Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[C:10]1(Cl)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>>[NH2:7][C:2]1[CH:3]=[C:4]([C:10]2([C:5]3[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: ClC1(Cl)c2ccccc2-c2ccccc21
Reactant: Nc1ccccc1N
Product: Nc1ccc(C2(c3ccc(N)c(N)c3)c3ccccc3-c3ccccc32)cc1N
Temperature: 105 °C
Reaction time: 4 h

Procedure:
Into a three-necked 100 mL round-bottomed flask is placed o-phenylene diamine (26 g). The flask is then equipped with a drying tube, magnetic stirbar, thermometer, powder addition funnel, and nitrogen inlet. The o-phenylene diamine is then stirred and heated to 105° C. and solid 9,9-dichlorofluorene is added to the melt. An immediate reaction occur s as evidenced by a color change to dark brown, formation of a copious precipitate and an increase in temperature to 110°-120° C. The temperature is then increased to 130° C. and held there for 4 hours during which time the mixture becomes more liquid. The reaction is then allowed to cool and the excess o-phenylenediamine is removed by pouring the reaction mixture into ethanol and filtering. The resulting dark brown solid is recrystallized from toluene to yield 9,9-bis(3,4-diaminophenyl)fluorene. HNMR (DMSO): delta 4.97 (bs, 8H, NH2), 6.07-6.11 (m, 2H), 6.31-6.42 (m, 4H), 7.17-7.33 (m, 6H), 7.76-7.79 (m, 2H). C-13 NMR (DMSO) (ppm): 152.55, 139.7 1,136.29, 134.37, 132.64, 127.56, 127.17, 126.40, 120.37, 118.36, 117.69, 115.63, 115.11, 64.4 (quaternary carbon) where s=singlet, m=multiplet, and bs=broad singlet.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])=[CH:16][CH:15]=1
Reactant: Brc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
In a 250 mL flask equipped with a nitrogen inlet, overhead stirring assembly, and reflux condenser were placed 3-nitrobenzoyl chloride (28 g, 0.15 mol), bromobenzene (130 g, 0.83 mol), and aluminum chloride (22 g, 0.16 mol). The mixture was heated for 3 h at 100° C., then cooled to room temperature and stirred for an additional 16 h. The mixture was poured into 1 L of acidic (HCl) ice water, and the organics were extracted using methylene chloride, dried over magnesium sulfate, and the solvents were removed under reduced pressure to yield a yellow powder. Recrystallization from acetone afforded 42.1 g (90% yield) of white crystals: m.p. 104°-105° C.
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]1.[NH2:25][NH2:26]>C(O)C>[CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:25][NH2:26])=[O:13])[CH2:9][CH2:10]1
Reactant: CCOC(=O)CN1CCN(Cc2c(C)c(C)c(C)c(C)c2C)CC1
Reactant: NN
Solvent: CCO
Product: Cc1c(C)c(C)c(CN2CCN(CC(=O)NN)CC2)c(C)c1C

Procedure:
Synthesized according to General Procedure C: 6{14} (2.40 g, 7.23 mmol, 1 equiv.), anhydrous hydrazine (0.68 mL, 21.7 mmol, 3 equiv.), ethanol (14.5 mL). Recrystallization from EtOH afforded 1{14} (1.88 g, 82%) as a light yellow crystalline solid. 1H-NMR (500 MHz, CDCl3): δ 8.19 (br s, 1H), 3.85 (d, 2H, J=5.0 Hz), 3.55 (s, 2H), 3.05 (s, 2H), 2.47 (br s, 8H), 2.30 (s, 6H), 2.25 (s, 3H), 2.23 (s, 6H). 13C-NMR (125 MHz, CDCl3): δ 170.7, 133.9, 133.9, 132.4, 131.6, 60.6, 56.4, 54.0, 52.5, 17.0, 16.8, 16.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH2:19]([NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCN
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: CC(C)CCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 75 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and isopentylamine in 75% yield using the procedure described for example 37, and was characterized by its mass spectrum as follows: MS (m/z): 310 ([M+H]+, 100).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1F>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: c1c[nH]nn1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1-n1ccnn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.8 %

Procedure:
A slurry of sodium hydride (60% in oil, 44 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) was stirred under an atmosphere of nitrogen and treated dropwise with a solution of 1,2,3-triazole (76 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) at 0°. The mixture was allowed to warm to ambient temperature over 20 minutes, then a solution of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-yl-methyl)-4,5-dihydroisoxazole (264 mg, 1 mM) in anhydrous N,N-dimethylformamide (2 ml) added, and the mixture stirred at 70° for 16 hours. After cooling, the mixture was partitioned between aqueous sodium bicarbonate solution (40 ml) and ethyl acetate (40 ml), and the organic extract washed with water (40 ml) and brine (40 ml). After drying (magnesium sulfate) and evaporation, the crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with ethyl acetate. Relevant fractions were combined to give the desired product (12 mg).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[CH2:7]1[CH:11]2[CH:12]3[CH:16]=[CH:15][CH:14]([CH:10]2[CH:9]=[CH:8]1)[CH2:13]3.C(OC(C1CC2CC1C=C2)=O)(=O)C.C1CC=CC=1>>[C:1]([O:4][CH:5]1[CH2:6][CH:7]2[CH2:8][CH:9]1[CH:10]1[CH:11]2[CH:12]2[CH2:13][CH:14]1[CH:15]=[CH:16]2)(=[O:3])[CH3:2]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=COC(C)=O
Agent: C1=CCC=C1
Agent: CC(=O)OC(=O)C1CC2C=CC1C2
Product: CC(=O)OC1CC2CC1C1C3C=CC(C3)C21
Yield: 36 %

