Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]([P:12]([CH:17](Br)[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:16])[O:13][CH2:14][CH3:15])Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:28]([O:35]CC)([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>>[C:1]([NH:9][CH:10]([P:12]([CH:17]([P:28]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:35])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:16])[O:13][CH2:14][CH3:15])[P:28]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(C(Br)NC(=O)c1ccccc1)C(Br)NC(=O)c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(NC(=O)c1ccccc1)P(=O)(OCC)C(NC(=O)c1ccccc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the bromide 7 (195 mg; 0.38 mmol) and triethyl phosphite (130 μl; 0.76 mmol) in abs. THF (50 ml) is concentrated under reduced pressure after stirring at room temperature for 4 hours. A mixture of the diastereomeric phosphinic acid esters 14 (145 mg, 64% of theory after recrystallization from ethyl acetate) is obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:35][C@@H:30]1[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]1[N:28]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:25]=[CH:26][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:12]([O:23][CH3:24])[CH:13]=2)[C:16]1=[O:17]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@@H]1CCCC[C@H]1O)C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 21 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methoxybenzoate (0.16 g), trans-2-aminocyclohexanol hydrochloride (0.07 g), triethylamine (0.06 ml) and anhydrous magnesium sulfate (0.10 g) in THF (3.50 mL) was stirred at room temperature for 2 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.50 mL) and THF (3.50 mL), sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred at room temperature for 3.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was 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 (0.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.CN(C)C=O.[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Reaction time: 8 h
Yield: 112.5 %

Procedure:
To a 0° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 0.0033 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (0.75 mL, 0.0043 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added sodium hydride (0.17 g, 0.0043 mol). The resulting mixture was stirred overnight and partitioned between ethyl acetate and water (×2), and the organic layer was washed with sat. NaCl. The organic layer was then dried under vacuum to produce 1.05 g of an orange oil which was chromatographed with 15% ethyl acetate/hex to give 830 mg of a colorless oil (89.6% yield).
Reaction SMILES: C(O[CH:5]1[O:21][C@H:20]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:11]([CH:31]=[CH2:32])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[NH:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:8]([O:7][C@@H:6]1[C@:11]([CH:31]=[CH2:32])([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:20]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:21][C@H:5]1[N:33]1[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]1=[O:35])(=[O:10])[CH3:9]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)OC(OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Yield: 82.9 %

