Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]([O:11]CC)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:14](OCC)=[O:15].C(O[K])(C)(C)C>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH:4]=[O:11])[CH:14]=[O:15])[CH3:10]
Reactant: CCOC=O
Reactant: CCOC(=O)CC(OCC)OCC
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Ethyl 3,3-diethoxypropionate (100 g, 525.7 mmol) was dissolved in THF (360 ml) at room temp. Ethyl formate (175.1 ml, 2.1 mol) was added at room temp. The solution was cooled in an ice-bath to 0° C. and tBuOK (1M solution in THF, 1,156 ml, 1.156 mol) was added via an addition funnel slowly over 30 min, maintaining internal temperature below 5° C. The color changed instantly from colorless to dark orange. The reaction mixture was allowed to warm up to room temp. and stirred for 2 h. The reaction was allowed to stir at room temp. for 18 h. The reaction mixture was concentrated in vacuo and 1 L of solvent was removed. The remaining brownish solution with white solid in it was cooled in an ice-bath and hydrochloric acid (6N, 200 ml) was added to adjust pH=3, maintaining internal temperature below 20° C. The resulting bright yellow suspension was then warmed up to room temp. and stirred for 1 h. Additional 700 ml solvent was removed in vacuo at room temp. Water (400 ml) was added to dissolve all the white solid and ethyl acetate (500 ml) was added and the mixture transferred to a separatory funnel. The aqueous was extracted once with ethyl acetate (200 ml). The combined organic extracts was washed once with brine (100 ml). After drying over MgSO4 and concentrating in vacuo, 2-formyl-3-oxo-propionic acid ethyl ester (75.85 g) was obtained as yellow oil.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[F:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CS(C)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:26]([F:32])[CH:27]=1
Reactant: [C-]#N
Reactant: CSCc1cc(F)cc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3F)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
190 mg (2.91 mmol) of potassium cyanide and 8.9 mg (0.07 mmol) of 4-N,N-dimethylaminopyridine were added to 670 mg (1.46 mmol) of the compound from Example 56A in 40 ml of DMSO. The mixture was stirred at 80° C. for 2 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 522 mg (92% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@@H:19](O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C=O)cc2)C1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
In 40 ml of tetrahydrofuran were dissolved 1.31 g of p-hydroxybenzaldehyde, 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphine. With stirring at room temperature, 1.91 g of diethyl azodicarboxylate was added to the thus prepared solution, and the mixture was stirred for 45 minutes. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a benzene/ethyl acetate mixture as an elution solvent. In this way, 2.9 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]benzaldehyde was obtained in an oily form.
Reaction SMILES: [CH:1]([C:3]1[S:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)=[O:2].[BH4-].[Na+]>CO.O>[OH:2][CH2:1][C:3]1[S:17][C:6]2[O:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: O=Cc1cc2c(s1)Oc1ccccc1NC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1Nc2ccccc2Oc2sc(CO)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
2-Formylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.6 g) was suspended in methanol (30 ml) and sodium borohydride (480 mg) was added. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted 3 times with chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. To the residue were added chloroform and diisopropyl ether and the precipitated crystals were collected by filtration to give 2-hydroxymethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.0 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]#[N:23]>>[C:22]([CH:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:24]([CH3:27])([CH3:26])[CH3:25])#[N:23]
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CC(C)(C)C(N)C#N
Product: C[C@H](Oc1cc(C(=O)NC(C#N)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3,3-dimethyl-butyronitrile (CAN 77425-86-6) as starting materials and isolated (2 g, 99%); MS (ESI, m/z): 370.6 (M+H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][CH:13]([Cl:35])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][CH:18]=1)=[O:15]>C(O)(=O)C>[Cl:35][CH:13]([Cl:12])[C:14]([NH:16][C:17]1[N:21]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([Cl:33])[C:23]=2[Cl:34])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])=[O:15]
Reactant: O=C(Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl)C(Cl)Cl
Reaction time: 20 h
Yield: 76.4 %

Procedure:
1.2 ml (0.0129 mol) of acetic anhydride and 0.6 ml (0.0143 mol) of 98% strength nitric acid are added in succession to 5 g (0.0113 mol) of 5-dichloroacetamido-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 10 ml of glacial acetic acid at room temperature. The mixture is stirred for 20 hours, after which it is evaporated down in vacuo, the residue is taken up in 50 ml of dichloromethane and the solution is washed in succession with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent in vacuo. 4.2 g (76.4% of theory) of 5-dichloroacetamido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 112° C.-120° C. are obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(F)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(F)c1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A solution of 2-bromo-1-(3-fluorophenyl)ethanone (1.00 g, 4.61 mmol) and potassium thiocyanate (448 mg, 4.61 mmol) in ethanol (10 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water (12 ml) was poured into the reaction solution, and a crystal was separated by filtration, which was washed with 50% aqueous ethanol solution to give the desired product (668 mg, 74.3%) as a solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.Cl.[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37].C(P(C#N)(CC)=O)C>ClCCl>[CH3:34][C:35]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:36]=1[NH:37][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1cccc(N)c1C
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Yield: 25.4 %

