Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[F:35][C:36]1[CH:43]=[C:42](F)[C:41]([F:45])=[CH:40][C:37]=1[C:38]#[N:39].O>O1CCCC1.C(O)(C)(C)C>[F:35][C:36]1[CH:43]=[C:42]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[C:41]([F:45])=[CH:40][C:37]=1[C:38]#[N:39]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 800 mg of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 4 mL of tetrahydrofuran at 5° C. was slowly added 2.13 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 296 mg of 2,4,5-trifluoro-benzonitrile in 1 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred for 1 h at −60° C. then stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from methanol and washed with diisopropyl ether to give 890 mg of 2,5-difluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:28]([NH:46][CH:47]([CH3:49])[CH3:48])[N:27]2[CH:50]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1>[CH:47]([NH:46][C:28]1[N:27]2[CH:50]=[C:24]([CH3:23])[N:25]=[C:26]2[N:31]=[C:30]([C:32]2[CH:39]=[CH:38][C:35]([CH2:36][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:34][CH:33]=2)[C:29]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:49])[CH3:48]
Reactant: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1cn2c(NC(C)C)c(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Reaction time: 1 h
Yield: 1.2 %

Procedure:
227.9 mg (0.83 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 6.5 mL NMP. 0.25 mL (1.8 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 280 mg (0.76 mmol) 4-(2-Methyl-5-isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.08 mL (1.36 mmol) acetic acid are added. The reaction mixture is stirred for three days at room temperature. 176.2 mg (0.83 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. Additional 88 mg NaBH(OAc)3 are added and stirring is continued for 26 hours. After the usual work-up and purification by column chromatography and by HPLC 4.9 mg (1.1%) of the desired title compound are obtained.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:7]([F:16])=[CH:6][C:5]=1[O:17][CH3:18].[OH-].[Na+]>C(O)C>[F:16][C:7]1[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:4]([C:3]([OH:19])=[O:2])=[C:5]([O:17][CH3:18])[CH:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)c(F)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(F)c(N2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A suspension of 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 4.46 mmol) in ethanol (22.0 mL) was treated with aq 2 N NaOH (13 mL, 26.7 mmol). The mixture was stirred at room temperature for 2 h, concentrated until most of the ethanol was removed and acidified with aq 2 N HCl to pH 1. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO4 and concentrated to give-4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid (0.90 g, 79%): 1H NMR (DMSO-d6 300 MHz) δ 12.62 (s, 1 H), 7.34 (d, J=10.5 Hz, 1 H), 7.04 (d, J=14.7 Hz, 1 H), 3.76 (s, 3 H), 3.70 (t, J=4.7 Hz, 4 H), 2.90 (t, J=4.7 Hz, 4 H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.CCOCC>CS(C)=O>[C:3]1([C:9]2([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of sodium hydride (60%, 18.8 g, 470.08 mmol) in dimethyl sulfoxide (125 mL) was added dropwise a mixture of phenyl acetonitrile (19-01) (25 g, 213.6 mmol) and 1,4-dibromo-butane (20) (25.5 mL, 213.67 mmol) dissolved in dimethyl sulfoxide:ether (300 mL, 1:1). The mixture was stirred at room temperature for 3 h. After completion of the reaction, it was quenched with 1N HCl. The mixture was extracted with ethyl acetate, the separated organic part was dried and concentrated to get a crude product which was purified using normal silica column using 3% ethyl acetate in hexane to of ford 1-phenyl-cyclopentanecarbonitrile (21-01) (34 g, 92.92%) as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([OH:20])=O)=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.[CH3:31][NH:32][CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[OH:35].C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][NH:11][C:10]=1[C:18]([N:32]([CH2:33][C@H:34]([OH:35])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC[C@H](O)c1ccccc1
Reactant: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1n[nH]c(C(=O)N(C)C[C@H](O)c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-benzyloxy-3-carboxy-1H-pyrazole-5-carboxylate (1.5 g, 5.43 mmol; prepared as in Example 31, Step 1) in DMF (20 mL) were added HOAT (1.11 g, 8.15 mmol), (1R)-2-(methylamino)-1-phenylethanol (1.23 g, 8.15 mmol; prepared as described in Gurjar, M. K., et al., Org. Process Res. Dev. 1998, 2, 422.), triethylamine (0.82 g, 8.15 mmol), and EDC (1.56 g, 8.15 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The DMF was removed in vacuo and the residue was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted twice more with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the title product. ES MS (M+1)=410.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][O:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]([CH3:8])([CH2:3][O:4][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH2:5][O:6][CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: COCC(C)(C)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 g of 2,2-dimethyl-3-methoxy-1-propanol was dissolved in 20 ml of dichloromethane. The resultant solution was cooled in ice-water bath to below 5° C., and 1.65 ml of triethyl amine was added thereto. After stirring the mixture 5 minutes, 1.29 ml of trimethylsilyl chloride was added drop-wise to the reaction mixture, and the mixture was stirred in ice-water bath for further 2 hours, and at room temperature for further 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.33 g of concentrate. The crude product was purified by column chromatography using petroleum ether as eluent, to give colorless pure compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][C:13]([CH3:15])=[CH:12][CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1cc(C)ccc1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(C)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-4-methylbenzonitrile (step 1) and 2-bromoacetophenone. tlc: Rf=0.6 (25% ethyl acetate in hexanes)
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[K+].C(OCC)(=O)C>C(O)C.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[CH:32][C:33]=1[CH2:38][C:49]#[N:50]
Reactant: [C-]#N
Reactant: Clc1ccc(C2O[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of (2S,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran (195 mmol) from Step 7 in ethanol (260 mL) and water (130 mL) was added potassium cyanide (31.8 g, 488 mmol). The reaction mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 5 to 40% ethyl acetate in hexanes gradient) gave the title compound (105 g, 156 mmol, 80%, mixture of α,β-anomer in about 1:2 ratio) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](=O)([O-])[O-].[Cs+].[Cs+].O.[OH-].[Na+].[CH2:22]([Cl:24])Cl>CN(C=O)C.CCOCC>[Cl:24][CH2:22][CH2:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=C([O-])[O-]
Reactant: ClCCl
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(OCCCl)ccc21
Temperature: 25 °C
Reaction time: 58 h
Yield: 96 %

