Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:24](=[S:25])[N:23]([C:26]3[CH:27]=[C:28]([C:34]([F:37])([F:36])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=3)[C:22](=[O:38])[C:18]32[CH2:21][CH2:20][CH2:19]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N:17]3[C:24](=[S:25])[N:23]([C:26]4[CH:27]=[C:28]([C:34]([F:36])([F:37])[F:35])[C:29]([C:32]#[N:33])=[N:30][CH:31]=4)[C:22](=[O:38])[C:18]43[CH2:19][CH2:20][CH2:21]4)=[CH:3][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OCCN4CCNCC4)c(F)c3)C2=S)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.6 %

Procedure:
A mixture of 5-(5-(3-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 174, 50 mg, 0.1 mmol), acetic anhydride (13 μL, 0.14 mmol), and triethylamine (40 μL, 0.27 mmol) in DCM (2 mL) was stirred at room temperature for 2 days. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford 34 mg of 5-(5-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.74 (s, 1H), 7.42 (t, 1H), 7.35 (dd, 1H), 7.22 (m, 1H), 4.28 (t, 2H), 3.42 (m, 4H), 2.80 (t, 2H), 2.65-2.59 (m, 2H), 2.54-2.44 (m, 6H), 1.98 (m, 4H), 1.57 (m, 1H). LCMS [M+1]+ 591.9.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)=[O:2].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>CN(C1C=CN=CC=1)C.C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)[C:35]([NH:8][C:6]2[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=2)=[O:36])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1ncc(C=O)s1
Reactant: CC1CCC(NC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 65 °C
Yield: 357.1 %

Procedure:
Prepared in a manner similar to general procedure (C) using 5-formyl-2-aminothiazole (1.88 g, 14.6 mmol), 4-(4-methyl-cyclohexylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.32 mg, 14.6 mmol), catalytic DMAP, CDI (2.60 g, 1.1 mmol) and THF with heating to 65° C. afforded 1.77 g (27%) of the desired product after purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[O:32][CH:33]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[C:29](=[O:42])[CH:30]=[C:31]([CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[O:32][CH:33]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (300 mg, 1.3 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (53 mg, 1.3 mmol) were successively added at 4° C. After 30 min a solution of 5-(8-bromo-octyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 5 (500 mg, 1.2 mmol) in DMF (5 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(8-(7-(trifluoromethyl)quinolin-4-ylthio)octyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 1006 (320 mg, 47% yield) as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH2:20][CH:21]=[N:22][OH:23]>CN(C=O)C.C(OCC)(=O)C>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:9])[N:11]1[CH2:20][C:21]([Cl:1])=[N:22][OH:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccccc2C(=O)N1CC=NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Temperature: 50 °C
Yield: 98.7 %

Procedure:
N-Chlorosuccinimide (8.50 g, 63.7 mmol) was added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime (13.0 g, 63.7 mmol) in DMF (100 mL), and the solution was heated at 50° C. gently for two hours and allowed to cool to room temperature. The solution was diluted with ethyl acetate and washed three times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to provide 15.0 g of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride as a pale yellow solid.
Reaction SMILES: [C:1]1([C:11]([O:13][CH3:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:14][O:13][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-:20])=[O:12]
Reactant: COC(=O)c1nccc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1c2ccccc2cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a suspension of methyl isoquinoline-1-carboxylate (11.2 g, 59.8 mmol) in DCM (150 mL) was added 3-chloroperoxybenzoic acid (15.5 g, 89.7 mmol) at 0° C. The mixture was warmed to RT and was stirred at RT for 24 hours. The reaction was quenched with saturated aqueous NaHCO3 and the mixture was extracted with DCM. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether and EtOAc (1:1) to give the title compound as a white solid (9.5 g, 78%). ESI-MS m/z [M+H]+ 204.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]#[N:29])=[O:22])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 67.8 %

Procedure:
In a similar manner to Example 2, 2-tetrahydropyranyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (90.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (70.0 mg) were used to obtain (2S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonyl bicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (85.2 mg).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCl>[ClH:25].[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:16]1[CH2:15][NH:14][CH2:17]1
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cl
Product: Clc1ccc(OC2CNC2)cc1Cl
Reaction time: 4 h

