Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:25])=[CH:26][CH:27]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:28])[C:7]=2[CH:29]=1
Reactant: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)O)cc3)c(C)c2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}benzoic acid (450 mg) synthesized above, β-alanine ethyl ester hydrochloride (252 mg), 1-hydroxybenzotriazole monohydrate (251 mg), triethylamine (456 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (314 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (518 mg, 93%) as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C.[C:14]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)(=[O:17])[CH2:15][CH3:16].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[C:14]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:40]2[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:42][CH2:41]2)=[O:25])=[CH:26][CH:27]=1)(=[O:17])[CH2:15][CH3:16]
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CCC(=O)Nc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2 g of triethylamine in 5 ml of anhydrous dimethylformamide and then a solution of 2.15 g of chloroformic acid ethyl ester in 10 ml of methylene chloride is added dropwise to a solution, stirred at from -5° to 0°, of 3.8 g of p-propionamidobenzoic acid in 30 ml of anhydrous dimethylformamide. The reaction mixture is stirred for 30 minutes at from 0° to 5° and then a solution of 4.4 g of 1-[2-(4-chlorophenyl)ethyl]-piperazine in 25 ml of anhydrous dimethylformamide is added dropwise thereto. The suspension is stirred overnight at approximately 5° and concentrated by evaporation. 50 ml of water are added to the residue and the solution is rendered alkaline with 2N sodium hydroxide solution and extracted by shaking with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed over silica gel and the resulting oil is crystallised from acetone/diethyl ether, yielding 1-[4-(N-propionylamino)-benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 131°-132°.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([C:47]2[CH:48]=[N:49][CH:50]=[C:51]([F:53])[CH:52]=2)[C:37]=1[CH3:54].[NH2:55][C:56]1[CH:57]=[C:58]([NH:68][C:69](=[O:71])[CH3:70])[CH:59]=[C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH:61]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:55][C:56]3[CH:57]=[C:58]([NH:68][C:69](=[O:71])[CH3:70])[CH:59]=[C:60]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)[CH:61]=3)=[C:37]([CH3:54])[C:38]([C:47]3[CH:48]=[N:49][CH:50]=[C:51]([F:53])[CH:52]=3)=[N:39]2)=[CH:44][CH:43]=1
Reactant: CC(=O)Nc1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2cncc(F)c2)nc2cc(F)ccc2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: CC(=O)Nc1cc(Nc2c(C)c(-c3cncc(F)c3)nc3cc(F)ccc23)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (1.545 mg, 6.88 μmol), XPhos (9.84 mg, 0.021 mmol), 4-chloro-7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (0.040 g, 0.138 mmol), N-(3-amino-5-morpholinophenyl)acetamide (0.032 g, 0.138 mmol), potassium carbonate (0.048 g, 0.344 mmol), and tert-butanol (1 mL) at 110° C. for 20 minutes. Purification by column chromatography (silica; 0-4% methanol in DCM) afforded N-(3-((7-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)acetamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.63 (1H, s), 8.65-8.79 (3H, m), 8.18 (1H, m), 8.02 (1H, m), 7.73 (1H, m), 7.50 (1H, m), 6.70 (1H, s), 6.55 (1H, s), 6.23 (1H, s), 3.66-3.78 (4H, m), 2.94-3.06 (4H, m), 2.14 (3H, s), 1.96 (3H, s). Mass Spectrum (ESI) m/e=490.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1.O.[C:38]1(C)[CH:43]=CC(S(O)(=O)=O)=C[CH:39]=1>CC(C)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[S:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=4)[C:7]4[C:8](=[O:9])[NH:10][C:38]([CH3:43])([CH3:39])[NH:1][C:2]=4[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N)c(C(N)=O)c1-c1ccc(OCCO)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)NC(=O)c2c(nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c2-c2ccc(OCCO)cc2)N1

