Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[CH2:12][OH:13].N1C=CC=CC=1.O1CCCC1.[CH3:25][C:26]1([CH3:36])[C@H:28]([CH:29]=[C:30]([CH3:32])[CH3:31])[C@H:27]1[C:33](Cl)=[O:34]>CCCCCC.C(OCC)(=O)C>[CH3:25][C:26]1([CH3:36])[C@H:28]([CH:29]=[C:30]([CH3:31])[CH3:32])[C@H:27]1[C:33]([O:13][CH2:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH3:9])=[C:5]([F:10])[C:4]=1[F:11])=[O:34]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a mixture solution of 1.78 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methanol, 0.87 g of pyridine and 20 ml of tetrahydrofuran, 2.06 g of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic chloride was added under ice-cooling and the mixture was stirred for 8 hours at room temperature. The reaction mixture was poured into about 100 ml of ice-water and extracted with each 100 ml of ethyl acetate twice. The combined ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 2.75 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)(O)[O-].[Na+].CN(C)C=O>CC(=O)CC>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([Cl:1])=[C:16]([Cl:17])[C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 71.3 %

Procedure:
A mixture of 5.1 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene. 3.5 g of ethyl bromoacetate and 5 g of sodium bicarbonate in 100 ml of 2-butanone containing 10 ml of dimethylformamide is stirred at 85°-90° for 16 hours. The mixture is concentrated at reduced pressure to remove the sovents and the residue is triturated with 50 g of ice-water. After 30 minutes the solid is filtered and air dried. Recrystallization from ether-hexane gives 4.7 g of ethyl[(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate as fine needles, mp 116.5°-117°.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.CCOC(C)=O.Cl>[Br:1][C:2]1[N:6]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(Br)n2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution (0.2 M) of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (from Step 1) in dry DMF was treated with sodium hydride (2 eq., 60% suspension in mineral oil) at 0° C. The reaction mixture was stirred at RT for 30 min then tert-butyl bromoacetate (3 eq.) was added. The reaction was heated to 50° C. for 1 h. After cooling, the solution was diluted with EtOAc and 1 N hydrochloric acid was added. The organic phase was washed with 1 N hydrochloric acid, saturated NaHCO3 solution and brine, dried over sodium sulfate and evaporated in vacuo to give a residue that was purified by flash chromatography (PE:EtOAc, 9:1) to afford the title compound (80%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.99 (s, 1H), 4.99 (s, 2H), 3.82 (s, 3H), 2.66-2.52 (m, 1H), 1.82-1.21 (m, 101H), 1.42 (s, 9H). MS (ES+) m/z: 456, 458 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([CH2:21][OH:22])=[CH:15][C:14]=1[O:23][CH2:24][CH2:25][CH:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31].C(N(CC)CC)C>ClCCl.O>[CH3:33][CH:26]([CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24][O:23][C:14]1[CH:15]=[C:16]([CH:21]=[O:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH:12]=[O:11]
Reactant: COc1cc(CO)c(OCCC(C)CCCC(C)C)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C=O)c(OCCC(C)CCCC(C)C)cc1C=O
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A 4 l four-neck flask with condenser, precision glass stirrer, internal thermometer and dropping funnel was initially charged with 176.8 g (1.39 mol) of oxalyl chloride and 450 ml of dichloromethane and cooled to −50° C. To this was added dropwise within 45 min a solution of 253.5 g (3.43 mol) of DMSO in 450 ml of dichloromethane. The mixture was stirred for a further 30 min. A solution of 183.8 g (0.57 mol) of 2,5-bis(hydroxymethyl)-1-(3,7-dimethyloctyl-oxy)-4-methoxybenzene in 500 ml of dichloromethane was then added dropwise over 2.5 h. After addition of 100 ml, a white precipitate formed. After addition of 400 ml of the solution, a further 500 ml of dichloromethane were added. After the addition had been completed, the mixture was stirred for a further 15 min, then 151.8 g (1.5 mol) of triethylamine were added dropwise within 1 h. The mixture was allowed to come to room temperature overnight, then 1500 ml of water were added and the mixture was stirred for 0.5 h. The phases were separated, and the aqueous phase was extracted with 2×300 ml of water. The combined organic phases were washed with 1×500 ml of water and dried over Na2SO4, and the solvent was removed under reduced pressure. 