Procedure:
A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath for 3 hours. The mixture is washed with H2O, 1M NaHCO3, H2O, 1N HCl, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness under vacuum and the residue crystallized from dichloromethane-hexane to give 0.11 g of crystals, m.p. 239°-240° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH:27]=[C:26]([C:31]([O:33]CC4C=CC=CC=4)=[O:32])[CH:25]=[CH:24]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O1CCOCC1.[Pd]>[C:1]12([C:11]3[CH:12]=[C:13]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19][OH:20])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(OCc1ccccc1)c1ccc2cc(-c3ccc(CCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)c1ccc2cc(-c3ccc(CCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
2.67 g (5 mmol) of the ester obtained in Example 42, in solution in 50 ml of dioxane, are stirred under a hydrogen pressure of 7 bar for 7 h at room temperature and then for 1 h at 50° C. in the presence of 800 mg of palladium on carbon (10%). After the same treatment as in Example 5 followed by a recrystallization from the ethanol/water mixture, 1.78 g (81%) of the expected derivative are isolated, which derivative melts at 262.4° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[O:22])[CH:19]=3)[CH:14]=[CH:13]2)[CH2:10][CH2:11]1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccccc3F)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2ccn(C3CCN(CCc4ccccc4F)CC3)c2c1
Yield: 78 %

Procedure:
A suspension of 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-formylindoline (2.50 g) obtained in Example 348-3) and activated manganese dioxide (5.0 g) in chloroform (100 ml) was heated under reflux for 4 hr under vigorous stirring. Further, activated manganese dioxide (5.0 g×1, 2.5 g×2) was added to the reaction mixture at 1 hr intervals and the resultant mixture was reacted for additional 2 hr. The reaction solution was filtered through celite and the residue was washed with chloroform. The filtrate was concentrated under reduced pressure to give the title compound (1.94 g) as a yellow powder (yield: 78.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](=[O:13])[CH2:11][OH:12])=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CO.[BH4-].[Na+].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:35][C:34]1[CH:36]=[CH:37][C:31]([S:28]([O:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:14]#[N:15])[CH:4]=[C:3]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[C:2]=2[Cl:1])(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(CCC(=O)CO)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC(O)CCc2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
To a round bottom flask was added tert-butyl (2-chloro-5-cyano-3-(4-hydroxy-3-oxobutyl)phenyl)carbamate (500 mg, 1.476 mmol) and MeOH (1 mL). The solution was then cooled to 0° C. before NaBH4 (100 mg) was added. The reaction was then stirred at 0° C. for 30 min and then slowly warmed to room temperature, and stirred for additional 1 h. The reaction was then quenched with aq. NaHCO3, extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was then dissolved in DCM (10 mL). Pyridine (1 mL) was added. After the reaction was cooled to 0° C. Ts-Cl (310 mg, 1.623 mmol) was added, and the reaction was then allowed to warm to room temperature and stirred for 5 h. The reaction was then taken up with DCM, washed with brine, and concentrated in vacuo to give 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxybutyl 4-methylbenzenesulfonate (810 mg) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH3:28])[CH:25]=[C:24]4[CH2:29][CH2:30][C:31](O)=[O:32])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].II>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH3:28])[CH:25]=[C:24]4[CH2:29][CH2:30][CH2:31][OH:32])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCO)cn(C)c34)no2)cc1Cl
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a suspension of NaBH4 (0.52 g) in THF (50 mL) was added a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E2) (1.5 g) in THF (20 mL) dropwise. The mixture was stirred for 15 mins and a solution of I2 (1.7 g) in THF (90 mL) was added dropwise. The reaction mixture was stirred at 20° C. for 20 h. The reaction mixture was quenched with water, the solvent was evaporated and the residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was washed with aqueous HCl (2 M), water and brine, dried over sodium sulphate and evaporated to give the crude product as yellow foam, which was purified by column chromatography (15% EtOAc in hexanes) to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-1-propanol (D128) (900 mg). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.80 (2H, m), 2.75 (2H, t), 3.48 (2H, t), 3.60 (3H, s), 4.47 (1H, t), 4.88 (1H, m), 7.16 (2H, m), 7.43 (2H, m), 7.77 (1H, d), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C23H24ClN3O3 requires 425; found 426.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=4)[C:20]3=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:41][CH2:40][C:39]5[CH:42]=[CH:43][CH:44]=[C:37]([Cl:36])[CH:38]=5)[N:27]=4)[C:20]3=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ncc3c(-c4ccnc(S(C)(=O)=O)n4)n[nH]c3n2)CC1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCN(CCNc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of 4-{2-[3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (from Example 27 supra) (153 mg, 0.304 mmol) and 3-chlorobenzylamine (171 mg, 1.21 mmol) was heated at 130° C. with stirring for 3 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 100-200 mesh, eluting with dichloromethane:methanol, 10:1) and further purified by prep-HPLC to afford 4-(2-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester. (Yield 90 mg, 52%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[OH:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[OH:16])[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccccc1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2O)C(=O)OC1=O