Procedure:
50 mg (0.093 mmol) of the compound from Example 22A were initially charged in 2 ml of acetone, a spatula tip of 4-toluenesulfonic acid monohydrate was added and the mixture was stirred at reflux for 1 h. After cooling, the reaction solution was concentrated and the residue was purified directly by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: B.[Cl:2][C:3]1[CH:20]=[C:19]([I:21])[C:6]2[O:7][C:8]([C:16]([NH2:18])=O)=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]=2[CH:4]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:18][CH2:16][C:8]1[O:7][C:6]2[C:19]([I:21])=[CH:20][C:3]([Cl:2])=[CH:4][C:5]=2[C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1oc2c(I)cc(Cl)cc2c1-c1ccccc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1oc2c(I)cc(Cl)cc2c1-c1ccccc1

Procedure:
Add 150 ml. of a 1M solution of borane in tetrahydrofuran to 15.0 g. (0.038 mole) of 5-chloro-7-iodo-3-phenylbenzo[b]furan-2-carboxamide in 130 ml. of tetrahydrofuran and boil under reflux for 16 hours. Treat the solution with 8 ml. of 5% hydrochloric acid and reflux for 45 minutes more. Cool and make basic with sodium hydroxide solution.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][CH:22]=1)[O:1][C:2]1([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:28][C:27]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(F)ccc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.9 mmol) in pyrrolidine (7.3 mL, 87.2 mmol) and anhydrous methanol (16.5 mL) was added 1-(5-fluoro-2-hydroxy-phenyl)ethanone (9.3 g, 60.7 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1 N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsed with hexanes to obtain tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 67%) as a light yellow solid. ESI-MS m/z calc. 335.2, found 336.7 (M+1)+. Retention time 1.85 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CCN)cc1
Yield: 112.4 %

Procedure:
4-Methylbenzyl cyanide (10 g) in ether was added dropwise under nitrogen to lithium aluminium hydride (2.9 g) in ether. The solution was refluxed for 1 h at the end of addition. The reaction mixture was cooled, water (3 ml), 2N.NaOH (3 ml), and further water (9 ml) were added, the reaction mixture filtered, the residue washed with chloroform and the combined solvents dried (MgSO4). Evaporation gave 2-(4-methylphenyl)ethanamine (11.59 g).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1.[CH3:22][CH:23]([CH3:29])[CH2:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:22][CH:23]([CH3:29])[CH2:24][S:25]([NH:8][C@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)CC(C)C)CC2
Reaction time: 0.17 h
Yield: 93 %

Procedure:
Triethylamine (750 μl, 5.15 mmol, 3 eq) was added at 0° C. to a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (1.72 mmol, 1 eq) in dichloromethane (10 ml), and stirring was carried out for 10 min. A solution of 2-methylpropane-1-sulfonyl chloride (404 mg, 2.58 mmol, 1.5 eq), dissolved in dichloromethane (5 ml), was added dropwise, and stirring was carried out for 16 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 30% ethyl acetate in hexane). The desired product was obtained in the form of a white solid. Yield: 93% (500 mg, 1.6 mmol).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].OP([O-])([O-])=O.[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[Br:28]Br>C(Cl)(Cl)Cl.O>[Br:28][C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[S:1][CH:2]=1
Reactant: BrBr
Reactant: c1cnc2ccsc2c1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1csc2cccnc12
Temperature: 25 °C
Yield: 71.9 %

Procedure:
Combine thieno[3,2-b]pyridine (3.45 g, 25.6 mmol), sodium bicarbonate (2.15 g, 25.6 mmol), K2HPO4 (6.69 g, 38.4 mmol) and MgSO4 (4.01 g, 33.3 mmol) in CHCl3 (60 mL). Stir the mixture under reflux and add Br2 (1.57 mL, 30.7 mmol) slowly. Stir the reaction mixture under reflux overnight. Add more bromine (0.7 mL) and stir the reaction under reflux for 4 h. Cool to room temperature, add water, and extract with CHCl3. Wash the organic portion with saturated Na2S2O3 solution and saturated brine. Dry over Na2SO4 and evaporate. Recrystallize the material from hexane/CH2Cl2 to obtain the title compound (3.94 g, 72%). ES/MS m/z (81Br) 215 (M+).
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[Zn:25](OC(C)=O)OC(C)=O.O.O>C(Cl)(Cl)Cl.CO>[C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[Zn:25]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: [Zn]