Procedure:
The reaction was carried out in the same manner as in the Synthesis Example 1(1), except for using vinyl acetate, dicyclopentadiene, and 5-acetoxycarbonylbicyclo[2.2.1]hept-2-ene at a molar ratio of 3:1(as cyclopentadiene):1 as reaction raw materials, to obtain 8-acetoxytetracyclo[4.4.0.12,5.17,10]dodec-3-ene of the following formula (13) at an yield of 36%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=[O:9].O.NN>[Rh].O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9]
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Rh]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: ONc1ccccc1F
Reaction time: 0.33 h

Procedure:
0.5 g of a commercial rhodium catalyst (5% on charcoal) was added to a stirred mixture of 25 g of 2-fluoronitrobenzene and 250 ml of tetrahydrofuran at room temperature. Then 16.5 g of hydrazine hydrate was added, drop-by-drop, to the stirred mixture, maintained at 15°-20° C. After 20 minutes, another 0.5 g of the rhodium catalyst was added, then another 2 g of hydrazine hydrate was added. The mixture was stirred at 15°-20° C. for 2 hours, then filtered through Celite. The filtrate was extracted with ether, the extract was washed with water, and dried (MgSO4) and the solvent was evaporated. The residue was triturated with ether and hexane, and kept cold until filtered. The filter cake was washed with cold hexane and air-dried to give N-(2-fluorophenyl)hydroxylamine (1B) as a colorless solid, mp: 70°-71° C. It is moderately unstable at room temperature.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C@@:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:38][CH2:37][C:26]3[N:27]=[C:28]([C:30]4([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from (S)-2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester (95% ee; Chiralpak AD separation, 8×28 cm, 10% IPA/heptane, 275 nm) by the procedure described in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COCCOC.Cl[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:30][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(CCl)cn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added 5-(chloromethyl)-2-methylpyridine (0.41 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate (0.55 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH:8]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[C:16](Cl)=[O:17])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[CH2:10][CH2:9]1
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(=O)C(C)C
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for example D1 using methyl 2-methylproponate and 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride as starting compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=397.1 [M+H]+.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([N:27]3[C:31]([CH3:32])=[N:30][N:29]=[N:28]3)[CH:18]=2)[C@@H:10]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:45][CH2:46][C:47]#[C:48]CCl.C(=O)([O-])O.[Na+]>C(O)C.O>[Cl:45][CH2:46][C:47]#[C:48][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([N:27]3[C:31]([CH3:32])=[N:30][N:29]=[N:28]3)[CH:18]=2)[C@@H:10]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1nnnn1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: ClCC#CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A solution of HCl in ethanol (5M, 4 ml) was added to a stirred solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (125 mg, 0.24 mmol) in ethanol (2 ml). The mixture was stirred at room temperature for 90 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 ml) and potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 16 hours. Further potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added and the mixture was stirred at 50° C. for 2 hours. Further potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added and the mixture was stirred at 50° C. for 1 hours. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (50:50 increasing to 80:20) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (90 mg, 74%) 1H (CDCl3) δ 7.54 (2H, s), 7.44-7.06 (6H, m), 4.63 (1H, d, J=12.9 Hz), 4.16 (3H, m), 3.61-3.22 (4H, m), 3.04 (1H, m), 2.65 (1H, m), 2.55 (3H, s), 2.21 (2H, m), and 1.63 (2H, m). m/z 504 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([S:18][CH3:19])=[O:17])=[CH:11][CH:10]=1)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[CH3:19][S:18][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[CH:10][CH:11]=1)=[O:17]
Reactant: CSC(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CSC(=O)Nc1ccc(CN)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The compound 6-3 (22 mg) prepared in Step 2 was dissolved in ethyl acetate (1 ml) and to the solution was added 5 N aqueous hydrochloric acid (1 ml). The mixture was stirred at 60° C. for 1 hour and concentrated under reduced pressure to yield the compound 6-4 (15 mg, 100%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].CN(C=N[C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22]C)=[O:21])=[N:15][CH:16]=1)C>O>[OH:2][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([OH:22])=[O:21])=[N:15][CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cccc(-c2ncc(N=CN(C)C)cn2)c1
Solvent: O
Product: O=C(O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 25 °C

