Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]#[N:14])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(C(N)=O)cc1CCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(C#N)cc1CCCCCl
Temperature: 90 °C

Procedure:
A modification of the method described in Part E of Examples 1-4 was used to treat 5-(4-hydroxybutyl)-1-methyl-1H-pyrazole-3-carboxamide (42.9 g, 218 mmol) with phosphorous oxychloride (130 mL). The reaction was heated for two hours at 90° C. before cooling to 0° C. and pouring into ice water. The mixture was adjusted to pH 12 with the addition of 2 N aqueous sodium carbonate and 50% aqueous sodium hydroxide. The mixture was extracted with chloroform. The combined extracts were passed through a layer of silica gel (eluting first with chloroform and then with ethyl acetate to provide 23.0 g of 5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile as a dark oil that was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:22])[CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:5]=[N:4][CH:3]=1.[CH3:23][N:24]1[C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[CH2:11][CH:10]([OH:22])[CH2:9][NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]3[N:26]=[CH:25][N:24]([CH3:23])[C:28]=3[CH:29]=2)[N:7]=1
Reactant: OC(CNc1cncc(Cl)n1)CN1CCc2ccccc2C1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3cncc(NCC(O)CN4CCc5ccccc5C4)n3)cc21
Yield: 12.9 %

Procedure:
To a flask containing 1-((6-chloropyrazin-2-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 0.6 mmol) in dioxane:H2O (3:1) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (200 mg, 0.8 mmol), Cs2CO3 (2 equiv.) and Pd(dppfCl2) (10 mol %). The mixture was degassed 3 times with N2 before being heated at 110 deg C. overnight. Upon completion, the solvents were evaporated and residue purified with prep-HPLC to afford the desired target compound (32 mg, yield 13%). 1H NMR (400 MHz, MeOD): δ 8.27 (s, 1H), 8.18 (d, J=9.6 Hz, 2H), 7.99 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.09-6.99 (m, 3H), 6.87 (d, J=7.6 Hz, 1H), 4.21 (br.s, 1H), 3.86 (s, 3H), 3.84-3.54 (m, 4H), 2.89-2.66 (m, 6H). LCMS (m/z): 415.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>C(O)CCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: NCCCO
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCNCCCO)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of 2-chloro-5-[2-chloroethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.15 g) and N,N-diisopropylethylamine (0.50 ml) in 1-butanol (4 ml) was added sodium iodide (0.06 g) and 3-aminopropan-1-ol (0.09 ml). The reaction vessel was sealed and the mixture heated at 110° C. for 24 h. The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN/0.1% AcONH4 aqueous) to give 2-chloro-5-[2-[(3-hydroxypropyl)amino]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentration under reduced pressure. Recrystalisation from isohexane/isopropanol gave the title compound as a white solid (0.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
4-Hydroxybenzaldehyde (10.0 g, 81.9 mmol) and 2-methyl benzyl bromide (40.0 g, 98.3 mmol) were dissolved in dimethylformamide (100 mL), and cesium carbonate (18.2 g, 123 mmol) was added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. Water was added to the reaction solution, and the organic matter was extracted with diethyl ether. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 60:40 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (19.2 g, yield: 103%).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@H](O)CN
Solvent: CCCCO
Product: Cc1nc(NC[C@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 μL of S-(+)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>C(#N)C>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 80.0 ml of acetonitrile, 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 25 ml of acetonitrile and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, 200 ml of ice water were poured into the reaction mixture to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.90 g (81.6%). Purity: 97.9%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>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]>[CH3:30][O:29][C:26]1[CH:25]=[C:24]([O:31][CH3:32])[CH:23]=[CH:28][C:27]=1[NH:11][C:7]1[N:8]=[CH:9][C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[N:5]2[N:6]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccc(C(F)(F)F)c4)n3n2)c(OC)c1
Yield: 46.6 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 1-bromo-2,4-dimethoxybenzene (0.019 g, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave N-(2,4-dimethoxyphenyl)-5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (0.018 g) as a yellow solid. 1H NMR (CDCl3): δ8.95 (s, 1H), 8.82 (s, 1H), 8.61 (d, J=7.3 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.72-7.59 (m, 2H), 7.45 (s, 1H), 6.61-6.53 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.62 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Br:24])=[C:12]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=1)C1C=CC=CC=1.[OH-].[Na+].CCOCC>C1COCC1.O>[CH2:17]([O:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]=1[Br:24])[C:9]([OH:33])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)c(Br)c(OCc2ccccc2)c1
Yield: 80.7 %

