Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](S(C)=O)=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:17]=2[F:26])[C:4]1=[O:27])[CH3:2]
Reactant: NCCCCO
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2F)Cc2cnc(NCCCCO)nc21

Procedure:
1-Ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.4 g (1.01 mmol) 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.27 g (3.03 mmol) 4-amino-butan-1-ol. The final product was purified by column chromatography (20:1 dichloromethane/methanol). This gave 0.375 g (88%) of 1-ethyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-(4-hydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid: mp 129° C.–131° C.; MS (APCI) m+1/z 420.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I.[Cl-].[NH4+]>C(COC)OC.CCCCCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:16]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: ClCCCCI
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCl)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 3.52 ml) was added to a dimethoxyethane solution (30 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.52 g, 5.02 mmol) obtained in Example 5. The temperature of the reaction mixture was elevated to room temperature, at which stirring was conducted for 15 minutes. After cooling the reaction mixture to −78° C., 4-chloro-1-iodobutane (672 μl, 5.52 mmol) was added thereto and the mixture was stirred at room temperature for 24 hours. A saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium thiosulfate and brine, dried over MgSO4, and then distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane, whereby the title compound (1.64 g, 83%) was obtained as colorless needle crystals.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[N:35]([CH:37]=[O:38])C.CO>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([C:37](=[O:38])[NH2:35])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(C(N)=O)c2C1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 71 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran (2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol), 1,3-bis(diphenylphosphino)propane (95 mg, catalytic amount), palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated two times). The reaction mixture was stirred at 70° C. for 7.5 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/sat. NaHCO3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a crude which was purified by flash chromatography (SiO2, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=1)[N:8]=[CH:7]2)([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]1[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=1)[N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc2nc(-c3ccc4c(c3)OCO4)ncc2c1
Yield: 63.4 %

