Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[NH2:53][C@H:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH2:55]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[C@H:54]1([NH:53][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=6)([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:44])[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH2:56][CH2:55]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCc2ccccc21)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (R)-(−)-1-aminoindane (0.239 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.292 g, 63% yield). ES-MS (m/z) 505 [M+1(−Tr)]+
Reaction SMILES: C(OC([NH:8][NH:9][C:10]1([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:15])[CH2:12][CH2:11]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:17]([O:16][C:14](=[S:15])[NH:13][C:10]1([NH:9][NH2:8])[CH2:11][CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NNC1(NC(=S)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NNC1(NC(=S)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N′-(1-benzyloxythiocarbonylamino-cyclopropyl)-hydrazinecarboxylic acid tert-butyl ester (0.25 g, 0.684 mmol) was dissolved in 4N HCl in dioxane (4 mL) and the reaction allowed to stir at room temperature overnight. The mixture was triturated with Et2O and the resulting precipitate collected by filtration. The precipitate was washed with Et2O to give (1-hydrazino-cyclopropyl)-thiocarbamic acid O-benzyl ester hydrochloride (0.15 g, 0.48 mmol) as a white solid, m/z 266.5 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.[CH3:35][C:36]([C:39](O)=[O:40])([CH3:38])[NH2:37]>>[Cl:33][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:30]([CH3:32])[CH3:31])[C:22]([NH:21][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:39](=[O:40])[C:36]([CH3:38])([CH3:35])[NH2:37])=[O:34]
Reactant: CC(C)(N)C(=O)O
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CN)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CNC(=O)C(C)(C)N)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12

Procedure:
Following the procedure described above with N-((1S)-2-amino-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide and N-[(1,1-dimethylethyl)oxy]carbonyl)-2-methylalanine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: Cn1ccnc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCc4nccn4C)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (488 mg, 1.5 mmol), 2-chloromethyl-1-methyl-1H-imidazole.HCl (100 mg, 0.6 mmol), tetrabutylammonium bromide (96 mg, 0.3 mmol), triethylamine (0.5 ml), and DMF (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The resulting solid was recrystallized from isopropanol/diethylether to yield 40 mg of 1-[4-amino-2-ethoxymethyl-7-(1-methyl-1H-imidazol-2-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off white solid, mp 200.0-202.0° C.
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.[Na].[CH2:9]([O:11][CH:12]([O:21][CH2:22][CH3:23])[C:13](=O)[CH2:14][C:15](OCC)=[O:16])[CH3:10].[Cl-].[NH4+]>O.C(O)C>[CH:2]1([C:5]2[NH:7][C:13]([CH:12]([O:21][CH2:22][CH3:23])[O:11][CH2:9][CH3:10])=[CH:14][C:15](=[O:16])[N:6]=2)[CH2:4][CH2:3]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)c1cc(=O)nc(C2CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A portion (˜40.4 mL) of the ethanol solution of cyclopropanecarboximidamide monohydrochloride as prepared in Example 1 was added to a portion (˜210 mL) of the solution of the sodium salt of ethyl 4,4-diethoxy-3-oxobutanoate as prepared in Example 2. The mixture was allowed to stir overnight at room temperature. The mixture was boiled for about 2 h and then allowed to cool to room temperature. The mixture was evaporated under reduced pressure, and the residue was redissolved in toluene (200 mL). A solution of ammonium chloride (0.68 g, 12.7 mmol) in water (30 mL) was added. After stirring for 10 minutes, the aqueous phase was removed. The organic phase was dried and evaporated to leave the product as pale yellow solid (27.27 g, 88% yield). Product recrystallized from hexanes melted at 111.5-112.0° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1>O>[F:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[CH:8][C:9]2[O:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(F)ccc2o1
Solvent: O
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
In a 500-ml flask, place 100 ml of concentrated nitric acid (70%) and warm to 45° C. Add 30.6 g (0.2 m) of 5-fluoro-benzoxazol-2-one (1a; X=F) and stir at 50° C. for 3 hrs. Add 240 ml of water slowly, and stir and cool to room temperature. Collect solid, wash with water, and dry in air to give 35.0 g (88%) of 5-fluoro-6-nitro-benzoxazol-2-one (2a; X=F) as pale yellow solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.C[Si]([N:20]=[C:21]=[O:22])(C)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21]([NH2:20])=[O:22])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)N=C=O
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Solvent: CC(C)O
Product: NC(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) in isopropanol (0.30 mL) was added trimethylsilyl isocyanate. The mixture was stirred at room temperature 15 hours, the solvent removed, and the residue purified by flash chromatography (0-5% methanol-dichloromethane) to give 23 mg (40% yield) of a brown solid. 1H-NMR (DMSO-d6): δ 10.91 (s, 1H), 7.57 (d, 1H), 7.30 (d, 1H), 7.16 (dd, 1H), 6.46 (d 1H), 4.87 (m, 1H), 2.64 (m, 2H), 1.97 (m, 1H), 1.90-1.65 (m, 3H); MS m/z 308 (M−1).