Procedure:
To a stirred solution of compound 22 (4.24 g, 9.6 mmol) and thymine (2.43 g, 19.3 mmol) in anhydrous acetonitrile (100 cm3) was added N,O-bis(trimethylsilyl)acetamide (11.9 cm3, 48.1 mmol). The reaction mixture was stirred at reflux for 30 min. After cooling to 0° C., trimethylsilyl triflate (3.2 cm3, 16.4 mmol) was added dropwise and the solution was stirred for 24 h at room temperature. The reaction was quenched with cold saturated aqueous sodium hydrogencarbonate (100 cm3) and the resulting mixture was extracted with dichloromethane (3×50 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (2×50 cm3) and brine (2×50 cm3) and dried (Na2SO4). The extract was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloro-methane/methanol (99:1, v/v) as eluent to give nucleoside 23 as a white foam (4.03 g, 83%). δH (CDCl3) 8.78 (1H, br s, NH), 7.75 (1H, s, 6-H), 7.38-7.26 (10H, m, Bn), 6.49 (1H, d, J 8.1, 1′-H), 5.99-5.88 (2H, m, 2′-H and 1″-H), 5.54-5.48 (2H, m, 2″-Ha, 2″-Hb), 4.91-4.50 (4H, m, Bn), 4.34 (1H, s, 4′-H), 3.80 (1H, m, 5′-Ha) 3.54 (1H, m, 5′-Hb), 2.11 (3H, s, COCH3), 1.48 (3H, s, CH3). δC (CDCl3) 170.1 (C═O), 163.8 (C-4), 151.0 (C-2), 138.9, 136.9 (Bn), 136.1 (C-6), 132.0 (C-1″), 128.7, 128.5, 128.2, 127.8, 127.7, 127.5, 127.5, 127.1 (Bn), 120.7 (C-2″), 111.3 (C-5), 85.4 (C-1′), 85.2 (C-3′), 84.3 (C-4′), 76.0 (C-2′), 73.7 (C-5′), 69.3, 67.6 (Bn), 20.6 (COCH3), 11.7 (CH3). Found: C, 66.3; H, 6.0; N, 5.1; C28H30N2O7 requires C, 66.4; H, 6.0; N, 5.5%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=O)[CH3:16])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[NH2:18][CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21].C1C=CC=CC=1.C([BH3-])#N.[Na+]>C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([NH:18][CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[OH:21])[CH3:16])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)COc1ccc(CCOC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CC(=O)OCCc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 14.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-[4-(2-oxopropoxy)phenyl]ethyl acetate (prepared as described in Preparation 37), 1.45 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 60 ml of dry benzene, 50 ml of absolute isopropanol and 2.06 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, 0.49 g of the title compound was obtained, having an Rf=0.34 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]2([CH3:19])[C:16]([CH3:18])([CH3:17])[CH:9]1[CH2:10][C:11]1[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-])([O-])=O.[K+].[K+].ICI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]2([CH3:19])[C:16]([CH3:17])([CH3:18])[CH:9]1[CH2:10][C:11]1[CH:23]=[C:22]3[O:24][CH2:26][O:25][C:21]3=[CH:20][C:12]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3cc(O)c(O)cc3CC1C2(C)C
Agent: [K+]
Solvent: ICI
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3cc4c(cc3CC1C2(C)C)OCO4
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 8,9-dihydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.21 g), K2CO3 (0.19 g), and diiodomethane (54 μL) in N,N-dimethylformamide (5 mL) is heated to 100° C. and stirred at this temperature for 2 h. Then, another portion of diiodomethane (54 μL) and K2CO3 (0.18 g) is added and the mixture is further stirred at 100° C. for 5 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine and dried (MgSO4). After removal of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][C@@:12]1([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:20])[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:29]>CC(O)=O>[BrH:29].[OH:28][C:24]1[CH:23]=[C:22]([NH:21][C:19]([C@@:12]2([C:13]([OH:15])=[O:14])[CH2:16][CH2:17][CH2:18][NH:11]2)=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@]1(C(=O)O)C(=O)Nc1cccc(O)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)[C@]1(C(=O)Nc2cccc(O)c2)CCCN1
Reaction time: 0.67 h
Yield: 70 %

Procedure:
To N-Cbz-[2-(3-hydroxyphenylaminocarbonyl)]-L-proline (5.0 mmol) in HOAc (10 mL) was added 30% HBr in acetic acid and the solution stirred for 40 min. The reaction was quenched by addition of 100 mL ethylether, and the resulting precipitate collected and recrystalized from MeOH/Et2O to afford 3.5 mmol 2-(3-hydroxyphenylaminocarbonyl)-L-proline hydrobromide (70%)
Reaction SMILES: [C:1]1([CH2:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15]C(=O)C)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH2:7][S:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCCCCS(=O)(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(CCCCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of acetic acid 4-phenylmethanesulfonylbutyl ester (1.6 g, 5.93 mmol) in MeOH (20 mL) is added NaOH (6.0 ml of 1.0N) and the mixture is stirred at RT for 90 min. The MeOH is removed under reduced pressure and the aqueous extracted with EtOAc. The organic solution is dried over magnesium sulfate and the solvent is removed under reduced pressure. The resulting solid is triturated with hexane to give the title compound as a white solid.
Reaction SMILES: CO[C:3]1[C:4]2[N:5]([CH:14]=[N:15][N:16]=2)[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][N:8]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:3]1[C:4]2[N:5]([CH:14]=[N:15][N:16]=2)[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(-c2cccs2)n2cnnc12
Product: Clc1ncc(-c2cccs2)n2cnnc12
Temperature: 130 °C
Yield: 75 %

