Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]3[C:22]4[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=4)[C:16]([CH:26]=[CH2:27])=[N:15]3)=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH2:26]([C:16]1[C:17]2[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][C:22]=2[N:14]([CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[N:9]=[CH:10][CH:11]=2)[N:15]=1)[CH3:27]
Reactant: C=Cc1nn(Cc2ccnn2Cc2ccc(OC)cc2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCc1nn(Cc2ccnn2Cc2ccc(OC)cc2)c2cccc(N)c12
Reaction time: 3 h

Procedure:
To 1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-4-nitro-3-vinyl-1H-indazole (0.86 g, 2.2 mmol) in EtOH/DCM (20 mL/2 mL) was added palladium hydroxide on carbon (400 mg, 20% wt). The reaction mixture was purged with nitrogen and hydrogen three times each. The mixture was then stirred under hydrogen for 3 hours. The reaction mixture was filtered, washed with MeOH/DCM (10:1, 50 mL) and concentrated under reduced pressure to give the crude product 3-ethyl-1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-1H-indazol-4-amine. To imidazo[1,2-a]pyridine-3-carboxylic acid (0.43 g, 2.7 mmol) in DCE (5 mL) was added thionyl chloride (1.3 g, 11 mmol). The slurry was stirred for one hour. The reaction mixture was then concentrated under reduced pressure and dried under vacuum for 30 minutes. The resulting acid chloride was then resuspended in THF/DCE (5 mL/5 mL), to which the previously prepared 3-ethyl-1-((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)methyl)-1H-indazol-4-amine was added. The reaction mixture was heated to 80° C. for three hours. The mixture was cooled to ambient temperature, diluted with DCM (20 mL), washed with saturated NaHCO3 aqueous solution (20 mL) and brine (10 mL), and then concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) provided the product (0.36 g).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[NH:5][C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH3:28]>CN(C)C=O>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:12][CH3:13])[C:7]=2[C:6](=[O:14])[N:5]([CH2:28][CH2:27][CH2:26][CH:25]=[CH:24][CH3:23])[C:4]1=[O:15])[CH3:2]
Reactant: CC=CCCCCl
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCCCn1c(=O)c2c(ncn2CC)n(CC)c1=O
Yield: 94.7 %

Procedure:
20.8 g (0.1 mole) of 3,7-diethylxanthine, 15.2 g (0.11 mole) of potassium carbonate and 13.0 g (0.11 mole) of 1-chloro-4-hexene in 600 ml of dimethylformamide were stirred at 110° C. for 18 hours. After cooling down, the mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was taken up in chloroform. The unreacted 3,7-diethylxanthine was removed by extracting with 1N sodium hydroxide solution by shaking, the organic phase was washed to neutrality with water, dried over sodium sulfate and the solvent was distilled off in a rotary evaporator. After drying the solid residue from evaporation, 27.5 g (94.7% of theory) of crude 3,7-diethyl-1-(4-hexenyl)xanthine were obtained, ##STR29## which, after dissolving in 350 ml of chloroform and adding 23.1 g (0.114 mole) of 3-chloroperbenzoic acid (85% pure), was stirred under a nitrogen atmosphere at room temperature for 48 hours. The mixture was then initially extracted by shaking with 10% strength sodium dithionite solution until the iodine-starch reaction disappeared, and then with 10% strength sodium bicarbonate solution, and the solution was washed with water until neutral and free of salt, dried and evaporated under reduced pressure. 29.0 g (100% of theory) of crude 3,7-diethyl-1-(4,5-epoxyhexyl)xanthine were obtained ##STR30## which, after being taken up in a solvent mixture composed of 150 ml of tetrahydrofuran and 100 ml of water and addition of 0.46 ml of perchloric acid (70% strength), was stirred at room temperature for 90 hours. The mixture was then neutralized with saturated sodium bicarbonate solution, the solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel with chloroform as the mobile phase. This produced 26.4 g (86% of theory) of a crystalline product, which was recrystallized from ethyl acetate/petroleum ether, and which was almost pure by thin-layer chromatography.