Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:12]=3[NH:11][C:10]=2[CH:28]=1)=O)C.CC1(C)C2NC3C=C(CO)C=CC=3C=2C(CCCCCCCC)CC1>>[CH3:18][C:17]1([CH3:19])[C:12]2[NH:11][C:10]3[CH2:28][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8][C:9]=3[C:13]=2[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]=[CH:16]1
Reactant: CCCCCCCCC1CCC(C)(C)c2[nH]c3cc(C(=O)OCC)ccc3c21
Agent: CCCCCCCCC1CCC(C)(C)c2[nH]c3cc(CO)ccc3c21
Product: CCCCCCCCC1C=CC(C)(C)c2[nH]c3c(c21)CCC(CO)C3

Procedure:
Using the condition described in Example 16, 4.6 g of the ethyl ester from Example 13 was reduced to 5,6,7,8-tetrahydro-6,6-dimethyl9-octyl-9H-dibenzo[b,d]pyrrole-3-methanol (3.9 g; 95%) as a yellow oil after purification on a small pad of silica gel.
Reaction SMILES: [CH2:1]([S:3][C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:28]C(OCC1C=CC=CC=1)=O)=[N:17]C(OCC1C=CC=CC=1)=O)[CH3:2].[ClH:39]>[Pd].CO.C(OCC)(=O)C>[ClH:39].[CH2:1]([S:3][C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH2:28])=[NH:17])[CH3:2]
Reactant: CCS[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 68 %

Procedure:
A methanol/ethyl acetate (1.5 mL/1.5 mL) solution of compound 18 (117 mg, 0.19 mmol) and 1N HCl (0.19 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC. indicated the disappearance of the starting material (about 1 h). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 40 mg (68%) of the title product as a foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: Fc1ccccc1CBr
Reactant: CN(C)c1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(Cl)nc2c1ncn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.31 g (16.8 mmol) of 2-chloro-6-(N,N-dimethylamino)-9H-purine are dissolved in 60 ml of N,N-dimethylformamide. 4.16 g (30.2 mmol) of potassium carbonate and 2.02 ml (16.8 mmol) of 2-fluorobenzyl bromide are added to the solution. The reaction mixture is then stirred for 3 hours at room temperature and then ice water is added and the whole is extracted three times with dichloromethane. The combined organic phases are washed twice with water, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with toluene/ethyl acetate (3:1) as eluant. The eluate is concentrated by evaporation and the residue obtained is recrystallised from ethyl acetate/diethyl ether. In this manner 2-chloro-6-(N,N-dimethylamino)-9-(2-fluorobenzyl)-9H-purine is obtained in the form of colourless needles having a melting range of from 130° to 131°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].C(O)C.C(O)(C)C.O.NN>O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Agent: [Ni]
Agent: NN
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Temperature: 95 °C

Procedure:
A solution of 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline (709 mg, 2.076 mmol) in 140 ml of 1:9:10 water:ethanol:iso-propylalcohol was heated to reflux temperature (95° C.). Additional 60 ml of the solvents mixture was added until complete dissolution. The reaction mixture was then cooled to 65° C., and 200 μl hydrazine hydrate (4.12 mmol) and 0.5 ml Raney®Nickel (in water) were added subsequently thereto. The resulting mixture was heated up to 80–85° C., additional 0.5 ml Raney®Nickel and 50 μl of hydrazine hydrate (1.03 mmol) were added, and gentle reflux was maintained for about 15–20 minutes. Filtration and evaporation gave 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline (compound 2) in 83% yield. m.p.=265° C.; MS (m/z): 323.4, 325.4 (M+); Anal. calcd.: C, 52.9; H, 2.78; N, 17.33. Found: C, 52.19; H, 2.99; N, 17.14. HPLC analysis. C-18 column, 55% acetate buffer, PH=3.8/45% acetonitrile, flow=1 ml/min; r.t=6.6 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([Cl:18])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (2.50 g, obtained in Example 116, step 5) in CH2Cl2 (40 mL) were added nine drops of DMF and oxalylchloride (1.78 mL). The mixture was stirred at room temperature for 2 hours and was then concentrated to dryness. The resulting solid was dried at high vacuum over night. The title compound was abtained as a colorless solid (2.85 g, 99%). MS (EI)=211.0 [M+].
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.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]>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][NH:22]2)=[CH:18][C:17]=1[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: COc1cc(Br)ccc1OCCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(OC)c3)cc12
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a mixture of 3-(4-bromo-2-methoxyphenoxy)propan-1-ol (97 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) in toluene/EtOH (5 mL, 3:1) and water (1 ml) was added Pd(dppf)Cl2 (22 mg, 0.031 mmol). The mixture was degassed and purged with nitrogen for 5 minutes, then allowed to heat to 110° C. and stirred for 30 minutes. The reaction mixture was concentrated in vacuo to give a brown residue. The residue was purification by flash chromatography to give the title compound (92 mg, 76% yield) as a pale solid. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.03 (m, 2H), 7.00 (m, 1H), 4.18 (m, 2H), 3.87 (s, 3H), 3.80 (m, 2H), 3.37 (s, 3H), 2.05 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18](=[O:19])[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)N1CCCC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC(=O)N3CCCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), 2-bromo-1-pyrrolidin-1-yl-ethanone (3 g, 20 mmol) and cesium carbonate (19.5 g, 60 mmol) in dimethylformamide (16 mL) was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 0.8 g (25%) 5-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carboxylic acid ethyl ester as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=2)[C:36]([O:38]C(C)(C)C)=[O:37])[C:30]([CH3:46])=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12]([NH:26][C:27]3[N:32]=[C:31]([C:33]4[CH:34]=[C:35]([CH:43]=[CH:44][CH:45]=4)[C:36]([OH:38])=[O:37])[C:30]([CH3:46])=[CH:29][CH:28]=3)=[O:14])[CH2:10][CH2:11]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(C(=O)Nc3ccc(C)c(-c4cccc(C(=O)O)c4)n3)CC2)cc1
Reaction time: 0.5 h