Procedure:
A suspension of 6-nitro-2-(1,3-benzodioxol-5-yl)-quinazoline (37 g, 0.126 mol) and SnCl2 2H2O (117.2 g, 0.504 mol) in ethanol (500 ml) was heated at reflux for 1 h. After cooling to r. t., the solvent was removed i.v., chloroform was added and the mixture was basified with ammonia. The precipitate was filtered off and washed with chloroform. The filtrates were collected, washed with water and dried over Na2SO4. The solution was concentrated i.v., and the residue triturated with diisopropyl ether/petroleum ether. The solid was filtered and dried i.v. to give the titled product (21.2 g, 64% yield). C15H11N3O2, MW: 265.27. mp 191-192° C.; 1H NMR (DMSO-d6) 9.24 (s, 1H), 8.05 (dd, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.39 (dd, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 6.11 (s, 2H), 5.93 (s, 2H); IR (KBr) 3319, 3203, 1631, 1500, 1446; TLC (CHCl3/MeOH 9/1) Rf=0.3.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[Cl:25]>>[Cl:22][C:21]1[CH:20]=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([Cl:25])[C:16]=1[CH2:15][CH:10]1[CH2:11][CH2:12][N:8]([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[CH3:1])[C:9]1=[O:13]
Reactant: C[C@H]1CCCC[C@H]1N1CCCC1=O
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Product: COc1cc(Cl)c(CC2CCN([C@@H]3CCCC[C@@H]3C)C2=O)c(Cl)c1
Yield: 63.1 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents 1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one (Preparation 32) (1.0 g, 5.52 mmol) and 2-(bromomethyl)-1,3-dichloro-5-methoxybenzene (1.24 g, 5.52 mmol) gives 1.29 g (63%) 3-(2,6-Dichloro-4-methoxybenzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][CH:16]([OH:21])[C:17]([OH:20])([CH3:19])[CH3:18])[CH2:11][C@@H:10]1[C@H:22]1[O:26]C(C)(C)[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:23]([NH:24][C:29](=[O:31])[CH3:30])[C@@H:22]([C@H:10]1[CH2:11][C@@H:12]([O:14][CH2:15][CH:16]([OH:21])[C:17]([OH:20])([CH3:19])[CH3:18])[CH2:13][NH:9]1)[OH:26]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCC(O)C(C)(C)O)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCC(O)C(C)(C)O)CN1
Reaction time: 4 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (5 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(2,3-dihydroxy-3-methyl-butoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.07 g, 0.126 mmol). Stir 4 hours and evaporate to give the title compound as a foam (0.062 g, 100%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20](Cl)=[O:21]>>[Br:18][CH2:19][C:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:21]
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Reactant: O=C(Cl)CBr
Product: O=C(CBr)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-benzylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22](O)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCCP(=O)=O>O1CCCC1>[F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([N:27]3[CH2:30][CH2:29][CH2:28]3)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: C1CNC1
Reactant: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Product: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A mixture of 5-(2-((2-fluoroethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 277 μmol), azetidine (74.6 μl, 1.11 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 408 μl, 692 μmol) in tetrahydrofuran (5 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid {2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide (93 mg, 83.9%) as a white solid. mp: 236-237° C., MS: m/z=401.1 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=1)=[CH:7]2.Cl.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:23])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=1)=[CH:7]2
Reactant: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 8-chloro-3-(3-fluoro-4-methoxyphenyl)-7-hydroxy-1-naphthonitrile (0.042 g, 0.13 mmol) with pyridinium HCl (1.8 g) according to method D to yield 0.033 g (78%) of a tan solid. This material was further purified by preparative reverse phase HPLC to yield the title compound as a white solid: mp 246-252° C.; 1H NMR (DMSO-d6): δ 7.04-7.10 (1H, m), 7.44 91H, d, J=8.94 Hz), 7.56 (1H, dd, J=1.66 Hz, J=8.37 Hz), 7.76 (1H, dd, J=2.20 Hz, J=12.88 Hz), 7.99 (1H, d, J=9.09 Hz), 8.43 (1H, d, J=1.98 Hz), 8.52 (1H, d, J=1.94 Hz), 10.19 (1H, bs), 11.05 (1H, bs); MS (ESI) m/z312/314 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1[nH]c2cc(F)cc(Br)c2c1Sc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(C(=O)OC)c(Sc2ccc(Cl)cc2)c2c(Br)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a solution of the indole of Step 1 (500 mg, 1.2 mmol) in DMF (10 mL) at 0° C. was added NaH (63 mg, 1.6 mmol, 60% in oil). The reaction mixture was stirred at 0° C. for 15 minutes and tetra-n-butylammonium iodide (300 mg) was added, followed by the addition of ethyl 4-bromobutyrate (360 mg, 1.8 mmol). The resulting mixture was stirred for 3 hours at r.t., quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 30% EtOAc in Hexanes to provide 500 mg of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O.[CH3:43][NH:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52]>C(Cl)Cl>[CH3:43][N:44]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH3:52])[C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20]
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Reactant: CNCc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1CN(C)C(=O)c1nn(-c2ccc(F)cc2)c(C=O)c1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.6 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.50 g, 5.43 mmol) in CH2Cl2 (100 mL) at 25° C. was added EDCI (1.56 g, 8.14 mmol) followed by HOBt.H2O (1.25 g, 8.14 mmol) and the reaction was stirred for 10 min at 25° C. Subsequently, methyl-(2-methyl-benzyl)-amine (1.10 g, 8.14 mmol) was added and the reaction was stirred for an additional 6 hrs at 25° C. The organic layer was then washed with HCl, saturated NaHCO3 and brine. After drying over Na2SO4 and concentration, the product was purified by column chromatography (10-25 % EtOAc/Hex) to afford desired 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl-(2-methyl-benzyl)-amide as an oil (1.53 g, 71.6%). MS(APCI+) 394.2 m/z (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.CCOCC.O.[NH2:20][CH:21]([CH3:24])[CH2:22]O>>[CH3:24][CH:21]1[N:20]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:3][CH2:22]1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: CC(N)CO
Solvent: CCOCC
Solvent: O
Product: CC1CN=C2C=CC(c3cccnc3)=NN21

Procedure:
A 4.0 g sample of 3-chloro-6-(3-pyridinyl)pyridazine in 56 ml of 2-amino-1-propanol was heated at 140° C. for 8 hours. The solution was cooled, then poured into a mixture comprised of 200 ml of ether and 300 ml of water. The water layer was concentrated under vacuum and the 2-amino-1-propanol was removed by bulb to bulb distillation under high vacuum. The residue in 50 ml of thionyl chloride was refluxed for 0.5 hours then the volatiles were removed in vacuo. To the residue was added 150 ml of ethanol and 5 g of potassium carbonate. The mixture was refluxed for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with three 50 ml portions of dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo. Ether was added to the residue and a brown solid was removed by filtration. The addition of hexane to the filtrate on chilling gave crystals which were recrystallized from ether-hexane to give 1.2 g of 2,3-dihydro-3-methyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine as orange crystals, mp 103.5°-105° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>O>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:22](=[NH:23])[C:21]1[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: Cc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccccc2C(C)(C)C)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Procedure as described for Amidine I using the following amounts: 7.80 mL of 2-t-butylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was dark brown. Addition of water yielded an orange solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 75 mL of pentane, stirred overnight, and filtered yielding 11.14 g (84%) of off-white material. 1H NMR (400 MHz, CDCl3): 7.82 (d, 2H), 7.41 (d, 1H), 7.27 (d, 2H), 7.17 (t, 1H), 7.00 (t, 1H), 6.82 (d, 1 H), 4.75 (s, 2H), 2.42 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:23].[Na+].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:12][CH:13]=3)[C:8](=[O:23])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1-2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)c1ccc2c(c1)C(=O)c1cc(C(=O)CCl)ccc1-2

