Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:12]2=[O:27])[CH2:9][CH2:8][C@@H:7]([NH:28]C(=O)OC(C)(C)C)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:6][C@H:7]([NH2:28])[CH2:8][CH2:9][C@@H:10]1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:12]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (100 g, 0.205 mol) in dichloromethane (400 ml) was added TFA (400 ml) at −20° C. The reaction solution was stirred at room temperature for 2 h. The solvent and most of TFA were removed under reduced pressure, and the residue was diluted with dichloromethane (2 L) and aqueous K2CO3 solution (2 L). The pH was adjusted to 10 with 1N HCl. The aqueous layer was extracted with dichloromethane (3×1 L). The combined organic layer was dried over Na2SO4, and concentrated to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate as an oil (81 g, 100% yield). This amine was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18]>C1COCC1>[CH3:15][O:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:19][CH2:16][CH2:17][CH3:18])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNc1nc2ccc(OC)cc2cc1C=O
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 101.6 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.50 g, 6.77 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added propan-1-amine (5.6 mL, 67.7 mmol) and the reaction mixture was stirred for 1.5 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 6-methoxy-2-(propylamino)quinoline-3-carbaldehyde SLA 28172 as an orange solid (1.68 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:40])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (97.2 mg) in tetrahydrofuran (5 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (100 mg, 72%) as white powder.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20]C(C)([O-])C.[K+].IC>O1CCCC1>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.0 g) in dry tetrahydrofuran (120 ml) was added potassium tert-butoxide (1.94 g). The mixture was stirred at room temperature for 15 mins, iodomethane (1.08 ml) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated potassium carbonate solution (150 ml) was added, and mixture was extracted twice with 150 ml portions of ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated. Trituration with diethyl ether/pentane gave 3.47 g (82%) of product. Recrystallization from methanol gave the analytical sample, mp 176.5°-177.5° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=1
Reactant: Cc1sc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: C#CCCO
Product: Cc1sc2cc(C#CCCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 13.1, the Trifluoro-methanesulfonic acid 2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester was reacted with 3-butyn-1-ol to yield the 4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-but-3-yn-1-ol as brown oil, MS: 360 (M+).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31](C(OC(C)(C)C)=O)[CH2:30]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C@@H:4]([C:5]([NH:24][C:25]2[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=2[CH2:27][CH2:28][C@H:29]2[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:41])([F:43])[F:42])[NH:31][CH2:30]2)=[O:7])[NH:1][C:37]([O:36][CH3:35])=[O:44])=[CH:17][C:18]=1[F:23]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1cncc(F)c1)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1cncc(F)c1)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=732 (M+H)+.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C@H:11]2[N:16]([CH2:17][C:18]([O:20]C)=[O:19])[C:15](=[O:22])[C:14]3([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23]3)[N:13]([CH3:29])[CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1>C1COCC1.O>[F:10][C:8]1[CH:7]=[C:6]([C@H:11]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[O:22])[C:14]3([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23]3)[N:13]([CH3:29])[CH2:12]2)[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C)C[C@H]1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.2 mg (0.30 mmol) lithium hydroxide were added to 75 mg (0.20 mmol) (R)-methyl 2-(3-(3,5-difluorophenyl)-1-methyl-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)acetate in 5 ml THF and 1 ml of water. The reaction mixture was stirred for 2 h at RT and then MeOH was distilled off. The residue was made neutral with a 0.1M hydrochloric acid solution and evaporated to dryness.
Reaction SMILES: [CH:1]([C:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)=O.C(N)CCC.[N+:19]([CH3:22])([O-:21])=[O:20]>C1(C)C=CC=CC=1>[C:8]1([N:5]2[CH2:6][CH:7]=[C:3]([CH:1]=[CH:22][N+:19]([O-:21])=[O:20])[NH:4]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=CC1=NN(c2ccccc2)CC1
Solvent: CCCCN
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=CC1=CCN(c2ccccc2)N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 3-formyl-1-phenyl-2-pyrazoline (3.48 g), n-butylamine (0.2 ml) and nitromethane (10 ml) was stirred at 100° C. for 1 hour, then was cooled to room temperature. The resultant dark red crystalline mass was dissolved in toluene and was eluted down a silica column with toluene. The major orange fraction was evaporated to dryness under reduced pressure and the residue was recrystallised from ethanol to give a 59% yield of dark red micro crystals (MP 150° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[O:4][C:5]2[C:6](=[C:8]([C:13]([O-:15])=O)[CH:9]=[C:10]([Cl:12])[CH:11]=2)[N:7]=1.[Li+].Cl.Cl.[NH2:20][C@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:22][C@@H:21]([NH:20][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:5]4[O:4][C:3]([N:2]([CH3:1])[CH3:16])=[N:7][C:6]=34)=[O:15])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH2:24]2
Reactant: CN(C)c1nc2c(C(=O)[O-])cc(Cl)cc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Li+]
Product: CN(C)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cc(Cl)cc2o1

