Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][C@@H:21]([OH:23])[CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl.CO>[OH:23][C@@H:21]1[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[C@@H:16]([C:17]([O:19][CH3:1])=[O:18])[CH2:20]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
(Trimethylsilyl)diazomethane (2N solution in hexane, 2.9 ml) was added dropwise over 5 minutes to a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline (1.0 g) in DCM (20 ml) and methanol (5 ml) at room temperature until a permanent faint yellow colour persisted. The reaction mixture was concentrated in vacuo and purified by column chromatography, using 0-50% ethyl acetate in hexane as eluent, to give 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate as a clear oil (1.03 g, 97%); NMR spectrum (CDCl3) 4.90-4.37 (m, 2H), 3.73 (s, 3H), 3.64 (dd, 1H), 3.53-3.43 (m, 1H), 2.34-2.27 (m, 1H), 2.12-1.97 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1)(C(C)(C)C)(C)C>CCO.Cl>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[CH:11]([C:12](=[O:29])[CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: CCO
Product: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 86 %

Procedure:
To a stirred suspension of 3β-tert-butyldimethylsilyloxyandrostane-6,17-dione (2.00 g) in EtOH (20 mL), 37% HCl (40 μL) was added. After 3 h the solution was quenched with 5% aqueous NaHCO3 to pH 7. The organic solvent was evaporated and the aqueous phase was extracted with CH2Cl2 (4×350 mL). The combined organic extracts were washed with saturated aqueous NH4Cl, brine, H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/EtOAc 90/10) to give 3β-hydroxyandrostane-6,17-dione (1.25 g, 86%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.56 (d, 1H), 3.31 (m, 1H), 2.45-1.15 (m, 20H), 0.77 (s, 3H), 0.65 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1([Cl:14])[CH2:9][C:8]1([CH3:13])[C:10](Cl)=[O:11]>[OH-].[Na+]>[Cl:6][C:7]1([Cl:14])[CH2:9][C:8]1([CH3:13])[C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11]
Reactant: CC1(C(=O)Cl)CC1(Cl)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1(C(=O)NCC(=O)O)CC1(Cl)Cl
Reaction time: 0.5 h
Yield: 74 %

Procedure:
2.0 g (0.027 mol) of glycine are dissolved in 7 ml of 4 N NaOH and 2,2-dichloro-1-methylcyclopropanecarbonyl chloride and 6.5 ml of 4 N NaOH solution are added in portions at 5 to 10° C., while cooling with ice, the pH being kept>8. The mixture is subsequently stirred for 30 minutes, the aqueous phase is extracted twice with ether and acidified to about pH 2 with 1 N HCl and the precipitate formed is filtered off with suction. After drying, 4.5 g (74% of theory) of N-(2,2-dichloro-1-methylcyclopropanoyl)-glycine of melting point 139-140° C. are obtained.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]Br)/[C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Reactant: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
o-Cresol (5.9 g, 0.542 mol) was added to a suspension solution of sodium hydride (95%, 2 g, 0.813 mol) in DMF (100 mL) at 0 ° C., the reaction mixture was stirred for 1 hour at room temperature. This above reaction solution was added dropwise to a solution of methyl E-2-bromomethyl-6-methylphenylglyoxylate O-methyl oxime (16.2 g, 0.542 mol) in DMF (100 mL) for 30 min at 0 ° C. After was stirred for 1 hour at room temperature, the reaction mixture was added water (200 mL) and extracted with ether (100 mL) three times. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude product which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([OH:14])=[O:13]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C(O)CCl
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of 4-aminobenzonitrile (12 g, 101.6 mmol) and chloroacetic acid (20 g, 211.6 mmol) in water (250 mL) was refluxed until the product began to separate out. After cooled down to the room temperature, the solids were collected by filtration, washed with ether, and dried in vacuo to afford 10.35 g (58%) of the title compound which was pure enough for the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.46 (dd, 2H), 6.93 (t, 1H), 6.65 (dd, 2H), 3.91 (d, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5 g, 21.6 mmol) in dichloromethane (50 mL) and pyridine (3.5 mL, 43.2 mmol, d=0.978), was added benzyl chloroformate (3.15 mL, 22.04 mmol, d=1.195). After stirring at room temperature for 16 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated to cream solid (6 g, 76%); 1H NMR (DMSO-d6): δ 1.65 (d, 2H, J=13.6 Hz), 2.32-2.40 (m, 2H), 3.51 (br, 2H), 3.95-3.99 (m, 2H), 4.59 (s, 2H), 5.11-5.15 (m, 2H), 6.68 (d, 2H, J=8 Hz), 6.75 (t, 1H, J=7.2 Hz), 7.18 (t, 2H, J=7.6 Hz), 7.30-7.38 (m, 5H), 8.81 (s, 1H); MS for C21H23N3O3 m/z 366 (M+H)+.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCC1
Reactant: Clc1ncccn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(c3ncccn3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Temperature: 100 °C