Procedure:
A 50 mL round bottom flask was charged with 8-methoxy-5-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (0.30 g, 1.3 mmol) and POCl3 (3 mL). The mixture was heated at 130° C. overnight. TLC indicated a complete conversion. Work-up: the reaction mixture was concentrated in vacuo. The residue was carefully poured into ice and extracted with EtOAc (10 mL). The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:5 EtOAc/petroleum ether, to afford 0.23 g (75%) of the product as a white solid. MS m/z: 237 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26]C)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCCC)CC4)=CC=3)=CN=2)=CC=1.FC1C=CC(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCCC)CC4)=CC=3)=CN=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)cc4)nc3)cc2)CC1
Agent: CCCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)cc4)nc3)cc2)CC1
Agent: CCCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)cc4)nc3)cc2)CC1
Product: C[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)cc4)nc3)cc2)CC1

Procedure:
2-(4'-fluorophenyl)-5-[4'-(trans-4"-ethylcyclohexyl)phenyl] pyrimidine ##STR41## 2-(4'-fluorophenyl)-5-[4'-(trans-4"-butylcyclohexyl)phenyl] pyrimidine ##STR42## 2-(4'-fluorophenyl)-5-[4'-(trans-4"-pentylcyclohexyl)phenyl] pyrimidine ##STR43## 2-(4'-fluorophenyl)-5-[4'-(trans-4"-hexylcyclohexyl)phenyl] pyrimidine 2-(4'-fluorophenyl)-5-[4'-(trans-4"-heptylcyclohexyl)phenyl] pyrimidine
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.420 g, 0.889 mmol) and diethylamine (1.0 mL, 9.7 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional diethylamine (1.0 mL, 9.7 mmol) was added, and the reaction mixture was stirred at 80° C. in a sealed tube for an 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5% methanol in chloroform. After drying in vacuo at 80° C. for 20 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-diethyl-amine as a pale yellow solid (0.155 g, 46.6%) was obtained. This was dissolved in methanol and chloroform and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 74° C. for 13.5 hours to yield the hydrochloride as a light orange foam (0.163 g); Mass Spectrum (+EI, [M+H]+) m/z 374. 1HNMR (500 MHz, DMSO-d6): δ14.24 (s, 1H), 9.94 (br, 1H), 7.96-7.99 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.20 Hz), 7.16-7.19 (m, 1H), 4.40-4.43 (m, 2H), 3.52 (br, 2H), 3.19-3.23 (m, 4H), 1.23 ppm (t, 6H, J=7.20 Hz). Elemental Analysis for C19H23N3O3S.1.00 mol HCl.0.20 mol H2O: Calcd: C, 55.18; H, 5.95; N, 10.16; Found: C, 54.85; H, 5.85; N, 10.02.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:11]1[NH:15][CH:14]=[C:13]([C:16]([O:18]CC)=O)[C:12]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=2[F:41])=[O:29])=[CH:23][CH:22]=1)(=[O:10])[NH2:9]>>[F:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:40])[F:39])=[CH:36][C:31]=1[NH:30][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]2[C:13]([C:16]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:18])=[CH:14][NH:15][C:11]=2[C:8]([NH2:9])=[O:10])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2c[nH]c(C(N)=O)c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)CC1

