was added to a stirred mixture of 5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (1.8 g, 5.97 mmol) and sodium hydride (60% oily suspension, 320 mg, 8 mmol) in N,N-dimethylformamide (60 ml) at room temperature. More ethyl bromide (2×600 ml, 2×8.03 mmol) was added after 2 and 3.5 h. After 8 h, the reaction mixture was neutralized with acetic acid and evaporated. The remainder was taken up in dichloromethane, the organic solution was washed with water, dried and evaporated. Flash chromatography on a column of silica gel (hexane-acetone=3:1, 2:1). provided in the second main fraction the title compound as a solid.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]3=[O:31])[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=c1ccc2ccccc2n1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
3-(1-piperazinyl)-1,2-benzisothiazole (0.44 g, 2.0 mmoles), 1-(4-bromobutyl)-2(1H)-quinolinone (0.56 g, 2.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles) were suspended in 4 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Insolubles were removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column to give 0.68 g (yield 80%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[NH:17][CH3:18].C[O-].[Na+].[NH:22]([CH2:29][CH2:30][C:31]#[N:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[NH:22]([CH:29]=[C:30]([CH2:6][C:5]1[CH:13]=[C:14]([NH:15][CH3:16])[C:2]([Cl:1])=[C:3]([NH:17][CH3:18])[CH:4]=1)[C:31]#[N:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(NC)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(NC)c1Cl

Procedure:
A mixture of 13.2 g. of 4-chloro-3,5-bis(methylamino)-α-[(methylsulfonyl)-methyl]benzyl alcohol, 3.6 g. of sodium methylate and 9.6 g. of β-anilinopropionitrile in 80 ml. of dimethylsulfoxide was stirred for 5 hours under nitrogen at 50° C. The mixture was poured into 200 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-4-chloro-3,5-bis(methylamino)hydrocinnamonitrile having a melting point of 142°-147° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[C:11]([F:14])([F:13])[F:12]
Reactant: CN1CCNCC1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Product: CN1CCN(C(c2c(O)c(=O)ccn2C)C(F)(F)F)CC1
Yield: 29 %

Procedure:
In a similar manner, Apo7073 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and 1-methylpiperazine (1.0 mL, 9.0 mmol). The title compound Apo7073 (401 mg) was obtained after purification by Biotage reverse C18 column. Yield=29%; 1H NMR (400 MHz, DMSO-d6, 75° C.) δ (ppm): 7.63 (d, J=6.8 Hz, 1H), 6.21 (d, J=7.4 Hz, 1H), 4.94 (q, J=8.5 Hz, 1H), 3.86 (s, 3H), 3.05 (br. s., 4H), 2.92 (br. s., 4H), 2.64 (s, 3H); MS m/z 306 [M+1]+, 206 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH:10]([OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([C:43]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH2:14][O:15][C:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH:10]([OH:36])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2CO)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccccc1COCCCOc1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (f), by reacting (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester with triphenylchloromethane there was obtained (3RS,4RS,5SR)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]5-trityloxymethyl-piperidine-1-carboxylic acid tert-butyl ester as a colorless foam; MS: 761 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[C:7]([O:11]C)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([S:23][CH3:24])=[S:22])[CH2:17][CH2:16]1.O.C(=O)([O-])O.[Na+]>ClCCl.B(Br)(Br)Br>[OH:2][C:3]1[C:8]([OH:9])=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]([S:23][CH3:24])=[S:22])[CH2:19][CH2:20]1
Reactant: COc1ccc(CCN2CCN(C(=S)SC)CC2)c(OC)c1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CSC(=S)N1CCN(CCc2ccc(O)c(O)c2O)CC1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
In 14 ml of dry dichloromethane was dissolved 1 ml of boron tribromide. 9.3 ml of the resulting solution containing 665 mmol. of boron tribromide was chilled to -50° C. in a nitrogen atmosphere. To the chilled solution was dropwise added a solution of 0.73 g of methyl 4-{2-(2,3,4-trimethoxyphenyl)ethyl}-1-piperazinecarbodithioate in 25 ml of dry dichloromethane for 15 min. The resulting mixture was left to reach room temperature, and then stirred overnight. To the mixture was added 3 ml of water, and further added a saturated aqueous sodium hydrogen carbonate solution until the mixture had pH 8. The mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to distill off the solvent, yielding 205 mg of the desired compound as a grayish powder, m.p. 156°-158° C. (decomp.), yield 31.5%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)([O:19][CH2:20][O:21][CH3:22])[CH3:18])[N:14]=[C:13]([NH2:30])[N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:17]([C:15]2[CH:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=5)[N:3]=4)[NH:8][CH:9]=3)[N:12]=[C:13]([NH2:30])[N:14]=2)([O:19][CH2:20][O:21][CH3:22])[CH3:18])[CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCOC(C)(c1cccc(F)c1)c1cc(-c2c[nH]c3ncc(Br)nc23)nc(N)n1
Solvent: CN(C)C=O
Product: COCOC(C)(c1cccc(F)c1)c1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)nc23)nc(N)n1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-6-[1-(3-fluorophenyl)-1-methoxymethoxyethyl]pyrimidin-2-ylamine (0.249 g, 0.395 mmol) is dissolved in DMF (7 ml), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.164 g, 0.790 mmol) and Pd[PPh3]4 (0.046 mg, 0.040 mmol) are added, the reaction solution is flushed with nitrogen for 5 min, 2N Na2CO3 solution (1.5 ml) is subsequently added. The mixture is stirred at 130° C. for 1 h. The mixture is cooled to room temperature, ethyl acetate is added, and the organic phase is extracted three times with water, the aqueous phase is separated off, and the organic phase is dried over sodium sulfate. The solid is filtered off, and the residue is evaporated in vacuo. The residue is purified by RP-HPLC, giving 4-[1-(3-fluorophenyl)-1-methoxymethoxyethyl]-6-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]pyrimidin-2-ylamine (“A2”), (HPLC/MS Rt=1.72 min, [M+H] 475); 1H-NMR [DMSO-d6]: δ [ppm]=12.72 (br, 1H), 8.72 (s, 1H), 8.49 (m, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.43 (m, 1H), 7.32 (m, 2H), 7.13 (m, 1H), 4.79 (s, 2H), 3.95 (s, 3H), 3.37 (s, 3H), 1.98 (s, 3H);
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[CH3:15])(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:16][CH2:2][C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:3]
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(C)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To a solution of N-(4-acetyl-3,5-dimethylphenyl)acetamide (5.00 g, 24.4 mmol) in acetonitrile (48.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 11.7 g, 24.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.00 g), which was used directly for the next step without further purification.
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: COc1cc(N)c(C#N)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCCl
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: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:40]3[CH:39]=[CH:38][C:37]([NH:36][S:33]([CH3:32])(=[O:34])=[O:35])=[CH:42][CH:41]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulfonylamino)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (19%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]>C1COCC1>[C:13]1(=[O:14])[N:9]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C#CCCCCO
Solvent: C1CCOC1
Product: C#CCCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5-Hexyn-1-ol is added N-hydroxyphthalimide (1.1 equivalent) in dry THF. To this mixture is added diethylazo-dicarboxylate (DEAD) dropwise with stirring at ambient temperature for 18 hours. Evaporation of the reaction mixture followed by silica column purification yielded the 1-phthalimidooxy-hex-5-yne.