Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:29]3[CH2:30][CH2:31][N:26]([CH2:25][C:21]4[O:20][CH:24]=[CH:23][CH:22]=4)[CH2:27][CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: c1coc(CN2CCNCC2)c1
Product: O=C(N1CCN(Cc2ccco2)CC1)N1Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
The title compound of Example 105 is reacted with the product of Example 63 by the method of Example 4. Following chromatographic separation, the title product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(OC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 20 %

Procedure:
The titled compound was prepared in 20% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethoxy-benzene according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.63 (d, 2 H, J=8.0 Hz), 7.43 (m, 4 H), 7.37 (s br, 1 H), 7.18 (d, 2 H, J=8.0 Hz), 6.81 (s br, 1 H), 4.36 (AB2, 2 H,Δv=12,Jab=72 Hz), 4.01 (s br, 1 H), 1.83 (m, 1 H), 1.30 (m, 8 H); MS m/e 490.97 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[O:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2)[Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1Cc2cccc(O)c2C1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cccc(O[Si](C)(C)C(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-hydroxy-2-methyl-1-indanone (6) (10.2 g, 37 mmol) and imidazole (3.02 g, 44 mmol) dissolved in DMF (200 ml) was added tert-butyldimethylchlorosilane (6.11 g, 41 mmol) in DMF (50 ml). The reaction mixture was stirred overnight at room temperature and treated with water (200 ml) and extracted with diethylether (2×200 ml). The combined organic phases were washed with aqueos NH4Cl (300 ml), brine (100 ml) and dried over sodium sulfate. Evaporation gave (7) as a yellow oil which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([N:8]([CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:9]([N:8]([CH2:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:27])[CH:15]=1)[C:4]1[C:3]([CH3:28])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Reactant: OB(O)c1ccc(F)cc1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(F)cc2)c1C

Procedure:
Prepared from ethyl (4-{[(3-bromo-2-methylphenyl)(butyl)amino]methyl}-2-methylphenoxy)acetate and 4-fluorophenylboronic acid using the procedure described for Example 25 (Method A).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:20](=[O:21])[O:22][CH2:23][CH3:24])=[CH:11][CH:12]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-[3-(trifluoromethyl)phenoxy]benzenamine (6.0 grams; 0.21 mol) and pyridine (50 ml) were placed in a glass reaction vessel equipped with a mechanical stirrer and placed in an ice bath. Ethyl chloroformate (5 ml) was added dropwise to the reaction mixture with continuous stirring. Stirring was continued overnight and the mixture was then poured into ice water (500 ml). The precipitate was washed with water and dried. It was found to have a melting point of 74°-75.5° C. In fraud analysis confirmed the identity of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)=[CH:4][CH:3]=1.[C:31]([Cu])#[N:32]>CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]#[N:32])=[CH:3][CH:4]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Brc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc([C@@H]2CN3CCC[C@@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Temperature: 150 °C