175.6 g (58% of theory) of the product were obtained, which was used for the next stage without further purification and without further characterization.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:25]C(=O)C)[CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([CH:17]=[C:18]([N:20]5[CH:24]=[CH:23][CH:22]=[N:21]5)[CH:19]=4)[NH2:25])[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccn3)c2)cn1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of the compound of Example 114 (4.0 g, 10.06 mmol) in ethanol (25 ml) was added 20% aqueous solution of NaOH (5 ml) and the reaction was heated at 100° C. for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 78% yield (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[C:34]#[C:33][CH2:32][OH:35]
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 3-chloro-4-iodobenzotrifluoride (5.00 g), copper(I) iodide (62.1 mg), triphenylphosphine (214 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (337 mg), propargyl alcohol (1.06 ml), diisopropylethylamine (11.4 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 17 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.05 g) as a brown solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([C:23]([OH:25])=O)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=[CH:7][N:6]=1)[CH3:4].[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH2:34])[CH3:33]>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH:34][C:23]([C:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:15]=[C:10]([N:9]2[C:5]([CH:3]([O:2][CH3:1])[CH3:4])=[N:6][CH:7]=[N:8]2)[CH:11]=1)=[O:25])[CH3:33]
Reactant: CC(N)c1cnccn1
Reactant: COC(C)c1ncnn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Product: COC(C)c1ncnn1-c1cc(C(=O)NC(C)c2cnccn2)cc(-c2ccc(C)cc2)c1

Procedure:
5-[5-(1-Methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-[5-(1-methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=443.
Reaction SMILES: CC(OC1C=CC(SC)=CC=1)(C)C(OCC)=O.ClC1C=CC=C(C(OO)=O)C=1.[CH3:29][C:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:36])[C:31](OCC)=[O:32].CC(C[AlH]CC(C)C)C>ClCCl>[CH3:36][C:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:29])[CH:31]=[O:32]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: CCOC(=O)C(C)(C)Oc1ccc(SC)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C=O)Oc1ccc(S(C)(=O)=O)cc1
Yield: 66 %

Procedure:
The necessary aldehyde was obtained by an analogous procedure to that described in connection with Example 19 starting from 4-(methylthio)phenol which was converted to ethyl 2-methyl-2-(4-(methylthio)phenoxy)propionate [oil, 20% yield; NMR: 1.25(3H,t J=7 Hz), 1.6(6H,s), 2.45(3H,s), 4.25(2H,q J=7 Hz), 6.75-7.2(4H,m)]. This ester was oxidised with m-chloroperbenzoic acid in dichloromethane at ambient temperature to give, after conventional work-up, ethyl 2-methyl-2-(4-methylsulphonylphenoxy)propionate [oil, slowly solidifying: 92% yield; NMR: 1.25(3H,q J=7 Hz), 1.65(6H,s), 3.0(3H,s), 4.25(2H,q J=7 Hz), 6.9-6.95(2H,m), 7.8-7.85(2H,m)] which was then reduced with DIBAL to give 2-methyl-2-(4-methylsulphonylphenoxy)propanal as a solid (66% yield); NMR: 1.5(6H,s), 3.05(3H,s), 6.9-7.0(2H,m), 7.8-7.9 (2H,m), 9.8(1H,s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[C:14](=[O:27])[CH2:13]3)[NH:8][C:7]=2[CH:28]=1.[NH3:29]>CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:29])=[NH:24])=[CH:25][CH:26]=4)[C:14](=[O:27])[CH2:13]3)[NH:8][C:7]=2[CH:28]=1
Reactant: N#Cc1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CN2CCC(Cc3nc4ccc(Cl)cc4[nH]3)CC2=O)cc1
Temperature: 0 °C

Procedure:
