Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[C:27]([CH3:37])[C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[N:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:30]=[N:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[C:27]([CH3:37])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Br)cnc1OC1CCOC1
Product: Cc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cnc1OC1CCOC1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-5-bromo-3-methyl-2-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 29) in analogy to Example 1a): MS (ISP): 481.3 and 483.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[C:4]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ncccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 2-ethoxycarbonyl-3-nitropyridine (0.5 g, 2.5 mmoL, 1 eq.) in 20 mL of methanol and 5 mL of water was added lithium hydroxide (0.2 g, 4.5 mmoL, 1.8 eq.) and the mixture stirred for 16 hours at ambient temperature. The reaction was concentrated and 50 mL of 1N KOH was were added. The solution was washed with 25 mL of ethyl actetate, acidified with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extractions were dried over sodium sulfate and concentrated to give 2-carboxy-3-nitropyridine as a yellow solid (0.4 g, 95% yield).
Reaction SMILES: [C:1]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([OH:35])=[C:29]([CH:34]=1)[C:30]([O:32]C)=[O:31])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].Cl>[OH-].[Na+].CO>[C:1]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([OH:35])=[C:29]([CH:34]=1)[C:30]([OH:32])=[O:31])(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22]
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)Nc1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A mixture of methyl 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoate (0.1 g, 0.2 mmol) in 2N NaOH (5 mL) and CH3OH (2.5 mL) was stirred (50° C., 24 h). The mixture was cooled and acidified to pH 1 with 2N aq. HCl, then extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (CH2Cl2-EtOAc, 20:1 to 1:1) to afford 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoic acid as a white solid (90.4 mg, yield: 90%). Mass calculated for C29H37NO4=463.61. found: [M+H]+=464.3.
Reaction SMILES: B(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]([O:15]C)=[C:10]([CH2:12][CH2:13]O)[CH:11]=1>C(Cl)Cl>[Br:2][CH2:13][CH2:12][C:10]1[CH:11]=[C:6]([Cl:5])[C:7]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][C:9]=1[OH:15]
Reactant: COc1cc(C2CCCCC2)c(Cl)cc1CCO
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(C2CCCCC2)c(Cl)cc1CCBr
Reaction time: 5 h

Procedure:
20 ml of boron tribromide are added slowly at 0° with stirring to 11 g of 2-(5-chloro-4-cyclohexyl-2- methoxyphenyl)-ethanol in 300 ml of dry methylene chloride. The mixture is then stirred for 5 hours at 22°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:18]3[CH2:19][O:20]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([CH3:15])=[CH:9][CH:8]=3
Reactant: Cc1ccc2[nH]c3ccc(C)cc3c2c1
Reactant: ClCC1CO1
Product: Cc1ccc2c(c1)c1cc(C)ccc1n2CC1CO1
Yield: 69 %

Procedure:
Following Representative Procedure 1, 3,6-dimethyl carbazole (Beyer et al., O. J. Org. Chem. 2003, 68, 2209-2215) was added to epichlorohydrin in 69% yield.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:3]1>CCOC(C)=O.[Pd]>[F:1][C:2]1([F:17])[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(OCc1ccccc1)C1CCC(F)(F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CCC(F)(F)C1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a stirred solution of Intermediate 332B (0.07 g, 0.291 mmol) in EtOAc (2 mL) was added 10% Pd/C (0.016 g, 0.015 mmol) and the resulting mixture was stirred for 16 h under an atmosphere of hydrogen (15 psi, balloon pressure). The reaction mixture was filtered through a pad of CELITE® and the filter cake was washed with EtOAc. The combined filtrate was concentrated under reduced pressure to afford Intermediate 332C as a colorless oil (0.035 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.41 (br. s., 1H), 3.04-2.94 (m, 1H), 2.39-2.23 (m, 2H), 2.20-2.01 (m, 3H), 1.95-1.84 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].CO.C1COCC1.[BH4-].[Na+]>[Cl-].[Na+].O>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38 mmol) in 1:1 MeOH/THF (90 mL) was added NaBH4 (1.6 g, 42 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with brine, and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous layer was extracted with Et2O (3×100 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which was used in the next step without further purification or characterization.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)[CH2:10][C:9]1=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:23]([O:22][C:20]([NH:19][C:13]1([CH:11]2[CH2:10][CH2:9][NH:8][CH2:12]2)[CH2:14][C:15]([F:17])([F:18])[CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)(F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CCNC2)CC(F)(F)C1
Reaction time: 2 h

