Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH:11]=[CH:10]2.CN([CH:25]=[O:26])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH:11]=[C:10]2[CH:25]=[O:26]
Reactant: O=c1c2ccc(Br)cc2ccn1CC1CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (10 mL) was cooled in an ice bath and phosphorus oxychloride (0.40 mL) was added over 20 seconds. The solution was stirred for 10 minutes at room temperature and then the product of step i) (0.6 g) in DMF (2 mL) was added over 5 minutes. The mixture was heated at 80° C. overnight. The mixture was allowed to cool then poured onto ice/water and stirred for 20 minutes. The aqueous was extracted with ethyl acetate, the organics were combined and evaporated under reduced pressure. The residue was purified (SiO2, eluting with 1:4 ethyl acetate:isohexane) to give the sub-title compound (0.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[C:6]([NH:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]12)=[O:7])(O)=O.C(N(CC)CC)C.ClC(OCC)=O.NN.C1(CC(Cl)=O)C=CC=CC=1>O1CCCC1>[C:32]1([CH2:5][C:6]([NH:8][CH:9]2[C:30](=[O:31])[N:11]3[C:12]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[O:18])=[C:13]([CH3:16])[CH2:14][S:15][C@H:10]23)=[O:7])[CH:33]=[CH:34][CH:35]=[CH:4][CH:1]=1
Reactant: CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1
Agent: CCOC(=O)Cl
Agent: NN
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
To a suspension of p-nitrobenzyl 7-(2-carboxybenzamido)-3-methyl-3-cephem-4-carboxylate (462 mg., 1 mmol.) in tetrahydrofuran at 0° C. is added triethylamine (0.14 ml., 1 mmol.). After 15 minutes, ethyl chloroformate (0.1 ml., 2 mmol.) is added, and then after 0.5 hour at 0° C., anhydrous hydrazine (0.03 ml., 1 mmol.) is added to the reaction mixture. After 15 minutes, the mixture is filtered, and the filtrate is evaporated to dryness in vacuo. The residue is taken up in acetone (15 ml.) and tetrahydrofuran (15 ml.), and phenylacetyl chloride (0.13 ml., 1 mmol.) is added. After refluxing for 30 min., the mixture is cooled and evaporated in vacuo to dryness. The produce is taken up in chloroform (50 ml.) and washed successively with 1N HCl (30 ml.), 10% sodium bicarbonate (40 ml.), and brine (40 ml.), dried over MgSO4, and evaporated in vacuo to dryness. The colorless product is slurried with ethyl acetate (12 ml.). Filtration gives p-nitrobenzyl 7-phenylacetamido-3-methyl-3-cephem-4-carboxylate. Recrystallization from ethyl acetate gives an analytical sample: m.p. 227°-230°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])[CH3:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2C=CC=CC=2N=N1.C(N(CC)CC)C.CN.O1CCCC1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13]([NH:34][CH3:38])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)ccc1C(=O)O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
80 mg of (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinic acid was dissolved in 1 ml of tetrahydrofuran, 86 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate salt (HBTU) and 59 mg of triethylamine were added thereto. The mixture was stirred at room temperature for 30 minutes, and then 119 μl of 2M methylamine/tetrahydrofuran solution was added thereto, and the mixture was stirred for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:8]=1[Cl:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:25][CH:24]=1)[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[Cl:20]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.7 %

Procedure:
N-[2-Chloro-4-(tert-butoxycarbonyl)benzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (305 mg) was dissolved in anhydrous CH2Cl2 (2 mL) under N2 and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 h to give N-[2-chloro-4-carboxybenzoyl]-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (315 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:12](=[O:14])[CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(=O)OCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(CCCCOC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Compound 3 was prepared by following a previously reported method.{Santra, 2004 #6} Briefly, diethyl malonate 1 (10 g, 62.5 mmol), 4-bromobutyl acetate 2 (15.84 g, 81.3 mmol) were placed in a round bottom flask containing acetonitrile (120 mL) and stirred for 2 min at room temperature. Then to this, we added potassium carbonate (34.5 g, 250.1 mmol) and refluxed for 36 h. Next, the mixture was filtered and the filtrate was concentrated to obtain a yellow liquid. This was extracted with ethyl acetate, and washed with water. The organic layers were combined and dried over Na2SO4, and purified by column chromatography using 4% ethyl acetate in petroleum ether as the eluent.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>C(#N)C.O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[NH2:11])=[CH:6][N:7]=1
Reactant: Cc1ccc(N(CCc2ccc(Cl)nc2)N=O)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(N(N)CCc2ccc(Cl)nc2)cc1
Reaction time: 1 h