Procedure:
Following general procedure GP-C1, lithium 2-(dimethylamino)-6-chlorobenzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-6-chloro-2-(dimethylamino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH2:33][C@@H:32]([CH2:39]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][CH2:37][CH2:38][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC[C@@H]1CN2CCC[C@H]2CO1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:10](=O)[C@H:9]([CH:12]([CH3:14])[CH3:13])[NH:8][C:7]1=[O:15].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:10][C@H:9]([CH:12]([CH3:14])[CH3:13])[NH:8][C:7]1=[O:15]
Reactant: COc1ccc(CN2C(=O)N[C@@H](C(C)C)C2=O)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@H](C(C)C)NC2=O)c(OC)c1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
To a solution of (S)-3-(2,4-dimethoxybenzyl)-5-isopropyl-imidazolidine-2,4-dione (0.550 g, 1.88 mmol) in THF (50 mL) at ambient temperature was added bis(2-methoxyethoxy)aluminumhydride (Red-Al) (2.69 ml, 9.41 mmol) and the resultant mixture heated at reflux for 1 hour. The reaction mixture was cooled to 0° C. and sodium sulfate decahydrate was added portion-wise. The resultant thick emulsion was diluted with THF and filtered through a pad of Celite. The filtrate was concentrated to a clear oil. Purification of the crude material by column chromatography, eluting with 1-5% MeOH/dichloromethane, afforded (S)-1-(2,4-dimethoxybenzyl)-4-isopropylimidazolidin-2-one as a colorless solid (0.329 g, 63%). LCMS (APCI+) m/z 279 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:17]O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1.O=S(Cl)[Cl:25]>C1COCC1>[C:19]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[C:9]([CH2:17][Cl:25])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=2)[N:5]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CO)c3ccccc3c2)n1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cc(CCl)c3ccccc3c2)n1
Yield: 88.5 %

