Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.N1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21](O)(=O)[CH3:22]>C1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]([C:8](=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:14])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)c1ccc(Br)s1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)c1ccc(Br)s1

Procedure:
A solution of ethyl 3-(5-bromothiophen-2-yl)-3-oxopropanoate (3.73 g, 13.46 mmol), benaldehyde (1.501 ml, 14.81 mmol), piperidine (0.133 ml, 1.346 mmol) and acetic acid (0.389 ml, 6.8 mmol) in benzene (50 ml) was heated at 85° C. for 5 h using a Dean-Stark trap for removal of the water formed. The reaction solution was concentrated. The resulting residue was purified via flash chromatography (silica gel cartridge with eluent of 0-5% ethyl acetate/hexane) to give ethyl 2-(5-bromothiophene-2-carbonyl)-3-phenylacrylate as a light amble viscous oil (4.25 g). LCMS m/z 388.99, 390.09 (M+23); HPLC: Rt 3.701 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:2]([O:4][C:5](=[O:34])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=3)=[CH:17][C:16]=2[CH2:30][N:31]([C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH3:33])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and benzoyl chloride.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][N:14]1[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C)C=O>[N:30]#[N:31].[CH2:3]([O:10][C:11]([C@@:13]1([C:27]([NH2:29])=[O:28])[CH2:17][C@@H:16]([N:30]=[N+:31]=[N-:32])[CH2:15][N:14]1[C:23]([CH3:24])([CH3:26])[CH3:25])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)N1C[C@@H](OS(C)(=O)=O)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N1C[C@H](N=[N+]=[N-])C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Temperature: 75 °C
Yield: 78.8 %

Procedure:
0.5 g of N2 -(benzyloxycarbonyl)-N1 -tert.butyl-4(S)-(methanesulphonyloxy)-L-prolinamide was dissolved in 10 ml of dry dimethylformamide and treated with 0.330 g of sodium azide. The heterogeneous mixture was stirred and heated at 75° C. for 18 hours. The mixture was evaporated under an oil pump vacuum to give a solid which was partitioned between ethyl acetate and water. The ethyl acetate phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.345 g of N2 -(benzyloxycarbonyl)-4(R)-azido-N1 -tert.butyl-L-prolinamide in the form of a gum.
Reaction SMILES: [OH-:1].[Na+].[SH:3][C:4]1[N:8]=[C:7]([SH:9])[S:6][N:5]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>O.CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([S:3][C:4]2[N:8]=[C:7]([S:9][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:18])=[O:1])=[CH:13][CH:12]=3)[S:6][N:5]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Sc1nsc(S)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2nsc(Sc3ccc([N+](=O)[O-])cc3)n2)cc1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
3 g of NaOH were dissolved in 5 ml of water in a 250 ml three-necked flask, 3.8 g (25 mmol) of 3,5-dimer-capto-1,2,4-thiadiazole (preparation analogous to U.S. No. 3,899,502 or Z. Anorgan. Allgem. Chemie volume 486 (1982), pages 111-115) were added and the mixture was heated to 100° C. 79 g (50 mmol) of 1-chloro-4-nitrobenzene, dissolved in 75 ml of DMF, were metered into the clear solution. After the mixture had been boiled under reflux for 4 hours, it was evaporated and the residue was taken up in water, washed and filtered off. After recrystallization from an acetone-water mixture, 9 g (92% of theory) of 3,5-bis-(4-nitrophenylthio)-1,2,4-thiadiazole were obtained.
Reaction SMILES: C(O)(=O)C.[C:5]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:10]=[CH:9][C:8]([CH:11]=[N:12][NH:13][C:14]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:18](=[O:29])[N:17]([CH3:30])[C:16](=[O:31])[CH:15]=2)=[CH:7][CH:6]=1.N1CCCCC1.[C:44]1([CH2:50][CH:51]=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[CH2:50]([C:51]1[N:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:10][CH:9]=2)[N:13]=[C:14]2[C:15]=1[C:16](=[O:31])[N:17]([CH3:30])[C:18](=[O:29])[N:19]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=CCc1ccccc1
Reactant: COc1ccc(Cn2c(NN=Cc3ccc(-c4ccccc4)cc3)cc(=O)n(C)c2=O)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Cc4ccccc4)n(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Temperature: 42.5 °C
Reaction time: 36 h
Yield: 31.2 %

