Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:3]1.[Br:13]Br.CO>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:13][C:5]1[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cn1ccc(-c2ccncc2)n1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c(-c2ccncc2)n1
Reaction time: 4 h

Procedure:
To a solution of 4-(1-methyl-1H-pyrazol-3-yl)pyridine 2.98 g; Example 3, Step 2) in 50 mL chloroform cooled in ice, was added dropwise, a solution of 1.15 mL bromine in 30 mL chloroform. About 15 mL methanol was added to help dissolution of the yellow precipitate that formed. After 4 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The dichloromethane layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to yield the crude product as a yellow semisolid. The crude material was slurried in ethyl acetate and filtered through celite. The filtrate was evaporated to yield 4.18 g product as a yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 240.5 by positive ESI.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17].Cl>CN(C=O)C>[C:3]1([S:9][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OCCCCBr
Reactant: Sc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCSc1ccccc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
To a suspension of NaH (60%, 0.91 g, 23 mmol) in anhydrous DMF (20 mL) at RT is added dropwise benzenethiol (2.5 g, 22.7 mmol) in DMF (5 mL). The mixture is stirred for 10-15 min, at which time it becomes clear and yellow. The mixture is cooled to 0° C. in an ice bath then 4-bromobutylacetate (4.5 g, 22.8 mmol) in DMF (5 mL) is added dropwise and the mixture is stirred at RT for 1 h. The mixture is poured into 1N HCl (50 mL) and extracted with MTBE (2×). The combined organic extracts are washed with brine (2×) and dried over MgSO4. The solvent is removed under reduced pressure to afford the title compound as a yellow oil.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)(OC(C)(C)C)=O.CN1CCOCC1.CN(C1C=CC=CN=1)C.[NH2:30][C:31]1[NH:32][C:33]2[CH:39]=[C:38]([CH3:40])[C:37]([CH3:41])=[CH:36][C:34]=2[N:35]=1.[Na+].[Cl-]>CN(C=O)C.C(Cl)CCl>[CH3:40][C:38]1[C:37]([CH3:41])=[CH:36][C:34]2[NH:35][C:31]([NH:30][C:11](=[O:13])[CH2:10][CH2:9][NH2:8])=[N:32][C:33]=2[CH:39]=1
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc2nc(NC(=O)CCN)[nH]c2cc1C
Reaction time: 1 h

Procedure:
Boc-β-alanine (1.89 g; 10 mmol) was dissolved in 15 ml of DMF and, after addition of 2.02 g of N-methylmorpholine, 0.122 g of dimethylaminopyridine and 1.92 g of EDC*HCl, stirred for 1 h. 1.93 g (12 mmol) of 2-amino-5,6-dimethylbenzimidazole were added to the clear solution, and the mixture was stirred at RT for 16 h and then at 60° C. for 1 h. After the reaction was complete, NaCl solution was added, followed by extraction 2× with ethyl acetate, and the organic phase was washed with 10% citric acid and 2× with water, dried and concentrated. The residue (1.3 g) was dissolved in 10 ml of CH2Cl2, and 10 ml TFA were added. After 2 h, the mixture was evaporated, the residue was taken up in diethyl ether, ethereal HCl was added. After 1 h, the crystals were filtered off with suction, washed until neutral and dried at 40° C. 0.90 g; ESI-MS [M+H+]=233.2
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.O>CN(C=O)C>[CH2:11]([NH:18][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(S)nc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(S)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
Combine 6-mercapto-nicotinic acid (0.64 g, 4.1 mmol), benzylamine (0.45 mL, 4.1 mmol) and EEDQ (1 g, 4 mmol) in anhydrous DMF (3 mL). Stir at room temperature for 12 h. Dilute the reaction with water and extract with DCM. Dry over MgSO4, filter and concentrate in vacuo to give a yellow solid. Purify by chromatography on silica gel eluting with 2M ammonia in methanol/DCM (2:98 and 10:90) to give the title compound as a yellow solid (440 mg, 44%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH2:13]([N:20]1[CH2:28][C:27]2([C:29]([O:31][CH3:32])=[O:30])[CH:22]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:13]([N:20]1[CH2:28][C:27]2([C:29]([O:31][CH3:32])=[O:30])[CH:22]([C:23]([OH:39])([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:12])([F:11])[F:2])=[CH:5][CH:6]=3)[CH2:24][CH2:25][CH:26]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C(F)(F)F)cc1)CCC2c1ccccc1
Temperature: 10 °C