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield by reaction of 3.70 g (9.0 mmol) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester with 18 ml trifluoroacetic acid in 75 ml dichloromethane, MS m/e (%): 293.1 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9].[H-].[Na+].IC.[C:43](OCC)(=O)C>C1COCC1>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:17]2[CH2:16][CH2:15][CH2:14][N:13]([CH3:43])[C:12]=2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CCOC(C)=O
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CCCN2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In THF (3 ml) was dissolved N-[3,5-bis(trifluoro methyl)benzyl]-8-(4-fluorophenyl)-1,2,3,4,5,6-hexahydro-N,6-dimethyl-5-oxo-7-pyrido[4,3-b]pyridinecarboxamide (Example 27)(68 mg). To the solution were added sodium hydride (60% oil) (6 mg) and iodomethane (1.5 ml). The mixture was stirred for 15 hours at room temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried, then the solvent was distilled off to give the above-titled compound as colorless crystals (39 mg), m.p.230°-232° C. (recrystallized from ethyl acetate-ethyl ether)
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[NH:19]1[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]1=[O:21]>C([O-])(=O)C.[NH4+]>[C@@H:1]1([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h
Yield: 56 %

Procedure:
The assay mixture contained 2 g (wet weight) of Bacillus stearothermophilus cells, 5 mM 2′-deoxyinosine and 5 mM thymine in 10 ml of 50 mM ammonium acetate buffer (pH 5.5). The conversions were run at 55° C. for 1 hour. The reaction mixture was centrifuged and then filtered using an Amicon Ultrafiltration device (YM-3 membrane) and the products were separated and analyzed by HPLC (C-18 column) in 5% methanol and 5 mM phosphate buffer at pH 4.6 using a flow rate of 0.5 ml/min. Blanks were run to check the authenticity of the reaction. No undesirable side reactions were detected. Thymidine was obtained in 56% yield (78% conversion).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)=[C:15]([CH3:29])[N:14]=[C:13]1[CH2:30][N:31]([CH3:33])[CH3:32])=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[C:13]([CH2:30][N:31]([CH3:32])[CH3:33])=[N:14][C:15]([CH3:29])=[C:16]2[CH2:17][N:18]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccccc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccc1Cl)c1ccccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 6-(o-chlorophenyl)-1-[(dimethylamino)-methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:30])[C@H:19]([CH2:28][SH:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:16][O:17][C:18](=[O:30])[CH:19]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:28][S:29][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CSCc1ccc(-c2ccc(Br)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-Bromo-4-bromomethyl-biphenyl, 9.1 g (27.9 mmol), N-(tert-Butoxy-carbonyl)-L-cysteine methyl ester, 5.74 mL (27.9 mmol), cesium carbonate, 18.2 g (55.8 mmol), and 100 mL of N,N-dimethylformamide was stirred at room temperature for 4 h. The mixture was diluted with 200 mL of water and extracted with 2×200 mL of ethyl acetate. The organic layer was washed with 2×200 mL portions of aq. LiCl, sat. aq. NaHCO3, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified through a short plug of silica gel (eluted with 20% EtOAc-Heptane) to afford the desired product in 8.8 g (66%) as a white solid. 1H NMR (CDCl3) 7.55 (d, 2H, J=9.3 Hz), 7.50 (d, 2H, J=9.0 Hz), 7.43 (d, 2H, J=9.3 Hz), 7.37 (d, 2H, J=9.0 Hz), 5.31 (d, 1H, J=9.0 Hz), 4.62-4.51 (m, 1H), 3.76 (s, 5H), 2.93 (dd, 1H, 15.7, 5.7 Hz), 2.84 (dd, 1H, 15.7, 6.3 Hz), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16].C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=C1CCCC1c1ccc(F)cc1F
Reactant: O=C=NC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1F)CC2
