Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:18][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][C@@H:3]2[CH2:18][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1
Reactant: OC[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Yield: 71.3 %

Procedure:
A solution of 0.25 g (0.93 mmol) of (7S,8aS)-7-hydroxymethyl-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 14), 0.157 g (1.40 mmol) of 4-fluorophenol, 0.29 g (1.12 mmol) of triphenylphosphine and 0.18 mL (1.1 mmol) of diethyl azodicarboxylate (DEAD) in 10 mL of dry THF was stirred at ambient temperature for 16 hours. The solvent was evaporated, the residue was dissolved in chloroform and washed with 1M sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 hexane:ethyl acetate gave 0.24 g (71%) of the title compound. Mp (.HCl) 221-224° C. HRMS calc'd for C19H22ClFN3O (MH+): 362.1435, found: 362.1415.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]([CH2:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[S:22][CH:23]=2)=[O:17])[CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:4]>CO>[Br:1][C:23]1[S:22][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:20][C:19]=1[NH:18][C:16]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][N:5]([CH2:6][CH3:7])[CH2:3][CH3:4])[N:14]=1)=[O:17]
Reactant: CCN(CC)Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Reactant: BrBr
Solvent: CO
Product: CCN(CC)Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (46 μL, 0.90 mmol) was added to a solution of 1-(6-diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea (190 mg, 0.45 mmol, Example 117) in MeOH (8 mL) and the resulting solution was stirred at RT for 1 h. The reaction was quenched with saturated sodium bisulfite solution and concentrated in vacuo. The residue was dissolved in CHCl3/IpOH (3/1, 10 mL) and washed with H2O (3×10 mL) followed by 1N NaOH solution (10 mL). (The organics were combined, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. MS m/z: 461.1 (M+H). Calc'd for C19H21BrN6OS-461.39.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Methyl 6-methyl nicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), followed by addition of NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol). After stirring at 80° C. for 3 hours, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane; 4/1) to give the title compound (682 mg, 28%) as orange amorphous product.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na].[OH-:21].[Na+]>N1C=CC=CC=1>[CH2:1]([S:19][CH:2]([CH3:1])[CH2:3][CH2:4][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: [Na+]
Agent: [Na]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(C)CCO
Yield: 12 %

Procedure:
The starting material is obtained as follows: Butylene-1,3-glycol is reacted with acetic anhydride at ambient temperature to give butane-1,3-diol 1-acetate in a yield of 63% of theory. It is then esterified with benzenesulphochloride in the presence of pyridine and the reaction product is eluted over a silica gel column with diethyl ether-ligroin (1:1 v/v). There is obtained a yield of 24% of theory of a colourless oil which is reacted with sodium octadecanethiol in the manner described in Example 20B and then treated with a dilute aqueous solution of sodium hydroxide to give a yield of 12% of theory of 3-octadecylthiobutanol; m.p. 35°-38° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][CH:31]([CH3:35])[C:32](Cl)=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:32](=[O:33])[CH:31]([CH3:35])[CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)C(=O)Cl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) and 2-methylpropanoyl chloride (16 mg, 150 μmol). Yield 17 mg (74%).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[C:31](=[O:32])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (0.83 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.91 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C(N(CC)CC)C>CN1CCCC1=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ccc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 120 °C

