Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:38]=[CH:37][C:24]([CH2:25][N:26]5[CH2:29][CH:28]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:27]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.CO>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:38]=[CH:37][C:24]([CH2:25][N:26]5[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A solution of tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (518 mg, 0.956 mmol) in trifluoroacetic acid (15 mL) was allowed to stand at room temperature for 1.5 h. The volatiles were removed under reduced pressure, and the residue was co-evaporated from ethyl acetate/hexanes. (2×10 mL). The residue was suspended in water (10 mL) and the pH was adjusted to ˜11 with 1N aqueous sodium hydroxide. To this solution was added sufficient 1N aqueous hydrochloric acid to adjust the pH ˜4.5. The resulting suspension was stirred at room temperature overnight. The white suspension was filtered through a medium porosity sintered glass filter, and the filter cake was washed thoroughly with water. The solid was dried, the white powder was suspended in methanol, and the suspension was sonicated until it was uniform. The methanol was removed under reduced pressure, and the procedure was repeated twice more to afford a white solid that was stirred as a suspension in methanol (−30 mL) overnight. Vacuum filtration and drying afforded 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)-azetidine-3-carboxylic acid (345 mg, 0.707 mmol, 74% yield) as a white powder. HPLC ret. time=3.45 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=486.12. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.39-3.45 (m, 2H), 3.64 (s, 2H), 7.50 (d, J=8.28 Hz, 2H), 7.58 (m, 5H), 8.02 (d, J=8.28 Hz, 2H), and 8.26 (d, J=1.25 Hz, 1H). Elemental Analysis: Calc. for C24H18N3O3SF3.0.1H2O: C 59.22; H, 3.76; N, 8.63, S 6.59, F 11.71. Found: C24H18N3O3SF3-0.1H2O: C 59.06; H, 3.45; N, 8.60, S 6.61, F 11.42; KF (Found)=0.25% water.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].Cl.CN(C)[CH:21]=[O:22]>O>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:21]=[O:22])=[CH:10][NH:11]2
Reactant: CN(C)C=O
Reactant: Oc1cccc2[nH]ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cccc(O)c12
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature. Water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials. Yield 82%. Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.C(O)C>Cl.C(#N)C>[OH:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:34])[C@@H:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2ccn(CCO)n2)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
In a flask containing (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (70 mg, 0.13 mmol) was added ethanol (2 mL) and concentrated hydrochloric acid (three drops) and it was stirred at 25° C. for 1 h. It was then diluted with acetonitrile and absorbed onto silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes to 10% methanol/ethyl acetate) to afford (R)—N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (49 mg, 89%) as a yellow foam: [α]25589=−79.3° (c=0.14, methanol); ES-HRMS m/e calcd for C20H22N3O3F3 (M+H)+ 410.1686, observed 410.1687; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.73-2.30 (m, 8H, 4×CH2), 3.66 (m, 2H, OCH2), 3.95 (m, 1H, ArCHCO), 3.99 (m, 2H, NCH2), 4.83 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.0 Hz, 1H, Ar), 7.54 (d, J=2.0 Hz, 1 H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](N)[C:5]([CH3:9])=[CH:4][N:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1-c1nccc2ccccc12

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-chloroisoquinoline (164 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 28, was used for next reaction without further purification.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[Na+].Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[CH2:1]([S:3][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Product: CCSCC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Under ice cooling, 4.6 ml of ethyl mercaptan was added to 62 ml of 1N-NaOH aqueous solution followed by stirring for 30 minutes. Furthermore, 10.1 ml of tert-butyl bromoacetate was gradually added to the mixture under ice cooling and the resulting mixture was reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted 4 times with ethyl acetate and the extract was washed with saturated sodium chloride aqueous solution. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off to give 12.0 g of crude tert-butyl (ethylthio)acetate.