Procedure:
To a sealed tube reaction vessel were added cis-6-(4-bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (0.21 mmol), CuCN (5.2 equiv.), and DMF (1.7 M). The tube was purged with nitrogen, sealed, and heated at 150° C. overnight. The reaction mixture was cooled to rt, diluted with aqueous NaCN, and extracted with diethyl ether. The organic layer was washed with water, satd. aq. NaHCO3, and brine, dried (Na2CO3), and concentrated to give the crude product. Chromatographic purification (NH3 in MeOH/CH2Cl2) followed by reverse-phase HPLC gave the desired product as a mixture with the 6-trans isomer (7% combined yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COc1ccccc1
Product: COc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The subtitle compound was prepared by the method of example 9 step (i) using 4-bromobenzenesulfonyl chloride and anisole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.Cl.C([O:19][C:20](=[O:23])[CH2:21][NH2:22])(C)(C)C>>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][CH2:21][C:20]([OH:23])=[O:19])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: Cl
Product: COc1cnc2c(NCC(=O)O)ccnc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
In a 100 mL round bottom flask were dissolved 8-chloro-3-methoxy-1,5-naphthyridine (5.00 g, 25.7 mmol) and glycine tert-butyl ester hydrochloride (17.2 g, 103 mmol) in 50 mL of 2-BuOH then stirred and heated at 100° C. After 5 h the solvent based on LC-MS was removed by reduced pressure and then the solid was dissolved in 200 mL of HCl 1N and stirred at 60° C. overnight. After 10 h the reaction mixture based on LC-MS was cooled down to rt then 0° C. and the desired acid precipitate. Filtered the solid (3.97 g) then evaporated the aqueous solution and triturated in 75 mL of H2O at 0° C. then filter again and washed with 25 mL of H2O at 0° C. (1.58 g) to afforded total 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (5.55 g, 80.1% yield) as a tan solid. MS m/z=234.1 [M+1]+. Calc'd for C11H11N3O3: 233.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[O:16]=[C:17]1[CH2:21][CH2:20][S:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[C:18]1[C:17](=[O:16])[CH2:21][CH2:20][S:19]1
Reactant: O=C1CCSC1
Reactant: COC(=O)C(C)c1ccc(C=O)c(Cl)c1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c(Cl)c1
Yield: 21.4 %

Procedure:
By using methyl 2-(3-chloro-4-formylphenyl)propionate (170 mg) obtained in Example 62 and 3-oxothiolane (115 mg), the title compound (50 mg, 21%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)cccc2n1
Yield: 69 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3,4-Dichlorobenzyl Chloride (72.3 mg; 0.37 mmol) to obtain 55.8 mg. (69% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.50 (s, 1H), 7.61 (m, 3H), 7.35 (dd, J=8.4, 1.4 Hz, 1H), 7.16 (m, 4H), 3.59 (s, 2H), 3.02 (br d, J=10.8 Hz, 3H), 2.90 (m, 3H), 2.31 (m, 2H). ESIMS+403.5 m/z
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17]Cl)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCCC1
Temperature: 70 °C

Procedure:
To a solution of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline (3.1 g, 0.0108 mole) NaI (2.4 g, 0.0162 mole), and potassium carbonate (7.5 g, 0.054 mole in DMF (100 mL), was added piperidine (6.4 mL, 0.065 mole). The mixture was heated to 70° C. for 16 h. The mixture was concentrated in vacuo then diluted with H2O (100 mL). The mixture was extracted with EtOAc (3×50 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 335 (M+1). Mass Calc'd for C18H23ClN2O2: 334.1.
Reaction SMILES: [CH2:1]([S:7][C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:17]O>C(O)(=O)C>[CH2:1]([S:7]([C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1c(O)cc(C)oc1=O
Reactant: OO
Solvent: CC(=O)O
Product: CCCCCCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
3-n-Hexylthio-4-hydroxy-6-methyl-2-pyrone (9.1 g., 0.040 mol), 30% hydrogen peroxide (4.85 g., 0.0440 mol), and 40 ml. glacial acetic acid were combined and stirred at room temperature over night. The clear solution was poured into 200 ml. ice water and the resulting white precipitate was collected and dried in vacuo: m.p. 59°-60°C. The solid was recrystallized from n-hexane to recover 8.0 g. (77%) of the desired compound as white crystalline platelets, m.p. 59°-60°C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(cc(-c3cncs3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.15 g, 0.47 mmol, from Example 62, Step 2) and 5-(tributylstannyl)-1,3-thiazole (0.17 g, 0.47 mmol, Synthonix) in toluene (9.0 mL) was degassed using a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol) was added and the mixture was heated to 110° C. for 5 hours. Solvent was removed in vacuo and the residue was dissolved in MeCN, filtered, and purified by flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes. Yield: (67 mg, 44%). LCMS (M+H)+: 325.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5](F)=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1ccc(Nc2ccnc(Nc3ccc(F)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to produce N2,N4-bis(3-chloro-4-fluorophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 9.48 (s, 1H), 8.17 (d, 1H, J=4.1 Hz), 7.94-7.90 (m, 2H), 7.73-7.67 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (t, 1H, J=8.8 Hz), 7.26 (t, 1H, J=8.8 Hz); LCMS: ret. time: 27.83 min.; purity: 99%; MS (m/e): 386 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9-[3-(tetrahydro-3-furanyl)propyl]-9H-purin-6-amine (110 mg, 0.315 mmol) in methanol (9 ml) at room temperature was added 4M HCl in dioxane (1.89 ml). The pale yellow solution was stirred at room temperature for 18 hrs and then neutralised with 2M sodium hydroxide solution and evaporated to give a white solid. Trituration with water and filtration afforded the title compound as a cream solid (74 mg).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc2c1SCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.1 %

