Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Si](OC[C@@H](N1C=CC(C2C=CN=C(S(C)(=O)=O)N=2)=CC1=O)C1C=CC(Cl)=C([F:60])C=1)(C(C)(C)C)(C)C>>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C@@H:4]3[CH2:5][CH2:6][O:1][CH2:2][C@H:3]3[F:60])[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(Cl)c1)n1ccc(-c2ccnc(N[C@@H]3CCOC[C@H]3F)n2)cc1=O

Procedure:
1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one was prepared according to the general procedure of Example 2, Step A, substituting (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine for tetrahydro-2H-pyran-4-amine and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one for (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one. m/z (APCI-pos) M+1=593.1, 595.2.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][C:26]1[CH:31]=[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[N:29]=[CH:28][C:27]=1[NH2:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:37][C:27]3[CH:28]=[N:29][C:30]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:31][C:26]=3[CH3:25])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1cc(N2CCCC2)ncc1N
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cnc(N3CCCC3)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 36.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 4-methyl-6-pyrrolidin-1-ylpyridin-3-amine (1.44 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (695 mg, 4.04 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was irradiated by microwave at 180° C. for 110 min. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/isopropyl ether to give the title compound (745 mg, 1.46 mmol, 36%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Ethyl (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-ethanol (6 mL), 1M aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and filtered. The obtained solid was washed successively with water, ethanol and diethyl ether to give the title compound (640 mg, yield 67%) as a pale-orange solid. The obtained solid was recrystallized from ethanol-hexane to give colorless crystals. melting point 218-219° C. MS 537 (MH+).
Reaction SMILES: C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.ClC(Cl)C.[Cl:20][C:21]1[C:26]([NH:27][C:28]2[N:33]=[C:32]([N:34]([CH:44]3[CH2:46][CH2:45]3)CC3C=CC(OC)=CC=3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:25][C:24]([C:52]#[N:53])=[CH:23][C:22]=1[N:54]1[CH2:59][CH2:58][CH:57]2[N:60]([C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:62][CH:56]2[CH2:55]1>>[Cl:20][C:21]1[C:26]([NH:27][C:28]2[N:33]=[C:32]([NH:34][CH:44]3[CH2:45][CH2:46]3)[C:31]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]3[N:29]=2)=[CH:25][C:24]([C:52]#[N:53])=[CH:23][C:22]=1[N:54]1[CH2:59][CH2:58][CH:57]2[N:60]([C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:62][CH:56]2[CH2:55]1
Reactant: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(Cl)Cl
Product: COC(=O)N1CCC2CN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CCC21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
Anisole (0.027 ml, 0.244 mmol) and 25% TFA in dichloroethane (2 ml, 6.49 mmol) were added to methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (28 mg, 0.0429 mmol) and the resulting solution was stirred at room temperature over the weekend. Solvent was evaporated in vacuo and the residue was dissolved in acetonitrile and neutralized with 2N ammonia in methanol. Desired product precipitated and was collected by filtration, methyl 5-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (17.2 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccccc2Cl)sc1C(=O)NCc1ccccc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 13% yield; 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=7.8 Hz, 1H), 7.46-7.27 (m, 8H), 5.95 (s, 1H), 4.57 (d, J=4.6 Hz, 2H), 2.33 (s, 3H); MS (ES+) m/z 386.1 (M+1).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:21])[CH2:18][O:19][CH2:20]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1
Reactant: [H][H]
Product: OC1(c2ccc3c(c2)CNC3)COC1

Procedure:
Prepared in analogy to Example A62(c) from 3-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-oxetan-3-ol and hydrogen. Brown solid. MS (m/e): 192.3 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:16]([N:4]1[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC1CNCC(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC(C)O1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a tetrahydrofuran solution (500 mL) of 2,6-dimethylmorpholine (Aldrich Co.) (mixture of cis/trans isomers) (25.02 g, 217.24 mmol), triethylamine (51.48 mL, 369.31 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Then, benzyl bromide (43.93 mL, 369.31 mmol) was added dropwise over 30 minutes, and the mixture was stirred for 4 days. A saturated aqueous solution of sodium hydrogen carbonate (200 mL) was added to the reaction liquor, and the mixture was stirred for 30 minutes, and then extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 65i, n-hexane to ethyl acetate/n-hexane 1:1), to obtain the title compound (10.7 g, 24%) as an oily matter.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: CN(CCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN(C)c1ccccc1