Reaction SMILES: [CH3:1][O:2]C(=O)C1C=CC(N)=C(C=O)C=1.[OH-].[K+].[Cl:16][C:17]1[CH:48]=[CH:47][C:20]([C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]([OH:39])=[O:38])[CH:33]=4)[N:28]=3)=[CH:25][C:24](C(N3CCCC3)=O)=[CH:23][CH:22]=2)=[CH:19][CH:18]=1>CCO>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[C:26]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]([OH:39])=[O:38])[CH:33]=4)[N:28]=3)=[CH:25][C:24]([O:2][CH3:1])=[CH:23][CH:22]=2)=[CH:47][CH:48]=1
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Yield: 91 %

Procedure:
Compound 7 (3.06 g. 11.72 mmol) was reacted with compound 525a (2.1 g, 11.72 mmol) and KOH (2.32 g, 35.16 mmol) in EtOH (150 mL) according to the procedure in the preparation of Compound 259e. Purification by chromatography using CHCl3-MeOH (7:1) as the eluent gave the title intermediate (3.1 g, 91%). MS: 388.07 (M+H+).
Reaction SMILES: [Na].Cl.C[O:4][C:5]([NH:7][N:8]=[C:9]([C:12]1[N:19]2[C:15]([S:16][CH:17]=[CH:18]2)=[N:14][C:13]=1[CH3:20])[CH2:10][OH:11])=O>C(O)C>[CH3:20][C:13]1[N:14]=[C:15]2[N:19]([C:12]=1[C:9]1[CH2:10][O:11][C:5](=[O:4])[NH:7][N:8]=1)[CH:18]=[CH:17][S:16]2
Reactant: COC(=O)NN=C(CO)c1c(C)nc2sccn12
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1nc2sccn2c1C1=NNC(=O)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 0.5 g of metallic sodium in 60 ml of ethanol is added 6 g of hydroxymethyl-(6-methylimidazo[2,1-b]thiazol-5-yl)ketone-N-methoxycarbonylhydrazone hydrochloride, and stirred at room temperature for 3 hours. Crystals are collected by filtration, washed with water and then recrystallized from 50 ml of a mixed solvent of chloroform and methanol to give 3.5 g of 5-(6-methylimidazo[2,1-b]thiazol-5-yl)-3,6-dihydro-1,3,4-oxadiazin-2-one as white crystals, melting at 294° C. with decomposition.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH2:28][NH:4][CH2:1][CH2:2][CH3:3])=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CCCN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from propylamine and 4-(4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 190-205° C.; LC-MS: 414 (MH+); HPLC RT: 4.15 minutes.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.CS(O[CH2:57][C:58]1([CH2:61][C:62]#[N:63])[CH2:60][CH2:59]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[C:62]([CH2:61][C:58]1([CH2:57][O:51][C:42]2[CH:41]=[C:40]([CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=2)[CH2:39][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:60][CH2:59]1)#[N:63]
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CS(=O)(=O)OCC1(CC#N)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC#N)CC2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate (appendage 4) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene) to afford the title compound as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[C:16]([F:15])[CH:17]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)c(F)c1
Yield: 65.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-fluoro-4-(3-fluorobenzyl)benzamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.075 g; 0.318 mmol), 3-fluoro-4-(3-fluorobenzyl)benzoic acid (0.087 g; 349 mmol), HATU (0.121 g: 0.318 mmol) and N,N-diisopropylethylamine (0.139 mL; 0.795 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) followed by recrystallization from a mixture of dichloromethane/heptane, furnished 0.088 g (65%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.C(OCC)(=O)C>C1COCC1>[CH2:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]([C:11]2([CH2:33][C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=3)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCC2CCCCC2)CC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C#N)cc2)(C(=O)OCC2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester (6.61 mmol; 2.15 g) in dry THF (30 mL) under argon at −78° C. was added, dropwise, a 2M solution of lithium diisopropylamide (2M solution in heptanes/THF/ethylbenzene; 8.59 mmol; 4.29 mL). The resulting solution was stirred at −78° C. for 2 hours. 4-Bromomethyl-benzonitrile (6.61 mmol; 1.30 g) was added and the resulting solution was stirred at −78° C. for 2 hours, then allowed to warm to room temperature overnight. Ethyl acetate (150 ml) was added. The resulting solution was washed with a 1M aqueous hydrochloric acid solution (2×50 mL) and brine (50 mL) and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-(4-cyano-benzyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-cyclohexylmethyl ester. MS (ESI) m/z 436.38 [M+Na]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:13])[C:9]([NH2:12])=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:21]=[C:22]1[O:26][C:24](=O)[CH2:23]1>C1C=CC=CC=1>[CH2:23]([C:24]1[O:11][N:10]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:13])[N:12]=1)[C:22]([CH3:21])=[O:26]