Procedure:
Under argon and with stirring, 1.5 g (9.02 mmol) of 8-thiochromanol are dissolved in 5 cm3 of dimethylformamide (DMF). 3.74 g (27.06 mmol) of K2CO3 are added and then 1.94 g (9.92 mmol) of ethyl 4-bromobutyrate dissolved in 6 cm3 of DMF are added dropwise. The mixture is heated at 60° C. for 5 hours. The DMF is evaporated off. The residue is taken up in H2O. The product is extracted with CH2Cl2 and then dried over MgSO4. Purification over a silica column (eluant: ether/petroleum ether 3: 7) yields 2.48 g of the title compound (white solid).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>C(O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCO
Product: COc1ccc(CNc2cncc(Cl)n2)cc1
Temperature: 115 °C
Yield: 85.1 %

Procedure:
To a stirred solution of 2,6-dichloropyrazine (25 g, 0.167 mol) and ethanol (120 mL) in a sealed tube is added 4-methoxybenzylamine (68.6 g, 0.5 mol). The mixture is heated to 115° C. for 12 h and cooled. The white solid is removed by filtration and the filtrate evaporated. The residue is dissolved in ethyl acetate and washed successively with 2 M sodium hydroxide, water and aqueous sodium chloride. The organics are dried (magnesium sulfate), filtered, and evaporated to give (6-chloropyrazin-2-yl)[(4-methoxyphenyl) methyl]amine (35.5 g), a white solid.
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[S:10]/[C:9](=[N:11]\[C:12](=[O:22])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])/[N:8]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:7]=1[CH3:30])(=[O:5])[CH3:4]>O1CCCC1>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([CH:18]=1)[C:12](/[N:11]=[C:9]1\[S:10][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[C:7]([CH3:30])[N:8]\1[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)=[O:22]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)=O)c(C)n1CC1CCCCO1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)O)c(C)n1CC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of methyllithium (Aldrich, 1.6 M in diethyl ether, 0.41 mL, 0.66 mmol) was added slowly a solution of Example 253 (0.14 g, 0.33 mmol) in tetrahydrofuran (3 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes and was allowed to reach room temperature. The reaction mixture was quenched with water (6 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in CH2Cl2) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.21-1.36 (m, 1H), 1.41-1.48 (m, 3H), 1.49 (s, 3H) 1.50 (s, 3H), 1.57-1.67 (m, 1H), 1.74-1.85 (m, 1H), 2.42 (s, 3H), 3.68-3.89 (m, 3H), 3.79 (s, 3H), 3.92-4.09 (m, 1H), 4.17-4.38 (m, 1H), 5.60 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 439 (M+H)+; Anal. Calculated for C21H27ClN2O4S: C, 57.46; H, 6.20; N, 6.38. Found: C, 57.44; H, 5.88; N, 6.06.
Reaction SMILES: Cl[CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]=[O:4].[O:15]=[C:16]([CH3:23])/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH2:5]([C@H:2]1[C@@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([CH3:23])[O:15][C:3]1=[O:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(Cl)C=O
Reactant: COC(=O)/C=C/C(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC[C@@H]1C(=O)OC(C)=C[C@@H]1C(=O)OC
Yield: 71 %