Procedure:
Acetic acid (4.4 mL) is added in to a solution of 6-(2-(Biphenyl-4-ylmethylene)hydrazinyl)-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (3.2 g, 7.26 mmol) in DMF (50 mL) and ButOH (25 mL) at 50° C. Piperidine (8.7 mL) is mixed with a solution of 2-phenylacetaldehyde (8.5 mL, 72.6 mmol) in DMF (20 mL), and the resulting greenish solution is added in to the above solution. The reaction mixture is stirred at 40-45° C. for 36 hours under argon, and the solvent is evaporated under high vacuum. The residue is treated with MeOH (200 mL) to precipitate out 1.23 g product as sandy solids (Yield: 31.4%). MS (FAB) m/z 543.4 [M+H]+.
Reaction SMILES: [N+]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.O=[N:23]C1C=CC=CC=1>CO.[Pd]>[NH2:23][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:4]=1)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2)=[O:9]
Reactant: O=C1Cc2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Reactant: O=Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.08 h

Procedure:
5-(4-Nitro-benzoyl)-1,3-dihydro-indol-2-one (1.51 g, 5.28 mmol) was dissolved in MeOH (600 mL). 10% Pd/C (0.150 g) was added to the flask and then placed under vacuum to remove any O2(g). The reaction mixture was kept under reduced pressure for ˜5 min and was then charged with H2(g). This evacuation/H2(g) fill procedure was repeated twice. The reaction mixture changed from a cloudy grayish/black color to a translucent dark green/black color, signifying complete consumption of the starting material. As the desired ketone product was prone to over-reduction to the alcohol, stopping the reaction immediately upon complete consumption of the starting material limited the amount over-reduction that occurred. The reaction was allowed to run for 0.75-1.0 hours after which, the reaction mixture was filtered over celite and concentrated in vacuo resulting in a yellowish solid that contained the desired keto-aniline product plus ˜5% of the overreduced alcohol-aniline. The crude solid was purified by triturating with MeOH. The desired keto-aniline product, 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one was soluble in MeOH and was filtered away from the insoluble over reduced alcohol by-product. In vacuo concentration of the methanolic filtrate provided pure 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 72% (0.957 g, 3.80 mmol) yield.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])(=O)C.C[OH:14]>N>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[OH:14]
Reactant: CO
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: N
Product: COc1ccc(O)c(F)c1
Yield: 94 %

Procedure:
A suspension of 2-fluoro-4-methyl acetophenone (10.0 g, 0.059 mol), mCPBA (26.0 g, 0.128 mol) and MgSO4 (30.0 g) in 500 mL of CHCl3 was stirred for 12 hrs. at RT. The mixture was then filtrated, washed with 2M NaOH, dried over Na2SO4 and concentrated in vacuo to give 1-acetyl-2-fluoro-4-methoxybenzene as a solid (10.7 g, 98%). A solution of the 1-acetyl-2-fluoro-4-methoxybenzene (5.3 g, 0.029 mol) in 100 mL of MeOH and 20 mL of 25% NH3 (aq) was stirred for 1 hr. at RT. The mixture was then concentrated in vacuo, diluted with water, extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give 2-fluoro-4-methoxyphenol as an oil (3.85 g, 94%). 2-Ethoxy-1-fluoro-4-methoxybenzaldehyde was prepared according to method described in Example 362 of WO 93/03022 and converted to a cis/trans mixture of 2-(2-ethoxy-1-fluoro-6-methoxyphenyl) cyclopropylisocyanates according to the methods described in Examples 375 and 348 of WO 93/03022. This product was then condensed with 2-amino-5-bromo-pyridine in a manner analogous to the method in Example 7 to provide cis/trans mixture of N-2-(2-ethoxy-1-fluoro-6-methoxyphenyl)cyclopropyl-N′-(5-bromopyrid-2-yl)-ureas. The two products were separated on a silica-gel column eluated with mixtures of hexane and ethylacetate to yield N-(cis)-(3-ethoxy-2-fluoro-6-methoxyphenyl)-cyclopropyl-N′-(5-bromopyrid-2-yl)-urea: 1H NMR (250 MHz, CDCl3) δ 7.88 (s, 1H), 7.55 (dd, 1H), 6.83 (t, 1H),6.58 (dd, 1H), 4.03 (q, 2H), 3.79 (s, 3H), 3.32-3.19 (m, 1H), 1.54-1.20 (m, 2H), 1.46 (t, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1)=O.[C:16]1([CH3:28])[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:26]([C:25]([S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:28])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[CH:5][CH:4]=1)#[N:27]
Reactant: N#Cc1ccsc1-c1ccc(C=O)cc1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Product: Cc1ccc(S(=O)(=O)C(C#N)=Cc2ccc(-c3sccc3C#N)cc2)cc1

Procedure:
In a manner analogous to the procedure set forth in example A-239, the title compound is prepared from 2-(4-formylphenyl)thiophene-3-carbonitrile, prepared directly above, and p-toluenesulphonylacetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C1C2C(=CC=CC=2)CCN1.C(O)C>[CH2:22]1[C:20]2[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=2)[CH2:6][CH2:26][N:23]1[CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 21. Purity by LC/MS=98%, [M+H]+=419.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[N:7]2NC(OC(C)(C)C)=O.O.[NH2:28][NH2:29]>O1CCOCC1>[NH:28]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6](=[O:20])[NH:7]2)[NH2:29]
Reactant: NN
Reactant: CC(C)(C)OC(=O)Nn1c(=O)c(-c2ccccc2)cc2c(Cl)nccc21
Solvent: C1COCCO1
Solvent: O
Product: NNc1nccc2[nH]c(=O)c(-c3ccccc3)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 5-chloro-2-oxo-3-phenyl-1,6-naphthyridine-1(2H)-carbamate (2-2) (2.0 g, 5.6 mmol) and hydrazine hydrate (7.2 g, 112 mmol) in 1,4-dioxane (28 mL) was heated under microwave irradiation at 120° C. for 20 minutes. The solvent was removed under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration to give 5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3) as a colorless solid.
Reaction SMILES: [C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([SH:17])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37](C)[CH:36]=1.[C:44](OCC)(=O)C>C(O)C>[C:1]1([N:7]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:8]([C:10]2[CH:20]=[CH:19][C:13]3[N:14]([CH3:18])[C:15]([S:17][CH2:44][C:35]4[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(S)n2C)c1ccccc1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(SCc1ccc(C#N)cc1)n2C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 1.30 g (3.4 mMol) of 1-methyl-2-mercapto-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, 0.52 g (3.74 mMol) of potassium carbonate and 0.66 g (3.4 mMol) of 4-bromo-methylbenzonitrile were dissolved in 40 ml of absolute ethanol, stirred for 4 hours at 60° C. and 16 hours at room temperature. Then the solvent was distilled off in vacuo, the crude product was taken up in 30 ml of methylene chloride, washed with 40 ml of water and dried with sodium sulphate. After filtration and distillation of the solvent the desired compound was obtained as a beige-white solid. Yield: 1.8 g (100% of theory), Rf value: 0.64 (silica gel; ethyl acetate)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:18]([NH:28][C@H:29]([C:34](O)=[O:35])[CH2:30][CH2:31][S:32][CH3:33])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:21]([O:20][C:18]([NH:28][C@@H:29]([CH2:30][CH2:31][S:32][CH3:33])[C:34]([NH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]2[CH2:9][C@H:3]1[C:4](=[O:17])[N:5]2[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:35])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Preparation A3, Step 2: A solution of (1R,2S,5R)-tert-butyl 2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g) was dissolved in DMF (34 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.3 g), 4-methyl morpholine (3.7 g), and BOP (8.3 g). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g). MS found: (M+H)+=506.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1ccc(F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(CCCBr)cc1F
Yield: 84.8 %

Procedure:
Compound 53-2 (3.11 g) was dissolved in methylene chloride (60 ml), triphenylphosphine (5.21 g) and N-bromosuccinimide (3.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.6 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:21][C:22](=O)[CH3:23]>C(O)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[C:11]3[C:22]([CH3:23])=[CH:21][O:15][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-fluorophenyl)cyclohexane-1,3-dione (mp175-176° C.; 1.03 g) in ethanol (10 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added a solution of chloroacetone (0.45 ml) in DMF (10 ml), and the mixture was stirred at 100° C. overnight (13 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.12 g).
Reaction SMILES: [C:1]([CH:5]([OH:7])[OH:6])([F:4])([F:3])Cl.Br[CH2:9][CH2:10]O.[Cl-:12].[Ca+2].[Cl-].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:5]1([CH:1]([F:4])[F:3])[O:7][CH2:10][CH2:9][O:6]1
Reactant: [Cl-]
Reactant: OC(O)C(F)(F)Cl
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)C1(Cl)OCCO1
Temperature: 90 °C

Procedure:
157 g (1.4 mole or less) of CClF2CH(OH)2, 197 g (1.5 mole) of 2-bromoethanol and 20 g of calcium chloride were placed in a 1 liter-sized flask with a condenser. The flask was heated at 90° C. for 7 hours and cooled to room temperature. The upper phase was transferred to a 5 liter-sized flask, and 2 liters of acetone and 386 g (2.8 moles) of potassium carbonate were added to the flask. The mixture was reacted at 50° C. for three days, and a solid was precipitated. The solvent was removed by distillation. The product was purified by distillation. The yield of the product was 88% (195 g) and has a boiling point of 62° C./30 mmHg.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: CC(C)(C)OC(=O)CCCCCBr
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC2(C)C
Yield: 103.3 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.36 g (5.8 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.6 g (6.3 mmol) of tert-butyl 6-bromohexanoate obtained above, 3.3 g (100%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:21](=[O:22])[C@H:20]3[N:11]([CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[CH2:19]3)[C:10]2=[O:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][C:20]23[C:21](=[O:22])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:10](=[O:23])[N:11]2[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:19]3)=[CH:27][CH:26]=1
Reactant: O=C1[C@@H]2Cc3ccccc3CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)Cc3ccccc3CN12
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of (S)-2-(3,5-dichloro-phenyl)-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-1,3-dione (100 mg) (0.1 mmol) (Prep. 22) in 2.5 mL of dry THF at −40° C. was added a 1 M solution of LIHMDS (0.5 mL) in THF. The reaction mixture was stirred for 15 min. at −40° C. and a solution of 4-bromobenzyl bromide (70 mg) in 1 mL of dry THF was added. The reaction mixture was stirred at −50 C. for 30 min., allowed to warm to RT, stirred overnight, then partitioned between brine and t-Bu methyl ether. The organic layer was dried over MgSO4, concentrated in vacuo, and the residue purified by HPLC to afford the above compound (34.5 mg). NMR (CDCl3, 200 MHz): 7.45 (2H, d), 7.25-7.35 (5H, m), 6.95-7.0 (4H, d+d), 5.15 (1H, d), 4.55 (1H, d), 3.25 (2H, s), 3.20 (1H, d), 2.95 (1H, d).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-:7].[Al+3].[Cl-].[Cl-].[CH:11]1([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>C1COCC1>[ClH:7].[ClH:7].[CH:11]1([CH2:20][CH2:21][N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: [Cl-]
Reactant: COc1ccc(N2CCN(C(=O)CC3CCc4ccccc43)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Product: Cl
Reaction time: 0.17 h

Procedure:
A suspension of lithium aluminum hydride (1.9 g, 50 mmol) in THF (250 ml) is cooled to -20° under a nitrogen atmosphere. Aluminum chloride (6.7 g, 50 mmol) is added slowly via a powder funnel and the mixture is stirred for 10 min. A mixture of 4-[(indan-1-yl)acetyl]-1-(4-methoxyphenyl)piperazine (CXI, EXAMPLE 68, 8.76 g, 25 mmol) in THF (100 ml) is added dropwise over 10 min. The mixture is allowed to warm to 0-5° and stirred for 1 hr. The reaction is quenched with sodium hydroxide (20%) and extracted with methylene chloride (2×800 ml). The organic phase is washed with water, saline, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The concentrate is purified by liquid chromatography on silica gel 60 (230-400 mesh, 400 g), eluting with hexane/ethyl acetate (1/2). The appropriate fractions homogeneous by TLC are combined and concentrated under reduced pressure to give the free base of the title compound, which is converted into the hydrochloric acid salt and crystallized from ethyl acetate/methanol to give the title compound, mp 237-239°; NMR (CDCl3, TMS) 7.80-6.92, 3.84 and 4.82-1.50 δ.