Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=[N:33][CH:32]=1.CN>>[CH3:32][NH:33][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: CN
Product: CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 72 %

Procedure:
As described for example 90, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester was converted, using methylamine (2 M in THF) instead of cyclopropylmethylamine, to the title compound (71 mg, 72%) which was obtained as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:15][C:14]2[N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:22]=[C:10]3[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Cc1cccc(Cl)c1)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 440 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 3-chlorophenylacetyl chloride.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:17]([C:19](=[S:21])[NH2:20])N.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:5]1([C:9]2([C:13]3[S:21][C:19]([NH2:20])=[N:17][N:14]=3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: NNC(N)=S
Reactant: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1nnc(C2(c3ccccc3)CCC2)s1
Temperature: 60 °C

Procedure:
To a T-vial containing 1-[3-(trifluoromethyl)phenyl]cyclobutanecarbonitrile (1 eq) and hydrazinecarbothioamide (1 eq) was added TFA (1 eq) dropwise at rt. Then the mixture was heated to 60° C. for 2 hrs and cooled to rt. Ethyl acetate and aq. NaHCO3 were added and extracted with ethyl acetate twice, the organic layers combined, dried with MgSO4, and concentrated to give the desired product which was used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=2)=[O:10])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][N:14]=1)[C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=3)=[N:26][CH:27]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCN(C(=O)c2ccnc(F)c2)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-(aminomethyl)piperidin-1-yl)(2-fluoropyridin-4-yl)methanone 93-4 (47 mg, 0.20 mmol), 6-(3-fluorophenyl)nicotinic acid 93-5 (43 mg, 0.20 mmol) and HATU (76 mg, 0.20 mmol) in DMF (1 mL) was added DIEA (0.16 mL, 0.50 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-41-(2-fluoroisonicotinoyl)piperidin-4-yl)methyl)-6-(3-fluorophenyl)nicotinamide 93 as a white powder. MS m/z 437.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.14 (d, 1H, J=1.6 Hz), 8.83 (t, 1H, J=6.0 Hz), 8.39-8.33 (m, 2H), 8.20 (d, 1H, J=8.4 Hz), 8.07-8.00 (m, 2H), 7.65-7.59 (m, 1H), 7.42-7.37 (m, 2H), 7.30 (m, 1H), 4.52 (d, 1H, J=13.2 Hz), 3.45-3.27 (m, 3H), 3.12-3.06 (m, 1H), 2.88-2.84 (m, 1H), 1.94-1.86 (m, 2H), 1.70 (d, 1H, J=12.8 Hz), 1.29-1.22 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][C@@H:36]([NH2:38])[CH3:37].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:38][C@@H:36]([CH3:37])[CH2:35][O:34][CH3:33])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: COC[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred suspension of carbaldehyde 321 (336 mg, 0.749 mmol), (S)-1-methoxy-2-aminopropane (200 mg, 2.248 mmol) and acetic acid (68 mg, 1.124 mmol) in DCM (20 ml) at rt under nitrogen was added NaBH(OAc)3 (418 mg, 1.873 mmol). The reaction mixture was stirred at rt overnight and quenched with a solution of 10% HCl. The layers were separated; the aqueous layer was collected, washed twice with DCM and basified with 4N NaOH (pH 12) to form a suspension that was stirred for 30 min. The solid was collected by filtration, rinsed with water and air-dried and purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 10/90) to afford the title compound 334 (182 mg, 0.35 mmol, 46% yield) as a yellow fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.91 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.17 (m, 1H), 6.64 (d, J=5.5 Hz, 1H), 6.57 (bd, J=2.7 Hz, 1H), 3.84 (d, J=14.5 Hz, 1H), 3.78 (d, J=14.5 Hz, 1H), 3.27 (dd, J=9.4, 6.3 Hz, 1H), 3.24 (s, 3H), 3.19 (dd, J=9.2, 5.5 Hz, 1H), 2.81-2.71 (m, 1H), 2.59-2.51 (m, 1H), 2.36-2.10 (m, 1H), 0.98 (d, J=6.3 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 522.4 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][C:12](OCC)=O)[CH2:5][C:6](OCC)=O)[CH:2]=[CH2:3].[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:12]1[CH2:11][N:4]([CH2:5][C:6]1[NH:24][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)OCC)CC(=O)OCC
Reactant: Nc1ccccc1N
Product: C=CCN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 7.3 g (32.0 mmol) diethyl N-allyliminodiacetate and 6.9 g (64 mmol) o-phenylene diamine was stirred at 190° C. for 4 hour and the formed volatile materials were distilled off. The reaction mixture was then left to cool down to room temperature and acetone (100 ml) was added. The mixture was sonicated for 10 minutes, the formed residue filtered, washed with 2×5 ml acetone and dried under vacuum. Yield—4.5 g (44.0%). 1H NMR (250 MHz, CDCl3□, ppm: 3.22 (d, 2H), 3.95 (m, 4H), 5.20 (m, 2H), 5.90 (m, 1H), 7.15 (m, 4H), 7.53 (m, 4H), 12.11 (br.s 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9](=O)O[C:7]2=[CH:11][CH:12]=[CH:13][C:14]([CH:16]([CH3:18])[CH3:17])=[CH:15][C:6]=12)=[O:4].[CH2:19](NCC)C>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([CH:11]=[CH:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)=[CH:19][CH:9]=1)=[O:4]
Reactant: CCNCC
Reactant: COC(=O)c1c2cc(C(C)C)cccc-2oc1=O
Product: COC(=O)c1ccc2cccc(C(C)C)cc1-2