Procedure:
1-(4-Methoxyphenyl)cyclopropanecarboxylic acid (57.7 mg, 0.300 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Thionyl chloride (0.3 mL) and N,N-dimethylformamide (0.03 mL) were added and the solution was allowed to stir for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting oil was re-dissolved in dichloromethane containing triethylamine (0.125 mL, 0.900 mmol). tert-Butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (85.3 mg, 0.300 mmol) was added and the reaction mixture was allowed to stir for 3 hours. Trifluoroacetic acid (1 mL) was added and the solution was allowed to stir for an additional 3 hours. The mixture was evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide and then purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 3-(6-(1-(4-methoxyphenyl)cyclopropane carboxamido)-3-methylpyridin-2-yl)benzoic acid. ESI-MS m/z calc. 402.2, found; 403.1 (M+1)+ Retention time 1.65 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:13]1[N:12]=[C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(F)n1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1cccc(Oc2cccc(CO)c2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-6-methyl-pyridine (3.00 g, 27 mmol,) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-50%, EtOAc:heptane) to afford the title compound (3.72 g, 64% yield) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([SH:27])=[CH:22][C:21]=1[CH3:28])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:28])[CH3:15]
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0.12 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.14 g; 0.25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Li]CCCC.[C@@H:21]12[C:30](=[O:31])[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[Cl-].[NH4+]>C1COCC1.O>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:30]([C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([OH:29])=[O:28])=[O:31])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)[C@H]2CCCC[C@H]2C(=O)O)cc1OC1CCCC1
Temperature: -90 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
4-Bromo-2-cyclopentyloxy-1-methoxybenzene (16.3 g, 60 mmol) was dissolved in THF (200 ml) and cooled with an ethanol/N2 bath to -90° C. BuLi (41 ml, 66 mmol) was added dropwise while keeping the temperature below -80° C. and stirred for another 15 min after the last addition. This mixture was then quickly added under a nitrogen atmosphere to a cooled solution (-90° C.) of cis-1,2-cyclohexanedicarboxylic anhydride (11.1 g, 72 mmol) in THF (200 ml). After stirring for 2 h at -80° C. solid ammoniumchloride was added and the reaction mixture was allowed to warm slowly to room temperature. Water (300 ml) was added and the anorganic layer was washed with ethyl acetate (200 ml). The combined organic extracts were washed with water (300 ml) and brine (2×300 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography (petroleum ether (60°-95° C.)/ethyl acetate: 7/13) and crystallized from petroleum ether (60°-95° C.)/ethyl acetate to give the title compound (10.1 g) as a white solid. M.p. 120°-121° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[Cl:23][C:24]1[C:29]2[C:30](=[O:45])[N:31]3[CH2:44][CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38](=[N:40]O)[NH2:39])[C:28]=2[CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[Cl:23][C:24]1[C:29]2[C:30](=[O:45])[N:31]3[CH2:44][CH2:43][CH2:42][C@H:32]3[C:33]3[N:34]([CH:35]=[N:36][C:37]=3[C:38]3[N:40]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:39]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: CN(C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Reaction time: 8 h
Yield: 37 %

