Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1
Reactant: COC(=O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Yield: 97 %

Procedure:
The methyl 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate prepared in Example 1 was suspended in 50 ml of ethanol and a solution of 1.15 g (29 mmol) of sodium hydroxide in 50 ml of water was added thereto. The mixture obtained was then heated on a steam bath until a clear solution was obtained and thin layer chromatography indicated no starting ester remaining. The solution was filtered and the filtrate was acidified while still hot to a pH of 2-3 with concentrated hydrochloric acid. On cooling, the acid crystallized out and was collected, was washed with water and dried over P2O5 under vacuum to obtain 3.20 g (97% yield) of 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylic acid in the form of colorless needles with a melting point of 276°-278° C.
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=[O:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 17.8 g, 97.8 mmol) and triethylamine (9.9 g, 97.8 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (11.21 g, 97.8 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 24.1 g (94%). 1H NMR (CDCl3, 300 MHz) δ0.99 (t, 3H), 1.54 (d, 3H), 1.68 (m, 2H), 2.48 (t, 2H), 3.81 (s, 3H), 5.54 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH+); [α]D +28.8 (c 1.0, MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC1CC(N(Cc2ccc(OC)cc2OC)C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2CC(CC(=O)O)C2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To methyl 2-(3-(tert-butoxycarbonyl(2,4-dimethoxybenzyl)amino)cyclobutyl)acetate from step 2 in a mixture of MeOH, THF and H2O was added 1N NaOH (10 mL). The resultant reaction mixture was stirred at RT for 2 hr. Half of the solvents were removed under reduce pressure and 1N HCl was added to adjust pH of the solution to 4. The aqueous phase was extracted with EtOAc for three times. The combined organic phase was then dried and concentrated in vacuo to afford the acid (0.67 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=CC=C(F)C=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: C[N+](C)=Cc1c(F)cccc1Cl
Agent: CNC
Agent: O=Cc1c(F)cccc1Cl
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1c(F)cccc1Cl)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-chloro-6-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-chloro-6-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][C:2]([OH:30])([CH3:29])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1.Br[C:32]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:35]2[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:29][C:2]([OH:30])([CH3:1])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[N:34]([CH:41]([CH3:43])[CH3:42])[N:33]=2)=[CH:16][CH:15]=1
Reactant: CC(C)n1nc(Br)c2ncccc21
Reactant: CC(C)(O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(Oc3nc4ccccc4n3CC(C)(C)O)cc2)c2ncccc21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A mixture of 2-methyl-1-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol (237 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (139 mg), Cs2CO3 (378 mg), Pd(PPh3)4 (20.1 mg), DME (5 mL), and water (1 mL) was stirred at 140° C. for 30 min under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (175 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1C[O:25]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)(C#N)c1cccc(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C=O)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 2-(3-chlorophenyl)-2-methylpropanenitrile (5.3 g, 29.2 mmol) in THF (80 mL, anhyd) at −78° C. was added dropwise DIBAL-H (1M in toluene, 87 mL, 87 mmol, 3 eq) over 2 h. After stirring 30 min at −78° C., the reaction mixture was allowed to warm to room temperature, quenched with 2N HCl and extracted with EtOAc. The combined extracts were dried over MgSO4 and evaporated in vacuo to give 2-(3-chlorophenyl)-2-methylpropanal (4.6 g, 88%). 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 7.32 (m, 3H), 7.14 (m, 1H), 1.51 (s, 6H).
Reaction SMILES: C[Si](I)(C)C.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26]CC3C=CC=CC=3)=[CH:22][CH:21]=1)[NH:16][N:15]=[C:14]2[NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38]>CO>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:16][N:15]=[C:14]2[NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccco3)cc12
Agent: C[Si](C)(C)I
Solvent: CO
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)c(-c3ccco3)cc12
Yield: 1.7 %

Procedure:
10 cm3 of trimethylsilyl iodide are added to 750 mg of N-[(5-(2-furyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl)]butanamide, described previously, and the mixture is refluxed for 18 hours. 40 cm3 of methanol are added and the reaction medium and the mixture is refluxed for 10 minutes and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 75 cm3 of ethyl acetate and 50 cm3 of tetrahydrofuran and the organic phase is washed with 2×75 cm3 of 10% sodium thiosulphate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure to give 700 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 3 cm3 of ethyl acetate, filtered off, washed with 2 cm3 of ethyl acetate, then with 15 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 10 mg of N-[5-(2-furyl)-6-(4-hydroxyphenyl)-1H-indazol-3-yl]butanamide in the form of white crystals melting at 190° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30](O)=[O:31])=[CH:24]2>>[CH2:13]([C@H:3]([NH:2][C:30]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([F:20])=[CH:29][CH:28]=2)=[O:31])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one hydrochloride (0.65 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (0.73 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 20, 30, 40, 50, 75 and 100% ethyl acetate in hexanes. Yield 228 mg, 84%; HPLC (60/40) 3.57 minutes (98%); PBMS 410 (MH+, 100%);
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[CH:7][CH:6]=1)(=O)C.[Br:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19](SC)[O:20][C:16]=2[CH:15]=1>C(O)(=O)C>[CH3:12][N:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)[C:19]1[O:20][C:16]2[CH:15]=[C:14]([Br:13])[CH:24]=[CH:23][C:17]=2[N:18]=1
Reactant: CNc1ccc(OC(C)=O)cc1
Reactant: CSc1nc2ccc(Br)cc2o1
Solvent: CC(=O)O
Product: CN(c1ccc(O)cc1)c1nc2ccc(Br)cc2o1
Temperature: 180 °C
Yield: 43.9 %