Procedure:
Add bis(4-methoxybenzyl)amine (35.7 g, 138.9 mmol) in 20 mL of N-methylpyrrolidone to a solution of 2,6-dichloro-3-trifluoromethylpyridine (20 g, 92.6 mmol) and triethylamine (19.4 mL, 138.9 mmol) in 100 mL of N-methylpyrrolidone. Raise the temperature to 120° C., and stir the reaction for 14 hours. Quench the reaction mixture by the addition of water (80 mL), followed by extraction with EtOAc (3×70 mL). Wash the combined organic extracts with water (2×70 mL) and brine (70 mL), and dry over anhydrous Na2SO4. Filter the dried extract and concentrate under vacuum to afford the crude product, which is purified by column chromatography to give a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=8.4 Hz), 7.15 (m, 4H), 6.85 (m, 4H), 6.31 (d, 1H, J=8.8 Hz), 4.70 (s, 4H), 3.80 (s, 6H). Mass spec. (436.99, M+H).
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13](O)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1([CH3:37])[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[O:30]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]12([O:11][CH2:12][C:13](=[C:32]3[C:33](=[O:35])[O:34][C:29]([CH3:37])([CH3:28])[O:30][C:31]3=[O:36])[OH:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)COC12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)COC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (adamantan-1-yloxy)-acetic acid (Example 216, step a) (32.3 g, 0.153 mol) and 1,1′-carbonyl-diimidazole (27.6 g, 0.17 mol) in anhydrous DCM (600 ml) was stirred at 0° C. for 15 min, then at room temperature for 75 min. The mixture was concentrated in vacuo (˜300 ml) and the solution was added dropwise over 20 min to a solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (22.1 g, 0.153 mol) and pyridine (30 ml, 0.371 mol) in anhydrous DCM (450 ml) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 h. The solution was washed with 2M HCl (2×500 ml), brine (500 ml) and dried (MgSO4). Filtration and evaporation gave the product as a white solid, which was washed with hexane, isolated by filtration and dried (50.1 g, 97%). 1H NMR (300MHz, CDCl3) 4.92 (2H, s), 2.19 (3H, br s), 1.82 (6H, s), 1.74 (6H, s), 1.64 (6H, m).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:36][CH:37]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)cc2)CC1
Yield: 35.3 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.05 g (0.20 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give 0.030 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-134).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][C:16]([OH:19])=[N:15]2)=[CH:10][CH:9]=1.Cl[C:21]1[C:26]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>C(O)(C)(C)C.CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[CH:17][C:16]([O:19][C:21]3[C:26]([C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:15]2)=[CH:12][CH:13]=1
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Reactant: COC(=O)C(=O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: COC(=O)C(=O)c1cccnc1Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
At 60° C., 4.7 g (42 mmol) of potassium tert-butoxide were added a little at a time to a solution of 7.4 g (38.1 mmol) of 1-(4-chlorophenyl)-3-hydroxypyrazole in 15 ml of tert-butanol. The mixture was stirred at this temperature for 1 hour and the solvent was then removed under reduced pressure. The residue was dissolved in 25 ml of abs. dimethyl sulfoxide, and a solution of 8.0 g (38.1 mmol) of methyl (2-chloropyridin-3-yl)glyoxylate in 10 ml of abs. dimethyl sulfoxide was then added at such a rate that the temperature did not exceed 30° C. After 30 minutes at room temperature, 50 ml of 0.5 N HCl were added and the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was subsequently removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using cyclohexane/ethyl acetate (10:1) as eluant. 5.5 g (40%) of the title compound were obtained as a clear oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)[N:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[N:17]1([CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=3)[N:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)c1ccc2nc(CCl)ccc2c1
Reactant: C1COCCN1
Solvent: CCO
Product: FC(F)(F)c1ccc2nc(CN3CCOCC3)ccc2c1
Yield: 96.7 %

Procedure:
2-(Morpholin-4-ylmethyl)-6-trifluoro-methylquinoline may be prepared by carrying out the procedure as in Example 29, but starting with 3 g of 2-chloromethyl-6-trifluoromethylquinoline and 3.18 g of morpholine in 30 ml of ethanol. The crude product obtained is chromatographed on a silica gel column, eluting with a mixture of dichloromethane and methanol (97.5-2.5 by volume). 3.5 g of 2-(morpholin-4-yl-methyl)-6-trifluoromethylquinoline are thus obtained in the form of an orange-coloured oil [1H NMR spectrum in CDCl3, T=300K, δ in ppm (300 MHz): 2.55 (4H, m, 2 NCH2), 3.75 (4H, m, 2 OCH2), 3.85 (2H, s, NCH2), 7.75 (1H, d, J=8 Hz, arom. CH), 7.85 (1H, dd, J=8 and 2 Hz, arom. CH), between 8.10 and 8.25 (3H, m, 3arom. CH)].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18](O)=[O:19])[CH:9]=2)=[CH:5][CH:4]=1.[Cl:23]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([Cl:23])=[O:19])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CSc1ccc(Cc2cc(CC(=O)O)cc3ccoc23)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2cc(CC(=O)Cl)cc3ccoc23)cc1