Procedure:
A 1 L flask was charged with 2-(N-methylanilino)ethanol (8) (151.3 g, 1 mole), methylene chloride (250 mL), and triethylamine (151 g, 1.48 mole). Acetic anhydride (153.35 g, 1.5 mole) was added to the solution at room temperature through an addition funnel. The product (7) was collected by vacuum distillation (122 g, bp 110° C. at 400 micron Hg).
Reaction SMILES: [Na].[CH2:2]([N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([C:7]1[C:8](=[O:20])[N:9]([CH3:19])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([Cl:18])[CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3].O.C([O-])(=O)C.[Ca+2:32].C([O-])(=O)C>C(O)C.O>[Ca:32].[CH2:2]([N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]([C:7]1[C:8](=[O:20])[N:9]([CH3:19])[C:10]2[C:15]([C:16]=1[OH:17])=[C:14]([Cl:18])[CH:13]=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: [Ca]
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
N-Ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide sodium salt (2.63 mmol, 1.0 g) was dissolved in a mixture of ethanol (10.5 ml) and water (5.3 ml). The solution was heated to 70° C. and a solution of calcium acetate hydrate in water (1M solution, 1.05 eq., 1.38 mmol, 1.38 ml) was added. The resulting suspension was stirred for 30 minutes, then cooled, and the crystals were isolated by filtration, washed with water, and dried under vacuum (966 mg, 98% yield). Anal. Calcd for C38H32Cl2N4O6Ca: C, 60.7; H, 4.29; N, 7.45. Found C, 60.5; H, 4.34; N, 7.41.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>CCCCCC.C1COCC1>[OH:11][C:12]1([C:7]2[S:6][CH:10]=[CH:9][N:8]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
1.600 M of n-Butyllithium in hexane (1.0×10−1 mL) was added to 1,3-thiazole (0.958 mL, 0.0135 mol) in THF (20 mL) at −78° C. After 30 minutes, tert-butyl 3-oxopyrrolidine-1-carboxylate (2.50 g, 0.0135 mol) in THF (10 mL) was added, and the mixture was slowly warmed to room temperature overnight. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate, dried with MgSO4, filtered and concentrated. The residue was purified by flash column (50% EtOAc/hexanes to pure EtOAc) to give the desired product (2.57 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl-:7].[C:11]1([CH2:10][CH2:9][CH2:8][N+:4]2[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCCCc1ccccc1
Reactant: Cn1ccnc1
Product: Cn1cc[n+](CCCc2ccccc2)c1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
0.15 mole of 1-methylimidazole and 0.125 mole of 1-chloro-3-phenylpropane were introduced into a 100 mL round bottom flask and stirred at 70° C. for one day to obtain 1-(3-phenylpropyl)-3-methylimidazolium chloride (yield 99%).
Reaction SMILES: [AlH4-].[Li+].[CH:3]([N:6]1[C:10]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([NH2:26])=O)=[CH:23][C:18]=4[O:17][CH2:16][CH2:15][N:14]3[CH:27]=2)=[CH:9][CH:8]=[N:7]1)([CH3:5])[CH3:4]>O1CCCC1>[CH:3]([N:6]1[C:10]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][C:22]([CH2:24][NH2:26])=[CH:23][C:18]=4[O:17][CH2:16][CH2:15][N:14]3[CH:27]=2)=[CH:9][CH:8]=[N:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(C(N)=O)cc1OCC2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(CN)cc1OCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Lithium tetrahydroaluminate (0.047 g, 1.3 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. A solution of 2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxamide (0.3 g, 0.9 mmol) in tetrahydrofuran (2 mL) was added and the reaction mixture was stirred at cold temperature for 10 min. The flask was gradually brought to room temperature and stirred for 16 h. The reaction was quenched by pouring into a mixture of diethyl ether and saturated aqueous Rochelle's salt solution (1:1). The mixture containing significant emulsion was stirred very vigorously until the phases separated (ca. 2 h). The phases were partitioned and the aqueous layer was extracted numerous times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give (0.15 g, 0.46 mmol) (2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)methanamine (MS (ESI+) m/z 323.1 (M+H+), calcd. 323.4) which was dissolved in glacial acetic acid (0.8 mL) and water (5 mL). A solution of potassium cyanate (0.114 g, 1.41 mmol) in water was added dropwise. N,N-dimethylformamide (3 mL) was added to help with dissolution. The resulting reaction mixture was stirred at room temperature for 12 h. Subsequently, the reaction was heated at 50° C. for 3 h. The mixture was cooled to room temperature and filtered to provide 0.02 g (10% yield) of 337. MS (ESI+) m/z 367.1 (M+H+), calcd. 367.4. 1H NMR (400 MHz, DMSO) δ 8.53 (s, 5H), 8.33 (d, J=8.2 Hz, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.43 (s, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 5.62 (s, 2H), 5.42 (s, 7H), 4.47 (s, 3H), 4.17 (d, J=5.8 Hz, 2H), 1.44 (d, J=6.4 Hz, 6H)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[C@@:36]([CH:38]=O)([CH3:37])[CH2:35][O:34][C:33]1([CH3:41])[CH3:40])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[C@:36]([CH:38]=[C:20]([Br:24])[Br:21])([CH3:37])[CH2:35][O:34][C:33]1([CH3:41])[CH3:40])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@@]1(C)C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C=C(Br)Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
Triphenylphosphine (17.3 g, 65.8 mmol) was dissolved in dichloromethane (25 ml), and a solution of carbon tetrabromide (10.9 g, 32.9 mmol) in dichloromethane (15 ml) was added dropwise thereto in an ice bath followed by stirring for 5 minutes in the ice bath. To the reaction solution was added dropwise a dichloromethane (40 ml) solution of 3-t-butoxycarbonyl-2,2-dimethyl-(4S)-formyl-4-methyloxazolidine (4.00 g, 16.4 mmol) obtained in Reference example 2(c). After stirring for 14 hours at room temperature, insoluble substances of the reaction mixture were filtered out, the filtrate was concentrated under reduced pressure to give the crude title compound (4.70 g, 71.2% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:3]=12.[I:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:20]=[C:21]([I:30])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)C(=O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cncc(-c2cnc3c(c(I)cn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 25 °C