Procedure:
An intimate mixture of 4-(N-methylamino)phenol acetate (7.3 g, 0.04 mole) and 6-bromo-2-(methylthio)benzoxazole (6.0 g, 0.025 mole) was prepared and heated on an oil bath to a temperature of 180° C. The mixture was heated at this temperature for a period of 4 hours during which time acetic acid distilled from the mixture and methyl mercaptan was evolved and was trapped in aqueous sodium hydroxide. The mixture was cooled to form a solid and the solid was extracted with hot toluene (4×100 ml). The toluene solution was filtered hot and the solvent removed by distillation to give a brown solid. The solid was recrystallised from toluene to give the title compound as a grey solid (3.5 g), mp 195° C.
Reaction SMILES: [CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[C:2](=[CH2:4])[CH3:3].[H-].[Na+].[CH2:16](Cl)[C:17](=[CH2:19])[CH3:18].O>CN(C=O)C>[CH2:1]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[N:8]([CH2:18][C:17](=[CH2:16])[CH3:19])[C:6]1=[O:7])[C:2](=[CH2:3])[CH3:4]
Reactant: C=C(C)CCl
Reactant: C=C(C)CN1C(=O)NC(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CN1C(=O)N(CC(=C)C)C(C)(C)C1=O
Temperature: 15 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
In a 100 ml three necked flask is placed 10 g (0.055 mol) of N-methallyl-5,5-dimethylhydantoin in 100 ml DMF under nitrogen. The solution is cooled to 15° C. and 2.7 g of sodium hydride/mineral oil is added. The reaction is stirred for 2 hours at 15° C. and then warmed to 25°C. Methallyl chloride (5.1 g, 0.056 mol) is added dropwise over 10 minutes, keeping the temperature at 30° C. The reaction is stirred overnight, then poured into 200 ml water, extracted with 2 X 100 ml ether and dried over magnesium sulfate. After removing the ether in vacuo, the residue is distilled under vacuum (BP 100°-105°0 C. 0.3 mm Hg) to give 11.9 g N,N'-bismethallyl-5,5-dimethylhydantoin.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)[CH2:3][CH3:4].O.NN.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Sc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)Sc1ccc(OCCN)cc1

Procedure:
To a solution of the above phthalimide (6.84 g, 19.7 mmol) in 100 ml of ethanol, heated to 60°, is added hydrazine hydrate (2.0 ml, 41.0 mmol) with stirring. Additional ethanol (100 ml) is added and the mixture is stirred overnight at 60°. After cooling, 5% sodium hydroxide is added and the basic mixture is extracted with ether. The combined organic layers are washed with water and brine, dried and rotoevaporated to give 2-[4-(1-methylpropylthio)phenoxy]ethylamine.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.Cl.[OH:34][C:35]1([C:39]([NH:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:38][NH:37][CH2:36]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:37]2[CH2:38][C:35]([OH:34])([C:39]([NH:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:36]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CCNC(=O)C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCNC(=O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 0.08 h
Yield: 9.2 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (1.20 g, 3.05 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (1.20 g, 9.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701 mg, 3.66 mmol) were dissolved in DMF (10 mL). The mixture was stirred at ambient for 5 minutes and then 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol) in DMF (5 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 60-85% ethyl acetate in hexanes) and then reverse phase HPLC gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide (150 mg, 0.282 mmol, 9% yield): 1H NMR (400 MHz, d6-DMSO): 8.64 (br s, 1H), 8.13 (t, 1H), 7.58 (dd, 1H), 7.38 (dd, 1H), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 1H), 6.84 (br s, 1H), 6.72 (ddd, 1H), 5.83-5.72 (m, 1H), 5.10-4.99 (m, 2H), 4.38 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.86 (d, 1H), 3.73-3.68 (m, 2H); MS (EI) for C20H17F3IN3O3: 532 (MH+).
Reaction SMILES: [Br:1][C:2]1([Br:15])[C:13](=[O:14])[N:4]2[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[Br:15][C:2]1([Br:1])[C:13](=[O:14])[N:4]2[CH:5]([C:10]([O:12][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)C1C(=O)OCc1ccccc1
Yield: 85 %