Procedure:
A 250 mL flask was charged with N-(2-(6-chloropyridin-3-yl)ethyl)-N-p-tolylnitrous amide (5.2 g, 18.9 mmol; Example 117C) and ammonium carbonate (3.62 g, 37.7 mmol; Aldrich) in acetonitrile (10 mL) and water (30 mL). The mixture was cooled in an ice bath and zinc dust (1.63 g, 24.5 mmol; Aldrich) was added very slowly over 2 hours. After stirring for an additional 1 hour, the reaction was filtered to remove the solid material. The filtrate was concentrated and extracted with ethyl acetate. The organic extracts were then purified by flash chromatography (silica gel, hexane/ethyl acetate, 2:1) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.22 (s, 3H), 2.89-2.99 (m, 2H), 3.52-3.60 (m, 2H), 6.81-6.90 (m, 2H), 6.98-7.04 (m, 2H), 7.36 (d, J=8 Hz, 1H), 7.74 (dd, J=8, 3 Hz, 1H), 8.25 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 262 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14]O)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.[F:16][C:17]([F:25])=[CH:18][CH:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14][N:22]3[CH2:23][CH:19]([CH:18]=[C:17]([F:25])[F:16])[CH2:20][C:21]3=[O:24])=[C:9]([CH:11]3[CH2:12][CH2:13]3)[N:10]=2)[N:7]=1
Reactant: OCc1c(C2CC2)nc2ccc(Cl)nn12
Reactant: O=C1CC(C=C(F)F)CN1
Solvent: Cc1ccccc1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 28 %

Procedure:
A solution of (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889 mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37 mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) in toluene (20 ml) is heated under reflux for 16 h. After cooling, the solvent is removed under reduced pressure, the crude product is dissolved in dichloromethane (100 ml). The organic layer is washed by water (150 ml). The aqueous layer is extracted by dichloromethane (100 ml). The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography over silicagel (benzine/AcOEt: 60/40) to afford 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 62 after recristallization in diisopropylether.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:8]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:20]2)=[N:9][C:10]([CH3:14])=[N:11][C:12]=1Cl)(=[O:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:8]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[CH:27][CH:26]=3)[CH2:23][CH2:22][N:21]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:20]2)=[N:9][C:10]([CH3:14])=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCNC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)ncc2CCNC(C)=O)cc1

Procedure:
A solution of 0.191 g of tert-butyl 3-{2-[5-(2-acetylaminoethyl)-6-chloro-2-methylpyrimidin-4-yloxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.055 ml of triethylamine in 6 ml of ethanol is hydrogenated in the presence of 0.060 g of 10% Pd/C (added 4 times) at room temperature over 60 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.22 (95:5 dichloromethane-methanol); Rt=4.54.
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([CH3:23])[C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 40 °C
Yield: 94.1 %

Procedure:
To a pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (400 mg at 69% purity) in N,N-dimethylformamide (0.5 mL) was introduced potassium carbonate (134 mg, 0.97 mmol) and methyl iodide (207 mg, 1.46 mol). The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr and room temperature for 12 hr. After concentrating the reaction mixture in vacuo, the residue was suspended in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2×10 m), water (2×10 ml) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo to furnish the crude title compound (389 mg of 77% purity LCMS-UV215) as an orange-brown sticky solid which was used for the next step without further purification. For characterisation purposes, some of the crude product was taken and suspended in ethyl acetate by sonnication and the product, an off-white solid, collected by filtration: 1H NMR (500 MHz, CDCl3) δ 1.48 (t, J=7.09 Hz, 3H), 1.69-1.74 (m, 2H), 2.92-3.00 (m, 2H), 3.50 (td, J=7.57, 3.78 Hz, 1H), 3.56 (td, J=8.35, 3.78 Hz, 1H), 3.94 (s, 3H), 4.46 (q, J=7.15 Hz, 2H), 6.79 (d, J=8.83 Hz, 1H), 8.83 (d, J=6.62 Hz, 1H); M+1=427.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].C(Cl)(Cl)Cl>CO.[C].[Pd]>[NH2:11][C@@H:12]([CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:14]
Reactant: O=C(N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
(1S,2S)-2-Benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (3.82 g, 10.3 mmol) was dissolved in methanol (10 ml), ammonium formate (2.6 g, 41.3 mmol) and 10% palladium-carbon (888.5 mg, 8.09 mol %) were added thereto, and the mixture thus obtained was stirred overnight at room temperature. After confirming completion of the reaction with TLC (chloroform:methanol=9:1 and 7:3), palladium-carbon was removed by filtration and the resulting filtrate was concentrated to obtain the objective compound as a colorless oily material (2.34 g, yield: 99.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:15][C:16](=[O:19])[CH2:17]Cl)([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[NH:15][C:16](=[O:19])[CH2:17][N:11]3[N:12]=[CH:13][CH:14]=[C:10]23)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)CCl)(c1cccc(Br)c1)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccc(Br)c2)NC(=O)Cn2nccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of rac-N-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-2-chloro-acetamide (1.22 g, 3.56 mmol) in THF (40 mL) was added dropwise to a suspension of sodium hydride (0.28 g, 7.12 mmol) in THF (40 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour. The mixture was diluted with water and the product extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 50/50 to 100/0). The desired fractions were collected and concentrated in vacuo to yield rac-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.7 g, 64% yield) as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:23][NH:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]1[CH2:26][C@H:25]1[C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[Si:1]([O:18][CH2:19][CH:20]1[CH2:23][N:22]([CH2:26][C@H:25]([OH:24])[C:27]([O:29][CH3:30])=[O:28])[CH2:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OCC1CNC1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1CO1
Solvent: CC#N
Product: COC(=O)[C@@H](O)CN1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 85 °C
Yield: 98 %

