Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][NH:29]4)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1ccc(OC2CN3CCC2CC3)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1cc(-c2ccc(OC3CN4CCC3CC4)nn2)c2cc[nH]c2c1
Temperature: 25 °C

Procedure:
Under N2, the mixture of Example 7A (168 mg, 0.7 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (ref. WO02055517, 170 mg, 0.7 mmol), Pd2(dba)3 (Aldrich, 19 mg, 0.02 mmol), 1,3-bis(2,6-iso-propylphenyl)imidazolium chloride (Strem Chemicals, 26 mg, 0.06 mmol) and aqueous Na2CO3 (2 M, 1 mL) in toluene (10 mL) was stirred at 110° C. overnight, After the reaction was complete, it was cooled down to room temperature and diluted with EtOAc (30 mL). The mixture was then washed with brine (2×5 mL) and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as solid (45 mg, yield, 20%). 1H NMR (300 MHz, CD3OD) δ 1.51-1.65 (m, 1H), 1.70-1.93 (m, 2H), 2.01-2.16 (m, 1H), 2.31-2.39 (m, 1H), 2.78-3.09 (m, 5H), 3.45-3.56 (m, 1H), 5.30-5.38 (m, 1H), 6.78 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.5 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.40 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (dt, J=8.1, 1.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]([NH2:17])=[S:16])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.CI.[C:24](OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][S:16][C:15](=[NH:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:18]=[CH:19][CH:20]=[N:21][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: COCN1c2cc(CC(N)=S)ccc2Sc2nccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 15 ml of a solution of 318 mg of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide in acetone was dropped 1.5 m of methyl iodide. After stirring at room temperature for 2 hours, the reaction mixture was distributed into ethyl acetate and an aqueous solution of potassium carbonate. The organic layer was extracted and the extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 350 mg of the title compound was obtained as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:2][CH2:3][CH3:4].[ClH:24].C(OCC)(=O)C>>[ClH:24].[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in step 1 (0.36 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.24 g, 84%) as a white powder.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][N:11]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(CO)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Thionyl chloride (1 mL) was added to (6-methyl-pyridin-3-yl)-methanol (300 mg, 2.44 mmol) at 0° C., and the solution was stirred at room temperature for 20 minutes. The reaction solution was partitioned in an aqueous solution of saturated sodium bicarbonate and ethyl acetate. This organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo. N,N-dimethylformamide (5 mL), phenol (230 mg, 2.44 mmol) and potassium carbonate (674 mg, 4.88 mmol) were added to this residue at room temperature. This reaction mixture was stirred at room temperature for 40 minutes, then, further stirred for at 60° C. 40 minutes. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with water and brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (323 mg, 66%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3Cl)=[CH:4][N:3]=1.[C:22]1([CH:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[C:14]3[N:33]2[CH2:34][CH2:35][N:30]([CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[CH2:31][CH2:32]2)=[CH:4][N:3]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: CN(C)c1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl
Solvent: CS(C)=O
Product: CC(c1ccccc1)N1CCN(c2ccnc3ccc(-c4cnc(Cl)c(N(C)C)c4)cc23)CC1
Temperature: 110 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
(Some starting materials may be obtained from Chess GmbH, Mannnheim, Germany) To a microwave vial (5 mL), 2-chloro-5-(4-chloroquinolin-6-yl)-N,N-dimethylpyridin-3-amine (0.0846 g, 0.266 mmol) and 1-(1-phenylethyl)-piperazine (0.125 mL, 0.665 mmol) were added into DMSO (4 mL). The mixture was stirred at 90 oC for 2.5 h, at 110° C. for 3 h, then at RT for overnight. The reaction was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: acetone in hexanes 0% -50%) to afford the title compound as a white solid (0.0886 g). m/z: calc'd for C28H30ClN5; 471.2, found: 472.2 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (d, J=6.6 Hz, 3 H), 2.63-2.89 (m, 4 H), 2.94 (s, 6 H), 3.29 (t, J=4.4 Hz, 4 H), 3.51 (d, J=6.7 Hz, 1 H), 6.88 (d, J=5.0 Hz, 1 H), 7.28-7.42 (m, 5 H), 7.56 (d, J=2.2 Hz, 1 H), 7.84 (dd, J=8.7, 2.1 Hz, 1 H), 8.10-8.20 (m, 2 H), 8.33 (d, J=2.2 Hz, 1 H), 8.75 (d, J=5.0 Hz, 1 H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:15])=[O:14])[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2([CH3:19])[CH3:18]
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21
Reactant: C1CCNC1
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)N3CCCC3)cc21
Yield: 64.9 %