Procedure:
To a stirred solution of 1646 g. of 6,6-dibromo-2,2-dimethyl-(5R)penam-3α-carboxylic acid in 10.1 liters of N,N-dimethylacetamide was added 709 ml. of triethylamine during 10 minutes at ca. 0° C. The temperature was adjusted to 10° C., and 602 ml. of benzyl bromide was added during 4 minutes. To the reaction mixture was then added 941 g. of 4A molecular sieves, and then the reaction mixture was stirred overnight without external cooling. At this point, the reaction mixture was filtered and the filtrate was added to a mixture of 44 liters of ice-water and 14 liters of ethyl acetate. The pH of the aqueous phase was adjusted to 2.0 using 6 N hydrochloric acid, and the layers were separated. The aqueous layer was extracted with further ethyl acetate and the combined ethyl acetate solutions were washed sequentially with 14 liters of saturated, aqueous sodium bicarbonate and 14 liters of saturated, aqueous sodium chloride. The ethyl acetate solution was dried (Na2SO4), and then it was evaporated in vacuo at 25° C. The residue was dissolved in 5.5 liters of isopropyl alcohol at 60° C., and then the isopropyl alcohol solution was cooled slowly with stirring. The solid which precipitated was recovered by filtration, washed with cold isopropyl alcohol and then air dried. This afforded 1777 g. (85% yield) of the title product. The NMR spectrum (CDCl3) showed absorptions at 1.40 (s, 3H), 1.55 (s, 3H), 4.55 (s, 1H), 5.20 (s, 2H), 5.75 (s, 1H) and 7.35 (s, 5H) ppm.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)#[C:19][CH3:20]>C(NCC)C.[Cu](I)I>[CH2:18]([C@H:21]1[CH2:26][CH2:25][C@H:24]([C:15]2[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)[CH2:19][CH3:20]
Reactant: CC#Cc1ccc(I)cc1
Reactant: CCC[C@H]1CC[C@H](C#Cc2ccccc2)CC1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc([C@H]3CC[C@H](CCC)CC3)cc2)cc1

Procedure:
Trans-4-propylcyclohexylphenylacetylene (2.3 g, 0.01 mol) and 4-(1-propynyl)iodobenzene (2.4 g, 0.01 mol) were dissolved in diethylamine (20 ml), and then copper iodide (0.11 g, 0.15 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g, 0.3 mmol) were added. The resulting mixture was subjected to reaction and purification operation in the same manner as in Example 1 to obtain the objective 4-(trans-4-propylcyclohexyl)-4'-(1-propyl)tolan (compound No. 57) (1.8 g). (CS point: 118.9° C., SN point: 127.4° C., NI point: 245.1° C.)
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[O:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:9]1)=O)[C:2]([CH3:4])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1COCC1>[CH3:4][C:2]1[S:40][C:6]([CH:8]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:9]2)=[N:5][CH:1]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Solvent: C1CCOC1
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)s1
Temperature: 70 °C
Yield: 121.2 %

Procedure:
Tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 0.18 mmol) was dissolved in anhydrous THF (1.5 mL) followed by the addition of Lawesson's reagent (114 mg, 0.27 mmol) and the reaction mixture was heated at 70° C. for 1 hour under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using 0-10% EtOAc in DCM as eluent to yield tert-butyl 10-(5-methylthiazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (95 mg, 100%). ESI-MS m/z calc. 435.5. found 436.5 (M+1)+; Retention time: 1.67 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 5.20 (dd, J=9.4, 0.8 Hz, 1H), 3.82-3.76 (m, 2H), 3.43 (d, J=10.1 Hz, 1H), 3.31-3.21 (m, 1H), 3.09-2.94 (m, 3H), 2.72 (dd, J=11.4, 0.5 Hz, 1H), 2.50 (s, 1H), 2.46 (s, 3H), 2.45-2.38 (m, 2H), 1.79-1.67 (m, 1H), 1.65-1.57 (m, 1H), 1.53 (dd, J=11.2, 4.8 Hz, 1H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:27]>C(O)(=O)C>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([C:11]2[NH:27][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[CH:8][CH:9]=3)[CH:10]=2)=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2cccc12
Temperature: 25 °C

Procedure:
A solution of 106 mg (0.34 mmol) 1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester and 789 mg (10.2 mmol) ammonium acetate in 2 ml acetic acid is heated to 80° C. under stirring. The mixture is stirred at this temperature for 5 hours and then cooled to room temperature. The mixture is partitioned between THF and saturated sodium chloride solution. The organic phase is washed two times with 25% aqueous ammonia and two times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as colourless crystals; HPLC/MS 2.11 (A), [M+H] 279;
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:23](Br)[CH:24]([CH3:26])[CH3:25].[NH4+].[Cl-]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:15]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Reactant: CC(C)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (2.2 g, 7.8 mmol) was dissolved in 20 mL anhydrous DMF and NaH (60% wt. in oil, 0.189 g, 7.8 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and isobutyl bromide (1.08 g, 7.8 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)-4-methylpentanoate (2.06 g) of colorless oil.