Procedure:
To a solution of 6-hydroxy tetralone (2.0 g, 12.3 mmol) in DMF (50 mL) was added dry cesium carbonate (8.02 g, 24.6 mmol). Neat 2-chloroethyl-p-tolensulfonate (3.49 g, 14.9 mmol) was added to this mixture and the reaction stirred at room temperature for 58 hours. The reaction was poured into 200 mL of water and to this mixture was added 10 mL of 1N NaOH followed by 200 mL of Et2O. The mixture stirred at room temperature for 2 hours. The aqueous portion was separated and extracted with Et2O (3×200 mL). The combined organic portions were washed successively with 1N NaOH (2×100 mL), water (2×100 mL), and brine, dried, filtered, and concentrated under vacuum to give 5.07 g of a faintly orange solid. The solid was dissolved in minimal DCM and chromatographed (silica gel, 190 g, DCM). The appropriate fractions were pooled and concentrated under vacuum to afford 2.65 g (96%) of a white crystalline solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([NH2:36])=[O:27])=[CH:15][CH:14]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Yield: 94.6 %

Procedure:
A solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.59 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g, 2.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.40 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.56 g, 94.9%) as crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:27].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][S:24]([CH3:23])(=[O:26])=[O:25])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 and 53.9 mg (470 μmol) methanesulfonic acid chloride are dissolved in 5 ml DMF under argon and while cooling with ice, 152 mg (1.18 mmol) N,N-diisopropylethylamine are added and the mixture is stirred overnight at RT. The reaction mixture is then purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[OH:18][C:19]1[CH:24]=[C:23]([OH:25])[N:22]=[C:21]([SH:26])[N:20]=1.N1CCCCC1.O>C(O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:15][C:12]([CH:13]=[C:24]2[C:23](=[O:25])[NH:22][C:21](=[S:26])[NH:20][C:19]2=[O:18])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: Oc1cc(O)nc(S)n1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Temperature: 80 °C
Yield: 55.7 %

Procedure:
A suspension of 0.242 g (1 mmol) of 5-(2-trifluoromethylphenyl)furfural, 0.144 g (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine, and a drop of piperidine in 6 ml of ethanol was stirred with heating at 80° C. for 4 hours. Upon cooling, the orange suspension was poured into 50 ml of water and sonicated for 10 minutes. Filtration of the orange solvent and drying provided 0.204 g of the product as an orange powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:15]=2)[CH2:10][C@@H:9]1[C:32]([OH:34])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][CH3:38].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:36][N:37]([CH3:38])[C:32]([C@H:9]1[CH2:10][C@H:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:34]
Reactant: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 89.7 %