Procedure:
A 317 mg (0.87 mmol) portion of 1-benzyl-3-[3-(tert-butoxycarbonylamino)-1,1-difluorocyclobutan-3-yl]pyrrolidine (Isomer F1) was dissolved in 20 ml of ethanol to which was subsequently added 350 mg of 10% palladium on carbon catalyst. The thus prepared mixture was stirred for 2 hours under irradiation of light and under a hydrogen pressure of 4 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under a reduced pressure to give 239 mg (quantitative) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:23]([O:26][C:27]1[CH:28]=[C:29]([C:33]2[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]=2[C:40]([CH3:57])([CH3:56])[CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([OH:55])=[O:54])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1>[C:23]([O:26][C:27]1[CH:28]=[C:29]([C:33]2[O:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]=2[C:40]([CH3:57])([CH3:56])[CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:1][CH3:2])=[O:54])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24]
Reactant: CCO
Reactant: CC(=O)Oc1cccc(C2=C(C(C)(C)COCCCCCCCCCCC(=O)O)C(C)(C)CO2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCCCCCOCC(C)(C)C1=C(c2cccc(OC(C)=O)c2)OCC1(C)C

Procedure:
To a solution having ethanol (34 mg, 0.74 mmol), triphenyl phosphine (204 mg, 0.78 mmol) and 5-(3-acetoxyphenyl)-4-(13-carboxy-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (22)) (126 mg, 0.258 mmol) dissolved in anhydrous THF (1.0 mL) in a nitrogen stream at room temperature and stirred, diethyl azodicarboxylate (135 mg, 0.77 mmol) dissolved in anhydrous THF (0.5 mL), was added, followed by stirring for 20 minutes. After completion of the reaction, the reaction mixture was put into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was put into a silica gel column and developed with a mixed solvent of hexane and ethyl acetate (20:1 to 10:1), whereby 5-(3-acetoxyphenyl)-4-(13-ethoxycarbonyl-1,1-dimethyl-3-oxatridecan-1-yl)-3,3-dimethyl-2,3-dihydrofuran (compound (24)) was obtained as a colorless oil in an amount of 111 mg in a yield of 83.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[CH2:18][CH:17]3[CH:15]([C:16]3([C:20]3[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:14]2)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH:17]3[CH:15]([C:16]3([C:20]3[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(Cl)c(Cl)c3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccc(Cl)c(Cl)c3)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.1 %

Procedure:
To a solution of N-(3-{3-[3-(3,4-dichlorophenyl)propanoyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 119, 30 mg, 0.06 mmol) in anhydrous tetrahydrofuran (1 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.12 ml, 0.12 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.12 ml), sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to give a colourless oil. This was purified by preparative HPLC (condition 8) to afford the title compound as a pale yellow oil (5.2 mg, 19%).
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[C:11](=[O:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CC(O)C.O>[CH2:1]([NH:8][CH2:9][CH2:10][CH:11]([OH:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C(=O)/C=C/NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(OC)C(O)CCNCc1ccccc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (4.71 g, 20 mmol) in a mixture of 2-Propanol (60 ml) and Water (4.80 ml) was added sodium borohydride (3.03 g, 80 mmol) in portions at 20-25° C., the mixture was stirred overnight. Quenched with 5N HCl to pH 7 (approx 10 ml), pH adjusted to 8-9 with 5N NaOH, diluted with MTBE (100 ml) and brine (50 ml). Organic phase was dried (MgSO4), evaporated, separated on a column with ethyl acetate-MeOH mixture 4:1, fractions collected to give 4-(benzylamino)-1,1-dimethoxybutan-2-ol (3.55 g, 14.83 mmol, 74.2% yield), colorless oil.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]([C:16]#[N:17])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:18]([CH:6]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:16]#[N:17])[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CC(C#N)(c2ccccn2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccn2)CC(N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
To a solution of 3-cyano-3-(pyridin-2-yl)cyclobutyl methanesulfonate (4.008 g, 15.89 mmol) in dry DMF (20 mL) was added sodium azide (2.066 g, 31.8 mmol), and the mixture was stirred in an oil bath at 90° C. for 48 hours under a N2 atmosphere. The reaction was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with water and concentrated under vacuum. The residue was chromatographed on silica gel, eluting with 40% EtOAc/hexane to afford the title compound, a 3:1 mixture of geometrical isomers, as a colourless oil m/z 200 MH+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:35])[C:20]4[C:21]([O:27][C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:22](Cl)[N:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH:41]=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:35])[C:20]4[C:21]([O:27][C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:22]([N:40]3[CH:39]=[N:38][N:37]=[CH:41]3)[N:23]=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-n5cnnc5)nccc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 185.3 %