Procedure:
3-((tert-Butyldiphenylsilyloxy)methyl)azetidine (Intermediate BG3) (7.461 g, 22.92 mmol) and (S)-methyl oxirane-2-carboxylate (2.340 g, 22.92 mmol) were dissolved in acetonitrile (50 mL) and heated to 85° C. for 90 minutes. The resulting mixture was cooled and evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM to afford the product (9.6 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:5][C:13]([C:14](=[O:16])[CH3:15])=[C:17]([CH3:18])[N:6]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Cc1ccc(C(N)=S)c(C)c1
Solvent: CCO
Product: CC(=O)c1sc(-c2ccc(C)cc2C)nc1C
Temperature: 25 °C
Yield: 37 %

Procedure:
To ethanol (20 ml), 2,4-dimethylthiobenzamide (2.00 g) and 3-chloropentane-2,4-dione (1.79 g) were added, and the mixture was stirred under heat reflux for 4 hours. After the mixture was allowed to cool to a room temperature, from the mixture ethanol was distilled off under a reduced pressure. To the resulting residue, ethyl acetate was added, and the mixture was heated and stirred. After the mixture was allowed to cool to a room temperature, the precipitate was separated by filtration, washed with ethyl acetate, and then dried under a reduced pressure to give the title compound (1.10 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:19]([O:22][CH3:23])[C:20]#[CH:21]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:21]#[C:20][CH2:19][O:22][CH3:23])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with methyl propargyl ether (0.71 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with a half-saturated aqueous sodium chloride solution (1×20 mL). The resulting aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (503 mg, 83.8%) as an amber oil: EI-HRMS m/e calcd for C19H24O3 (M+) 300.1725, found 300.1728.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([CH3:18])(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(CCl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
873 mg (4.903 mmol) of 3-(chloromethyl)aniline hydrochloride (Example 89A) were initially charged in 4 ml of tetrahydrofuran, and 2.48 g (24.514 mmol) of triethylamine were added. A solution of 421 mg (3.677 mmol) of methanesulfonyl chloride in 3 ml of tetrahydrofuran was slowly added dropwise, and the reaction solution was stirred at RT for 2 h. The reaction solution was concentrated using a rotary evaporator and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: C(=O)C1C=CC=CC=1.[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.COC1C=CC(/C=[C:42]2/[C:43]([NH:45][C:46]([S:48]/2)=[NH:47])=[O:44])=CC=1OC1CCCC1>>[O:9]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[C:42]4[S:48][C:46](=[NH:47])[NH:45][C:43]4=[O:44])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: O=Cc1ccccc1
Product: N=C1NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and pseudothiohydantoin according to the procedure of Example 35 as an orange solid; 1H NMR (300 MHz, DMSO-d6) δ 1.68 (t, J=5.6 Hz, 4H), 3.43 (t, J=5.6 Hz, 4H), 3.91 (s, 4H), 7.06 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.9 Hz, 2H), 7.48 (s, 1H), 8.99 (brs, 1H), 9.33 (brs, 1H); MS (ES) m/z: 345.9 (MH+); HRMS Calcd. for C17H20N3O3S(MH+): 346.1226. Found: 346.1205. Anal. Calcd. for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.16. Found: C, 58.80; H, 5.71; N, 12.38.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][N:32]([C:41]1[CH:42]=[CH:43][C:44]([NH:45]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:47]=1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(C(=O)c1ccccc1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H32N4O4
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1.C(N(CC)CC)C.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH:28][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[S:26][CH:27]=1
Reactant: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-amine (26-4, 0.500 g, 1.29 mmol) in THF (6.4 mL) was added triethylamine (0.39 g, 3.86 mmol) followed by isonicotinoyl chloride hydrochloride (0.46 g, 2.58 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and dried to give N-{4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-yl}isonicotinamide (26, 0.51 g) as light yellow solids in 80% yield: 1H NMR (500 MHz, CDCl3) δ 8.72 (m, 2 H), 7.61 (m, 2 H), 7.31-7.34 (m, 2 H), 7.08-7.10 (m, 1 H), 6.94-7.02 (m, 6 H), 6.80 (s, 1H), 6.49 (s, 2 H), 1.94 (s, 6 H). ESI-MS: m/z 494.2 (M+H)+.