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine (149 mg, 0.42 mmol), 2-chloropyrimidine (60 mg, 0.53 mmol), diisopropylethylamine (150 μL, 0.86 mmol), and DMSO (2 mL). The reaction mixture was heated at 100° C. for 12 h then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed 3× with water followed by brine, concentrated, and adsorbed onto silica gel and purified by silica gel flash chromatography with a 0-50% EtOAc/Hexanes gradient to afford the title compound as a an off-white solid (43 mg, 23%). LC/MS (Method B) 4.62 min, [[M+1]+ 431
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH:17]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[CH3:16]
Reactant: O=C1CCc2ccccc21
Reactant: CCOC(OCC)N(C)C
Product: CN(C)C=C1Cc2ccccc2C1=O

Procedure:
The 2-(dimethylaminomethylene)-indan-1-one starting material was prepared from 1-indanone (3.17 g, 24 mmol) and N,N-dimethylformamide diethyl acetal (21 ml, 120 mmol) to give the desired product as golden yellow crystals (2.61 g) m.p. 156-161°. MS (ES+) 188 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:37]([CH2:36][C:35]3[CH:46]=[C:47]([Cl:49])[CH:48]=[C:33]([Cl:32])[CH:34]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:28])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Reactant: Fc1ccc(CNCc2cc(Cl)cc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1)N(Cc1ccc(F)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (48 mg, 0.10 mol) in DMF, were added. N-(3,5-dichlorobenzyl)-1-(4-fluorophenyl)methanamine (28 mg, 0.1 mmol), HATU (48 mg, 0.15 mmol), and DIPEA (0.052 mL, 0.30 mmol). The reaction mixture was stirred at room temperature for 2 h and purified by preparative HPLC (Column YMC S5 ODS C18 20×100 mm; Solvent A=10% MeOH-90% H2O with 0.1% TFA; Solvent B=10% H2O-90% MeOH with 0.1% TFA). The desired fractions were combined, concentrated and lyophilized to give the title compound (40 mg, 51%) as a white solid. 1H NMR (CD3OD) δ 7.71 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=2.5 Hz), 7.37-7.05 (m, 13H), 6.85 (t, 2H, J=8.8 Hz), 4.70 (br, 1H), 4.64 (br, 1H), 4.54 (s, 2H), 4.50 (s, 2H), 4.46 (br, 1H), 4.42 (br, 1H). MS (ESI): 750.8 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9](=[O:28])[N:10]([C:21]2[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1)[NH2:34].C(O)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[N:10]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:34][C:33]2[CH:35]=[CH:36][C:37]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)=[C:31]([O:30][CH3:29])[CH:32]=2)[N:22]=1)[C:9](=[O:28])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(N)ccc1N1CCN(C)CC1
Reactant: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Cl)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Nc3ccc(N4CCN(C)CC4)c(OC)c3)n2)c(OC)c1
Temperature: 60 °C