Procedure:
To a stirred solution of 3,5-bis-benzyloxy-4-bromo-benzoic acid benzyl ester (200a) (225 g, 0.45 mol) in THF (400 mL) and H2O (500 mL) was added NaOH (89.4 g, 2.24 mol) in one portion. The mixture was refluxed for 4 hr. TLC (EtOAc/petroleum ether=1/4) showed that the reaction was complete. Et2O (100 mL) was added to the mixture and the organic layer was separated. The aqueous layer was acidified with conc. HCl, and the resulting solid was filtered and dried in vacuo to give the title compound (150 g, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 4H), 7.39(t, 4H), 7.31 (m, 4H), 5.27(s, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([F:19])[CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C([O:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.N1C=CC=CC=1.CO.C(OCC)(=O)C.CO.CS(C)=O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 54) (100 mg, 0.208 mmol) (intermediate) was dissolved in dichloromethane (0.5 mL) and pyridine (0.5 mL), and then treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.031 mL, 0.218 mmol). The mixture was stirred for 2 h. LCMS showed starting material remaining so more 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.021 mL, 0.146 mmol) was added to the reaction mixture and stirred for 1.5 hr. LCMS showed starting material remaining so a further portion of 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.015 mL, 0.104 mmol) was added to the reaction and stirred for 1.25 h. The reaction mixture was concentrated under a stream of nitrogen to leave a yellow residue, which was dissolved in methanol (1 mL) and potassium carbonate (86 mg, 0.624 mmol) was added to the solution. The reaction mixture was heated to 40° C. for 1 hand then neutralised with 2M HCl and concetrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed three times with water (50 mL) and once with brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to leave a yellow residue. The sample was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (60 mg, 51%). LCMS (System A) RT=1.04 min, ES+ve m/z 481/483 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[C:6]([NH2:8])[CH:7]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[C:18]([CH3:34])=[CH:17][N:16]=1.CS(O)(=O)=O>CC(O)C>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[C:6]([NH:8][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])[C:18]([CH3:34])=[CH:17][N:16]=2)[CH:7]=1
Reactant: Cc1cc(OC(C)C)c(N)cc1Br
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1Br