Procedure:
A solution of 7-(4-methylthiobenzyl)benzofuran-5-ylacetic acid (10 g), dichloromethane (100 ml), thionyl chloride (10.0 ml) and dimethylformamide (0.2 ml) was stirred at room temperature for 6 hours. The solvent was then evaporated to give a residue which contained the title compound.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[CH3:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=O>CS(C)=O>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]([CH3:2])=[CH2:26])=[CH:30][CH:31]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Product: C=C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of triphenylphosphonium bromide (17.94 g, 50.24 mmol) in DMSO (10 ml) was added n-BuLi (39.25 ml, 1.6M solution in hexane, 62.80 mmol). The solution was stirred at rt for 1 h and to this was added a solution of 4-bromoacetophenone (10.00 g, 50.24 mmol) in DMSO (4 ml). The reaction mixture was then stirred at rt overnight and then quenched with water and the product was extracted with pentane. The organic layers were combined washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by filtration through a short pad of silica using pentane as eluant to give 1-bromo-4-isopropenylbenzene (5.23 g, 53%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.45 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 5.36 (m, 1H), 5.10 (m, 1H), 2.12 (m, 3H).
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]([CH2:26][OH:27])[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([O:2][CH2:3][CH:4]([CH2:26][O:27][C:35](=[O:36])[NH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7][N:6]2[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)N(Cc1ccccc1)CC2
Agent: Cl
Product: COc1cc2c(cc1OC)C(C(COC(=O)Nc1ccccc1)COC(=O)Nc1ccccc1)N(Cc1ccccc1)CC2

Procedure:
0.01 mole of the compound obtained in Step (A) is boiled with 0.02 mole of phenyl isocyanate for 4 to 6 hours. Evaporation of the reaction mixture yields the aimed compound in a crystalline form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:24]([NH:25][C:14]([C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:16])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 2-phenylethylamine.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13](#[N:17])[CH2:14][CH:15]=[CH2:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>C1COCC1>[C:13]([CH:14]([CH:15]=[CH2:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:17]
Reactant: CCOC(=O)CBr
Reactant: C=CCC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CC(C#N)CC(=O)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M in THF, 33 mL, 82 mmol) was added dropwise to a solution of diisopropylamine (9.0 g, 90 mmol) in THF at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. To the mixture was added a solution of 3-butenenitrile (5.0 g, 74.6 mmol) in THF (30 mL) dropwise at −78° C. The resultant mixture was stirred at the temperature for 1 hour, then a solution of ethyl bromoacetate (13.7 g, 82.06 mmol) in THF (30 mL) was added dropwise at −78° C. to the reaction mixture. The reaction mixture was stirred at −78° C. for an additional 1 hour. The reaction mixture was poured into a solution of saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×300 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to afford ethyl 3-cyanopent-4-enoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.83-5.71 (m, 1H), 5.53-5.49 (m, 1H), 5.36-5.33 (m, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.79-3.71 (m, 1H), 2.81-2.73 (m, 1H), 2.69-2.61 (m, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: O.[OH-].[Na+].O.Cl.[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].Cl[C:14](OC1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[O:15]=[C:14]1[NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A aqueous solution comprising 0.88 liter of water and 184.0 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride monohydrate under ice-cooling, 0.35 liter of a toluene solution containing 313.2 g of phenyl chloroformate was added to the above solution within a range not exceeding 30° C. After stirring the mixture at room temperature for 2 hours, it was allowed to stand and the liquids were separated. The aqueous layer was washed with 0.35 liter of toluene, the layers were separated, and the aqueous layer was concentrated to give 139.84 g of (4R)-2-oxothiazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH:56]([CH2:59][O:60][Si](C(C)C)(C(C)C)C(C)C)[CH2:55][CH2:54]5)=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:26]([CH3:28])[N:27]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.C(Cl)Cl>[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH:56]([CH2:59][OH:60])[CH2:55][CH2:54]5)=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:26]([CH3:28])[N:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(CO)CC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 211 μL, 0.211 mmol) was added to a solution of Intermediate 14f (110 mg, 0.151 mmol) in THF (3 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (52 mg, 60%). LCMS (Method 3): Rt: 2.91 min, m/z 573 [MH+].
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C(OC(=O)[NH:25][CH2:26][CH:27](O)[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:28][CH:27]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[CH2:4][NH:25][CH2:26]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Product: CC1CNCc2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and rac-2-hydroxy-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).