Procedure:
A mixture of 5.0g (0.016 mole) of 2,7-bis(chloroacetyl)fluorene, 6.3g (0.020 mole) of sodium dichromate and 125 ml of glacial acetic acid was refluxed with stirring for seventeen hours. The resulting precipitate was filtered while the solution was hot, then washed with acetic acid and dried in vacuo to yield the desired product.
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3[F:23])=[N+:2]=[N-:3].[CH3:25][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:27]#[CH:28].BrC(C1C=CC=CC=1)C.C([Si](C)(C)C)#C>>[F:23][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]1[CH2:24][CH:4]([N:1]3[C:27]([CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:25])=[CH:28][N:3]=[N:2]3)[CH2:5][CH2:6][C:7]1=[C:15]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(C)c1ccccc1
Agent: C#C[Si](C)(C)C
Agent: CC(Br)c1ccccc1
Product: CC(c1ccccc1)c1cnnn1C1CCc2c(CC(=O)O)c3cccc(F)c3n2C1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and (1-methylprop-2-yn-1-yl)benzene prepared from (1-bromoethyl)benzene and ethynyltrimethylsilane. Separation of the resulting diastereoisomeric esters by flash chromatography using a gradient of 10-70% EA/Hex afforded 2 enantiomeric mixtures. The less polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralpak AD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. The resulting chiral esters (retention times=7.8 and 11.9 min) were hydrolyzed separately to afford EXAMPLE 32.1 and 32.2 respectively. The more polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% MeOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. The resulting chiral esters (retention times=9.6 and 10.5 min) were hydrolyzed separately to afford EXAMPLE 32.3 and 32.4 respectively. MS (+ESI) m/z: 419.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (500 g, 2.94 mol), ethane-1,2-diol (656 mL, 11.76 mol) and p-toluene sulfonic acid (10.06 g, 0.053 mol) was stirred at room temperature under nitrogen atmosphere for 3 days. After pouring in to diethyl ether (1 L), the mixture was washed with water (500 ml), dilute NaHCO3 solution (300 mL) followed by brine (500 mL). The organic layer was then dried (Na2SO4) filtered and concentrated to afford (590 g, 94% yield) the title compound as a colorless oil. Ref. J. Org. Chem. 1997, 62, 5284-5292.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:36](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[O:23][CH:36]=[N:25][N:24]=4)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4nnco4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 130 °C
Yield: 47.6 %

Procedure:
To a suspension of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)-phenyl)-1H-imidazole-4-carbohydrazide (198 mg, 0.395 mmol) and triethyl orthoformate (1 mL, 6.01 mmol) in 1 mL xylenes was added a catalytic amount of p-toluenesulfonic acid. The reaction was heated at 130° C. for 12 h. The reaction was cooled and the mixture was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 2-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole (96 mgs, 48%) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.12 (s, 1H), 8.11-8.10 (m, 1H), 7.97-7.94 (m, 1H), 7.85-7.82 (m, 1H), 7.77-7.75 (m, 1H), 7.67 (t, J=7.83 Hz, 1H), 7.61-7.58 (m, 4H), 7.48-7.45 (m, 1H), 7.29-7.27 (m, 2H), 3.09 (s, 3H); MS (ES): 511.4 [M+H]+ and 533.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nnc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3nnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (17 mg, 0.033 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., treated with sodium cyanoborohydride (4.1 mg, 0.065 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 10.4 mg (73%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.28 (s, 1H), 7.42 (s, 1H), 7.12 (m, 2H), 6.89 (m, 2H), 4.69 (s, 2H), 4.08 (s, 3H), 3.44 (s, 2H), 2.51 (m, 2H), 2.19 (s, 3H), 2.12 (m, 4H), 1.89 (m, 2H). Mass spec.: 437.14 (MH)+.