Procedure:
To a diethylamine (120 ml) suspension of 3-methoxycarbonyl-5-isopropyl-2H-cyclohepta[b]furan-2-one (16) (5.0 g) acetaldehyde (5.7 ml) was added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCO)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1OC
Reaction time: 0.5 h

Procedure:
A solution of 2.0 g (10.2 mmol) of the aldehyde prepared in step A in 40 ml CH2Cl2 is oxidised in the dark by the addition of 4.32 g (10.2 mmol) Dess-Marin periodinane. The reaction is complete after 30 minutes. The suspension formed is taken up into 50 ml CH2Cl2 and washed twice with sodium bicarbonate and 20% sodium thiosulphate solution. Concentration of the organic layer affords a beige crude product which is purified by chromatography hexane/ethyl acetate) to yield a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[O:14][CH2:13][CH2:12][O:3]1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: OCCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
A suspension of 3-acetylbenzonitrile (50.0 g), ethylene glycol (34.0 g) and boron trifluoride etherate (1 ml) in benzene (200 ml) was heated at 100° C. by means of a Dean-Stark apparatus for 5 hours. After cooling, a saturated aqueous sodium hydrogencarbonate solution (200 ml) was added. The benzene layer was collected and then dried with sodium sulfate. The solvent was removed under reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.0 g) (oil).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][NH:30][CH3:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]1[C:41]([OH:43])=O.C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][N:30]([CH3:31])[C:41]([C:33]2[NH:32][C:40]3[C:35]([CH:34]=2)=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:43])(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2cc3ccccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
To a solution of 0.05 g (0.114 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide prepared as described in step A of Example 28 in 2 mL of CH2Cl2 and 0.1 mL DMF, 0.018 g (0.114 mmol) of indole-2-carboxylic acid and 0.021 g (0.142 mmol) of 1,3-diisopropylcarbodiimide were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 80% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 20% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.024 g (36%) of the title compound of this Example as a white solid. m.p. 135°-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of benzyl ester (1) (25.7 mg, 0.0664 mmol) in 1:1 THF/H2O (3 mL) at 0° C. was added LiOH (9 mg, 0.348 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h at room temperature. The desired product (3) was obtained in 99% yield after purification by column chromatography (CH2Cl2/MeOH=85:15). FABMS: 298 (M+1); HREIMS calcd. for C17H15NO4 298.1079, found 298.1078.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][C@@H:8]2[N:10](CC3NC(C4SC=CN=4)=N[C@@H](C4C=CC(F)=CC=4Cl)C=3C(OC)=O)[C@@H:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[Br:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C@H:43]1[C:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:47]([CH2:54]Br)[NH:46][C:45]([C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[N:44]1>>[NH2:1][CH:2]1[CH2:3][C@@H:4]2[N:10]([CH2:54][C:47]3[NH:46][C:45]([C:56]4[S:57][CH:58]=[CH:59][N:60]=4)=[N:44][C@@H:43]([C:37]4[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=4[Br:35])[C:48]=3[C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br

Procedure:
Compound 71a was prepared in analogy to 60b in Example 60 by using ethyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 70a instead of compound C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH2:13][CH2:12]1>C(OCC)C.ClCCl>[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:16]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CN(C)CCC1c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A 2 molar solution of 4-fluorophenylmagnesium bromide in diethyl ether (3.5 ml, 1.4 molar equivalents) was stirred at −5 to −10° C. under nitrogen, and a solution of arecoline (0.78 g) in dichloromethane (4.0 ml) added over 15 minutes at −5° C. The clear solution was stirred at −5° C. for 1 hour, then quenched by the addition of a mixture of water (25 ml) and concentrated hydrochloric acid (3 ml). Analysis of the aqueous phase by HPLC showed that yield of cis/trans 1 ethyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine was about 965 mg (77 %).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCCl>[OH:23][C:19]1[CH:18]=[C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:22]=[CH:21][C:20]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Oc1cccc(N2CCCC2)c1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCCC2)cc1O
Temperature: 60 °C
Yield: 36.3 %