Temperature: 120 °C
Yield: 36.4 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)cyclopentanone (1.014 g, 5.17 mmol) and 50% wt. carbonisocyanatidic chloride solution in toluene (1.963 g, 9.30 mmol) was heated at 58° C. for 1 h and at 120° C. for 3 h. The reaction mixture was dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(2,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (499.3 mg, 1.883 mmol, 36.4% yield) as brown solid. LC-MS (M+H)+=265.1.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
804 mg (3.2 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 16 ml dry THF and cooled to −78° C. After the addition of 2.21 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 680 μl (640 mg=3.84 mmol) (2-chloromethoxyethyl)-trimethylsilane (SEM-Cl) is added and stirring is continued at −20° C. for 5 h. The mixture is then allowed to warm up to room temperature overnight. The reaction is then quenched by addition of 10 ml saturated NH4Cl solution followed by 10 ml water and extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer dried over MgSO4, filtered and evaporated. The resulting residue (1.33 g) is purified using column chromatography (dichloromethane:triethylamine=99.5:0.5→dichloromethane:methanol:triethylamine=98.5:1:0.5) to give (S)-5-Biphenyl-4-ylmethyl-1-(2-trimethylsilanylethoxymethyl)pyrrolidin-2-one (1-a, R1=SEM) as a yellow oil. NMR (400 MHz, CDCl3, δ/ppm): 7.58 (m, 4 H); 7.47 (m, 2 H); 7.37 (m, 1 H); 7.30 (m, 2 H); 5.04 (d, J=10.6, 1 H); 4.70 (d, J=10.6, 1 H); 4.03 (m, 1 H); 3.59 (m, 2 H); 3.24 (dd, J=4.2, 13.4, 1 H); 2.67 (dd, J=9.1, 13.4, 1 H); 2.33 (t, J=8.2, 2 H); 2.10 (m, 1H); 1.81 (m, 1 H); 1.00 (m, 2 H); 0.06 (s, 9 H). MS (ESI, m/e) 382 [M+H]+; 763 [2M+H]+. IR (solution in CH2Cl2, ν/cm−1): 3057; 2951; 1702; 1487; 1414; 1249; 1073; 859; 836; 759; 697.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:16]=[C:17]=S)[CH:14]=[CH2:15]>C(OCC)(=O)C>[CH2:13]([NH:16][C:17]1[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9](=[O:11])(=[O:10])[N:12]=1)[CH:14]=[CH2:15]
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: C=CCN=C=S
Solvent: CCOC(C)=O
Product: C=CCNC1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and allyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 284-286° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 3.88 (distorted t, 2H, NHCH2), 5.1-5.3 (m, 2H, ═CH2), 5.78-6.0 (m, 1H, ═CH), 7.22-7.35 (m, 2H, ArH), 7.50 (br.t, 1H, NH), 7.69 (d, 1H, ArH), 10.73 (br.s, 1H, NH); MS: m/e 271/273 (M+); (C10H10N3Cl1O2S1) calc. C, 44.20; H, 3.71 N, 15.46; found C, 44.10; H, 3.79; N, 15.32.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)([CH3:4])[CH3:3].[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:27]([O:26][CH:7]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)NCC(O)COc1ccccc1Cc1cccc2[nH]ccc12
Reactant: O=C(O)c1ccccc1
Product: CC(C)(C)NCC(COc1ccccc1Cc1cccc2[nH]ccc12)OC(=O)c1ccccc1
Yield: 39.3 %

Procedure:
Using the procedure of Step G of Example 3, 16.3 g of the product of Step C and 5.65 g of the benzoic acid were reacted to obtain 8.29 g of the desired product melting at 195° C. (ethanol).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[O:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOC(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCOC(Cn2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-((4-methylmorpholin-2-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (63 mg, 97.9 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring at room temperature for 15 h the mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added. After 1 h the mixture was concentrated and purified by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) to give 2-[5-difluoromethoxy-1-(4-methyl-morpholin-2-ylmethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (22 mg, 43%). MS (M+H)+=514; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=2.3 Hz, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.39 (dd, J=9.0, 2.3 Hz, 1H), 7.20 (s, 1H), 4.58-4.68 (m, 2H), 3.74 (d, J=11.9 Hz, 1H), 3.37-3.48 (m, 1H), 2.79 (d, J=11.3 Hz, 1H), 2.57 (br. s., 3H), 2.18 (s, 3H), 1.84-2.01 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][N@@:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:20].CO>>[NH2:20][CH2:12][C@H:10]([NH:11][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CN)CO[Si](C)(C)C(C)(C)C