Procedure:
To [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]methanol (1.6 g, 5.4 mmol) in THF (20 mL) was added SOCl2 (3.0 g, 25 mmol). The mixture was heated at reflux for 3 h and then concentrated under pressure to yield crude 3-t-butyl-1-[4-(chloromethyl)naphthalen-2-yl]-1H-pyrazol-5-amine (1.5 g), which was used for the next reaction without further purification. MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][C:41]2=[O:46])(=O)=O)=CC=1>C(#N)C>[F:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]3=[O:46])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccc(C2CCCNC2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCCN1c1ccccc1CCN1CCCC(c2cccc(F)c2)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
3-(3-Fluorophenyl)piperidine hydrochloride a2-4 (432 mg, 2 mmol, 1 eq) and K2CO3 (829 mg, 6 mmol, 3 eq) are added to a solution 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3 (747 mg, 2 mmol, 1 eq) in acetonitrile (10 ml). The reaction mixture is stirred at 85° C. overnight, then filtered and the filtrate is condensed under reduced pressure. The residue is purified by basic reverse phase chromatography over silicagel (gradient CH3CN/H2O/NH4OH from 50/50/0.1 to 80/20/0.1) to afford 472 mg (1.24 mmol) of 1-(2-{2-[3-(3-fluorophenyl)piperidin-1-yl]ethyl}phenyl)piperidin-2-one as a free base. Oxalic acid (111 mg, 1.24 mmol, 1 eq) is added to the residue dissolved in diethylether. The precipitate obtained is filtered and dried under vacuum to afford 517 mg of 1-(2-{2-[3-(3-fluorophenyl)piperidin-1-yl]ethyl}phenyl)piperidin-2-one oxalate 24.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].O>C1COCC1>[CH3:28][O:29][C:30]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:39][CH2:40][C@H:41]([C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=[CH2:2])[CH2:46][CH2:45]3)[CH2:42][CH2:43]2)[CH2:34][CH2:33]1)=[O:31]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](C(=O)OC)CC3)CC2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A mixture of 30.2 g (74.7 mmol) of methyltriphenylphosphonium iodide and 400 ml of THF was cooled to -50° C. To this mixture was added 9.23 g (82.2 mmol) of t-BuOK and the resulting mixture was stirred for one hour. To this mixture was added dropwise a solution of 20.0 g (59.8 mmol) of trans-4-(trans-4-(trans-4-formylcyclohexyl)cyclohexyl)cyclohexane carboxylic acid methyl ester in 500 ml of THF, while maintaining a temperature at below -50° C. After the dropwise addition, the reaction temperature was gradually allowed to rise up to room temperature. After 300 ml of water was added to the reaction mixture, the reaction mixture was extracted with 1000 ml of toluene. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to a silica gel column chromatography (a developing solvent: heptane) to give 9.90 g of crude trans-4-(trans-4-(trans-4-ethenylcyclohexyl)cyclohexyl)-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25]
Reactant: ClCCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Reactant: CC1CCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 1-({2-[3-chloro-4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidine i71 (0.12 g, 0.32 mmol, 1 eq) and 2-methylpyrrolidine (63 PI, 0.65 mmol, 2 eq) in acetonitrile (10 ml) is treated with sodium iodide (5 mg, 0.03 mmol, 0.1 eq) and stirred at room temperature overnight. The mixture is then washed with water, dried over magnesium sulfate, and concentrated to give the crude product. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 90:10:0.1) gives 75 mg of 1-[(2-{3-chloro-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]piperidine 124 as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(O)(=O)C.[O-:18][C:19]#[N:20].[K+]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([NH:10][C:19]([NH2:20])=[O:18])[CH:11]=[CH:12][CH:13]=1
Reactant: N#C[O-]
Reactant: COCCCOc1cccc(N)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COCCCOc1cccc(NC(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a flask containing 3-(3-methoxypropoxy)aniline (11A) (2.00 g, 11.04 mmol) was charged a 100 mL solution of 80% glacial acetic acid and 20% water. This mixture was chilled to 0° C. A solution of potassium cyanate (1.34 g, 16.56 mmol) in 5 mL of water was slowly added portion-wise to the reaction mixture. The reaction was then stirred for about 1 hour at RT. The glacial acetic acid was then removed under reduced pressure. The resulting white solid residue was then rinsed with copious amounts of water then dried under vacuum to give title compound 11B (1.70 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-1.95 (m, 2H) 3.24 (s, 3H) 3.46 (t, J=6.32 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 5.82 (br. s., 2H) 6.45 (dd, J=8.08, 2.27 Hz, 1H) 6.81 (d, J=7.33 Hz, 1H) 7.00-7.17 (m, 2H) 8.49 (s, 1H). ESI-MS: m/z 225.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:20])[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.Br[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH:20][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][NH:26]3)[CH3:19])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2
Reactant: CC(N)c1cc2c(Cl)cccc2nc1-c1ccccn1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc2c(Cl)cccc2nc1-c1ccccn1
Temperature: 110 °C
Yield: 68.6 %

Procedure:
Added 1-(5-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (103 mg, 363 μmol), 6-bromopurine (72 mg, 363 μmol), n-butanol (2 mL) and DIPEA (190 μl, 1089 μmol) to a 10 mL flask. Submerged in an oil bath and heated at 110° C. for 40 h. The reaction mixture was concentrated on the rotavap to ˜0.5 mL of solvent, diluted with DCM, and chromatographed with 0-15% MeOH:DCM on 12 g silica gel column. The desired fractions were combined and concentrated to an oil which was dissolved in ACN:H2O and lyophilized to obtained 100 mg (69%) of a light tan solid. LC-MS (+esi, M+H+=402.1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])[C:2]1C=CC=CC=1.[CH:40](N)(C)C>>[CH2:34]([CH:26]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[C:25]([NH:24][CH:15]1[CH:14]2[C:13](=[O:39])[CH2:12][CH:11]([C:9](=[O:10])[NH:8][CH:1]([CH3:40])[CH3:2])[CH2:23][N:21]3[C:22]2=[C:18]([CH:19]=[CH:20]3)[CH2:17][CH2:16]1)=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)N
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NC(C)C)C3
Yield: 60 %

Procedure:
The compound of Example 3g was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using isopropylamine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.55 mmol/g) and purification by RP-HPLC provided 15.5 mg (60%) of the title compound as a white powder. MS (M+H)+=485.5.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])C.Cl.[CH:18]([NH:21]N)([CH3:20])[CH3:19]>>[CH3:19][CH:18]([N:21]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][CH:4]=[N:2]1)[CH3:20]
Reactant: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)NN
Agent: Cl
Product: CC(C)n1ncnc1-c1ccccc1[N+](=O)[O-]

Procedure:
N-[(Dimethylamino)methylene]-2-nitrobenzamide, prepared in Example 90, and isopropylhydrazine hydrochloric acid salt were reacted as in Example 90 to give 1-(2-propyl)-5-(2-nitrophenyl)-1,2,4-triazole, which was reduced and coupled with CMI similarly to give the fumaric acid salt of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(2-propyl-1H-1,2,4-triazol-5-yl)aniline.