Procedure:
To a microwave vial were added {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (6.7 mg, 0.0133 mmol), 1,2,4-triazole (4.6 mg, 0.067 mmol), cesium carbonate (8.7 mg, 0.0266 mmol), copper(I) iodide (0.8 mg, 0.004 mmol) and NMP (0.5 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. The reaction was repeated with {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (20 mg, 0.04 mmol), 1,2,4-triazole (13.8 mg, 0.2 mmol), cesium carbonate (26.1 mg, 0.08 mmol), copper(I) iodide (2.4 mg, 0.012 mmol) and NMP (0.7 mL). The reaction mixtures were combined and partitioned between EtOAc and water. The organic phase was extracted further with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (13.2 mg, 46%) as a colourless gum. LCMS (Method H): RT=3.84 min, [M+H]+=536.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][N:9]2[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC(=O)N2
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC(=O)N2
Yield: 74 %

Procedure:
Reaction of intermediate 10, 3-benzyloxy-4,8-dioxo-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidine-2-carboxylic acid ethyl ester, (0.543 g, 1.58 mmol) with trifluoroacetic acid (20 ml) as described in the preparation of intermediate 5 gave 0.296 g (74% yield) of the title ester as white crystals; mp 282° C. (dec) (ethyl acetate). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.26 (3H, t, J=7.1 Hz, CH3), 2.66 (2H, t, J=6.8 Hz, CH2), 4.13 (2H, t, J=6.8 Hz, CH2), 4.29 (2H, q, J=7.1 Hz, OCH2), 9.94 (1H, s, NH), 11.19 (1H, broad s, OH). HRMS (FAB POS) calculated for C10H12N3O5 [M+H+]: 254.077696. found: 254.078383.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)c(C)c1Br
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(C)c1Br
Reaction time: 12 h

Procedure:
3-Bromo-2,4-dimethylbenzoic acid (6.50 g, 28.4 mmol), in THF (50 mL) was treated with borane tetrahydrofuran complex (42.6 mL, 42.6 mmol) and stirred for 12 h. Analysis by LC indicated that reaction had gone to completion. The solution was concentrated to dryness, redissolved in DCM, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting (3-bromo-2,4-dimethylphenyl)methanol was used for the next step with out further purification. 1H-NMR (CDCl3, 500 MHz), δ 7.227 (d, J=7.5 Hz, 1H), 7.122 (d, J=7.5 Hz, 1H), 4.730 (m, 2H), 2.492 (s, 3H), 2.456 (s, 3H).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:24](NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]C.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCC.CC(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=C(C(OC)=O)C=C(C=1)C(OC)=O.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCCCCCCC.C(NC1C=C(C(OC)=O)C=C(C=1)C(OC)=O)CCCCCCCCCCCCCCCCCC>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCNc1cc(C(=O)OC)cc(C(=O)OC)c1
Reactant: CCCCCCCCCNc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: CCCCCCCCCCC(C)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: CCCCCCCCCCCCCCCCCCCNc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: CCCCCCCCCCCCCCCCCCNc1cc(C(=O)OC)cc(C(=O)OC)c1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)OC)cc(C(=O)OC)c1

