Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([F:16])[C:12]([F:15])([F:14])[F:13].CCCCCC>C(Cl)Cl>[C:2]1([C:1]([C:11]([F:16])([F:10])[C:12]([F:15])([F:14])[F:13])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: O=C(Cl)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1ccccc1)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
Under protective gas, 35 g (0.25 mol) of benzoyl chloride in 150 ml of CH2Cl2 are initially introduced at about -20° C. into a round-bottomed flask. 67 g (0.27 mol) of pentafluoroethyl iodide are first condensed in and 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide are then metered in. The reaction mixture is subsequently stirred at 0° C. for 5 hours more. After addition of the same volume of hexane to the reaction mixture, 2 phases are formed. After phase separation, the lower phase is carefully extracted using hexane; the combined hexane phases are concentrated and distilled under reduced pressure. 20.8 g (58% yield) of pentafluoroethyl phenyl ketone of b.p. 76-77/40 mbar are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][NH:20][C:21]1[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=1>CC(C)=O.CN(C=O)C>[CH3:19][N:20]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: CNc1ccccc1C
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1N(C)c1nc(=O)c2cccnc2s1
Yield: 80.6 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.613 mg (10.24 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride, two droplets of DMF, 780 mg of ammonium thiocyanate, 15 ml of acetone, 1.21 g of N-methyl-o-toluidine and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 2.28 g of 2-(N-methyl-N-(2-methylphenyl)amino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>>[ClH:2].[C:11]1([CH3:15])[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[CH:8]=2)[CH:10]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: Cc1cccc(-c2cc(Nc3ccc(CCO)cc3)c3c(n2)CCC3)c1
Yield: 75.8 %

Procedure:
Following General Procedure A2, 4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.075 g, 0.27 mmol) was reacted with 4-aminophenethyl alcohol (0.044 g, 0.32 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.078 g, 100%) as a brown solid. MW=380.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.88 (s, 1H), 9.75 (s, 1H), 7.56 (s, 1H), 7.52-7.44 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 7.38-7.26 (m, 4H), 6.93 (s, 1H), 3.64 (t, J=6.9, 2H), 3.59 (t, J=6.9 Hz, 1H), 3.15 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.39 (m, 3H), 2.24 (quin, J=7.6, 2H); APCI MS m/z 345 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 61.8 %

Procedure:
2-Bromo-4-fluoro-6-nitro-phenol 2b (24.7 g, 104.7 mmol) and potassium carbonate (17.34 g, 125.6 mmol) were dissolved in 300 mL of acetone followed by addition of iodomethane (9.8 mL, 157.1 mmol). The reaction mixture was heated to reflux at 80° C. for 22 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and diluted with 200 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 4 N hydrochloric acid and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-5-fluoro-2-methoxy-3-nitro-benzene 2c (16.18 g, yield 61.8%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[CH3:33][N:34]1[CH:38]=[C:37]([CH:39]=O)[CH:36]=[N:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:55]CCl>>[ClH:55].[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:39][C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: Cn1cc(C=O)cn1
Reactant: ClCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: Cn1cc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cn1
Reaction time: 4 h

Procedure:
to a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.2 g) and 1-methyl-4-formyl-1H-pyrazole (0.05 g) in dichloromethane (2 ml) under nitrogen atmosphere was added sodium triacetoxyborohydride (151 mg) at room temperature. After 4 hours, the reaction mixture was evaporated under reduced pressure, and ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate solution (10 ml) were added to the residue. The organic layer was separated and washed wit brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (50:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride (154 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:30]=[C:26]([C:27]([OH:29])=[O:28])[C:25]([OH:31])=[CH:24][CH:23]=1>>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH:20]=2)=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: O=C(O)c1cc(I)ccc1O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)c(C(=O)O)c2)c1)c1ccccc1
Yield: 45 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 5-iodosalicyclic acid were reacted to give the title compound as a light tan solid (28 mg, 45%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[OH:3][N:1]=[C:8]([C:7]([CH2:6][Br:5])=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.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>[Cl:16][C:15]1[C:10]2[N:9]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:8]=[C:7]([C:37]3[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1csc(CC#N)c1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A mixture of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (84.0 mg) obtained in Step A of Example 93, tetrakis(triphenylphosphine)palladium(0) (13.0 mg) and 2M aqueous sodium carbonate solution (0.200 mL) in DMF (2 mL) was stirred under microwave irradiation at 130° C. for 1.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (70.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(C)=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:29][CH:28]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccc(F)cc1
Temperature: 50 °C