Procedure:
1.4 g (13.5 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.6 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 elimination the solution was stirred at 70° for 30'. Then, 4.02 g (15 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. By evaporation of the solution and chromatography of the residue on 340 g of silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.99 g (40%) of (S)-8-chloro-1-(5-dimethylaminomethyl-1,2.4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 261°.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.[Pd]>[S:1]1[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=[C:5]1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2sc(-c3nccc4ccccc34)cc2c1
Yield: 79 %

Procedure:
Benzo[b]thiophene-2-ylboronic acid (997 mg, 5.6 mmol) and 1-chloroisoquinoline (946 mg, 5.8 mmol) were dissolved in toluene (20 ml) and ethanol (10 ml), and palladium catalyst (220 mg, 0.19 mmol) and 2M sodium carbonate solution (20 ml) were added thereto, followed by refluxing under a N2 atmosphere for 5 hours. The reaction solution was added to H2O, and the mixture was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 1.16 g, yield: 79%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>>[CH3:26][O:27][CH2:28][C:29]([NH:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:14]3[CH:13]=[N:12][CH:11]=[C:10]([NH:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[N:15]=3)[C:20]=2[CH:21]=1)=[O:30]
Reactant: COCC(=O)Cl
Reactant: C[C@H](Nc1cncc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Product: COCC(=O)Nc1ccc2ncn(-c3cncc(N[C@@H](C)c4ccccc4)n3)c2c1
Yield: 24.8 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and methoxyacetyl chloride (20 mg, 0.11 mmol) furnished the product (10 mg, 25%) after chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (3.97 g) and triethylamine (3.5 ml) in chloroform (80 ml) was added a solution of 2-nitrobenzenesulfonyl chloride (5 g) in chloroform (20 ml) at 0° C. with stirring and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed successively with diluted hydrochloric acid and water, and then dried. Evaporation of the solvent gave N-(3,4-dichlorobenzyl)-2-nitrobenzenesulfonamide (6.87 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([S:17][CH3:18])=[N:5][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1nc(Cl)c(C)c(-c2ccc(F)cc2F)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nc(Cl)c(CBr)c(-c2ccc(F)cc2F)n1
Reaction time: 6 h

Procedure:
A suspension of 5.4 g of 4-chloro-6-(2,4-difluorophenyl)-5-methyl-2-(methylthio)pyrimidine. 3.69 g of N-bromosuccinimide, and 460 mg of benzoyl peroxide in 75 mL of CCl4 was heated to reflux and stirred at this temperature for 6 h, then cooled in the freezer for 1 h. The solids were filtered and washed liberally with cold CCl4, and the filtrate was concentrated. The residue was purified by flash chromatography on a Biotage 40M column, eluting with a gradient system of 99:1 to 97:3 hexanes-acetone to yield the title compound. Mass spectrum (ESI) 367 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][CH:43]=2)O1>>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])=[CH:3][C:2]([C:38]3[CH:43]=[N:42][C:41]([N:44]4[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]4)=[CH:40][CH:39]=3)=[CH:10][C:9]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (65 mg, 0.141 mmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (61 mg, 0.212 mmol). The product was collected as a white solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br. s., 1H) 8.49-8.63 (m, 2H) 8.43 (br. s., 1H) 7.97 (dd, J=8.84, 2.53 Hz, 1H) 7.89 (s, 1H) 7.32 (s, 1H) 6.87-6.96 (m, 1H) 5.91 (s, 1H) 5.03 (dt, J=13.07, 6.47 Hz, 1H) 4.38 (d, J=4.55 Hz, 2H) 3.40-3.61 (m, 5H) 2.77-2.82 (m, 3H) 2.53-2.57 (m, 2H) 2.43 (s, 3H) 2.13 (s, 3H) 1.53-1.60 (m, 2H) 1.46 (s, 3H) 1.44 (s, 3H) 0.93 (t, J=7.33 Hz, 3H); LC-MS (ES) m/z=542.2 [M+H]+
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:39]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Yield: 25.7 %

Procedure:
3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.648 mmol), tert-butyl 3-{[(4-methylphenyl)sulfonyl]oxy}-1-pyrrolidinecarboxylate (1.12 g, 3.30 mmol) and cesium carbonate (1.07 g, 3.30 mmol) in N,N-dimethyl formamide (12 mL) was heated at 75° C. overnight. The reaction mixture was poured on to ice-water (100 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate as mobile phase to give tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinecarboxylate (0.20 g, 28%). 1H NMR (DMSO-d6) δ 1.38 (m, 9H), 2.37 (m 2H), 3.32 (s, 3H), 3.44 (m, 1H), 3.59 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.44 (m, 1H), 7.16 (m, 5H), 7.43 (m, 2H), 7.65 (m, 2H), 8.26 (s, 1H).