Reactant: CN(Cc1ccccc1)C(N)=NO
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(=O)Cc1nc(N(C)Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled mixture of 2.8 g of 1-benzyl-1-methylhydroxyguanidine and 1.3 g of triethylamine in 30 ml of benzene was added dropwise 1.3 ml of diketene under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. After adding 50 ml of toluene to the residue, the resultant solution was heated under reflux for 4 hours with a water separator. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using chloroform-methanol (70:1) as eluent to give 1.7 g of 5-acetonyl-3-(N-benzyl-N-methylamino)-1,2,4-oxadiazole as a colorless oil, IR νmaxneat cm-1 : 1725, 1590, 1410, 1355, 1155.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])C=CC=CC=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28]>C1C=CC=CC=1>[CH3:9][C:8](=[CH:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=Cc1cccc([N+](=O)[O-])c1

Procedure:
To a stirred slurry of 79.8 g. of triphenyl(1-[ethoxycarbonyl]ethylidene)phosphorane in 300 ml. of benzene was added 30.2 g. of 3-nitrobenzaldehyde and the resulting mixture was heated under reflux overnight. The reaction mixture was cooled and the solvent was removed by evaporation in vacuo. The residue was extracted with 300 ml. of isopropyl ether. The isopropyl ether solution was filtered, and the filtrate was evaporated in vacuo. The residue was distilled under reduced pressure, giving 37.6 g. of the title product, b.p. 147°-162° C./0.25 mm Hg. The NMR spectrum (in CDCl3) showed absorptions at 1.4 (t), 2.1 (d), 4.3 (q), 7.4 (m) and 8.1 (m) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:5]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@H:4]2[NH:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([F:14])([F:15])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:5]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@H:4]2[N:3]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Ic1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(c3ccccc3)[C@@H]2C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 1, Part H (50 mg, 0.14 mmol) in 4 mL of toluene in a screw-cap vial was added copper (I) iodide (2.6 mg, 0.014 mmol) and potassium phosphate (65 mg, 0.31 mmol). The reaction was degassed with a stream of argon for several minutes, and then there was added iodobenzene (17 μL, 0.154 mmol) and N,N′-dimethylethylenediamine (3.0 μL, 0.028 mmol). The reaction was allowed to stir at 90° C. in the sealed vial for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 2:1 hexane/EtOAc) to afford 48 mg (80%) of the title compound. LRMS (ESI): 377.23 (M+H—C4H8)+.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:38]([CH3:39])[CH3:37])=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and dimethylamine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.017 g, 11% yield). LCMS: 516.35 (M+1)+; HPLC: 90.32% (@ 254 nm) (Rt; 4.203; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.78 (s, 1H), 8.18 (t, 1H), 8.05 (d, 1H, J=6 Hz), 7.50 (d, 1H, J=8.4 Hz), 7.34 (s, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.75 (bs, 2H), 2.75 (m, 1H), 2.65 (s, 3H), 2.34 (bs, 6H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.71 (m, 4H), 1.54-1.56 (m, 2H), 1.42-1.45 (m, 2H), 1.08-1.23 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([OH:22])[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:23][O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:22][C:12]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:11]=1
Reactant: Cc1ccc(Nc2cc(O)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1C
Reactant: COC(=O)CCCCCBr
Product: COC(=O)CCCCCOc1cc(Nc2ccc(C)c(C)c2)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
5 g of 3-[(3,4-dimethylphenyl)amino]-4,6-dinitrophenol was O-alkylated with 6-bromohexanoic acid methyl ester at 70° C. analogously to general operating instructions 8.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[N-]=C=O>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: CCNCC
Agent: [N-]=C=O
Solvent: CCCCC
Product: CCN(CC)C(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C

Procedure:
To 7.4 grams (0.0354 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.49 grams (0.0354 moles) of diethylamine and the reaction mixture stirred at room temperature. When the reaction mixture became viscous pentane was added. The reaction mixture was stirred for 3 hours and the pentane evaporated under reduced pressure leaving a white wax weighing 10.0 grams (96% crude yield). The infrared spectrum of the product contained a strong carbonyl band at 1640 cm-1 and a sharp NH band at 3380 cm-1. The isocyanate band at 2225 cm-1 was absent.