Procedure:
1.117 g (2.59 mmol) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide was dissolved in 19 ml of anhydrous 1,2-dichloroethane. 1.506 g (6.69 mmol) of N-iodosuccinimide was added and the mixture irradiated in a microwave reactor to 140° C. for 30 minutes. Saturated aqueous solution of sodium thiosulfate was added and the resulting mixture stirred at ambient temperature, then diluted with water and dichloromethane. The aqueous phase was separated and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of 10% v/v methanol in ethyl acetate and hexanes to afford 904.7 mg (62%, 1.625 mmol) of (5-[4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide as a brown oil. 1H-NMR [500 MHz, d6-DMSO] d 8.75 (m, 1H), 8.69 (m, 1H), 8.39 (m, 1H), 8.12 (s, 1H), 8.02 (m, 1H), 5.64 (s, 2H), 3.54 (t, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 0.84 (t, 2H), 0.09 (s, 9H); MS [MH+] m/z: 557.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]1[O:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][O:40]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CC2CCCO2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 3 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added tetrahydrofurfurylbromide (125 μL). The reaction mixture is heated to 60° C. for 4 h and then allowed to stand at room temperature for 18 h. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 15 mg (3%) of the title compound as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2.Cl>O.C(O)C.CN(C)C=O>[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([S:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)=[O:2])[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(SCc3ccc(C(=O)O)cc3)ccc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(S(=O)Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A solution of 3.4 g (16 mmol) of sodium periodate in 30 ml of water was added dropwise to 5.3 g (15 mmol) of the thioether from Example 10 in a mixture of 150 ml of ethanol and 40 ml of dimethylformamide at 0° C., and the mixture was then stirred at the same temperature for 2 hours and at room temperature overnight. The reaction solution was then poured into water, the pH was adjusted to 5 with 2N hydrochloric acid, the mixture was extracted with dichloromethane, and the organic extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. Crystallization of the oily residue from ethanol yielded 2.2 g of title compound of melting point 198°-200° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C[O:12][C:13]1C=CC=C[C:14]=1N1CCN(CCO)CC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:14][CH2:13][OH:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1ccccc1N1CCN(CCO)CC1
Product: OCCN1CCc2ccccc2C1
Yield: 60 %

Procedure:
2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethanol (31A) is prepared from 1,2,3,4-tetrahydro-isoquinoline as described for 28A.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCCCCCN
Reactant: CCCCC1CO1
Product: CCCCC(O)CNCCCCCCNCC(O)CCCC

Procedure:
Condensation of 1-hexene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexylamine] (I: R= CH3 (CH2)3, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([OH:15])[CH:6]=1)(=[O:3])[CH3:2].[N+](C1C=C(S(O[CH2:29][C@@H:30]2[CH2:32][O:31]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN1CCCC1=O.CO.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([O:15][CH2:29][C@@H:30]2[CH2:32][O:31]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(=O)Nc1ccc(OC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(OC(C)=O)cc1OC[C@@H]1CO1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 4-(acetylamino)-3-hydroxyphenyl acetate (669 mg, 3.2 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (748 mg, 2.9 mmol) and Cs2CO3 ((1.05 g, 3.2 mmol) in 1-methyl-pyrrolidinone (10 mL) was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetatwe and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil which was suspended in methanol/diethyl ether. The precipitate was filtered off and dried to give the sub-title compound (296 mg).