Procedure:
To a solution of methyl 2-hydroxy-5-(4-morpholinylcarbonyl)benzoate (may be prepared as described in Description 108, 270 mg, 1.02 mmol) in acetone (3 ml) was added cesium carbonate (663 mg, 2.04 mmol) and 4-fluorobenzyl bromide (0.16 ml, 1.32 mmol). The mixture was heated at 50° C. for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (15 ml) and water (5 ml). The organic layer was dried and the solvent removed in vacuo and the residue purified by column chromatography (silicon, 4:1 ethyl acetate/cyclohexane) to give the title compound as a yellow gum. 96 mg.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[C@H:5]([OH:26])[C@@H:4]1[OH:27].CO[C:30](OC)([CH3:32])[CH3:31].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH3:31][C:30]1([CH3:32])[O:26][C@H:5]2[C@H:6]([NH:8][C:9]3[CH:14]=[C:13]([NH:15][C:16]4[C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[CH:19]=[CH:18][CH:17]=4)[N:12]=[CH:11][N:10]=3)[CH2:7][C@H:3]([CH2:2][OH:1])[C@H:4]2[O:27]1
Reactant: OC[C@H]1C[C@@H](Nc2cc(Nc3cccc4c3CCCC4)ncn2)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Nc4cccc5c4CCCC5)ncn3)[C@@H]2O1
Reaction time: 55 h
Yield: 92.3 %

Procedure:
To a stirred solution of (1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentane-1,2-diol (70.0 mg, 0.19 mmol) in acetone (5.00 mL) was added 2,2-dimethoxypropane (0.21 mL, 1.70 mmol) and pyridinium p-toluenesulfonate (57.0 mg, 0.23 mmol), and the mixture was stirred for 55 h. The reaction mixture was quenched by addition of saturated NaHCO3 solution (50.0 mL) and then extracted with ethyl acetate (3×50.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by flash chromatography (2 to 10% Methanol/DCM) to afford the title compound (72.0 mg, 85%) as a light yellow amorphous solid. LC/MS: Rt=1.59 min, ES+ 411.3 (AA standard).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1C(N)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30].O.C(=O)([O-])O.[Na+].C(#[N:39])C>>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:30][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[C:3]([NH2:39])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: CC#N
Reactant: NCc1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(NCc3cccs3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 80 °C

Procedure:
To a magnetically stirred solution 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 1.5 g) in acetonitrile (10 ml) in a Shlenk tube was added (2-thienylmethyl)amine (1.53 g). The Shlenk tube was sealed and the reaction mixture heated at 80° C. for 24 h. The water was added to the reaction followed by an aqueous saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic phase dried over Na2SO4, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel (25 g) eluting with DCM/methanol (95:5) to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine (1.493 g) as a cream coloured powder. LC/MS: MH+409.12, [M−H]− 407.17, Rt 2.70 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:14]([C:17](O)=[O:18])[N:15]([CH3:16])[C:9]=2[N:8]=[C:7]1[CH3:26].Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:41])[CH2:39][OH:40])[CH2:34][CH2:33]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[C:14]([C:17]([NH:31][CH:32]3[CH2:33][CH2:34][N:35]([C:38](=[O:41])[CH2:39][OH:40])[CH2:36][CH2:37]3)=[O:18])[N:15]([CH3:16])[C:9]=2[N:8]=[C:7]1[CH3:26]
Reactant: NC1CCN(C(=O)CO)CC1
Reactant: Cc1nc2c(c(OCC(F)(F)F)c(C(=O)O)n2C)c(=O)n1Cc1cccc(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(c(OCC(F)(F)F)c(C(=O)NC3CCN(C(=O)CO)CC3)n2C)c(=O)n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.8 %