Procedure:
A solution of 1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine (2.14 g, 6.4 mmol) in dry dichloromethane (20 ml) is treated with 1-chloroethylchloroformate (0.832 ml, 7.7 mmol) with stirring for 4 hours. The solvent is evaporated and the residue dissolved in methanol and refluxed for 18 hrs. The methanol is evaporated to a saturated solution, and then treated with diethylether. The resulting precipitate is filtered and dried under vacuum to afford 3-(3,4-Dichloro-phenoxy)-azetidine hydrochloride. 1H NMR (D6 DMSO, 400 Mhz) δ 9.5 (2H, brS), 7.6 (1H, d), 7.2 (1H, s), 6.9 (1H, d), 5.1 (1H, m), 4.4 (2H, m), 3.95 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[C@@H:11]([CH2:42][C@H:43](OS(C)(=O)=O)[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[NH:50]1[CH:54]=[CH:53][N:52]=[CH:51]1>>[N:50]1([C@@H:43]([CH3:44])[CH2:42][C@@H:11]2[NH:12][CH2:13][C@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[C@@H:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH:54]=[CH:53][N:52]=[CH:51]1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](C[C@@H](C)OS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: c1c[nH]cn1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN[C@@H](C[C@H](C)n4ccnc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 42a, methanesulfonic acid (R)-2-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethyl ester (from example 38b) are reacted with imidazol to afford the title compound as a colourless oil. Rf=0.22 (dichlormethane-methanol 10:1); Rt=4.60.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:19])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of trans-4-methyl-1-cyclohexane carboxylic acid (8.2 g, 56.5 mmol) in CH2Cl2 (350 mL) at 0° C. was added DMF (44 μl, 0.6 mmol) and oxalyl chloride (11.5 g, 90.0 mmol) dropwise. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated. The product was used without further purification.
Reaction SMILES: C([N:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28](N)=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)=O.[OH-:43].[Na+].O>CO>[NH:3]1[C:7]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[N:20]=[CH:21][C:22]5[S:27][C:26]([C:28]([OH:43])=[O:29])=[C:25]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=6[O:37][CH3:38])[C:23]=5[N:24]=4)=[C:14]([O:39][CH:40]([CH3:42])[CH3:41])[CH:13]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccccc1-c1c(C(N)=O)sc2cnc(Nc3ccc(N4CCC5(CCCN5C=O)C4)cc3OC(C)C)nc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1c(C(=O)O)sc2cnc(Nc3ccc(N4CCC5(CCCN5)C4)cc3OC(C)C)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 76 mg of 2-{[4-(1-formyl-1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxamide and 2 ml of 5N sodium hydroxide in 15 ml of methanol is stirred at ambient temperature for 3 hours, and then maintained at reflux for 1 h 30. The mixture is stirred at AT for 15 h and then again maintained at reflux for 5 h 30. The reaction medium is then run into 20 ml of water and then the methanol is eliminated by concentration under reduced pressure. The resulting aqueous phase is washed several times with dichloromethane (3 times 20 ml) and then acidified so as to obtain a pH with a value of about 7/8, and then the aqueous phase is extracted a further three times with 20 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum, so as to obtain 72 mg of 2-{[4-(1,7-diazaspiro[4.4]non-7-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC#CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of (4-Amino-but-2-ynyl)-carbamic acid tert-butyl ester (0.8 g, 4.34 mmol) in dry CH2Cl2 (40 ml) was added 6,6-bis-(4-fluorophenyl)-hexanoic acid (1.32 g, 4.4 mmol) under nitrogen. To the reaction was added EDC (1.66 g, 8.68 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give the desired product in 72% yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22](O)[CH2:23][O:24][CH3:25])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:12][CH:11]=1)[CH2:23][O:24][CH3:25])[CH3:18]
Reactant: c1ccc(Cc2cccc3[nH]ccc23)cc1
Reactant: CCOC(=O)C(C(O)COC)[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(COC)c1c[nH]c2cccc(Cc3ccccc3)c12)[N+](=O)[O-]
Yield: 87 %

Procedure:
Under argon, 2.80 g (13.5 mmol) of 4-benzylindole is refluxed for 15 hours with 7.48 g (18 mmol) of a 50% strength solution of 4-methoxy-3-hydroxy-2-nitrobutyric acid ethyl ester in 84 ml of toluene with 8.3 ml of glacial acetic acid. After cooling, the reaction mixture is diluted with ethyl acetate and washed with water. The organic phase is dried, filtered, and concentrated, and the residue is chromatographed over silica gel with methylene chloride as the eluent, thus producing 4.7 g (87%) of 3-(4-benzylindol-3-yl)-2-nitro-5-oxahexanoic acid ethyl ester, which latter is hydrogenated in 50 ml of ethanol with 4.7 g of Raney nickel B 115-Z under normal pressure and at room temperature. After separation of the catalyst and evaporation, the product is chromatographed over silica gel with methylene chloride:ethanol=10:1, thus obtaining 1.16 g (24%) of 2-amino-3-(4-benzylindol-3-yl)-5-oxahexanoic acid ethyl ester; this product is combined with 349 mg of glyoxylic acid hydrate in 4 ml of ethyl acetate and 4 ml of water, adjusted to pH 4 with 10% potassium carbonate solution, and stirred overnight at room temperature. After the ethyl acetate has been removed by distillation, the product is diluted with water, extracted with methylene chloride, and the organic phase is dried, filtered, and concentrated, thus obtaining 1.7 g of a crude product which, without further purification, is refluxed in 40 ml of xylene for 5 hours. After concentration, the mixture is taken up in 40 ml of dimethyl sulfoxide, combined with 200 mg of sulfur, and heated for 75 minutes to 140° C. After the dimethyl sulfoxide has been removed by distillation, the mixture is chromatographed twice over silica gel, first with methylene chloride:ethanol=10:1 and then again with hexane:acetone=1:1, yielding 45 mg of 5-benzyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 160°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C([N:15]([CH:19]([CH3:21])[CH3:20])C(C)C)C.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([NH:15][CH:19]2[CH2:21][CH2:20]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1cccc(CCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(CCC(=O)NC2CC2)c1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a stirred solution of 3-(3-aminophenyl)propanoic acid (1 g, 6.05 mmol) in 10 ml DMF, N-ethyl-N-isopropylpropan-2-amine (1.174 g, 9.08 mmol), cyclopropanamine (0.415 g, 7.26 mmol) were added, resulting clear solution was stirred at room temperature, HATU (3.45 g, 9.08 mmol) was added and the resulting mixture was stirred for 24 h at room temperature. Reaction Mixture was diluted with cold water and extraction with Ethyl Acetate (3×30 ml). The Combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the crude compound, the crude compound was purified by column chromatography to afford the pure title compound (500 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C[O:11][C:12](=O)[CH2:13][CH2:14][CH2:15][N+:16]([O-:18])=[O:17].C([O-])(=O)C.[NH4+:24]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:5]2[NH:24][C:12](=[O:11])[CH2:13][CH2:14][C@H:15]2[N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cccc(Br)c2)N1