Procedure:
The title compound was prepared starting from 1-acetyl-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (400 mg, 1.3 mmol) and pyrrolidine (650 μL, 7.87 mmol) following similar methods to those described in Preparation 69 to give the title compound (287 mg) as a dark orange solid. MS: [M+H]+=341.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:26][CH2:25][N:24]([O:27][CH3:28])[CH2:23][CH2:22]4)[C:20]=3[OH:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].N1C=CC=CC=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16]3[C:17](=[O:29])[NH:18][C:19]4([CH2:22][CH2:23][N:24]([O:27][CH3:28])[CH2:25][CH2:26]4)[C:20]=3[O:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CON1CCC2(CC1)NC(=O)C(c1cc(-c3ccc(Cl)cc3)c(F)cc1C)=C2OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-4-hydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (170 mg) and pivaloyl chloride (98 mg) in acetonitrile (5 ml) is added pyridine (64 mg) and the reaction mixture stirred at room temperature for 8 hours. The mixture is poured on diluted HCl and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is triturated with heptane, filtered and dried. Yield: 100 mg of 2,2-dimethyl-propionic acid 3-(4′-chloro-6-fluoro-4-methyl-biphenyl-3-yl)-8-methoxy-2-oxo-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester as a solid, mp: 150-151° C.
Reaction SMILES: Cl.[C:2]1([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[C:5]1([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]([C:8](=[O:16])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(C(=O)Cc2ccccc2)cc1

Procedure:
Chromatographed (E),(E)-1,1'-[1,4-phenylene]bis[2-phenyl-1-(diphenylamino)ethylene](1.0 g, 0.0016 mol) was refluxed in a solution of THF (30 mL) and aqueous HCl (1.2 M, 3.0 mL) for 1.25 h. The solution was worked-up as for the preparation of 1,2-diphenylethanone. Chromatography on silica (30 g) eluting with petroleum ether/benzene 3:2 removed the diketone. After solvent evaporation of the combined fractions and recrystallization of the residue from benzene/methanol gave small plates mp 171°-3° C. (85%). FTIR (CDCl3)ν: 3089, 3066, 3033, 2900, 1592(C=O), 1676, 1568, 1492, 1454, 1404, 1325, 1309, 1272, 1217, 1202 cm-1. 1H NMR (200 MHz, CDCl3)δ4.30(s, 4H, --CH2Ph), 7.24-7.37(m, 10 H, ending phenyls), 8.06(s,4 H, phenylene).MS [m/e(70eV,% of base peak)]C22H18O2 314(M+·, 0.8), 223(M+ · --PhCH2·, 100), 104(C6H4CO+, 42.9), 91(C7H7+, 29).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:8])=[CH:4][CH:3]=1.[CH3:16][N:17](C)C=O.Cl>O>[C:16]([C:2]1[S:6][C:5]([C:7]([C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:8])=[CH:4][CH:3]=1)#[N:17]
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(Br)s1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(C#N)s1

Procedure:
A stirred mixture of 4-[(5-bromo-2-thienyl)carbonyl]-5-methyl-1,3-dihydro-2H-imidazol-2-one (10 grams, 0.034 mole), cuprous cyanide (3.0 grams, 0.034 mole) and dimethylformamide (150 ml) are refluxed for 4 hours. The resulting mixture is poured into a solution of 200 grams ferric chloride and 50 ml concentrated hydrochloric acid in 300 ml water. After the reaction mixture is maintained at 60°-70° C. for 20 minutes, the layers were separated. The aqueous layer is extracted with toluene and the combined organic layers are washed with water and dried. Evaporation of solvent gives the title compound which is recrystallized from methanol.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:6]1[C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C(F)(F)F)cccc2s1
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
A mixture of 1.00 g of 2-fluoro-6-(trifluoromethyl)benzaldehyde, 633 mg of methyl thioglycolate, 1.21 g of potassium carbonate and 15 ml of DMF was stirred at 130° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 480 mg of methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: NO
Reactant: O=C1CCN(Cc2ccccn2)CC1
Agent: Cl
Product: ON=C1CCN(Cc2ccccn2)CC1

Procedure:
1-(2-Pyridinylmethyl)-4-piperidone oxime is prepared from 1-(2-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([CH2:3][C:4]([O:6][CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CC(C)=CCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCOC(=O)CC#N

