Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)[CH:5]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH:7]=[C:8]([O:10][CH2:11][CH3:12])[CH:9]=1
Reactant: CCOc1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
3-(4-Chloro-butanoylamino)-5-ethoxy-benzoic acid methyl ester (D51) (7 g, 20 mmol, 1 equiv) in THF (50 ml) was treated portionwise with NaH (60% in mineral oil, 0.88 g, 22 mmol, 1.1 equiv) over 15 min at room temperature. The resulting mixture was stirred for 30 min and then diluted with AcOEt (300 ml). The resulting solution was washed with 2N aqueous HCl solution (200 ml), dried over MgSO4 and concentrated in vacuo. Recrystallisation of the residue from Et2O/hexane gave 3-ethoxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B11) (3.5 g, 66%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.CN1C(=O)C[CH2:16][CH2:15]1.CC[Mg+].[Br-]>C1COCC1.CCOCC.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)[CH3:16]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1ccc(Cl)cc1C
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: CC[Mg+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(C(=O)OC)c(C)c1
Yield: 83 %

Procedure:
4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron (III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (1M, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).
Reaction SMILES: [CH:1]1([CH2:8][C:9]2[NH:13][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[N:11][C:10]=2[C:24](O)=[O:25])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][O:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[C:38]([CH2:40][O:41][C:42]([O:44][CH3:45])=[O:43])[CH:39]=1)[NH2:36])=[O:30]>>[CH3:45][O:44][C:42]([O:41][CH2:40][C:38]1[CH:37]=[C:35]([NH:36][C:24]([C:10]2[N:11]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[NH:13][C:9]=2[CH2:8][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:25])[CH:34]=[C:33]([CH2:32][O:31][C:29]([O:28][CH3:27])=[O:30])[CH:39]=1)=[O:43]
Reactant: COC(=O)OCc1cc(N)cc(COC(=O)OC)c1
Reactant: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Product: COC(=O)OCc1cc(COC(=O)OC)cc(NC(=O)c2nc(-c3ccc4ccccc4c3)[nH]c2CC2CCCCCC2)c1
Yield: 41.7 %

Procedure:
5-Cycloheptylmethyl-2-naphthalen-2-yl-1H-imidazole-4-carboxylic acid (Example 20, step c) (605 mg, 1.75 mmol) was reacted with 3,5-bis-methoxycarbonyloxymethyl-aniline (492 mg, 1.75 mmol) according to the procedure of Example 20, step d to afford the product as a white solid (438 mg, 42%). 1H NMR (300 MHz, CDCl3) 9.42 (1H, br s), 9.35 (1H, s), 8.27 (1H, s), 8.06-7.89 (4H, m), 7.79 (2H, s), 7.56 (2H, m), 7.14 (1H, s), 5.18 (4H, s), 3.83 (6H, s), 3.12 (2H, d), 2.00-1.29 (13H, m).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[Cl:18].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>CCOCC>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[C:19]([O:20][CH2:21][CH3:22])=[O:23]
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 65.2 ml of n-butyllithium (1.61M in hexane) and 100 ml of anhydrous ether was added dropwise 29.3 g of 4-bromo-3,5-dichlorobenzo-trifluoride (3) in 30 ml of anhydrous ether at -78° C., followed by stirring for 20 minutes. Subsequently, 13.3 ml of diethyl carbonate in 50 ml of anhydrous ether was added dropwise to the mixture, followed by stirring at -78° C. for 30 minutes and then at 0° C. for 30 minutes. Ice water was added to the reaction mixture, the mixture was extracted with ether, and the combined ethereal layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure, giving 18.3 g of the desired product in the form of a colorless oil (yield 63.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[O:25]([C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Oc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
To a solution of ethyl 2-chloropyrimidine-5-carboxylate (0.5 g, 2.7 mmol) in N,N-dimethylformamide (6.0 mL) was added cesium carbonate (676 mg, 2.1 mmol) and phenol (205 mg, 2.18 mmol). The mixture was stirred at 100° C. for 24 hours. The mixture was concentrated in vacuo. To the residue, was added water (50 mL) and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1) to give the product ethyl 2-phenoxypyrimidine-5-carboxylate (472 mg, 81%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.55 (s, 2H), 7.43-7.06 (m, 5H), 4.29 (q, J=8.9 Hz, 2H), 1.31 (t, J=8.9 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Br[CH:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: CCCCC(Br)c1ccccc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.011 g, 0.27 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (6 mL). After stirring for 10 minutes, (1-bromopentyl)benzene (0.061 g, 0.27 mmol, from Step 1) was added. After stirring for 45 minutes, the reaction was quenched by the addition of water and the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.01 g, 10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([NH2:8])[CH:7]=1.CCO[C:13]([S-:15])=[S:14].[K+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]([SH:15])=[N:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2cc(Br)ccc2s1
Temperature: 140 °C
Yield: 95.2 %

