Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([OH:15])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[CH3:19][Si](C=[N+]=[N-])(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([O:15][CH3:19])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](c2cccc(Br)c2)[C@@H](C(=O)O)O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of (4R,5S)-4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylic acid (20 mg, 0.070 mmol) in tetrahydrofuran (2 mL)/methanol (0.500 mL) was added trimethylsilyldiazomethane (0.063 mL, 0.126 mmol) dropwise at 0° C. After 3 h, the reaction was allowed to warm to ambient temperature and stirred for an additional 15 h, at which time it was concentrated in vacuo to provide (4R,5S)-methyl 4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylate (18.2 mg, 0.058 mmol, 82% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 4.98 (d, J=4.88 Hz, 1H) 5.01-5.04 (m, 1H) 7.37-7.45 (m, 2H) 7.56 (s, 1H) 7.57-7.61 (m, 1H) 8.60 (s, 1H). Mass spec.: 301.77 (MH)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C[O-].[Na+].CO>>[CH3:40][O:41][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c(-c2ccccc2)c(C(F)(F)F)nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc12
Temperature: 70 °C

Procedure:
A mixture of (4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol•TFA (78 mg, 0.099 mmol, Example 172) and 0.5 M NaOMe in MeOH (0.46 mL, 0.23 mmol) in a sealed tube was heated at 70° C. for 7 hours. More 0.5 M NaOMe in MeOH (0.33 mL, 0.17 mmol) was added and the mixture was heated at the same temperature for another hour. The solvent was evaporated, and DMSO was added. After filtering through a syringe filter, the filtrate was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 9.07 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.34 (d, J=2.53 Hz, 1H), 8.27 (d, J=8.59 Hz, 1H), 8.13 (dd, J=2.02, 8.08 Hz, 1H), 7.84-7.95 (m, 2H), 7.46-7.56 (m, 3H), 7.35-7.45 (m, 2H), 7.15 (s, 1H), 3.72 (s, 3H), 3.55 (s, 3H); MS m/e 559.2 [M+H]+.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[O-]S([O-])(=O)=O.[Mg+2].[Si:16]([O:23][CH2:24][CH:25]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:23][CH2:24]/[CH:25]=[N:2]/[NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N/N=C/CO[Si](C)(C)C(C)(C)C
Yield: 93.1 %

Procedure:
A mixture of tert-butyl hydrazinecarboxylate (2.5 g, 19 mmol), MgSO4 (11.4 g, 95.0 mmol), and 2-(tert-butyldimethylsilyloxy)acetaldehyde (9.9 g, 57 mmol) in DCM (100 mL) was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5) to give (E)-tert-butyl 2-(2-(tert-butyldimethylsilyloxy)ethylidene)hydrazinecarboxylate (5.1 g, 94% yield) as colorless oil. LCMS (ESI) m/z: 233.3 [M-56+H+].
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C)C.[CH2:17]([O:29][CH2:30][CH:31]1[O:33][CH2:32]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[ClH:34]>O>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:32][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Yield: 33.1 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 24.2 g (0.1 mols) of dodecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that dodecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride (yield 36.0%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:9]2[C:8]([CH3:12])=[CH:7][C:6]3[C:5]([CH3:14])([CH3:13])[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=3[CH:10]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)c1ccc(Br)cc1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (2 g, 9.9 mmol) and 4-bromobenzoyl chloride (2.17 g, 9.9 mol) were dissolved in 20 mL of CH2Cl2 and cooled to 0° C. using an ice-water-NaCl bath. AlCl3 (3.95 g, 29.7 mmol) was added in portions at over 5 min. The dark reaction mixture was allowed to stir at 0° C. for 5 min. The reaction was quenched by slow addition of ice at 0° C. The mixture was diluted with water and 150 mL of EtOAc was added and the layers were separated. The aqueous layer was washed with additional EtOAc (150 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL) and dried over MgSO4. The filtrate was concentrated in vacuo to yield a yellow foamy solid residue that was recrystallized from MeOH (40 mL).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12>ClCCl>[CH3:8][S:9]([NH:13][CH2:14][C:15]1[N:16]=[CH:17][N:18]2[CH:22]=[CH:21][S:20][C:19]=12)(=[O:11])=[O:10]
Reactant: NCc1ncn2ccsc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.18 ml) and 0.075 ml of methanesulfonyl chloride were added in that order under ice cooling to a solution of 134 mg of 7-aminomethylimidazo[5,1-b]thiazole in 2.5 ml of dry dichloromethane. In this state, the system was stirred for 2 hr while gradually raising the temperature to room temperature. The reaction solution was diluted with 20 ml of dichloromethane, followed by washing with saturated brine. The aqueous layer was extracted with 10 ml of dichloromethane. The organic layers were combined together, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation. The oil thus obtained was purified using Sephadex LH-20 (dichloromethane:methanol=1:1) to give 130 mg of 7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazole as a light yellow solid.