Procedure:
Cyanoacetic acid (25.9 mmol), 3-methyl-2-butenyl chloride (24.9 mmol), triethylamine (25.7 mmol) and a solvent (30 ml) were placed in a 50-ml flask equipped with a magnetic stirrer and a reflux condenser. The mixture was heated until no more of the title ester was formed. The Table states the solvents, temperatures and heating times used and presents the results. In all cases, the conversion of the 3-methyl-2-butenyl chloride was higher than 85%.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[S-:20][C:21]#[N:22].[K+]>CN(C=O)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:3]2[NH:2][C:21](=[S:20])[NH:22][C:4]=2[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1

Procedure:
With gentle heating, 23a (2.9 g; about 9.6 mmol) was dissolved in absolute DMF (75 ml). Potassium thiocyanate (1.9 g; 19.6 mmol) was introduced into the clear orange-red solution: immediate opalescence and a lighter color. The reaction mixture was stirred under reflux for 1.5 h. The suspension was cooled to room temperature and, with H2O cooling, diluted dropwise with H2O (about 140 ml). The yellow precipitate was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:38])[F:37])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:37])[F:38])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)ccc2C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of methyl 3-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-(trifluoromethyl)benzoyl]amino]-2,4-dimethyl-benzoate (180 mg, 0.32 mmol) in THF (10.0 ml) is added Bu4NF 1.0 M in THF (2.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 8 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (neutral alumina) over a gradient using 100% ethyl acetate in hexane to afford the title compound as a white solid (0.11 g, 76%). Mass spectrum (m/z): 451.2 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:12][C@@H:11]2[C@@H:7]([CH2:8][CH:9]=[CH:10]2)[O:6][C:5]1=[O:13])(=[O:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([N:4]1[CH2:12][C@@H:11]2[C@@H:7]([CH2:8][CH2:9][CH2:10]2)[O:6][C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H]2C=CC[C@H]2OC1=O
Agent: O=[Pt]=O
Solvent: CO
Product: CC(=O)N1C[C@H]2CCC[C@H]2OC1=O
Yield: 99.9 %

Procedure:
181 g (1.0 mol) of cis-4-acetyl-2-oxa-4-aza-bicyclo-[4.3.0]non-7-en-3-one, in 1,000 ml of methanol, are hydrogenated at 25° C. under normal pressure in the presence of platinum dioxide. After the catalyst has been filtered off, the reaction solution is freed from the solvent by distillation. Distillation of the residue gives 183 g (100% of theory) of cis-4-acetyl-2-oxa-4-aza-bicyclo[4.3.0]nonan-3-one (melting point: 80°-83° C.; from methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:19]([O:23][CH2:24][CH2:25]O)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:25][CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cc2)c1C
Reactant: CC(C)(C)OCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(OCCOC(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a solution of 1-(4-Hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg) in Reference Example 39 (2), 2-tert-butoxyethanol (480 mg) and triphenylphosphine (1.06 g) in tetrahydrofuran (20 ml) was added dropwise a solution of 40% azodicarboxylic acid diisopropylester in toluene (2.14 ml) under ice-cooling, and then stirred at room temperature overnight. After completion of the reaction, water was added thereto, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(4-tert-butoxyethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (870 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Cl:30])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Cl
Reaction time: 1.5 h
Yield: 148.2 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-chlorosuccinimide (0.018 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light for 1.5 hour at 80° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.08 g, 15%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH2:27](Br)[CH:28]=[CH:29][CH3:30]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CCOCC>[CH2:27]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])[C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH:28]=[CH:29][CH3:30]
Reactant: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Reactant: CC=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC=CCN(CCc1cc(OC)ccc1I)C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (6.68 g, 17.9 mmol) in toluene (100 mL) was treated with K2CO3 (3.22 g, 23.3 mmol), KOH (3.01 g, 53.7 mmol), n-Bu4NBr (0.580 g, 1.80 mmol) and crotyl bromide (3.15 g, 23.3 mmol). The mixture was stirred at 75 C for 16 hours, cooled to 20 C, diluted with Et2O (500 mL), washed with 10% aqueous HCl (500 mL) and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 5.22 g of a clear oil. MS calculated for C15H17F3INO2+H: 428, observed: 428.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cl)ccc1CO
Product: Cc1cc(Cl)ccc1CCl
Temperature: 100 °C
Yield: 93 %

Procedure:
Step A A mixture of 4-chloro-2-methylbenzyl alcohol (Aldrich) (5 g, 32 mmol) in thionyl chloride (20 mL) was heated at refluxing (100° C.) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 4-chloro-2-methylbenzyl chloride as a light yellow oil (5.2 g, 93%).