Procedure:
0.8 g of magnesium turnings was added to a solution of 7.2 9 of 4-(trifluoromethyl)bromobenzene in 40 cm3 of dry diethyl ether. The reaction mixture was spontaneously brought to reflux for ten minutes and was then heated at reflux for twenty minutes. The reaction mixture was subsequently cooled and a solution of 5.6 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 40 cm3 of dry diethyl ether was added over fifteen minutes at a temperature in the region of 10° C. The reaction mixture was stirred for ten minutes at a temperature in the region of 10° C. and then poured into 150 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with three times 75 cm3 of diethyl ether. The organic phases were combined, washed successively with three times 75 cm3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After crystallization from 25 cm3 of pentane, 5.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[4-(trifluoromethyl)phenyl]-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a beige solid, the characteristic of which was as follows:
Reaction SMILES: O[C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].FC(F)(F)C(O)=O>ClCCl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11](/[C:2](/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:3]/[C:4]#[N:5])=[CH:12][CH:13]=1
Reactant: CCCCCC(O)(CC#N)c1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC/C(=C\C#N)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of the above carbinol (107.8 g) in dichloromethane (540 mL) containing trifluoroacetic acid (21.6 mL) was heated at reflux for 7 hours and then was left at room tempertature overnight. The solution was washed in turn with water (250 mL). 1N NaOH solution (500 mL) and with brine (100 mL). After the aqueous layers were backwashed with dichloromethane (2×100 mL). the combined organic phases were dried (MgSO4) and evaporated to yield 99.2 g of crude (E)-3-(4-methoxyphenyl)-2-octenenitrile as an oil. The crude contained <8% of the (Z)-isomer.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:12]\[C:13](Cl)=[O:14].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>ClCCl>[CH:16]1([NH:19][C:13](=[O:14])/[CH:12]=[C:6]2\[CH2:5][CH2:4][C:3]3[C:7]\2=[CH:8][C:9]([F:11])=[CH:10][C:2]=3[F:1])[CH2:18][CH2:17]1
Reactant: O=C(Cl)/C=C1\CCc2c(F)cc(F)cc21
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(/C=C1\CCc2c(F)cc(F)cc21)NC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
An ice cold solution of (E)-2-(4,6-difluoro-1-indanylidene)acetyl chloride (2.97 g, 0.013 mol) in dichloromethane (30 mL) was treated with cyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture was stirred for 4 h. The mixture was concentrated in vacuo and the residue was taken up in a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase was washed with 5% aqueous sodium bicarbonate, saturated aqueous NaCl and dried (Na2SO4). Chromatography on silica gel with ethyl acetate:hexanes (1:1) as eluent and trituration of the resulting solid with pentane gave 1.92 g (59%) of (E)-N-cyclopropyl-2-(4,6-difluoro-1-indanylidene)acetamide as a white solid: m.p., 156-158° C.;
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](/[C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13]\[CH3:14].C(=O)(O)[O-].[Na+].[N+:32]([CH3:35])([O-:34])=[O:33]>>[CH:12](/[C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]([CH2:35][N+:32]([O-:34])=[O:33])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13]\[CH3:14]
Reactant: C[N+](=O)[O-]
Reactant: C/C=C/c1ccccc1C=CC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Product: C/C=C/c1ccccc1C(CC(=O)OC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
1,8-Diazabicyclo[5.4.0]-7-undecene (0.1 mL) was added to a solution (10 mL) of methyl 2-((E)-1-propenyl)cinnamate (102 mg, 0.50 mmol) in nitromethane, followed by-stirring at room temperature for 3 hours. Next, the reaction solution was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling to neutralize the reaction solution, and the mixture was then extracted with diethyl ether. After the extract was washed with a saturated brine and then dried over sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developed with diethyl ether/hexane=1/4) to give methyl 3-[2-((E)-1-propenyl)phenyl]-4-nitrobutyrate (52 g, yield 40%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH3:13]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=S(=O)(Cl)Cc1cccc(I)c1
Solvent: C1CCOC1
Product: NS(=O)(=O)Cc1cccc(I)c1