Procedure:
160 ml (2.88 mol) of concentrated sulfuric acid are added to a suspension of 103.5 g (364 mmol) of methyl 3-[5-(dimethylaminomethyleneamino)-pyrimidin-2-yl]benzoate in 1.3 l of water, and the mixture is heated at the boil for 4 hours. The reaction mixture is cooled to room temperature, diluted with water and filtered with suction. The residue is washed with water and dried in vacuo: 3-(5-hydroxypyrimidin-2-yl)benzoic acid as brownish crystals; m.p. 293-295° C.; ESI 217 (M+H); HPLC: Rt=3.25 min (method C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[C:20](Cl)[N:19]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=1.[NH2:28][NH2:29]>CC(O)C.O>[NH2:25][C:24]1[C:21]2[C:20](=[N:19][C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[F:27])(=[O:10])=[O:9])=[CH:13][CH:14]=3)=[CH:23][N:22]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)nc1Cl
Solvent: O
Solvent: CC(C)O
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cc(Cl)ccc4F)cc3)cnc12
Temperature: 120 °C
Yield: 22 %

Procedure:
5-Chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (160 mg) was suspended in a mixture of 1 ml iPrOH and 1 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT and the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield 38 mg (22%) of the title compound in the form of N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide hydrochloride after lyophilizing with aqueous hydrogen chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=1)=[O:5])C.[OH-].[K+]>>[C:4]([C:6]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:7]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:15]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCc2cc(F)ccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2cc(F)ccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-ethoxycarbonyl-5-fluorobenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-5-fluorobenzyloxy)phenylacetic acid.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH:24](OS(C)(=O)=O)[CH3:25])=[N:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4].C(N(C(C)C)CC)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(#N)C>[F:33][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[N:22][C:21]([CH:24]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH3:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4]
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)N1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a stirred solution of Methanesulfonic acid 1-(5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-ethyl ester (0.150 g, 0.309 mmol) in acetonitrile (2 mL) is added diisopropylethylamine (0.161 mL, 0.926 mmol) and morphline (0.054 mL, 0.617 mmol). Reaction mixture is stirred at 60° C. for 16 h. The solvent is evaporated in vacuo and the crude material is purified by combiflash using 1% methanol:CH2Cl2 as an eluent to afford the title compound (0.101 g). 1H NMR (400 MHz, CDCl3) δ 1.33 (d, J=6.48 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 2.32-2.33 (m, 2H), 2.45-2.50 (m, 2H), 3.53-3.58 (m, 4H), 3.60-3.63 (m, 1H), 4.54-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H) 5.26 (d, J=4 Hz, 1H), 6.64 (t, J=52.32, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.12 Hz, 2H), 7.78 (d, J=8.24 Hz, 2H), 8.06-8.10 (dd, J1=8.8 Hz, J2=6.48 Hz, 1H), 8.83 (d, J=2.24 Hz, 1H). LCMS—not ionized.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([C:16]([O:18]C)=[O:17])[CH:9]=2)=O.O.NN.[OH-].[K+].Cl>C(O)CO.O>[C:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([CH3:15])=[C:6]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=3[Cl:1])[NH:7]2)=[CH:12][CH:11]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)[nH]c2c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: Cc1c(Cc2ccc(Cl)cc2Cl)[nH]c2cc(C(=O)O)ccc12
Temperature: 160 °C
Yield: 68.3 %

Procedure:
2-(2,4-Dichlorobenzoyl)-6-(methoxycarbonyl)-3-methylindole (1.00 g) is suspended in ethylene glycol (10 ml), to which is added hydrazine monohydrate (0.83 g), and stirred under heat at 160° C. for 3 hours. After this is once cooled, potassium hydroxide (1.1 g) is added thereto, and again stirred under heat at 155° C. for 3 hours. After cooled, the reaction mixture is made acidic with water and 1 M HCl added thereto. Then, this is extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous sodium sulfate. Then, the drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystalline residue is washed with a mixed solution of ethyl acetate and hexane, and dried to obtain 6-carboxy-2-(2,4-dichlorobenzyl)-3-methylindole (86) (0.63 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:12][N:13]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[N:30][CH:29]=[CH:28]4)[CH:21]=2)C(=O)OCC=C)=[CH:2]1.C[Si](C)(C)NO[Si](C)(C)C>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:35][S:36]([C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[CH2:12][NH:13][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[N:30][CH:29]=[CH:28]4)[CH:21]=2)=[CH:2]1
Reactant: C=CCOC(=O)N(C[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(-c2ccc3cnccc3c2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)NO[Si](C)(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N[C@H](CNc2cc(-c3ccc4cnccc4c3)no2)Cc2c[nH]c3ccccc23)cc1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
To a solution of allyl(S)-3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(3-(isoquinolin-6-yl)isoxazol-5-yl)carbamate (100 mg, 153 μmol) in 2.5 mL of DCM was added Pd(PPh3)4 (5.3 mg, 4.6 μmol) and N,O-bis(trimethylsilyl)hydroxylamine (27 mg, 153 μmol). The mixture was stirred for 15 minutes and was then quenched with 2.5 mL saturated aqueous NH4Cl and the biphasic mixture was stirred for 2 hours. The mixture was then partitioned and the aqueous portion was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative LC to give N-((S)-3-(1H-indol-3-yl)-1-(3-(isoquinolin-6-yl)isoxazol-5-ylamino)propan-2-yl)-4-nitrobenzenesulfonamide (75 mg, 86% yield). MS m/z: 569 (M+1).