Procedure:
To a solution of 5-bromo-2-fluorobenzenamine (200 mg, 1.28 mmol) in N-methyl-2-pyrrolidine (1.5 mL) was added potassium o-ethyl carbonodithioate (410 mg, 2.56 mmol). The mixture was heated at 140° C. for 2 h. The reaction mixture was poured into a large amount of water, acidified with concentrated hydrochloric acid, and filtered to give 5-bromo-benzothiazole-2-thiol 300 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)[S:5][CH:6]=1.C(#N)C.CC(O)=O.C1C(=O)N([Br:27])C(=O)C1>O>[Br:27][C:6]1[S:5][C:4]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1ncnc1-c1cc(Cl)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1ncnc1-c1cc(Cl)c(Br)s1
Yield: 83.8 %

Procedure:
A 3-L reaction flask equipped with a cooling bath, air stirrer, and thermometer probe is charged with 5-(4-Chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (105.3 g, 0.527 moles), ACN (1053 mL) and HOAc (105 mL) to form a solution. NBS (103.2 g, 0.580 moles) is added portion-wise over 30-60 minutes while maintaining the temperature at ≦31° C. After stirring for 1 hour2, GC analysis indicated reaction completion. The reaction mixture is poured into de-ionized H2O (2.1 L, 20 vol), stirred for 30 minutes, filtered, and washed with de-ionized H2O (2×1 L). The product is dried in a vacuum oven at 45° C. overnight to give the title compound as a pale yellow solid (123.0 g, 83.8%; 96.6% area-% by GC). 2 The reaction temperature decreased after 1 hour to 26.7° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([C:19]2([NH2:22])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:22][C:19]1([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)[CH2:20][CH2:21]1)=[O:12])[CH2:2]2
Reactant: Cc1ccc(C2(N)CC2)cc1
Reactant: O=C(O)CC1CN2CCC1CC2
Product: Cc1ccc(C2(NC(=O)CC3CN4CCC3CC4)CC2)cc1
Yield: 20.1 %

Procedure:
Using general procedure I, 2-(quinuclidin-3-yl)acetic acid (169 mg, 1.00 mmol) and 1-p-tolylcyclopropanamine (149 mg, 1.10 mmol) gave the title compound as a white solid (60 mg, 18%). 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 6.96-7.07 (m, 4H), 3.22-3.37 (m, 2H), 2.85-3.05 (m, 4H), 2.39-2.45 (m, 2H), 2.21 (s, 3H), 1.45-1.92 (m, 5H), 1.07-1.23 (m, 5H) ppm. 13C NMR (400 MHz, CDCl3) δ 171.6, 139.8, 136.1, 129.2, 125.6, 52.1, 50.9, 46.5, 46.0, 39.2, 34.9, 30.8, 24.5, 21.1, 18.7, 17.6 ppm. Purity: 96.2% HPLCMS (210 nm); retention time 1.21 min; (M+1) 299.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=2[C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)=[O:14])[CH2:6][CH2:5]1)([OH:3])=O.Cl.C[N:35](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.N>[C:1]([CH:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=2[C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)=[O:14])[CH2:8][CH2:9]1)(=[O:3])[NH2:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCC(C(=O)O)CC1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)C1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.2 %

Procedure:
To a mixture of 2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (52.1 mg), 1-hydroxybenzotriazole (36.7 mg) in dimethylformamide (1 mL) was added 28% ammonia solution (10 drops). After stirring for 15 hours at ambient temperature, the mixture was partitioned between water and ethyl acetate. The separated organic layer was washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with ciisopropyl ether to give 2-(4-carbamoylcyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (60.0 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
Copper (II) acetate (960 mg, 5.28 mmol) was added to a flame-dried flask charged with pyrazole (240 mg, 3.52 mmol), 4-methoxyphenylboronic acid (1.07 g, 7.04 mmol), 4 A molecular sieves (1.35 activated powder), and pyridine (570 μl, 7.04 mmol) in methylene chloride. The reaction was stirred for approximately two days at room temperature and then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel; isocratic 8% ethyl acetate/hexanes) to yield 381 mg (2.18 mmol, 62% yield) of the title compound. LRMS ([M+H]+)=175.2.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([CH2:27][CH2:28][CH3:29])[C:25]#[N:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=4[O:23][CH:24]([C:25]4[NH:36][N:35]=[N:34][N:26]=4)[CH2:27][CH2:28][CH3:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)c1nnn[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
2-{2-{[2-(4-tert-Butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanenitrile (430 mg) was dissolved in dimethylformamide (5 ml), and sodium azide (364 mg) and ammonium chloride (0.3 g) were added. The mixture was stirred at 120° C. for three hours. The reaction mixture was cooled and poured into water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again and the combined organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was purified on a silica gel column (15 g) eluting with a mixed solvent of methylene chloride and methanol (2% vol.) to give 2-(4-tert-butylthiazol-2-yl)-5-{2-[1-(1H-tetrazol-5-yl)butoxy]phenylmethoxy}benzofuran (400 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1C1CN(Cc2ccccc2)CC1N
Temperature: 25 °C
Yield: 78.1 %