Procedure:
5-Bromo-2-isopropoxy-4-methyl-phenylamine from the previous step (537 mg, 2.20 mmol) and 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine (Intermediate 1, 652 mg, 2.00 mmol) in the presence of methanesulfonic acid (0.143 mL) in 4 mL 2-propanol are condensed at 140° C. for 30 min in a sealed tube under microwave irradiation. Following workup, N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine is obtained. MS (ES+): 535.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:23][C:24]([F:37])([F:36])[C:25]([NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[O:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH2:30][CH2:29][CH2:28][NH:27][C:25](=[O:26])[C:24]([F:37])([F:36])[F:23])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CC3CCC(C2)N3)cc1
Reactant: CS(=O)(=O)OCCCNC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1C2C=C(c3ccc(Cl)cc3)CC1CC2)C(F)(F)F
Yield: 46.6 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (1.0 g, 4.55 mmol), triethylamine (0.70 mL, 5.01 mmol), and methanesulfonic acid 3-(2,2,2-trifluoro-acetylamino)-propyl ester (1.13 g, 4.55 mmol) in ethanol (20 mL) were refluxed for 15 hours. The mix was concentrated, diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×150 mL). Combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded racemic N-{3-[3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-en-8-yl]-propyl}-2,2,2-trifluoro-acetamide (0.79 g, 46.5%) as a light brown oil which had the following properties: 1H NMR CDCl3 δ: 10.00 (brd s, 1H), 7.27 (s, 4H), 6.23 (d, J=5.4 Hz, 1H), 3.69-3.43 (m, 4H), 2.82-2.71 (m, 3H), 2.19-1.88 (m, 4H), 1.77-1.57 (m, 3H). IR (CHCl3): 3157, 2949, 2880, 1714, 1544, 1494, 1466, 1446, 1403, 1377, 1346, 1315, 1245, 1162, 1094, 1012, 973, 937, 817, (cm−1). Analysis calculated for C18H20ClF3N2O.3/4 H2O: C, 55.96; H, 5.61; N, 7.25; Found: C, 55.80; H, 5.09; N, 7.33.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Na].[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13](/[N:27]=[N:28]/N2CCCC2)[CH:12]=1>>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:13](=[CH:12][C:11]=1[O:10][CH3:9])[NH:27][N:28]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]2=[O:26]
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)cc1/N=N/N1CCCC1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1n[nH]c2cc(OC)c(OC)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a 100 mL round bottom flask charged with a magnetic stir bar was added TFA (30 mL). The flask was cooled to 0° C. in an ice bath and ethyl 3-{4,5-dimethoxy-2-[(E)-pyrrolidin-1-yldiazenyl]phenyl}-3-oxopropanoate sodium salt (4.03 g, 10.83 mmol) (Method 3) was added to the reaction mixture in portions over 10 minutes. The mixture was stirred at this temperature for an additional 2 h before being poured over 0° C. ice-water (˜300 mL). The desired product precipitated from the mixture and was collected via vacuum filtration using a Buchner funnel. The solid was rinsed with water (1×100 mL) and diethyl ether (1×100 mL) to yield 1.55 g (51%) of the title compound as an off white solid that was used without further purification. 1H NMR: 13.70 (s, NH, 1H), 7.39 (s, 1H), 7.00 (s, 1H), 4.30 (q, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 1.30 (t, 3H); m/z 279.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=1[N+:12]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:5]=1[NH2:12]
Reactant: C=Cc1ccc(C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)OC)c(N)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 2-nitro-4-vinyl-benzoic acid methyl ester (820 mg, 3.96 mmol) in MeOH (15 mL) was shaken under H2 (0.1 bar) in the presence of Pd/C (10%, 0.2 g) at 50° C. for 5 h. After cooling to r.t., the reaction mixture was filtered and the solvent was removed in vacuo to provide the title product (680 mg, 96%) which was used in the next step without further purification. ESI-MS: m/z 180.1 [M+H]+, rt 5.13 min
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH:29]=[O:30])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCC1CCC(C2CCC(OCCC=O)CC2)CC1
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
DMSO in an amount of 2.13 ml (0.03 mol) was added dropwise to a mixture of 1.74 ml (0.02 mol) of oxalic acid chloride and 40 ml of dichloromethane at -50° C. and stirred for 10 min. While keeping inside of the reaction system at -60°C., this solution was added dropwise with a solution of 2.82 g (0.01 mol) of the 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in the second stage and dissolved in 20 ml of dichloromethane and stirred for 1 hour. To this solution was added 14 ml of triethylamine, temperature of the solution was returned to a room temperature, stirred for 15 min, and the solution was added with 80 ml of an aqueous solution saturated with ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. After the magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue was subjected to a silica gel column chromatography (eluate: toluene/ethylacetate (9/1)) to obtain 1.93 g of a crude 4-(4-propylcyclohexyl)-(3-oxopropyoxy) cyclohexane. This product was recrystallized from 12 ml of ethanol to obtain 1.3 g (yield 46%) of 4-(4-propylcyclohexyl)-(3-oxopropyloxy)cyclohexane.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\[N:8](C)[CH3:9])[CH2:3][CH2:2]1.C(O)(=O)C.C(N)=[NH:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:8]=[CH:9][N:25]=2)[CH2:3][CH2:2]1
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Reactant: N=CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cncnc2CC2CC2)n1
Reaction time: 18 h
Yield: 33.6 %

Procedure:
A solution of (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(methylsulfanyl)pyrimidin-4-yl]but-3-en-2-one (3) (200 mg, 0.721 mmol), formamidine acetate (75 mg, 0.721 mmol), and K2CO3 (299 mg, 2.163 mmol) in DMF (6 mL) was stirred at 120° C. for 30 minutes, followed by stifling at rt for 18 hours. The reaction was partitioned between water and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [10 g SNAP column, 30% EtOAc/heptane to 100% EtOAc] to obtain the desired product as a white solid (62.5 mg, 29.4% yield). The desired product contained a small amount of an unknown by-product and was carried on to the next step without further purification. MS (ES+): m/z=259.3 (100) [MH+2]. HPLC: tR=1.77 minutes over 3 minutes. Purity: 87.5% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:27][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CC(C)CCN
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and isopentylamine (0.18 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give light yellow solid (0.49 g, 82%): GCMS m/z 393.00 (M+). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 7.09 (s, 1H), 6.31 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.27 (m, 2H), 3.19 (m, 2H), 1.71 (m, 1H), 1.57 (m, 2H), 1.31 (m, 3H), 0.96 (m, 6H).