Reaction SMILES: C1(S([N:10]2[C:22]3[CH:21]=[C:20]([CH:23]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)[CH3:24])[CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C>[N:25]1([CH:23]([C:20]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:22]=3[CH:21]=2)[CH3:24])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CC(c1ccc2c3ccccc3n(S(=O)(=O)c3ccccc3)c2c1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccc2c(c1)[nH]c1ccccc12)n1ccnc1
Yield: 61.1 %

Procedure:
A mixed solution of the thus obtained 9-benzenesulfonyl-2-[1-(1H-imidazol-1-yl)ethyl]carbazole (0.436 g, 1.09 mmol), ethanol (50 ml) and 2N sodium hydroxide aqueous solution (10 ml) was heated under reflux for 4 hours. After evaporation of volatile components under reduced pressure, the resulting residue was mixed with chloroform and washed with saturated sodium chloride aqueous solution, and the organic layer was dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain crude crystals from the eluate of chloroform-methanol (100:1). By recrystallizing the crude crystals from ethyl acetate, 0.174 g of 2-[1-(1H-imidazol-1-yl) ethyl]carbazole was obtained.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]2([CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[CH2:4][C:3]1=O.Cl.[CH2:16](O)C>>[CH3:1][CH:2]1[S:6][C:5]2([CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[CH2:4][C:3]1=[CH2:16]
Reactant: CCO
Reactant: CC1SC2(CC1=O)CN1CCC2CC1
Agent: Cl
Product: C=C1CC2(CN3CCC2CC3)SC1C

Procedure:
5'-Methyl-4'-methylenespiro[1-azabicyclo[2.2.2]-octane-3,2'-thiolane] was prepared in much the same manner as in Example 5 by using 5'-methylspiro[1-azabicyclo[2.2.2]-octane-3,2'-thiolan]-4'-one. It was dissolved in ethanol, and then convereted to hydrochloride by addition of ethanolic hydrogen chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C@@H:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:22][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-(Dimethylamino)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1
Reactant: COc1cc(Br)c(C)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-c2ccncc2)c(C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A solution of 5-bromo-4-methyl-2-nitrophenyl methyl ether (6.0 g, 24.38 mmol), PdCl2(dppf)*DCM (1.43 g, 1.95 mmol) and 4-pyridylboronic acid (20.4 g, 165.8 mmol) in dioxane was deoxygenated by bubbling with N2 (g) for ca 15 min. To this solution was added degassed 2.0 N Na2CO3 (aq) (170 mL, 14.0 equiv.) and the resulting slurry was warmed to 80° C. for 24 h. The dioxane was removed under reduced pressure and the solids were dissolved in EtOAc and washed with H2O, dried (Na2SO4), and purified by flash chromatography to give the title compound of step A (2.81 g, 11.5 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (d, J=4.77 Hz, 2H), 7.79 (s, 1H), 7.22-7.31 (m, 2H), 6.90 (s, 1H), 3.95 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]([CH2:23][CH2:24][OH:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]([CH2:23][CH2:24][O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCC[C@H](O)CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCC[C@@H](CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under an argon atmosphere, triethylamine (324 ml, 2.32 mmol) and methanesulfonyl chloride (132 ml, 1.70 mmol) were added to a solution of (6S)-(-)-methyl 6,8dihydroxyoctanoate (147 mg, 0.77 mmol) in dichloromethane (3.9 ml) at 0° C. The mixture was stirred at 0° C. for 30 min, then quenched with ice water (10 ml) and extracted with dichloromethane (10 ml). The extract was washed with 2 M hydrochloric acid (10 ml), saturated sodium bicarbonate solution (10 ml) and brine (10 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (2:3) to give (6S)-(+)-methyl 6,8-bis(methylsulfonyloxy)octanoate (247 mg, 92% yield) as a clear yellow oil. Rf 0.30 (hexane-ethyl acetate, 3:2).