Procedure:
Prepared according to the general procedure from 2-chlorododecanal and (E)-methyl 4-oxopent-2-enoate using 0.5 mol % 1 as the catalyst in 71% yield as a single diastereomer (white solid). [α]D20 (c 1.20, CHCl3)=+204.8; mp=40-42° C.; 1H NMR (400 MHz, CDCl3) δ 5.09 (dd, 1H, J=6.3, 1.1 Hz), 3.68 (s, 3H), 3.30 (dt, 1H, J=6.3, 1.0 Hz), 2.66 (dd, 1H, J=7.0, 6.3 Hz), 1.90 (t, 3H, J=1.0 Hz), 1.35-1.24 (m, 18H), 0.86 (t, 3H, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 171.4, 169.8, 152.3, 98.4, 52.5, 41.5, 40.6, 32.0, 29.7, 29.7, 29.5, 29.5, 27.3, 27.2, 22.8, 18.9, 14.3; IR (thin film) ν 3062, 2925, 2854, 1777, 1740, 1463, 1436, 1383, 1167, 1142 cm−1; HRMS (ESI) calcd for C18H30O4 [M+Na]+ 333.1996, found 333.2021; >99% ee (3S,4S)-isomer as determined by HPLC(OD-H, 20:1 hexanes/i-PrOH), tr (3S,4S)=6.7 min, tr (3R,4R)=6.0 min.
Reaction SMILES: [CH3:1][NH:2][S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4].Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH2:29]([O:28][C:26]([N:2]([CH3:1])[S:3](=[O:24])([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:7]([N+:21]([O-:23])=[O:22])[CH:6]=1)=[O:4])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)Cl
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCOC(=O)N(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N(CCC)CCC)c([N+](=O)[O-])c1

Procedure:
A mixture of 4.5 g (0.0125 mol) N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide, 3.4 g (0.025 mol) n-butyl chloroformate, 3.5 g (0.25 mol) potassium carbonate and 50 ml dimethoxyethane was reacted to produce N1 -butoxycarbonyl-N1 -methyl-3,5-dinitro-N4,N4 -dipropylsulfanilamide by a procedure similar to that of Example 4. The product was a yellow-orange solid having a melting point of 99°-101°C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[CH:20]=[C:19]([OH:22])[CH:18]=[CH:17]4)=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[CH:20]=[C:19]([O:22][C:36](=[O:37])[NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:18]=[CH:17]4)=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2cccc(-c3[nH]c(-c4ccccc4)nc3-c3ccncc3)c2c1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Oc1ccc2cccc(-c3[nH]c(-c4ccccc4)nc3-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 8-(2-phenyl-5-pyridin-4-yl-3H-imidazol-4-yl)-naphthalen-2-ol (31 mg, 0.085 mmol), phenyl isocyanate (11 mg, 0.094 mmol) and triethylamine (17.8 μL, 12.9 mg, 0.128 mmol) in N,N-dimethylformamide (1.5 mL) is stirred for 2 hours at room temperature. Preparative LCMS afforded phenyl-carbamic acid 8-(2-phenyl-5-pyridin-4-yl-3H-imidazol-4-yl)-naphthalen-2-yl ester (17 mg, 41% yield); 1H NMR 400 Hz (CD3OD) δ 7.01 (m, 2H), 7.25 (m, 4H), 7.39 (m, 5H), 7.45 (dd, J=2.28, 8.86 Hz, 1H), 7.53 (m, 3H), 7.72 (dd, J=7.14, 8.23 Hz, 1H), 7.83 (d, J=6.02 Hz, 1H), 7.90 (d, J=6.99 Hz, 2H), 8.10 (m, 3H), 8.19 (d, J=8.29 Hz, 1H), 8.43 (d, J=7.00 Hz, 2H); MS m/z (M+H+) 483.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N+:3]=1[O-:14]
Reactant: NC(N)=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloropyridine-5-carbonitrile (7.01 g) was dissolved in acetonitrile (70 mL), and urea hydrogen peroxide addition compound (10 g) was added. Trifluoroacetic anhydride was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to aqueous sodium thiosulfate solution and the mixture was extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give 2-chloro-5-cyanopyridine 1-oxide (0.779 g) as a white solid.