Hydrochloric acid is bubbled into an ice cooled solution of 4-[4-(6-chloro-1H-benzoimidazol-2-ylmethyl)-2-oxo-piperidin-1-ylmethyl]-benzonitrile (127 mg, 0.336 mmol) in 10 mL of methanol. The solution also contained 3Å molecular sieves. The reaction is stored at −30 for forty-eight hours. The methanol is condensed on the rotovap. Fresh methanol (15 mL) is added followed by a stream of ammonia gas. The reaction is heated to reflux for two and half hours. The reaction mixture is filtered at room temperature. Methanol is removed from the mother liquor. The resulting residue is purified by reverse phase HPLC (0-50% ACN/H2O). The product is isolated as a white solid with a melting point of 105-110° C. C21H22ClN5O MS m/z: 396,398. Anal. cald. for C21H22ClN5O.2C2HF3O2: C; 48.13; H, 3.88; N,11.22. Found: C, 45.05; H, 3.52; N, 9.89.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:21][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 10.0 g of 4-bromo-2-fluoro-1-nitrobenzene, 44.4 g of caesium carbonate and 100 ml of isopropanol is heated at 85° C. (bath) for 1 h 30, and then left to cool to ambient temperature. The mixture is concentrated under vacuum and the residue is taken up with 400 ml of water and 300 ml of ethyl acetate. The aqueous phase is extracted with 100 ml of ethyl acetate and the combined organic phases are washed twice with 200 ml of water. The organic phases are dried over magnesium sulfate and concentrated under vacuum, so as to obtain 11.59 g of crude 4-bromo-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow oil which crystallizes. TLC: Rf=0.52 (dichloromethane/heptane (1/1)).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([NH:14][CH2:15][CH2:16][OH:17])([CH3:13])[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH:11]([N:14]([CH2:15][CH2:16][OH:17])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)([CH3:13])[CH3:12]
Reactant: CC(C)NCCO
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CCO)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chlorobenzoxazole (23.04 g) was added dropwise to an ice-cooled solution of 2-(isopropylamino)ethanol (15.45 g) and triethylamine (30.3 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 30 minutes, then heated at reflux overnight before being cooled and evaporated. The residue was dissolved in dichloromethane (800 ml) and washed with saturated sodium bicarbonate solution (500 ml), water (3×1 l) brine (1 l), dried (MgSO4), filtered and evaporated. The title compound was obtained as an oil following chromatography on silica gel using 1.5% methanol-dichloromethane as solvent.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:13][C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C@@H:25]([CH2:26][OH:27])[CH2:24][C:23]([CH3:29])([CH3:28])[C:22]1=[O:30])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C@@H:25]([CH:26]=[O:27])[CH2:24][C:23]([CH3:28])([CH3:29])[C:22]1=[O:30])[CH3:12]
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of dimethylsulfoxide (0.93 mL, 12 mmol) in dichloromethane (40 mL) was cooled to −78° C. under nitrogen, and a solution of oxalyl chloride (0.820 mL, 9.4 mmol) in dichloromethane (3 mL) was added to it, over a 2 minute period. The reaction mixture was left stirring at −78° C. for 30 minutes. A solution of 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester (2.25 g, 7.5 mmol) in dichloromethane (20 mL) was added slowly. When the addition was complete, the reaction flask was stirred for 15 minutes at −78° C. Finally, triethylamine (2.1 mL, 15.0 mmol) was added slowly to the reaction flask; it was left to reach room temperature and stirred for an additional 15 minutes. It was then quenched by adding 20 mL of water and 20 mL of diethyl ether, and extracted with dichloromethane. The organic phase was dried over potassium carbonate and concentrated to dryness. The crude mixture was purified by chromatography on silica gel using hexane:ethyl acetate 2:1 as a solvent giving 1.5 g of 7-((R)-5-formyl-3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-heptanoic acid ethyl ester.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:15]1[C:14](=[C:23]3[C:18](=[CH:17][CH:16]=1)[CH:19]=[CH:20][CH:21]=[N:22]3)[NH:13][S:10]2(=[O:11])=[O:12]