Procedure:
To a stirred solution of rac-(3R,4S)-1-benzyl-3-(4-fluoro-2-methyl-phenyl)-4-nitro-pyrrolidine (56 mg, 0.18 mmol) in EtOAc (5 ml) was added in one portion SnCl2.2H2O (201 mg, 0.89 mmol). The reaction mixture was then heated at reflux for 2 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (100 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 40 mg (79%) of rac-(3S,4R)-1-benzyl-4-(4-fluoro-2-methyl-phenyl)-pyrrolidin-3-ylamine as a light yellow oil. The product was then used in the next step without further purification. ES-MS m/e: 285.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[H-].[Na+]>O1CCOCC1>[CH:14]1([N:13]2[C:17]3[C:3](=[C:2]([CH3:1])[C:20]([F:21])=[C:19]([F:22])[CH:18]=3)[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(F)c(F)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-cyclopropylaminoacrylate (2.6 g) is dissolved in anhydrous dioxane (26 ml) and thereto 60 % sodium hydride (0.38 g) is gradually added under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture is poured into ice-water and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated. The residue is added with diethyl ether and crystals are filtered, which are recrystallized from ethanol to give ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.0 g), m.p. 185°-187° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[C:19]([NH:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)=[O:20]>CO.ClCCl>[ClH:2].[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH:5]=1)[C:19]([NH:21][CH2:22][C:23]12[CH2:30][CH:29]3[CH2:31][CH:25]([CH2:26][CH:27]([CH2:28]3)[CH2:32]1)[CH2:24]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 196.1 %

Procedure:
Hydrochloric acid (4M in 1,4-dioxane, 3.0 ml) was added to a solution of [2-[4-chloro-3-[[(tricyclo(3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]ethyl]carbamic acid, 1,1-dimethylethyl ester (2.2 g, Example 30b) in methanol/dichloromethane (1:1) (50 ml). After 24 h the solvent was evaporated to leave the title compound as a foam (1.85 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].C([N:21](CC)[C:22](=[O:33])[C:23]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31])C.O>CS(C)=O.C1C=CC=CC=1.CCCCCC>[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][C:27]1[CH:26]=[CH:25][C:24]([N+:30]([O-:32])=[O:31])=[C:23]([CH:28]=1)[C:22]([NH2:21])=[O:33]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)C(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a 100 ml flask fitted with a magnetic stirrer and drying tube is added dimethyl sulfoxide (30 ml), anhydrous potassium carbonate (7.55 g, 0.054 mole) and 2-chloro-4-trifluoromethylphenol (10.3 g, 0.052 mole). The mixture is stirred at room temperature overnight. A solution of N,N-diethyl-5-fluoro-2-nitrobenzamide (12.5 g, 0.052 mole) in dimethyl sulfoxide (20 ml) is then added rapidly and the reaction mixture is stirred at room temperature for 60 hours. The reaction mixture is poured into water (500 ml) and the product extracted into carbon tetrachloride (4×100 ml), the combined extracts are dried over anhydrous magnesium sulfate and the solvent removed under vacuum to afford 15.3 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzamide (75% yield) Recrystallization from benzene/hexane affords substantially pure product mp. 75°-79° C. Elemental anal, Calcd. for C18H16ClF3N2O4 : C, 51.80; H, 3.88; Cl, 8.55; F, 13.68; N, 6.73. Found: C, 52.03; H, 3.90; Cl, 8.54; F, 13.59; N, 6.83.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])=[CH:29][CH:30]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 4-(trifluoromethyl)phenyl isocyanate gave the titled compound in 32% yield as white foam. MS: 497.2 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1
Reactant: COc1cc(Cc2nccc3c(OCc4ccccc4)cc(OCc4ccccc4)cc23)cc(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(Cc2nccc3c(O)cc(O)cc23)cc(OC)c1OC
Yield: 95.5 %

Procedure:
0.2 g of 5.7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline is dissolved in 250 ml of ethanol, and 0.05 g ot 10% palladium-carbon is added thereto. The mixture is shaken at 25° C in a hydrogen atmosphere. After the hydrogen uptake is completed, the catalyst is removed by filtration. The filtrate is evaporated to remove solvent. 0.125 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline is thereby obtained as a crude product. Yield: 95% M.p. 270° - 275° C (decomp.) (recrystallized from ethanol).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=O)[CH2:3]1.Cl.CN(C)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C.O.C(N(CC)CC)C>[C:19]1([S:25]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]#[N:13])=[O:10])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
(2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (1.20 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour and trifluoroacetic anhydride (0.34 mL) was added dropwise. The mixture was further stirred for 1 hour. Subsequently, water (10 mL) was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The resulting crystal was collected by filtration, resuspended in diethylether (10 mL) and collected again by filtration. The collected crystal was dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (472 mg, 75% yield). This compound was identical to the compound obtained in Example 3.