Reaction SMILES: Cl.[CH:2]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)([CH3:4])[CH3:3].[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH:2]([N:5]1[C:6]2[C:7](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]1=[O:21])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Nc1ccccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Yield: 147.4 %

Procedure:
A solution of 133.7 g of 2-isopropylaminobenzaldehyde hydrochloride, 200 g of diethyl malonate, 70 ml of piperidine, 70 ml of acetic acid, 50 g of potassium carbonate and 1.5 liter of toluene was heated to reflux for 10 hours. The reaction solution was washed with water and then with saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 256 g of ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as the crude product.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH:27]=4)=[CH:22][C:21]3=[O:37])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[CH:27]=3)=[CH:22][C:21]2=[O:37])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A solution of (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 237, 0.175 g, 0.32 mmol) in tetrahydrofuran (5 mL) was treated with hydrochloric acid (1 M, 1 mL). The reaction mixture was stirred at room temperature overnight and then neutralized with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo which afforded (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.097 g, 61%) as a white solid: HR-ES-MS m/z calculated for C26H36N4O6 [M+H]+ 501.2708, observed 501.2705; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.06 (s, 6H), 1.36-1.65 (m, 2H), 1.65-1.83 (m, 1H), 2.68 (s, 2H), 3.19-3.33 (m, 2H), 3.78 (d, J=5.1 Hz, 1H), 3.86 (dd, J=13.5, 7.5 Hz, 1H), 4.09 (dd, J=13.5, 3.8 Hz, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.37 (s, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.83 (s, 1H), 4.87 (dd, J=11.0, 4.7 Hz, 1H), 4.94 (d, J=5.1 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.06-7.19 (m, 3H), 7.28-7.43 (m, 1H), 7.53 (d, J=2.1 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][N:10]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 4′-[(7-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (2-bromoethyl)benzene (0.19 mL) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.055 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.27 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][C:34]1[CH:41]=[CH:40][C:37](CO)=[CH:36][CH:35]=1>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:37]2[CH:40]=[CH:41][C:34]([CH3:33])=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: Cc1ccc(CO)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Solvent: CC(C)O
Product: Cc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
Compound 22 was prepared in a similar manner to compound 7, substituting the commercially available 4-methyl-benzylalcohol for 2-propanol in part C. MS (M+1)=426.41
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:29]([NH2:28])[C:30]=4[NH2:31])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc(N)c4N)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in general procedure A. Purification by column chromatography yielded 3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine which was heated in formic acid at reflux for 4 h. After cooling to room temperature, the solution was poured into saturated aqueous sodiumhydrogen carbonate solution (20 mL) and extracted into dichloromethane (3×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Cl[CH2:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1.[Cl-].[NH4+]>O1CCOCC1.C1COCC1.O>[C:25]([O:24][C:22]([C:21]1[CH:29]=[CH:30][C:18]([CH2:17][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:19][CH:20]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(CCl)cc1
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 6.29 g (0.16 mol) of sodium hydride (careful: evolution of hydrogen) are added a little at a time to a solution of 48.24 g (0.26 mol) of diallyl malonate in 100 ml of dioxane and 40 ml of THF. After warming to room temperature, the mixture is stirred at 40° C. for 1 hour. At 40° C., 29.69 g (0.13 mol) of tert-butyl 4-chloromethylbenzoate, dissolved in 100 ml of dioxane and 40 ml of THF, are slowly added dropwise, and the reaction solution is then stirred at a bath temperature of 110° C. overnight. After cooling to room temperature, 40 ml of saturated ammonium chloride solution and 100 ml of water are added carefully to the reaction mixture. The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated to dryness under reduced pressure. The crude product obtained is purified by flash chromatography on 2 kg of silica gel (mobile phase: petroleum ether/ethyl acetate 20:1). This gives 30.4 g (81 mmol, 62% of theory) of a colorless solid.