Procedure:
Synthesis. A sample of 4-bromobenzaldehyde dimethylacetal46 was coupled with di-tert-butylphosphite to give 4-(di-tert-butyloxyphosphoryl)benzaldehyde dimethylacetal. The latter was used in a mixed-aldehyde condensation47 with pyrrole under standard conditions of BF3.O(Et)2-ethanol cocatalysis48 followed by oxidation with DDQ to give porphyrin 1. Porphyrin 1 was metalated with Zn(OAc)2.2H2O in CHCl3/methanol to afford zinc porphyrin Zn1 in 73% yield (Scheme 1). Cleavage of the tert-butyl groups was achieved by following the known procedure45 with TMS—Cl/TEA in refluxing CHCl3 (stabilized with amylenes). In this manner, the porphyrin Zn2 was obtained without demetalation in 89% yield. Note that CHCl3 stabilized with amylenes rather than ethanol was used to avoid the possible reaction of ethanol with TMS—Cl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4](I)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OO.CCCCCC.C(OCC)(=O)C>CS(C)=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].S([O-])([O-])(=O)=O.[Fe+2].O>[CH3:1][O:2][C:3]([CH:4]1[C:11]2=[CH:10][CH:9]=[C:8]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:19])[N:7]2[CH2:6][CH2:5]1)=[O:21]
Reactant: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 0.08 h

Procedure:
4-(2-Benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV, 3.17 grams, 8 mmol) was dissolved in dimethylsulfoxide (32 mL). Iron (II) sulfate heptahydrate (230 mg, 0.827 mmol) was added, and the mixture was stirred for 5 minutes. Hydrogen peroxide (30% aqueous solution, 6 mL) was added dropwise while the internal temperature of the reaction was kept below 35° C. by application of an external water bath. After 45 minutes, TLC (4:1 hexane:ethyl acetate, silica) indicated the reaction was about 60% complete. Additional hydrogen peroxide (2 mL) was added. After 20 minutes more, an additional 2 mL of peroxide and 70 mg of iron sulfate were added) and 15 minutes later, an additional 0.5 mL of peroxide. 20 Minutes after the final peroxide addition, the mixture was poured into water (200 mL). The resulting mixture was extracted with ether (50 mL), then saturated with sodium chloride and extracted twice more with ether. The combined organic extracts were washed twice with water (50 mL each), then once with brine (25 mL), dried over magnesium sulfate, and evaporated in vacuo to afford ketorolac methyl ester (2.095 g, still containing traces of ether (1%) and DMSO (<0.3%) by NMR. Yield calculated on the basis of weight and NMR purity is 96%. The product may be crystallized from methanol, m.p. 80°-82° C.
Reaction SMILES: [F:1][C:2]1([CH:12]([O:17][Si](CC)(CC)CC)[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(S(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(F)(C(O)C(F)(F)F)CC1
Yield: 55 %