Yield: 47 %

Procedure:
A solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (5 g, 17.42 mmol) in NH3/MeOH (50 mL) was stirred at 50-60° C. for 48 h. After the reaction was complete, the mixture was concentrated in vacuo. The residue was purified on silica gel chromatography to afford (S)-tert-butyl 1-amino-3-(tert-butyldimethylsilyloxy)propan-2-ylcarbamate (2.5 g, 47%). 1H NMR (CDCl3, 300 MHz) δ 3.67 (m, 3H), 2.88 (d, 2H), 2.71 (s, 3H), 1.44 (s, 9H), 0.88 (s, 9H), 0.0 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:15][OH:16]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
5.2 g (29.2 mmol) of 6-methoxychroman-4-one were dissolved in ethanol and 2.53 g (36.5 mmol) hydroxylamine hydrochloride and 2.99 g (36.5 mmol) sodium acetate dissolved in 10 ml of water were added. The mixture was stirred at 65° C. for 1.5 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was dissolved in methyl-tert-butylether. The organic phase was washed with water, dried over MgSO4 and concentrated to give 5.6 g (29.4 mmol, quant.) of crude product, which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:40])[CH3:39])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:43])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([CH3:42])([CH3:41])[CH2:37][N:38]([CH3:39])[CH3:40])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)CN(C)C)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-19 (0.165 g) and lithium hydroxide (45 mg) were added to tetrahydrofuran (4 ml) and water (2 ml). The same manner to Example 2-12 was conducted to give the titled compound as a white solid. Yield: 80 mg (51%); mp 175-176° C., MS APC−ve 604 (M−H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][O:10][C:9]=2[CH:16]=1)[CH3:4].Cl.[CH3:18][O:19][C:20](=O)[O:21]C>>[CH3:18][O:19][C:20]([CH:13]1[CH2:12][CH2:11][O:10][C:9]2[CH:16]=[C:5]([CH2:3][CH3:4])[CH:6]=[CH:7][C:8]=2[C:14]1=[O:15])=[O:21]
Reactant: COC(=O)OC
Reactant: CCc1ccc2c(c1)OCCCC2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCc1ccc2c(c1)OCCC(C(=O)OC)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of sodiumhydride in paraffin (0.42 g, 60%) was added to 4 ml of dimethylcarbonate. To this suspension 8-Ethyl-3,4-dihydro-2H-benzo[b]oxepin-5-one (5.3 mmol) dissolved in 2 ml dimethylcarbonate was added dropwise at room temperature. The mixture was refluxed for two hours, cooled to room temperature and stirred overnight. 25 ml of 2 mol/l hydrochloric acid were added to the mixture. The resulting solution was extracted by ethyl acetate. The organic phase was dried over sodiumsulfate and the solvent removed in vacuo. 8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester was obtained as a brown oil in a yield of 87%. LC-MS: 2.2 min, 249.0 (MH+), 2.7 min, 249.0 (MH+)
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].[OH-].[Na+].O1CCOCC1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1ncc(N)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)Oc2ccccc2)c1N
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 4,5-diamino-1-methylpyrazole sulfuric acid salt (158 g) in water (1.1 L) was neutralized to pH 6.9 with 4N aqueous sodium hydroxide solution, and dioxane (474 ml) was added to this solution. To the resulting mixture was added dropwise phenyl chloroformate (124 g) maintaining pH of the mixture at 6.9 with 4N aqueous sodium hydroxide solution at a temperature below 10° C. The reaction mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried to give 5-amino-1-methyl-4-phenoxycarbonylaminopyrazole (155 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2cccc(Cl)c2)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (50%).