Procedure:
A stirred solution of (3-iodophenyl)methanesulfonyl chloride (1 g) in THF (20 ml) was treated with 0.88 ammonia (25 ml) at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (0.35 g). LCMS RT=2.71 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([N:26]=[N+:27]=[N-:28])=[O:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccco1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1ccco1
Temperature: -1 °C
Reaction time: 1 h

Procedure:
In an oven dried three-necked round-bottom flask (3 L) fitted with a mechanical stirrer, a nitrogen inlet, a thermometer and addition funnel was placed a mixture of β-(2-furyl)acrylic acid (60.0 g, 434 mmol) and dry triethylamine (51.6 g, 510 mmol) in acetone (600 mL, dried over anhydrous MgSO4). The mixture was cooled to −2 to 0° C. To the cold mixture, isobutyl chloroformate (79.2 g, 580 mmol) was added at 0° C. gradually over a period of time. After completion of addition, the reaction mixture was stirred at 0˜2° C. for 1 h. Then a solution of sodium azide (42.0 g, 646 mmol) in water (180 mL) was added slowly at 0˜5° C. The resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was then quenched with ice-cold water (1.7 L). The desired product was extracted with toluene (4×500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was used in next reaction as such.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[C:4]1[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)=O.[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O)[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:4]1[N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)[CH3:38]
Reactant: CCOc1ccccc1B(O)O
Reactant: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1C1=CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 40 °C

Procedure:
A mixture of 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate (140 mg; 0.13 mmol; 1.0 equiv.), (2-ethoxyphenyl)boronic acid (34 mg; 0.20 mmol; 1.5 equiv.), PdCl2(PPh3)2 (5 mg; 0.007 mmol; 0.05 equiv.), Na2CO3 (188 mg; 1.78 mmol; 13.2 equiv.) in THF (2 ml) and water (0.9 ml) was heated to 40° C., under nitrogen, for 1.5 h. After cooling to rt, water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were dried over anh. K2CO3, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded 6-(2-ethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-3,4-dihydropyridin-2(1H)-one. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 392.2 g/mol.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]1([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:41](=[O:42])[CH2:40][CH2:39][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure I using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a white powder (44%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.42 (m, 4H), 7.14 (m, 4H), 6.77 (m, 1H), 6.60 (br s, 1H), 4.89 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.16 (m, 2H), 1.71 (s, 6H). 1.68-1.28 (m, 13H), 1.03-0.88 (m, 5H). HPLC, Rt: 6.24 min (Purity: 99%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:44])[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:44])[CH2:33][C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc2ccccc2c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Cc1ccc2ccccc2c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
160 mg (0.269 mmol) of (2R*,4S*)-2-benzyl-1-(2-naphthylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 42 mg (1.13 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR38## is obtained as colourless oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.27, FD-MS: M+ =499.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[CH:5][CH:4]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(CN)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(CNS(C)(=O)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 1 h
Yield: 36515.5 %

Procedure:
To a solution of rac-(2R,3S,4R,5S)—N-(4-(aminomethyl)phenyl)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamide (21.0 mg, 0.0367 mmol, example XJ-2) in CH2Cl2 (4 ml) was treated with METHANESULFONYL CHLORIDE (8.5 mg, 5.78 μl, 0.0742 μmol) and the reaction was stirred at 0 C for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 1% to 10% MeOH/CH2Cl2) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(methanesulfonylamino-methyl)-phenyl]-amide as off-white solid (17.6 mg, 73%). MS (ES+) m/z Calcd: [(M+H)+]: 649. found: 649.
Reaction SMILES: C(CCC=N[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)#N>C(Cl)(Cl)Cl>[C:8]([CH2:9][C:10]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH2:14][S:15]([NH2:18])(=[O:16])=[O:17])[CH:10]=2)[NH:7][CH:11]=1)#[N:7]
Reactant: N#CCCC=NNc1ccc(CS(N)(=O)=O)cc1
Solvent: ClC(Cl)Cl
Product: N#CCc1c[nH]c2ccc(CS(N)(=O)=O)cc12
Yield: 22.1 %