Reactant: COc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)S(=O)(=O)Nc1c-2ccc2cccnc12
Yield: 4.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-5-methoxy-N-quinolin-8-yl-benzenesulfonamide (Intermediate 293) (450 mg, 1.36 mmol), t-butyl nitrite (0.24 ml, 2.04 mmol), AcOH (4.5 ml) and THF (4.5 ml) gave the title compound (19 mg, 4%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]([OH:17])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+](=[CH2:22])=[N-]>C1COCC1.CCOCC>[CH3:22][O:16][C:15](=[O:17])[C:14]#[C:13][C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C#Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid was dissolved in a mixture of THF and ether and treated with diazomethane until all acid was methylated. All solvent was removed and the resulting oil was purified by chromatography (10% ether/hexane) to give 30.5 g of 3-[3,5-bis(trifluoromethyl)phenyl]-propynoic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH:37]1([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@H:12]3[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]3)=[C:5]([NH:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCCC4)nc32)[C@H](O)[C@@H]1O
Yield: 40.9 %

Procedure:
The title compound was prepared by a similar method to example 6 from (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol), cyclopentanone (18 mg, 0.21 mmol), sodium triacetoxyborohydride (70 mg, 0.33 mmol) and acetic acid (0.14 ml, 0.25 mmol) to afford the title compound as a solid (48 mg). MS: 559 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)[N:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Yield: 20.7 %

Procedure:
To a mixture of the amidine of Step 1 (4.9 g, 16.95 mmol) and sodium bicarbonate (2.85 g, 33.9 mmol) in isopropanol (300 ml), 3-bromo-1,1,1-trifluoroacetone (2.65 ml, 25.4 mmol) was added. After heating at 80–85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (9 g) was purified by chromatography (silica gel, ethyl acetate/isopropanol/ammonium hydroxide 95/5/0.5) to give 2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.4 g, 21%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3: C, 51.12; H, 4.02; N, 10.52. Found: C, 51.43; H, 3.96; N, 10.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([O:31]CC=C)=[O:30])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>ClCCl.Cl.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:35])[CH2:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([OH:31])=[O:30])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C=CCOC(=O)c1c(CCCC(=O)c2ccc(-c3ccc(OC)cc3)cc2)ccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(=O)CCCc3ccc4ccccc4c3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
A solution of Example 11F (200 mg, 0.431 mmol) in dichloromethane (5 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium (43 mg, 0.0375 mmol), triphenylphosphine (19.6 mg, 0.075 mmol), piperidine (0.0447 mL, 0.452 mmol), and allowed to stir at room temperature for 30 minutes. The reaction mixture was diluted with 0.5 N HCl, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, concentrated, and purified on silica gel with 10% methanol/CH2Cl2 to provide 197 mg (100%) of the desired compound as an white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+:19]>O1CCCC1.CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]([O-:16])=[O:15])[N:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[K+:19]
Reactant: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 1-[(6-bromopyridin-2-yl)methyl]-1H-1,2,3-triazole-4-carboxylate (840 mg, 2.83 mmol) in tetrahydrofuran (6.0 mL) and methanol (3.0 mL) was added 1 M aqueous potassium hydroxide (3.11 mL, 3.11 mmol). The solution was stirred at room temperature for 3 h, during which time it became a white slurry. The solvent was evaporated to afford the title salt as a colorless solid that was carried forward without purification. LRMS (APCI) calc'd for C9H8BrN4O2 [M+H]+: 283, Found: 283.