Procedure:
A mixture of the compound of Reference Example 47 (84 mg, 0.19 mmol), 1N aqueous sodium hydroxide solution (2 mL), THF (2 mL) and ethanol (2 mL) was stirred at 60° C. for 3 hr. The reaction mixture was neutralized with 2N hydrochloric acid (1 mL), and concentrated under reduced pressure, and the precipitate was filtered and washed with water to give 3-(3-fluorobenzyl)-2,7-dimethyl-4-oxo-5-(2,2,2-trifluoroethoxy)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid as a powder (59 mg, 75%). A mixture of 3-(3-fluorobenzyl)-2,7-dimethyl-4-oxo-5-(2,2,2-trifluoroethoxy)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (59 mg, 0.14 mmol), 2-(4-aminopiperidin-1-yl)-2-oxoethanol hydrochloride (35 mg, 0.18 mmol), HOBt (28 mg, 0.18 mmol), WSCD (35 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluate, hexane:ethyl acetate=1:1→0:100), and recrystallized from ethyl acetate-hexane to give the title compound (13 mg, 17%) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C.O1CCCC1>O>[C:35]([N:16]1[CH2:17][CH2:18][C:19]2[C:10]3[C:11]([S:13][C:14]=2[CH2:15]1)=[N:12][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]=3[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(C)=O)C3
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture of the compound obtained in Example 5A (2.00 g), acetyl chloride (0.19 g), triethylamine (0.37 ml) and tetrahydrofuran (10 ml) was stirred under ice cooling conditions for 3 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1, v/v) to yield ethyl 7-acetyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (0.65 g, 60%) as an amorphous solid having a melting point of 72 to 75° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.C(=O)([O-])O.[Na+]>[CH3:15][S:16]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:18])=[O:17]
Reactant: N#CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(C#N)CC1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A stirred mixture of 1-(hydroxymethyl)cyclopropanecarbonitrile (24.30 mmol, 2.36 g) in dichloromethane (30 mL) was treated with triethylamine (48.6 mmol, 6.83 mL, 4.92 g) and portionwise with methanesulfonyl chloride (31.6 mmol, 2.445 mL, 3.62 g) keeping the reaction mixture at 0° C. The solution was allowed to stir for 1 hour then diluted with saturated sodium hydrogencarbonate and extracted with 10% methanol/dichloromethane (×3). The organic layers were combined and concentrated under reduced pressure to give the intermediate (1-cyanocyclopropyl)methyl methanesulfonate (3.77 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:18]([CH2:32][C:33]#[N:34])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[C:33]([CH2:32][C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][C@H:19]1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:34]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CC[C@H]1CC[C@H](N)C[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (22.0 mg, 0.102 mmol), benzyl [(1R,2R,5S)-5-amino-2-(cyanomethyl)cyclohexyl]carbamate (32 mg, 0.11 mmol) and triethylamine (35.7 μL, 0.256 mmol) in isopropyl alcohol (0.4 mL) was stirred at 90° C. for 2 h. The mixture was cooled and purified on silica gel, eluted with 10-90% EtOAc in hexanes to give 28 mg (59%) of the desired product. LCMS calculated for C23H24N5O4S (M+H)+: m/z=466.2. Found: 466.1.
Reaction SMILES: C(O)CO.[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14](C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:13][C:8]=2[CH:7]=[CH:6]1.[OH-].[K+].O>C1(C)C=CC=CC=1>[S:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH:13][C:8]=2[CH:7]=[CH:6]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccc2sccc2c1
Yield: 12.2 %

Procedure:
To ethylene glycol (1.0 mL) suspension of 0.25 g of diethyl 2-(1-benzothiophen-5-yl)malonate were added 1.0 mL of 40% (w/w) potassium hydroxide aqueous solution and 0.3 mL of water, which was then refluxed for 2 hours. To the reaction mixture were added water and toluene, and the aqueous layer was separated. The pH was adjusted to 2 with 6 mol/L hydrochloric acid, and thereto was added ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was suspended to 5 mL of xylene, and thereto was added 0.01 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 30 minutes. The solvent was distilled off under reduced pressure, and to the resultant residue were added toluene and cyclohexane. The precipitate was collected by filtration to provide 0.02 g of 2-(1-benzothiophen-5-yl)acetic acid as pale yellow solid form.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[C:15]1(=[O:24])[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17][O:16]1>C1COCC1>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:17][C:18]2([C:15]([OH:24])=[O:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:12][CH:13]=1)[C:4]#[C:5][CH3:6]
Reactant: O=C1OCC12CCOCC2
Reactant: CC#CCOc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SCC2(C(=O)O)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.112 g (2.81 mmol) of 60% sodium hydride in 2 mL of THF, cooled to 0° C., was added a solution of 0.500 g (2.81 mmol) of 4-but-2-ynyloxy-benzenethiol, dissolved in 3 mL of THF. The resulting mixture was stirred for 0.5 h at room temperature, then cooled to 5° C., followed by the addition of 0.518 g (3.65 on mol) of neat 2,7-dioxaspiro[3,5]nonane-1-one while keeping the reaction temperature below 10° C. The reaction was allowed to warm to room temperature and stirred for an additional 0.5 h and then quenched with 3 mL of 3N HCl solution and 3 mL of water. The resulting mixture was extracted with dichloromethane and the combined organics were washed with water and brine, dried over Na2SO4, filtered through a plug of silica gel and concentrated in vacuo. The residue was triturated with hexanes and acetonitrile and filtered to give 0.72 g of the carboxylic acid as a semi-solid. Electrospray Mass Spec: 319 (M−H)−