Procedure:
A mixture of 14.8 g (0.1 mole) of phthalic anhydride, 16.3 g (0.1 mole) of 100 percent 3-pyrrolidinophenol and 50.0 ml of 1,2-dichloroethane was maintained at approximately 40° C. for approximately twenty-four hours, at approximately 60° C. for approximately twenty-four hours and at reflux temperature for approximately twelve hours. After cooling the reaction mixture to ambient temperature, the solid which precipitated was collected by filtration and washed with 500.0 ml of 1,2 dichloroethane. The solid was dissolved in dilute aqueous soduim hydroxide, the resulting mixture was filtered to remove insolubles. The filtrate was adjusted to pH 7.0 with the addition of glacial acetic acid and the solid tar-like material which formed was collected by filtration. To the filtrate, an additional amount of glacial acetic acid was added. The solid which precipitated was collected by filtration, washed with water and dried to obtain 11.3 g of 2-(2-hydroxy-4-pyrrolidinophenyl)carbonylbenzoic acid, a pale pink-colored solid which melted at 190° to 192° C. To the filtrate, there was added an additional portion of glacial acetic acid and the solid which was collected by filtration, washed with water and dried to obtain 0.3 g of pale yellow-colored crystals of the desired product which melted at 193° to 195° C. The infrared spectra of the two solids were identical having significant maxima at 1100 cm-1 (C=O;m). The nuclear magnetic spectra were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[C:8]([O:10][CH3:11])[C:5]=1[CH2:6][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: COc1cc(O)cc(OC)c1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(O)cc(OC)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (0.30 g, 1.65 mmol), piperidine (0.20 mL, 1.98 mmol) and acetic acid (0.47 mL, 8.25 mmol) in methanol (20 mL) was stirred for 20 minutes before addition of sodium cyanoborohydride (0.27 g, 4.30 mmol). The reaction mixture was allowed to stir at ambient temperature for 4 h then loaded onto a 10 g SCX-2 cartridge which was then washed with methanol (30 mL) and then eluted with 2N ammonia in methanol (50 mL). Concentration of the combined basic fractions in vacuo afforded the title compound (220 mg, 53%) as a white solid. 1H NMR (DMSO-D6, 300 MHz): 9.39 (s, 1H), 6.03 (s, 2H), 3.66 (s, 6H), 3.30 (s, 2H), 2.32-2.24 (m, 4H), 1.42-1.35 (m, 4H), 1.34-1.26 (m, 2H). LCMS (Method B): RT=1.90 min, M+H+=252.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][OH:25])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:26](I)[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]1[CH2:23][CH2:24][O:25][CH2:26][CH3:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Add sodium hydride (0.558 g, 14.0 mmol) in portions to (S)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylic acid di-tert-butyl ester (3.075 g, 9.31 mmol) in dimethylformamide (60 mL) and stir for 15 minutes. Cool to 0° C. and add ethyl iodide (1.5 mL, 18.6 mmol) dropwise and stir at 0° C. After 30 minutes warm the mixture to room temperature and stir overnight. Dilute the mixture with ethyl acetate and wash the organics six times with brine. Dry over sodium sulfate and concentrate under reduced pressure to give (S)-2-(2-ethoxyethyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (3.17 g, 95%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>C(#N)C>[F:19][CH:20]([F:28])[O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Yield: 60.7 %

Procedure:
A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), Cul (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL). The reaction was heated to 45° C. (ext. oil bath). 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45° C. over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice. Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40% EtOAc/Hexanes) to afford (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21 [M+H−Boc]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:16])=[CH:10][C:9]=1[Cl:41])[CH2:5][CH2:6][Cl:7]>C(OCC)(=O)C.[Pd]>[Cl:7][CH2:6][CH2:5][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:10][C:9]=1[Cl:41])[CH2:3][CH2:2][Cl:1]
Reactant: O=C(Nc1ccc(N(CCCl)CCCl)c(Cl)c1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)c(Cl)c1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of dibenzyl N-((4[N,N-bis-(2-chloroethyl)amino]3-chlorophenylcarbamoyl))-L-glutamate (350 mg) in ethyl acetate (30 ml ) containing 30% palladium on carbon 70 mg (50% moist) was stirred under an atmosphere of hydrogen for 1 hour. After filtration of the catalyst the filtrate was evaporated to dryness and the residue triturated with ether/ethyl acetate to obtain N-(4-[N,N-bis(2-chloroethyl)amino]-3-chlorophenylcarbamoyl)-L glutamic acid as an oil. NMR: 8.7 (s) 1H; 7.6 (s) 1H; 7.1-7.4 (m) 2H; 6.5 (d) 1H; 4.2 (m) 1H; 3.3-3.6 (m) 8H; 1.7-2.4 (m) 4H.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O.Cl.Cl.[CH:28]([C@H:41]1[N:46]2[CH2:47][CH2:48][CH2:49][C@H:45]2[CH2:44][NH:43][CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH:28]([C@H:41]1[N:46]2[CH2:47][CH2:48][CH2:49][C@H:45]2[CH2:44][N:43]([CH2:18][C:17]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])[CH2:42]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COc1cccc(Cl)c1C=O
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CNC[C@@H]3CCCN32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cl)c1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Yield: 49.1 %

Procedure:
A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-chloro-6-methoxybenzaldehyde (9.4 mg) and a solution of (4R,8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (18.3 mg) in N,N-dimethylformamide (50 μl) at 25° C. and the whole was stirred at room temperature for 2 hours. The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90). The solution was concentrated in vacuo. To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution. The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) and eluted with ethyl acetate. The eluate was concentrated in vacuo to give (4R,8aS)-4-benzhydryl-2-(2-chloro-6-methoxybenzyl)octahydropyrrolo[1,2-a]pyrazine (11.0 mg)