Procedure:
To a boiling solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of o-hydroxyaniline. The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[1-(o-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 210° -212° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1[S:7][CH:8]=[C:9]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[NH:10]2>C(Cl)Cl>[Cl:4][C:8]1[S:7][CH:6]=[C:15]2[C:14](=[O:16])[NH:13][C:12]3[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=3[NH:10][C:9]=12
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: ClCCl
Product: O=C1Nc2ccccc2Nc2c1csc2Cl

Procedure:
13.5 g of sulfuryl chloride in 100 ml of methylene chloride are added dropwise to a solution of 21.6 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 300 ml of methylene chloride at -40° C. The mixture is left to stand at room temperature for a further hour and is then extracted by shaking it with sodium bicarbonate solution and washing it with water; the organic phase is dried and concentrated. The residue is made to crystallize with a little methanol. 3-Chloro-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one is thus obtained.
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19]>O1CCCC1>[N:14]1[CH:13]=[CH:12][CH:17]=[N:16][C:15]=1[C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][CH:21]=[C:20]2[CH2:18][OH:19]
Reactant: O=Cc1cccc2ccccc12
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cccc2c(-c3ncccn3)cccc12
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck flask round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet is added 100 ml of anhydrous diethyl ether and 62.5 ml of 1.6 molar butyllithium solution (in hexane). The system is cooled to -120° C. and 15.90 gm of 5-bromopyrimidine in 50 ml of tetrahydrofuran is added over 2 hours. After addition of the 5-bromopyrimidine, the system is stirred for an additional 45 minutes. At this time, 15.60 gm of 1-formylnaphthalene in 50 ml of tetrahydrofuran is added to the system while still maintaining a temperature of -120° C. The system is kept at -120° C. for an additional 3 hours after addition of the 1-formylnaphthalene and afterwards is allowed to come to room temperature. After 10 hours at room temperature, the system is quenched with saturated ammonium chloride (in water). The system is adjusted to pH2 with HCl solution. The product is extracted with methylene chloride. The methylene chloride is washed with a 10% NaOH solution and then is dried over sodium sulfate. The methylene chloride is removed by stripping and the residue is triturated with hexane to give the 5-pyrimidyl-1-naphthylcarbinol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=1)=[CH:9][CH:8]=2)=[O:4].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:35](Cl)=[O:36].O>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:40]([Cl:41])=[C:32]([Cl:31])[CH:33]=3)=[CH:17][N:16]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2cc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
5-(5-Nitropyridin-2-yloxy)-1H-indole-2-carboxylic acid methyl ester (0.750 g, 2.39 mmol) was dissolved in THF (20 mL). To the solution was added 5% Pd/C (0.10 g), and the resulting mixture was subjected to catalytic reduction for 2 hours at room temperature under atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated to yield of a pale yellow oil (0.677 g). This product was dissolved in THF (30 mL). To the solution were added triethylamine (0.333 mL, 2.39 mmol), subsequently 3,4-Dichlorobenzoyl chloride (0.501 g, 2.39 mmol) and the resulting solution was stirred for 1 hour at room temperature. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate to yield 1.00 g of the title compound as a white powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.O[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C:55]1=[O:60]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:52][CH2:53][N:54]5[CH2:59][CH2:58][CH2:57][CH2:56][C:55]5=[O:60])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: O=C1CCCCN1CCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCCCC4=O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 33 mg (0.23 mmol) 1-(2-hydroxyethyl)-piperidin-2-one. After the elimination of the desiccant and solvent the residue was taken up in DCM and again purified by chromatography (silica gel, DCM/EtOH/NH3 95:5:0.5). The fractions containing the product were combined, concentrated by evaporation i. vac., triturated with DIPE, suction filtered and dried.