Reaction SMILES: [C:1]1([C@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:28]1([C@H:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH2:36][C@@H:35]2[CH:46]=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]1([C@H:11]([NH:13][CH2:46][CH:35]2[CH:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:39][CH2:38][N:37]([C:40](=[O:45])[C:41]([F:44])([F:42])[F:43])[CH2:36]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C[C@H]1CN(C(=O)C(F)(F)F)CC[C@@H]1c1ccccc1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H](NCC1CN(C(=O)C(F)(F)F)CCC1c1ccccc1)c1cccc2ccccc12
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of 868 mg of (1R)-1-(1-naphthyl)ethaneamine, 0.073 mL of acetic acid, 1.29 g of sodium triacetoxyborohydride, and 75 mL of 1,2-dichloroethane was added dropwise a solution of 1.446 g of a crude rel-(3R,4S)-4-phenyl-1-(trifluoroacetyl)piperidine-3-carbaldehyde in 25 mL of 1,2-dichloroethane at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by vigorously stirring for 10 minutes, and then extracting with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 1.84 g of (1R)-1-(1-naphthyl)-N-{[4-phenyl-1-(trifluoroacetyl)piperidin-3-yl]methyl}ethaneamine as a colorless foamy substance.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[O:9][C:13](=[O:14])[NH:11][N:10]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccccc1O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 10 g of salicylhydrazide in 100 ml of p-dioxane was added dropwise 13.1 g of trichloromethyl chloroformate while maintaining the temperature at 20°-30° C. with external cooling. After stirring at 25° C. for 0.5 hours, the suspension was refluxed for 4 hours then cooled to 25° C. and poured into excess ice-water. The mixture was filtered and the residue was recrystallized from acetonitrile to yield 9.0 g of the subject compound; m.p. 198°-200° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:25][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:28][CH2:27]3)[S:25][C:21]=2[CH:20]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccc(Cl)cc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-chloro-2-piperazin-1-yl-benzothiazole. The crude material was purified by chromatography (SiO2, CH2Cl2/MeOH=95/5) to yield the title compound as a yellowish solid. MS (m/e): 552.3 (M+CH3COOH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:3][CH2:2]1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1.CO>N1C=CC=CC=1>[CH:19]1([S:22]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:3][CH2:2]2)(=[O:24])=[O:23])[CH2:21][CH2:20]1
Reactant: c1cc2c(ncc3[nH]nc(C4CCNCC4)c32)[nH]1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CO
Product: O=S(=O)(C1CC1)N1CCC(c2n[nH]c3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a solution of 1-(piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.023 g, 0.095 mmol) in pyridine (0.5 mL) was added cyclopropanesulfonyl chloride (0.015 g, 0.105 mmol). The reaction was stirred at about 25° C. for about 1 h. MeOH (0.5 mL) was added to quench the reaction and the crude reaction mixture was purified by RP-HPLC (Table 2, Method p) to afford 1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a solid (0.004 g, 6.5%): LC/MS (Table 2, Method a) Rt=1.74 min; MS m/z: 346 (M+H)+, 344 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cc(Br)cnc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(Br)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
5-Bromo-2-chloro-pyridin-3-ol (500 mg, 2.399 mmol) and Cs2CO3 (1.2 g, 3.68 mmol) were combined in DMF (10 mL) at RT. To this was added benzyl bromide (0.34 mL, 2.86 mmol). After stirring overnight the mixture was diluted with H2O and extracted with Et2O (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-50 g, 0-10% EtOAc/hexanes) gave the title compound (674 mg, 94%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J=2.0 Hz, 1 H); 7.53-7.35 (m, 6 H); 5.16 (s, 2 H). LC/MS (M+H)+ 298/300/302.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3]1)[CH2:14][CH2:13][CH2:12][CH2:11]3.[CH3:21][C:22](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:21]([N:7]1[C:6]2=[C:10]3[C:15](=[N:16][C:17]4=[CH:18][CH:19]=[CH:20][C:4](=[C:5]24)[O:3][CH:2]([CH3:1])[C:8]1=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH3:22]
Reactant: CC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1C(=O)C(C)Oc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-3-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.82 g) in dry tetrahydrofuran (150 ml) was added potassium tert-butoxide (2.42 g), with stirring. After 20 mins, bromoethane (5.37 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, concentrated, and the residue was adhered to silica and flash chromatographed (30% ethyl acetate/hexane). The appropriate fractions were concentrated. Trituration of the residue with diethyl ether/pentane (1/1) gave 4.51 g (85%) of 1-ethyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCOCC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=432.1, tR (minutes, Method F)=2.6