Procedure:
A resealable tube was charged with (2-chloro-pyrimidin-4-yl)-(2,4-dimethoxy-phenyl)carbamic acid pyridin-3-ylmethyl ester (0.100 g, 0.249 mol), 3-(methyloxy)-4-(4-methyl-1-piperazinyl)aniline (0.100 g, 0.45 mmol), and isopropanol (2 mL). Trifluoroacetic acid (0.074 g, 0.050 mL, 0.65 mmol) was added. The tube was sealed and the mixture was heated at 60° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated to afford a pale purple oil. The resulting solution was diluted with ethyl acetate and the mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-100% dichloromethane-(90:10:1, dichloromethane/methanol/ammonium hydroxide)) to afford 3-pyridinylmethyl 2,4-bis(methyloxy)-phenyl(2-((3-(methyloxy)-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-pyrimidinyl)-carbamate as an off-white solid. MS (MH+) 586; Calculated 585.66 for C31H35N7O5.
Reaction SMILES: FC1C=C(F)C=CC=1C(Cl)=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[F:47].C1(C)C=CC=CC=1>C(O)C>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([F:47])[CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: O=C(N=C=S)c1ccc(F)cc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4F)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2,4-Difluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-difluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Difluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (66 mg, yield 81%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)=[N:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)=[N:4]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cn1cc(-c2n[nH]c(=O)c3ccccc23)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)c2ccccc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The product of step c) was dissolved in DMF (4 mL) and treated with K2CO3 (55 mg, 0.4 mmol) and benzyl bromide (0.25 mmol). The reaction was heated to 70° C. for 12 h. Additional K2CO3 (0.2 mmol) and benzyl bromide (0.25 mmol) was added and heating was continued for 3 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was washed 3 times with water and concentrated. The residue was dissolved in EtOH (2 mL) and treated with NaOH (0.5 mL, 1 M). After heating to 70° C. for 1 h, the reaction was cooled, acidified with HCl, and extracted into DCM. The organic layer was concentrated, dissolved in DMF, and purified by preparative LCMS. 1H NMR (DMSO-d6) δ 8.41 (d, J=6.9 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.98-7.89 (m, 2H), 7.87 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44-7.27 (m, 6H), 7.17 (t, J=7.3 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 5.43 (s, 2H), 4.80 (s, 2H); MS: ESI (negative): 408 (M−H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][C:18](N(C)C)=[N+](C)C)[C:12]2C=CC=CC=2N=N1.Cl.CONC.CN(C)C=O.[F:35][C:36]1[CH:37]=[C:38](/[CH:43]=[CH:44]/[C:45]([OH:47])=O)[CH:39]=[CH:40][C:41]=1[F:42]>O1CCCC1.C(OCC)(=O)C>[F:35][C:36]1[CH:37]=[C:38](/[CH:43]=[CH:44]/[C:45]([N:8]([O:17][CH3:18])[CH3:12])=[O:47])[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
2-(1H-Benzotriazole-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (2.060 g, 5.43 mmol), O,N-dimethylhydroxylamine hydrochloride (0.583 g, 5.97 mmol) and a catalytic amount of dimethylformamide are added to a suspension of (E)-3-(3,4-difluorophenyl)prop-2-enoic acid (1 g, 5.43 mmol) in tetrahydrofuran (20 mL). The resulting solution is stirred at room temperature for 3 h. The solution is diluted with ethyl acetate (20 mL) and is washed with sequentially with aqueous saturated ammonium chloride (10 mL), water (10 mL), aqueous saturated sodium hydrogen carbonate (10 mL) and with brine (10 mL). The organic layer is then dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product isolated is purified by flash column chromatography on silica gel (heptane/ethyl acetate 0 to 60% as eluent) to afford the desired product as a white solid (478 mg, 2.104 mmol, 39% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18](=[O:20])[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][C:17](=[CH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][CH:31]([NH:35][CH2:36][C@H:37]([OH:47])[CH2:38][O:39][C:40]5[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=5)[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[C:18](=[O:20])[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(NC4CCN(Cc5ccccc5)CC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(NC2CCN(Cc3ccccc3)CC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 21) and 4-[(2S)-3-amino-2-hydroxy-propoxyl]-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a pale yellowish solid; mp>175° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt, J=9.5 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.70-4.00 (m, 5 H), 4.92 (brs, 1 H), 6.66 (d, J=6.8 Hz, 2 H), 6.75 (d, J=6.8 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 8.89 (brs, 1 H), 9.29 (brs, 1 H); MS (ES) m/z:321.6 ((M+2H)2+, 100%); 642.1 (MH+, 5%); HRMS Calcd. for C36H44N5O4S (MH+): 642.3114. Found: 642.3095.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:10]1[N:9]=[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)[C:7]([CH:26]=[CH2:27])=[CH:12][CH:11]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a mixture of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (200 mg, 0.51 mmol), tributyl(vinyl)stannane (170 mg, 0.54 mmol) and anhydrous LiCl (70 mg, 1.65 mmol) in DMF (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was added under N2 protection. The reaction mixture was stirred at 50° C. for 1 h. Then it was filtered and concentrated in vacuo, the residue was purified by column chromatography (PE: EA=20:1) to give the product of 2-(6-chloro-3-vinylpyridin-2-yl)-5-fluoro-1H-indole (100 mg, yield: 72.4%). 1H-NMR (CDCl3, 400 MHz) δ 11.67 (br s, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.45˜7.55 (m, 2H), 7.38 (d, J=10.0 Hz, 1H), 7.15 (dd, J=17.2, 11.2 Hz, 1H), 7.00˜7.06 (m, 1H), 6.84 (d, J=2.0 Hz, 1H), 5.93 (d, J=17.2 Hz, 1H), 5.59 (d, J=11.2 Hz, 1H). MS (M+H)+: 273/275.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12]C=C[CH:15]=2)[N:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(COC)OC.C1COCC1>[CH2:3]([C:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[CH3:4]
Reactant: Clc1ccnc2ccccc12
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Ethyltriphenylphosphonium bromide (45.0 g, 0.122 m) was suspended in anhydrous dimethoxyethane under a nitrogen atmosphere and cooled to -30° C. n-Butyllithium (12.2 mL of a 1 molar solution in THF) was added and the reaction mixture was stirred at -30° to -40° C. for 1 hour. 4-Chloroquinoline (9.0 g, 0.055 m) was added and the suspension was slowly warmed to room temperature and allowed to stir overnight. After heating under reflux for 2-3 hours, 50-100 mL of solvent was distilled out and replaced by a solution of sodium carbonate (12.9 g) in water (60-80 mL). After refluxing for another 2-3 hours, the solvents were evaporated and the residue was partitioned between methylene chloride and aqueous HCl. The organic phase was extracted twice with HCl, and the combined aqueous phases were basified with sodium hydroxide (50:50) to pH 9-10, extracted with ether, dried, and evaporated to give an oil which was purified by HPLC on silica gel eluting with 1:1 ethyl acetate: hexane to give 5.54 g (64%) of 4-ethylquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].S(=O)(=O)(O)O>C(O)C>[CH3:15][C:16]1[CH:17]=[C:18]([CH3:19])[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1cc(C)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (5.0 g), 2,4-pentanedione (2.1 ml) and conc. sulphuric acid (0.8 ml) in ethanol (40 ml) was heated under reflux for 20 hours. The ethanol was evaporated under reduced pressure and the residue dissolved in dichloromethane. The extract was washed with sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give 3,5-dimethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole.