Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:40][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][N:31]([C:29]([O:28][C@H:26]1[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:42][C@@:18]4([C:43](=[O:45])[NH:64][S:61]([CH:58]4[CH2:60][CH2:59]4)(=[O:63])=[O:62])[NH:19][C:20](=[O:41])[C@@H:21]3[CH2:27]1)=[O:30])[CH2:32]2
Reactant: CC(C)(C)OC(=O)N[C@H]1COCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)OC(=O)N[C@H]1COCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1COCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1COCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecine-14a-carboxylic acid (0.085 g, 0.13 mmol) in toluene (3 mL) was added di(1H-imidazol-1-yl)methanone (0.028 g, 0.18 mmol) in rt. The reaction was stirred at 60° C. for 3 hrs. Cyclopropanesulfonamide (0.029 g, 0.24 mmol) was added, followed by addition of DBU (0.036 ml, 0.24 mmol). The reaction was then stirred at rt for 17 hrs. Water (5 mL) was added and acidified with saturated potassium hydrogen sulfate until pH=2˜3. The mixture was extracted with ethyl acetate (20 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:3) to give (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i)pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.092 g, 93%). MS: Calcd.: 733; Found: [M+H]+ 734. 1H NMR (400 MHz, d6-DMSO) δ11.20 (s, 1H), 8.28 (m, 1H), 7.35 (m, 1H), 7.12-7.20 (m, 2H), 7.00 (m, 1H), 5.57 (m, 1H), 5.35 (m, 1H), 5.16 (m, 1H), 4.67 (s, 4H), 4.41 (m, 2H), 4.15 (m, 1H), 3.86 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 3.31 (m, 1H), 2.91 (m, 1H), 2.33 (m, 4H), 1.68 (m, 2H), 1.49 (m, 3H), 1.11-1.26 (m, 14H).
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([N+:18]([O-])=O)[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[C:12]=1[F:13]>C(O)(=O)C.C(OCC)(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[C:12]=1[F:13])[NH2:18]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114 %

Procedure:
In a mixture of 7.0 g of reduced iron, 4 mL of acetic acid and 50 mL of water, a solution of 6.0 g of 5-chloro-6-fluoro-3-nitrobenzotrifluoride in 80 mL of acetic acid-ethyl acetate (1:1) was added dropwise at 80° C. with stirring over 30 minutes. After the completion of the addition dropwise, it was continued to stir at the same temperature further for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off through Celite, the organic phase was collected and washed with 100 mL of water and then 100 mL of saturated sodium hydrogen carbonate aqueous solution. The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.0 g of the crude aimed product as red-brown oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:4]1[OH:16])#[N:2].C(C1C(O)CCN(C(OC(C)(C)C)=O)C1)#N.O.[SH2:34].[Na].[Cl-].[NH4+]>CN(C)C=O>[OH:16][CH:4]1[CH:3]([C:1](=[S:34])[NH2:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)C(O)C1
Reactant: S
Agent: CC(C)(C)OC(=O)N1CCC(O)C(C#N)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(N)=S)C(O)C1
Yield: 52 %

Procedure:
A solution of 5.8 g (25.6 mmol) of a 4:1 mixture of tert-butyl (3RS,4RS)-4-cyano-3-hydroxy-piperidine-1-carboxylate and tert-butyl (3RS,4SR)-3-cyano-4-hydroxy-piperidine-1-carboxylate in 50 ml of N,N-dimethylformamide was stirred at room temperature under argon for 4 hours with 1.8 g (38.4 mmol) of sodium hydrogen sulphide monohydrate and 2.05 g (38.4 mmol) of ammonium chloride. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was taken up in 150 ml of methylene chloride. The solution obtained was washed twice with 10 ml of water each time and the organic phase was separated, dried over sodium sulphate and then evaporated under reduced pressure. For purification and separation of the isomer mixture, the residue was chromatographed on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 3.48 g (52% of theory) of tert-butyl (3RS,4SR)-3-hydroxy-4-thiocarbamoyl-piperidine-1-carboxylate, (Rf : 0.37, silica gel; methylene chloride:methanol:ammonia=90:10:0.1 v/v/v), MS: 260 (M)+, as well as 1.2 g of a mixture of tert-butyl (3RS,4SR)-3-hydroxy-4-thiocarbamoyl-piperidine-1-carboxylate and tert-butyl (3RS,4RS)-4-hydroxy-3-thiocarbamoyl-piperidine-1-carboxylate, each as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8](Br)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:65][N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:7](=[C:8]([N:69]3[CH2:70][CH2:71][N:66]([CH3:65])[CH2:67][CH2:68]3)[CH:9]=[C:10]([F:17])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(OC)c2cc(F)cc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)c2cc(F)cc(N3CCN(C)CC3)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
Into a 250 mL, 3 neck round bottom flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet is added 2.1 g (6.68 mmol, 1.0 equiv.) of 8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic acid methyl ester (Reference Example 29a) (122 mg, 0.134 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 499 mg (0.802 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 1 g of 4 A molecular sieves and 80 mL of dry toluene. To the stirred suspension is then added 736 mg, 815 μL, (7.35 mmol, 1.1 equiv.) of 1-methylpiperazine, followed by 3.05 g (9.35 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 36 hr. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of celite, with toluene washing to remove solid by products. Purification by flash chromatography using a gradient of 5 to 20% methanol in methylene chloride as eluent yielded 2.0 g, (90%) of the desired product. Mass Spec.: calc. for [C17H20FN3O3+H]+ Theor. m/z=334; Obs.=334.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH:31]([CH3:33])[CH3:32])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]([CH:31]([CH3:33])[CH3:32])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@@H:15]([CH2:25][C:26]([OH:28])=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](N(C(=O)OCc2ccccc2)C(C)C)CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CC(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (8.5 g) in ethanol (100 mL) was added a 2N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at 50° C. for one hour. The reaction solution was cooled with ice, and thereto was added an aqueous potassium hydrogen sulfate solution in order to adjust the pH value to pH 3. The mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.0 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].CC1(C)N([Br:19])C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1ccc2c(c1)C(=O)CCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: O=C1CCOc2ccc(CBr)cc21
Temperature: 25 °C
Yield: 119.8 %

Procedure:
A solution of 6-Methyl-2,3-dihydro-4H-chromen-4-one (7.2 g, 44 mmol), 5,5-Dimethyl-1,3-dibromohydantoin (7.7 g, 27 mmol), and Azobisisobutyronitrile (1.5 g, 9 mmol) in monochlorobenzene (140 mL) was stirred at 80° C. for 3 hours. The reaction solution was poured into ice water (100 mL), and the mixture was warmed to room temperature and then separated into aqueous and organic layers. The aqueous layer was extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (7.8 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:35][CH3:36])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:37]1([C:43](=[O:51])[CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH2:35][CH3:36])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[O:51])[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)Cl)C1c1ccc(Cl)cc1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CC[C@@]1(c2ccc(Cl)cc2)N=C(c2ccc(OC)cc2OC(C)C)N(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)[C@@H]1c1ccc(Cl)cc1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4-ethyl-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give the title compound. LC-MS: 722.3 [(M+H)+]
Reaction SMILES: CI.[CH2:3]1CCN2C(=NCCC2)CC1.[OH:14][C@@H:15]1[CH2:19][C@H:18]([OH:20])[C@H:17]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[C@H:16]1/[CH:34]=[CH:35]/[C@@H:36]([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CC(C)=O.CCOC(C)=O>[OH:14][C@@H:15]1[CH2:19][C@H:18]([OH:20])[C@H:17]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][C:27]([N:29]([CH3:3])[S:30]([CH3:33])(=[O:32])=[O:31])=[O:28])[C@H:16]1/[CH:34]=[CH:35]/[C@@H:36]([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)NS(C)(=O)=O)[C@@H](O)C[C@H]1O
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)N(C)S(C)(=O)=O)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl iodide (38 μL, 0.61 mmol) and DBU (45 μL, 0.30 mmol) were added to a solution of N-{(Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)cyclopentyl]hept-5-enoyl}methanesulfonamide (44 mg, 0.10 mmol) in acetone (1.5 mL). After stirring for 2.5 h at room temperature, the reaction was diluted with EtOAc, washed with water (2×) and brine then concentrated in vacuo to afford the title compound. See FIG. 1.
Reaction SMILES: C#C.[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:28].[Li+]>>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][I:28])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: C#C
Agent: [Li+]
Product: ICC1CN(Cc2ccccc2)CCO1

Procedure:
The starting material for use in processes (a), (b) and (h) in which A is a vinylene radical may be prepared, as described in Example 1, by reaction of 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine and lithium iodide to give 4-benzyl-2-iodomethylmorpholine. This compound is then reacted with triphenyl phosphine to give 4-benzylmorpholin-2-ylmethyl triphenyl phosphonium iodide which is subsequently reacted with a base to form the corresponding phosphorane. This intermediate is reacted in situ with the appropriate substituted benzaldehyde to give 4-benzyl-2-(β-substituted phenylvinyl)-morpholine as a mixture of cis and trans isomers. These isomers are, if necessary, separated by chromatography, or by fractional crystallisation of an acid-addition salt, and if required this N-benzyl derivative is used to form other N-substituted starting materials. Thus reaction with an aryl or optionally substituted alkyl chloroformate gives the corresponding phenoxy- or alkoxy-carbonyl derivative, or reaction with cyanogen bromide gives the corresponding N-cyano derivative.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2 CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4, and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]-propyl]-4-piperidinyl]-1,2-l benzisoxazole as a beige solid, m.p.=156°-158° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([O:14]CC2C=CC(C3C(C(O)=O)=CC=CC=3)=CC=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C(C1C=C(OCC2C=CC(C3C(C(OC)=O)=CC=CC=3)=CC=2)C2C(=CC=CC=2)N=1)CC>CS(C)=O>[CH2:1]([C:4]1[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(OCc2ccc(-c3ccccc3C(=O)O)cc2)c2ccccc2n1
Agent: CCCc1cc(OCc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2n1
Solvent: CS(C)=O
Product: CCCC1=Nc2ccccc2C(=O)C1

Procedure:
(Example 3): 4'-[(2-Propylquinolin-4-yloxy)methyl]biphenyl-2-carboxylic acid*, m.p. 198°-200° C.; NMR (d6 -DMSO): 0.97(t,3H), 1.8(m,2H), 2.85(t,2H), 5.43(s,2H), 7.08(s,1H), 7.35-7.65(complex m,8H), 7.73(dt,2H),7.87(d,1H), 8.15(dd,1H), 12.7(br s,1H); mass spectrum (-ve FAB, DMSO/GLY): 396 (M-H)-, 186; microanalysis, found: C,77.5; H,6.0; N,3.5%; C26H23NO3.0.33C2H5OH requires: C,77.8; H,6.1; N,3,4%; starting from methyl 4'-[(2-propylquinolin-4-yloxy)methyl]biphenyl-2-carboxylate, obtained as a viscous oil; NMR: 1.03(t,3H), 1.87(m,2H), 2.94(t,2H), 3.68(s,3H), 5.36(s,2H), 6.75(s,1H), 7.34-7.6(complex m,8H), 7.68(dt,1H), 7.85(dd,21H), 8.03(d, 1H), 8.25(dd,1H); 13C NMR (CDCl3): (benzylic CH2) 69.8; itself obtained from 2-propyl-4-quinolone using analogous procedures to those described in Example 1; [*Note: 1M aqueous citric acid solution was used in place of 2M hydrochloric acid in the work-up procedure].
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:11]=2[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[O:6])[CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:13][CH2:12][C:11]1[N:10]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN)cc1
Yield: 99 %

Procedure:
A solution of N-cyclopropyl-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (0.9 g, 2.0 mmol) obtained in Example 1196 and hydrazine hydrate (200 mg, 4.0 mmol) in ethanol (20 ml) was boiled under reflux for 1 hr, and precipitated insoluble material was filtered off. The filtrate was concentrated to dryness to give the title compound as a white powder (0.65 g, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>O>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(O)c1
Solvent: O
Product: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Temperature: 85 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
2,2-Dimethyl-1,3-dioxane-4,6-dione 66.6Q (available from Aldrich) (28.8 g, 200 mmol) was added to a mixture of 3-hydroxybenzaldehyde 66.6R (available from Aldrich) (24.4 g, 200 mmol) in water (1000 mL) at 85° C. The resulting mixture was stirred at 85° C. for 2 hours. The reaction was allowed to cool and then filtered to provide 5-(3-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 66.6S (41.4 g, 83% yield) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])#[N:2].I([O-])(=O)(=O)=[O:20].[Na+].[K+].[Br-]>O1CCOCC1.O>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:20])#[N:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)CC#N
Temperature: 40 °C

Procedure:
A solution of N-(2-cyanomethylsulfanyl-5-trifluoromethylphenyl)acetamide(0.42 g) in dioxane (2.50 ml) was added dropwise to a stirred solution of sodium periodate (0.69 g) in a mixture of water (6 ml) and dioxane (1.50 ml) at ambient temperature. An additional amount of dioxane (2.50 ml) was added. The mixture was stirred at 40° C. for 6½ h, then at room temperature overnight. A precipitate was removed by filtration and washed on the filter with dichlorometane (20 ml). The two phases of the filtrate were shaken and separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The more polar component of the residue was isolated by flash chromatography on silica gel eluted with 1) ether and 2) ethyl acetate to give a slowly crystallizing oil. Trituration with petroleum ether and subsequent drying gave white crystals. Yield 0.16 g (38%); mp 149-151° C.; 1H-NMR(CDCl3) δ (ppm): 9.9 (br, 1H), 8.70 (d, J=2 Hz, 1H), 7.68-7.46 (d+dd, J=8Hz and 8 Hz/2 Hz, 1H+1H), ABX-system at 4.13 (d, J=16 Hz, 1H) and 3.98 (d, J=16 Hz, 1H), 2.25 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 170.1, 141.3, 135.8, 132.7 (q, J=32 Hz), 127.0, 123.5 (CF3, J=273 Hz), 123.1 (J=3.6 Hz), 122.0 (J=3.6 Hz), 113.3 (C≡N), 42.6 (CH2), 23.2 (CH3); IR (KBr) ν (cm−1): 3220 (NH), 2252 (C≡N), 1691 (C═O), 1532, 1476, 1337, 1273, 1176, 1128, 1033, 888, 675.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=[O:12])=[N+]=[N-].O.[OH-].[Na+]>C1COCC1>[NH2:7][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[OH:12]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a suspension of LiAlH4 (8.18 g; 215.6 mmol) in THF (100 mL), was added dropwise a solution of 2-azido-1-(4-benzyloxy-phenyl)-ethanone (23.05 g; 86.2 mmol) in THF (200 mL), at 0° C. The mixture was stirred at 0° C. for 20 min. and subsequently 2 hours at RT. Thereafter, water (50 mL), and 2M aqueous NaOH-solution (150 mL) were added consecutively. The formed precipitate was removed by filtration over kieselguhr, and washed with MeOH. The filtrate was concentrated in vacuo and the remaining aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-amino-1-(4-benzyloxy-phenyl)ethanol (20.10 g)