Procedure:
A suspension of the product of stage (a) (3.1 g) and polyphosphate ester (30 g) in chloroform (60 ml) was heated at reflux for 10 min then poured onto ice and extracted with chloroform (4×20 ml). The combined organic extracts were dried, the solvent evaporated and the resulting oil purified by chromatography (G) to give the title compound as a yellow solid (0.32 g), m.p. 184°-185°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:25][N:26]=[C:27]=[O:28]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:27](=[O:28])[NH:26][CH3:25])=[CH:9][CH:8]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)OCc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a sealed glass tube, a solution of 1.0 g of [4-(3-fluoro-benzyloxy)-phenyl]-methanol [Example 25b)], 0.03 ml of triethylamine and 0.245 g of methyl isocyanate in 40 ml of dichloromethane was heated at 40° C. for 3 d. At that time a transformation rate of 50% was reached, determined by NMR. For the working-up, the reaction mixture was cooled and evaporated. The residue was dissolved in 2 ml of pyridine and 1 ml of acetic acid anhydride and the solution stirred at room temperature for 3 h. Thereafter, the mixture was evaporated under reduced pressure. For purification, the crude material obtained was chromatographed on silica gel using a 2:1-mixture of heptane and ethyl acetate as the eluent. There were obtained 580 mg (47% of theory) of methyl-carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=289 (M)+.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14](OCC)C.C[Mg]Cl>[Ni+2].ClC(Cl)(CP(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=2[CH3:14])[N:7]=1
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: CCOCC
Agent: [Ni+2]
Agent: C[Mg]Cl
Agent: ClC(Cl)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2c(C)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 24.0 g (0.1 mole) of 5-bromo-6-fluoro-2-methylquinoline, 2.8 g (0.005 mole) of dichloro[1,3-bisdiphenylphosphinopropane] nickel (II) catalyst, and 380 ml of diethyl ether were combined. 44 ml of 3.17M methylmagnesium chloride in tetrahydrofuran was added dropwise at a rapid rate. The reaction was allowed to stir at room temperature overnight. The ether solution was decanted off into 200 ml of 3N hydrochloric acid in an ice bath, accompanied by vigorous stirring. The aqueous and organic layers were then separated. The aqueous layer was extracted with 100 ml of ethyl acetate and cooled in an ice bath, and the pH was adjusted to pH 10 with concentrated ammonium hydroxide. This was extracted twice with 100 ml of portions of ethyl acetate. The extracts were combined and washed with 30 ml of brine, dried over magnesium sulfate, and filtered and evaporated to give 14.9 g of 2,5-dimethyl-6-fluoroquinoline of 94.4% purity as determined by gas chromatography analysis.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][NH:10][C:11]2[N:19]=[C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:44]1[C@H:48]([O:49][C:50](=[O:57])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@H:47]([O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:46]([C:67]2[N:71]=[CH:70][N:69]([CH2:72][CH3:73])[N:68]=2)[O:45]1)(=O)C1C=CC=CC=1.C(O[C@H]1[C@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)[C@@H](C2N=CN(CC)N=2)O1)(=O)C1C=CC=CC=1>>[C:50]([O:49][C@@H:48]1[C@H:47]([O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:46]([C:67]2[N:71]=[CH:70][N:69]([CH2:72][CH3:73])[N:68]=2)[O:45][C@H:44]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([CH2:20][NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:24])=[N:19][C:11]=2[NH:10][CH2:9][CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:57])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CCn1cnc([C@H]2O[C@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: CCn1cnc([C@H]2O[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1
Agent: Cl
Product: CCn1cnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)n1

Procedure:
Prepared by the same method as Preparation 26 from N-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulphonamide hydrochloride (Preparation 8) and a mixture of (2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate and (2S,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(1-ethyl-1H-1,2,4-triazol-3-yl)tetrahydro-2-furanyl benzoate (Preparation 22).