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)/C=C/c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Under nitrogen, to a solution of (2E)-3-(3-hydroxyphenyl)-2-propenoic acid (330 mg, 2.0 mmol) in THF (20 mL), was added 1-methylpiperazine (400 mg, 4.0 mmol), HOBT (810 mg, 6.0 mmol), HBTU (760 mg, 2 mmol), followed with 4-methylmorpholine (670 μL, 6.0 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→60% MeCN/H2O) to afford the title compound as a white solid (397 mg, 81%). MS (S+) m/e 247 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC[C@H](O)CO[Si](C)(C)C(C)(C)C)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred, ice-cold solution of 23.19 g (64.68 mmol) of the alcohol (16) and 13.5 ml (96.86 mmol) of triethylamine in 200 ml of CH2Cl2 was added 6.0 ml (77.52 mmol) of methanesulfonyl chloride. After 30 minutes at 0° C., the reaction mixture was warmed to room temperature. After another 30 minutes, the reaction mixture was diluted with CH2Cl2 and then washed sequentially with 0.5N HCl, saturated NaHCO3 and saturated NaCl. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure, yielding 26.61 g (94%) of the desired mesylate (17) as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:42](Cl)(=[O:45])[CH2:43][CH3:44].[Na]>O1CCCC1>[F:30][C:29]([F:31])([F:32])[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([NH:19][C:15]2[CH:14]=[C:13]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:7]=4)=[CH:12][NH:11][N:10]=3)[CH:18]=[CH:17][CH:16]=2)=[O:21])=[CH:24][CH:25]=1
Reactant: Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Reactant: CCC(=O)Cl
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)Nc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
35 mg (0.08 mmol) of 1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]urea were dissolved in 2 ml of dry tetrahydrofuran and 27 μl (0.16 mmol) of N,N-diisopropylethylamine and 14 μl of propionyl chloride (0.16 mmol) were added consecutively. The mixture was stirred overnight at room temperature, then poured into aqueous sodium hydrogenocarbonate, extracted with dichloromethane, dried over sodium sulphate ed evaporated. Without any further purification the crude was redissolved with 10 mL of methanol and 5 mL of triethylamine were added. After 7 hours at room temperature the solvent was removed in vacuo, the residue partitioned between dichloromethane and water, dried over sodium sulphate and evaporated. After trituration with diethylether, 30 mg (77%) of the title compound were collected by filtration.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][N:6]1[CH:11]([CH3:12])[CH2:10][N:9]([C:13]2[C:22]([O:23][CH3:24])=[C:21]3[C:16]([C:17](=[O:42])[C:18]([C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])=[O:31])=[CH:19][N:20]3[CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:15][C:14]=2[F:43])[CH2:8][CH:7]1[CH3:44])C.[OH-].[Li+].CS(C)=O>O1CCOCC1>[Cl:41][C:35]1[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=1[CH2:33][NH:32][C:30]([C:18]1[C:17](=[O:42])[C:16]2[C:21](=[C:22]([O:23][CH3:24])[C:13]([N:9]3[CH2:8][CH:7]([CH3:44])[N:6]([CH2:5][C:4]([OH:45])=[O:3])[CH:11]([CH3:12])[CH2:10]3)=[C:14]([F:43])[CH:15]=2)[N:20]([CH2:25][C:26]([F:27])([F:28])[F:29])[CH:19]=1)=[O:31]
Reactant: CCOC(=O)CN1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1C
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1c(N2CC(C)N(CC(=O)O)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45.0 mg (0.06 mmol) of the compound from Example 1 are dissolved in 1 ml of dioxane, and 0.31 ml (0.31 mmol) of a 1M lithium hydroxide solution are subsequently added and the mixture is stirred at room temperature overnight. For the work-up, the solvent is removed on a rotary evaporator, the residue is taken up in water and acidified (pH 3) using 1M hydrochloric acid, and the precipitate formed is dissolved with a little dimethyl sulfoxide. After fine purification via preparative RP-HPLC (method 5), 38 mg of the target compound are obtained from the solution.
Reaction SMILES: ClC1C=[C:4](C=CC=1)[CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[C:27]([O:31][C:32](=[O:44])[N:33](CCN)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[N:33]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:4][CH2:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccccc1
Reactant: O=C(NCc1cccc(Cl)c1)c1occc1Nc1ncnc2[nH]ccc12
Product: CC(C)(C)OC(=O)N(CCNC(=O)c1occc1Nc1ncnc2[nH]ccc12)Cc1ccccc1
Yield: 8 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-furan-2-carboxylic acid 3-chloro-benzylamide using (2-aminoethyl)-benzyl carbamic acid tert-butyl ester instead of 3-chlorobenzylamine and obtained in 8% yield (HPLC: 90%, RT: 6.60 min). 1H NMR (DMSO-d6) 11.99 (br s, 1H), 9.80 (br s, 1H), 8.44 (br s, 1H), 8.38 (s, 1H), 7.80 (br s, 1H), 7.71 (br s, 1H), 7.37 (dd, J=3.3, 2.6 Hz, 1H), 7.33 (d, J=7.3 Hz, 2H), 7.28-7.21 (m, 3H), 6.42 (br s, 1H), 4.44 (s, 2H), 3.40 (br s, 2H), 1.34 (s, 9H); MS (m/z) 477 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(Cl)c(Cl)c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,4-dichlorobenzoic acid