Procedure:
The process is performed in a manner similar to that described in Example 39 but starting with N-methylpiperazine and ethyl 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxylate. After a similar work-up, 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide is obtained; ES+: m/z=533 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][N:12]2C(OC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][C@H:15]([C:17]3[O:21][NH:20][C:19](=[O:22])[CH:18]=3)[CH2:14][CH2:13][NH:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)cc1
Agent: Br
Product: CC(C)(C)c1ccc([C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Trans-methyl 2-(4-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.26 g, 0.73 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5 mL, 71.37 mmol) and stirred at room temperature for 18 h. Solvents were evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-tert-butylphenyl)piperidin-4-yl)isoxazol-3(2H)-one (182 mg, 84%). 1H NMR (600 MHz, dmso) δ 1.23 (s, 9H), 1.76-1.85 (m, 2H), 1.86-1.93 (m, 1H), 1.96-2.03 (m, 1H), 2.71 (td, 1H), 2.81-2.88 (m, 1H), 3.10-3.15 (m, 1H), 3.65 (dd, 1H), 5.90 (s, 1H), 7.24-7.33 (m, 4H). HRMS Calculated for [C18H24N2O2+H]+: 301.1916. Found: 301.1919
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1cccc(Cl)c1
Product: COc1ccc2c(Oc3cccc(Cl)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-chloro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-Chloro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([O:21][CH:22]([C:24]1[S:25][CH:26]=[C:27]([C:29](O)=[O:30])[N:28]=1)[CH3:23])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:27]3[N:28]=[C:24]([CH:22]([O:21][CH2:19][CH3:20])[CH3:23])[S:25][CH:26]=3)=[O:30])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CCOC(C)c1nc(C(=O)O)cs1
Product: CCOC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 31.7 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-ethoxyethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (350 mg, 1.342 mmo) and 2-(1-ethoxyethyl)thiazole-4-carboxylic acid (661 mg, 3.28 mmol). The product purified by Flash-chromatography (reverse phase). Yield 31.7%. 1H-NMR (400 MHz; MeOD): δ 1.19-1.24 (m, 3H), 1.26 (dd, 3H), 1.51 (t, 3H), 3.48-3.58 (m, 1H), 3.58-3.66 (m, 1H), 4.33-4.46 (m, 2H), 4.52-4.62 (m, 1H), 4.72-4.79 (m, 1H), 6.77 (dd, 1H), 7.70-7.72 (m, 1H), 7.75-7.79 (m, 1H), 7.85-7.89 (m, 1H), 8.02 (m, 1H), 8.08 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:32](=[O:33])[CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(Cl)cc3)sc2n1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(Cl)cc5)nc34)CC2)cc1
Yield: 63 %

Procedure:
This compound was prepared from 2-(4-chlorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 63%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1.[C:18](=[O:21])([O-])[OH:19].[Na+]>O1CCOCC1.O>[CH2:2]([O:19][C:18]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1-c1ccccc1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 163.3 %

Procedure:
500 mg (2 mmol) of benzyl N-succinimidocarbonate dissolved in 2.5 ml of dioxane were added dropwise at 0° C. to a solution of 455 mg (2 mmol) of 2′-aminomethylbiphenyl-2-carboxylic acid (precursor 3) and 336 mg (4 mmol) of sodium hydrogencarbonate in 5 ml of dioxane and 5 ml of water. After stirring at RT for 4 h, the mixture was concentrated in vacuo, diluted with water, acidified and extracted with ethyl acetate. 590 mg of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>C(O)C>[OH:10][C:9]1[C:4]2[C:5](=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=2)[C:6](=[O:8])[C:19]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1ccncc1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: CCO
Product: Cc1ccc2c(c1)C(O)=C(c1ccncc1)C2=O
Temperature: 165 °C

Procedure:
A mixture of 47.5 g (293 mmol) 4-methyl-phthalic anhydride and 28.6 ml (293 mmol) 4-pi-coline is heated to 165° C. for 18 h. The resulting material is stirred in 190 ml of boiling ethanol, filtered and washed with ethanol and diethyl ether, yielding the title compound: An. calc. (C15H11NO2) C, 75.94%; H, 4.67%; N, 5.90%; O, 13.49%; An. meas. C, 75.60%; H, 4.64%; N, 6.02%; O, 13.60%; 1H NMR (DMSO-d6) δ8.70 (d, 2H), 8.14 (d, 2H), 7.34 (m, 2H), 7.29 (s, 1H), 2.38 (s, 3H); FAB MS (M+H)+=238.