Procedure:
A mixture of 3-bromobenzaldehyde (82.20 g), methyl-4-nitrobutyrate (65.3 g) and ammonium acetate (68.5 g) in ethanol (400 ml), was heated to reflux for 18 hours. The solvent was removed in vacuo and the resultant mixture triturated with ethanol (400 ml) to give the title compound as a white solid. (97.46 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:8][CH2:9][F:10])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 56.9 %

Procedure:
Potassium carbonate (1.85 g, 13.4 mmol) and 1-bromo-2-fluoroethane (440 μl, 5.9 mmol) were added to a solution of tert-butyl-1-piperazinecarboxylate (1 g, 5.4 mmol) in acetonitrile (12 ml). The reaction mixture was stirred at 65° C. for 3.5 hours after which time more 1-bromo-2-fluoroethane (160 μl, 2.1 mmol) was added. The reaction was heated for a further 3 hours then filtered to remove the inorganic solids. The filtrate was concentrated and the crude product was purified using column chromatography eluting with ethyl acetate to give 4-(2-fluoroethyl)-piperazine-1-carboxylic acid tert-butyl ester (714 mg, 57%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][OH:19].[H-].[Na+]>C1COCC1>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][O:19][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (0.5, 2.207 mmol) and 2-(dimethylamino)ethanol (0.393 g, 4.41 mmol) in THF (10 mL) was added NaH (0.177 g, 4.41 mmol) at 0° C. The resulting mixture was stirred at rt. After 5 h, TLC analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 mL) and washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (DCM/MeOH=20/1) to yield a white solid of N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine (0.5 g, 1.717 mmol, 78.0% yield): 1H NMR (400 MHz, CD3OD) δ 9.25 (d, J=2.4 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 4.73 (t, J=5.4 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:30][CH2:31][CH3:32])[CH2:5][C@@H:6]([CH2:9][O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:7][OH:8])[CH3:2].C(N([CH2:38][CH3:39])CC)C.[C:40]1(C)[CH:45]=C[C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[C:38]1([CH3:39])[C:43]([S:46]([O:8][CH2:7][C@H:6]([CH2:9][O:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:30][CH2:31][CH3:32])(=[O:48])=[O:47])=[CH:42][CH:41]=[CH:40][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](CO)CC(OCC)OCC
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](COS(=O)(=O)c1ccccc1C)CC(OCC)OCC
Temperature: 46 °C

Procedure:
The product of Example 31, step a) (26.21 g, 0.057 mol) was dissolved in methylene chloride (75 mL) and charged into a 250 mL 3 necked flask equipped with a magnetic stir bar, condenser, N2 inlet, and temperature probe. Triethylamine (14.4 g) was added followed by p-toluenesulfonyl chloride (16.3 g). The flask was purged with N2 and heated to reflux (46° C.). The reaction was stirred at reflux 6 hours. The reaction was cooled to room temperature. Water (10 mL) was added and the reaction was stirred vigorously for 16 hours. The reaction mixture was poured into a 1 L separatory funnel containing ethyl acetate (350 mL) and water (350 mL). The organic layer was separated and washed with 7% (w/w) aq. sodium bicarbonate (100 mL). The organic layer was then washed with 23% (w/w) aq. sodium chloride (100 mL). The organic layer was dried with Na2SO4 and filtered. The solution was concentrated to give the desired product (29.4 g) as an oil that formed a wet solid when cooled to room temperature.