Procedure:
Similarly, 1-bromooctane, 1-bromononane, 1-bromodecane, 1-bromoundecane, 1-bromododecane, 2-bromododecane, 1-bromotridecane, 1-bromotetradecane, 1-bromopentadecane, 1-bromo-14-methylpentadecane, 1-bromoheptadecane, 1-bromooctadecane, and 1-bromononadecane gave respectively, dimethyl 5-octylaminoisophthalate, dimethyl 5-nonylaminoisophthalate, dimethyl 5-decylaminoisophthalate, dimethyl 5-undecylaminoisophthalate, dimethyl 5-dodecylaminoisophthalate, dimethyl 5-(1-methylundecylamino)isophthalate, dimethyl 5-tridecylaminoisophthalate, dimethyl 5-tetradecylaminoisophthalate, dimethyl 5-pentadecylaminoisophthalate, dimethyl 5(14-methylpentadecyl)aminoisophthalate, dimethyl 5-heptadecylaminoisophthalate, dimethyl 5-octadecylaminoisophthalate, and dimethyl 5-nonadecylaminoisophthalate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C:19]4([OH:26])[CH2:24][CH:23]5C[CH:20]4C[CH2:22]5)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:27])[N:3]=1.C(C1(O)CCC[O:32]C1)#C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][C:19]4([OH:26])[CH2:24][CH2:23][CH2:22][O:32][CH2:20]4)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:27])[N:3]=1
Reactant: Cc1nc2ccc(C#CC3(O)CC4CCC3C4)cc2n1-c1ncnc(N)n1
Reactant: C#CC1(O)CCCOC1
Product: Cc1nc2ccc(C#CC3(O)CCCOC3)cc2n1-c1ncnc(N)n1

Procedure:
The title compound was prepared by the procedure described for 2-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)bicyclo[2.2.1]heptan-2-ol, by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol (1-b) with 3-ethynyltetrahydro-2H-pyran-3-ol. The title product, 3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)tetrahydro-2H-pyran-3-ol was purified by silica gel chromatography: 1H NMR (400 MHz, DMSO) delta 1.66-1.78 (m, 4H), 1.97-2.05 (m, 1H), 3.01 (s, 3H), 3.36-3.71 (m, 4H), 7.47 (dd, J=1.6, 8.4 Hz, 1H), 7.71 (dd, J=0.4, 8.4 Hz, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.48 (dd, J=0.4, 1.6 Hz, 1H), 8.71 (s, 1H); LC-MS: m/z=+350.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:29].[Na+]>COCCOC.O.CCOC(C)=O>[I:29][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)Oc1ccc(Oc2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In a 300 mL round bottom flask, 6.92 g (25.63 mmol) 4-(4-(trifluoromethoxy)phenoxy)aniline was dissolved in 40 mL DME and cooled to 0° C. in a brine/ice bath. Using a dropping funnel, 10 equivalents aqueous H2SO4 (10N aqueous) were slowly added to the DME solution, immediately creating a salt suspension. The suspension was stirred at 0° C. for 10 minutes. Then, a solution of 1.5 equivalents sodium nitrite (2.65 g, 38.45 mmol) in 20 mL water was dropped slowly into the suspension while keeping the temperature below 5° C. After adding the sodium nitrite, the mixture was stirred at 0° C. for 30 minutes. Then, an aqueous solution of 3 equivalents sodium iodide was dropped slowly into the mixture. LC/MS showed the reaction was complete. The reaction mixture was diluted with 400 mL EtOAc and washed with 700 mL water and then 700 mL 1M sodium bisulfate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was then chromatographed by combiflash using a 330 gram silica column and a gradient of EtOAc (15% max) in hexane to provide 6.53 g of 1-iodo-4-(4-(trifluoromethoxy)-phenoxy)benzene (67%, white solid). m/z 380, 1H NMR (CHCl3): 7.67-7.61 (m, 2H), 7.23-7.16 (m, 2H), 7.04-6.97 (m, 2H), 6.81-6.75 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:14][OH:15])=[C:12]=[CH2:13])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:14][O:15][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]=[CH2:13])=[CH:16][CH:17]=1
Reactant: C=C=C(CO)CCOCc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1

Procedure:
Combine 5-(p-methoxybenzyloxy)-3-hydroxymethylpent-1,2-diene (25.0 mmol) and benzoyl chloride (25.0 mmol) in pyridine (25 mL) and stir for 16 hours. Partition the reaction mixture between diethyl ether and water, wash the organic layer 3X with saturated sodium bicarbonate and 1X with water, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]Br.[CH3:11][NH2:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][CH2:11][NH2:12]
Reactant: Cc1cccc(CCBr)c1
Reactant: CN
Product: Cc1cccc(CCCN)c1
Temperature: 80 °C

Procedure:
A mixture of 3-methylphenethyl bromide (2.22 g) and 33% ethanolic methylamine solution (30 ml) was heated in a bomb at 80° C. for 16 hours and evaporated. The residue was partitioned between water and dichloromethane and the organic layer dried over MgSO4 and evaporated. The residue was purified by 421 chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil, 0.44 g (27%), which was used directly in the preparation of Example 21 without characterisation.