Procedure:
A solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid (0.095 g, 0.204 mmol), dimethylamine hydrochloride (0.017 g, 0.204 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.077 g, 0.204 mmol), and triethylamine (0.037 mL, 0.265 mmol) in DMF (1 mL) was stirred for 24 hours. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). The organic extracts were combined, dried (MgSO4) and concentrated. Purification by silica gel chromatography (10% methanol in dichloromethane) gave the title compound as a solid (0.090 g, 90%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5](=[O:25])[NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([C:22]([NH2:24])=[O:23])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.CC(O[CH:33](N(C)C)[N:34]([CH3:36])[CH3:35])(C)C.CCOCC>CN(C=O)C>[CH3:33][N:34]([CH3:36])/[CH:35]=[N:24]/[C:22]([C:20]1[CH:19]=[CH:18][N:17]2[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:5]([NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])=[O:25])[CH:8]=3)=[CH:14][N:15]=[C:16]2[CH:21]=1)=[O:23]
Reactant: NC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a stirred solution of 3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl}imidazo[1,2-a]pyridine-7-carboxylic acid amide (20 mg, 0.053 mmol) in dry DMF (0.5 ml) was added Bredereck's reagent (25 μl, 0.12 mmol) and the reaction mixture stirred for 1 h. Et2O was added to the reaction and the resulting precipitate filtered off. The precipitate was redissolved in MeOH, transferred to a flask and the solvent removed in vacuo to afford a pale yellow solid (17 mg). MS: [M+H]+433.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc(C)c1
Temperature: 25 °C

Procedure:
23.36 g (233 mmol) Acetylacetone, 5.00 g (47 mmol) 3-methylaniline, and 0.8 g (4.7 mmol) 4-toluenesulfonic acid are dissolved in 50 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethylacetate mixtures as eluent.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]1.CCN(C(C)C)C(C)C>C(O)C>[S:8]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:13]2)=[N:7][CH:6]=1)(=[O:10])(=[O:9])[NH2:11]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(S(N)(=O)=O)cn2)C1
Temperature: 0 °C

Procedure:
6-chloropyridine-3-sulfonamide (0.32 g, 1.66 mmol) was added to a stirred solution of tert-butyl azetidin-3-ylcarbamate (0.30 g, 1.74 mmol) and DIPEA (0.9 ml, 0.65 g, 4.98 mmol) in 10 ml of ethanol and heated to reflux for 16 h. Reaction mass was cooled to 0° C. The solid formed was filtered and dried under vacuum to obtain desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].C(O)C>[Pd].C(OCC)(=O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:5]2[N:6]3[C:15]4[C:10]([CH:9]=[CH:8][C:7]3=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[O:26])=[CH:22][CH:21]=1
Reactant: N#Cc1cc(C(=O)c2ccc([N+](=O)[O-])cc2)n2c1ccc1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cc(C(=O)c2ccc(N)cc2)n2c1ccc1ccccc12
Yield: 13.1 %

Procedure:
A solution of 3-cyano-1-(4-nitro-benzoyl)-pyrrolo[1,2-a]quinoline (44.3 mg, 0.130 mmol), 5 wt % Palladium on Carbon (23.4 mg), ethanol (12.0 mL), and ethyl acetate (90.0 mL) was agitated under hydrogen (30 PSI) for 1.5 h. The solution was filtered through Celite and purified by flash column chromatography (9:1 dichloromethane/ethyl acetate) to yield 5.3 mg (13%) of a light brown solid. 1H NMR (DMSO-d6): 8.04 (d, J=6.86 Hz, 1H), 7.88 (d, J=9.34 Hz, 1H), 7.81 (d, J=8.79 Hz, 2H), 7.75 (d, J=9.07 Hz, 2H), 7.55–7.70 (m, 3H), 6.66 (d, J=8.79 Hz, 2H), 6.42 (s, 2H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[C:6]([OH:10])(=O)[CH2:7][CH3:8].O[C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:33])[CH2:24][C@@H:25]1[CH3:32])[CH2:20][CH2:19]3.[CH2:34](OC(OCC)OCC)[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>O1CCCC1.N1C=CC=CC=1>[C:1]([O:5][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][O:28][C:6](=[O:10])[CH2:7][CH3:8])[C:21]([CH:22]=[C:23]([O:33][CH2:34][CH3:35])[CH2:24][C@@H:25]1[CH3:32])=[CH:20][CH2:19]3)(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CCC(=O)O
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC1=CC2=CC[C@H]3[C@@H]4CC[C@H](OC(=O)CC)[C@@]4(C)CC[C@@H]3[C@@]2(COC(=O)CC)[C@@H](C)C1

Procedure:
A solution of 17β,19-dihydroxy-1α-methyl-4-androsten3-one dipropionate, triethylorthoformate, p-toluenesulfonic acid and ethanol in tetrahydrofuran is stirred at room temperature for about 2 hours. The reaction mixture is poured onto ice water containing a few drops of pyridine and stirred well. The solid which forms is filtered and crystallized from ethanol to yield pure 3-ethoxy-1α-methyl-3,5-androstadiene-17β,19-diol dipropionate.