Procedure:
By use of 4-fluoro-1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethyl-siloxy)ethyl]piperidine (309 mg, 0.785 mmol) dissolved in tetrahydrofuran (5 mL) and a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.18 mL, 1.18 mmol), the mixture was stirred and reacted at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound EAS (120 mg, yield: 55%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[NH:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.[OH-].[Na+]>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2CCC(=O)N2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CCCN2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred solution of lithium aluminum hydride (2.26 g) and tetrahydrofuran (185 ml) was added 5-(4-methoxyphenyl)pyrrolidin-2-one in tetrahydrofuran (250 ml). The mixture was heated under reflux for 6 hrs, cooled to ambient temperature, and water (2.5 ml) in tetrahydrofuran and 15% aqueous sodium hydroxide solution (2.5 ml) were added slowly. Additional water (8.5 ml) was added. The suspension was stirred over anhydrous sodium sulfate, filtered through a pad of celite, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated to give 6.74 g, (96.0%) of 2-(4-methoxyphenyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>O1CCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: OCc1c[nH]nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 12 g of ethyl-(4-chloro-phenyl-4-ethoxycarbonyl-pyrazole in 150 ml of tetrahydrofuran is cooled in an ice bath. Then 25 ml of a 1 molar solution of aluminum hydride triethylamine complex in benzene is added dropwise. After the addition, the ice bath is removed and the gelatinous mixture stirred at room temperature for 2 1/2 hours. Excess reagent is then destroyed by the dropwise addition of water followed by 30 ml of an aqueous 2N solution of sodium hydroxide. The layers are separated, the aqueous phase reextracted with ethyl acetate and the combined organic layers dried over anhydrous sodium sulfate. The recrystallization of the solid residue from hot ethyl acetate gives the 3-(4-chloro-phenyl)-4-hyroxymethyl-pyrazole, m.p. 149°-150°.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]Cl)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][SH:3])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Yield: 176.1 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.3 g of thiourea, 6.4 g of 1-(4-chlorophenethyl)-4-(3-chloropropyl)piperazine dihydrochloride, 1.6 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 3.5 g of sodium hydroxide and 40 ml of water. Work-up, as described above, gave 5.6 g (89% of theory) of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 279°-281° C.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:16]3[CH:17]4[CH2:25][C:18]4([CH3:26])[CH2:19][O:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C1CCCCC1.C(OCC)(=O)C>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:28](=[O:30])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:16]4[CH:17]5[CH2:25][C:18]5([CH3:26])[CH2:19][O:20][C:21]=4[CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2CC2(C)CO3)nc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3CC3(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 2-methyl-N1-{6-[(1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yl)oxy]-3-pyridinyl}alaninamide (Intermediate 129, 100 mg) in dry dichloromethane (10 ml) TEA (0.177 ml, 1.273 mmol) was added and the reaction mixture was cooled to 0° C. At this point a solution of triphosgene (37.8 mg, 0.127 mmol) in dry dichloromethane (2.5 ml) was slowly added (over 30 minutes) and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was then quenched with water and the two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Companion system, with a gradient from cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1) to give the title compound as a white solid (40 mg, 0.103 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]([CH:20]1[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:22]([OH:31])[C:21]1=[O:32])=[O:19])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([C:20]1([C:18]([O:17][CH2:15][CH3:16])=[O:19])[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:29])[CH3:30])[N:22]([O:31][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:21]1=[O:32])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccccc2)NC(=O)C(CC(C)C)N(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.60 g of potassium carbonate and 6.3 ml of benzyl chloride were added to 100 ml of a solution of 9.57 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione in anhydrous N,N-dimethylformamide, on ice-cooling. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 450 ml of ethyl acetate, then washed three times with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The resulting solution was subjected to distillation to remove the solvent. The residue was allowed to stand. The resulting crystals were collected by filtration and washed with methanol to obtain 4.51 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-dione as colorless columnar crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Li])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(OC(Cl)=O)C=CC=CC=1.[N].N1C=CC=CC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:11]=1
Reactant: Clc1ccncc1
Reactant: [Li]c1cccc(Br)c1
Agent: O=C(Cl)Oc1ccccc1
Agent: [N]
Solvent: c1ccncc1
Product: Clc1ccnc(-c2cccc(Br)c2)c1

Procedure:
Starting from 3-bromophenyllithium, 4-chloropyridine and chloroformic acid phenyl ester (for the acylation of the pyridine nitrogen), the title compound is prepared analogously to J. Org. Chem. 50, 4410 (1985). A corresponding 1-acyl-1,2-dihydropyridine is formed as intermediate and is aromatised by reaction with o-chloroanil ##STR23## to form the title compound. (b) 4-cyano-2-(3-cyanophenyl)-pyridine