Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-:24].[K+].[K+]>>[CH2:15]([O:24][CH:8]1[O:7][C:6]2[C:5]([C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=[CH:2][C:11]=2[O:10][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2c1OCCO2
Agent: [K+]
Product: CC(=O)c1cccc2c1OC(OCc1ccccc1)CO2
Yield: 95 %

Procedure:
A suspension of 97 g (0.5 mole) of 5 hydroxy-8-acetyl-1,4-benzodioxane (VIIi), of 127 g (1 mole) of benzyl chloride and 155 g (1.12 mole) of potassium carbonate in 150 ml of absolute alcohol was brought to reflux for 24 hours. After filtration the solvent was evaporated, the residue was taken up in chloroform, washed with a solution of soda (NaOH) 1 N, the solvent was evaporated and the product was crystallized in alcohol, 135 g of product expected were obtained.
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].N.[Li]>C(OCC)C.C(O)C>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/C1CCC(=O)CC1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CCC/C=C/[C@H]1CC[C@H](O)CC1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
1.63 g of 4-(trans-1-pentenyl)cyclohexanone were dissolved in 8 ml of diethyl ether and 14 ml of ethanol. Subsequently, the solution was treated dropwise with about 70 ml of ammonia and portionwise with lithium wire until the colour of the mixture remained constant for 1.5 hours (about 1.3 g of lithium). Thereafter, the ammonia was removed by evaporation and the mixture was made acid with ammonium chloride and hydrochloric acid and left to stand for 3 days. The mixture was then partitioned in diethyl ether/water and the aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate, filtered and freed from solvent on a rotary evaporator. Low-pressure chromatography of the resulting, yellow oil on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 1.47 g (89.1%) of trans-4-(trans-1-pentenyl)cyclohexanol as a light yellow, viscous oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[CH:23]=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[C:19]=2[N:18]=[C:17]1[CH2:27][O:28][CH2:29][CH3:30]>>[NH2:26][C:20]1[C:19]2[N:18]=[C:17]([CH2:27][O:28][CH2:29][CH3:30])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:24]=2[CH:23]=[C:22]([CH3:25])[N:21]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=S)NC(=O)c1ccco1

Procedure:
Using the method of Examples 36-45, 2-furoylisothiocyanate was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 431.887.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:2].Cl.[CH3:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][Mg][Cl:22]>>[Cl-:22].[CH3:16][NH+:17]([CH2:18][CH2:19][CH2:20][CH:1]([OH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:23]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CN(C)CCC[Mg]Cl
Agent: Cl
Product: C[NH+](C)CCCC(O)c1ccccc1-c1ccccc1
Product: [Cl-]

Procedure:
By a similar procedure, 2-formyl-1,1'-biphenyl was reacted with 3-dimethylaminopropyl magnesium chloride hydrochloride to provide N,N-dimethyl-4-hydroxy-4-(1,1'-biphenyl-2-yl)butylaminium chloride. M.P. 161°-164° C.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CC1CCO
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.4 %

Procedure:
To a solution of the TBDPS-protected alcohol 11b (320 mg, 0.588 mmol) in dry THF (5 mL) at 0° C. was added TBAF (1.0M/THF, 0.74 mL, 0.735 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon for 7 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 166 mg (92%) of the title compound as a colorless oil. [α]D23-21.6 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 5 H), 5.10 (m, 2 H), 4.76 (appbd, 1H, J=5.7 Hz), 3.63 (bs, 2 H), 3.04 (m, 1 H), 2.12-1.98 (bs, 1 H), 1.83-1.62 (m, 2 H), 1.42 (t, 2H, J=7.0 Hz), 1.16-0.95 (m, 2 H), 0.90 (appt, 6H, J=7.0 Hz), 0.53 (sept, 1H, J=4.3 Hz), 0.42 (dt, 1H, J=8.4, 4.5 Hz), 0.34 (dt, 1H, J=8.4, 5.0 Hz); HRMS (ESI) m/z calcd for C18H27NO3Na 328.1889, found 328.1860.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CCN(C(C)C)C(C)C>[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([C:2]2[S:3][C:4]([Br:7])=[CH:5][N:6]=2)[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 110 °C

Procedure:
A solution of 2,5-dibromothiazole (1.00 g, 4.12 mmol) in DIPEA (3.00 mL) was charged with tert-butyl 1-piperazinecarboxylate (0.767 g, 4.12 mmol) and heated to 110° C. for 3 h and then an additional 16 h at rt. The reaction mixture was partitioned between CHCl3 and H2O, and the layers were separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 0.5% EtOAc in CHCl3] resulting in the title compound as a light orange solid. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 3.37-3.44 (m, 4H), 3.51-3.59 (m, 4H), 7.08 (s, 1H). MS (ES+): m/z=348.09 (51/49) [MH+]. HPLC: tR=3.73 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].II.[I-].[K+]>CO.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])=[CH:5][NH:6]2
Reactant: Fc1cc(F)c2cc[nH]c2c1
Reactant: COC(=O)CS
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CSc1c[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 15.1 %

Procedure:
To a solution of 4,6-difluoro-indole (1.00 g, 6.53 mmol) and methyl thioglycolate (584 μL, 6.53 mmol) in methanol:water (25 mL:7.0 mL) was added iodine (1.65 g, 6.53 mmol) and potassium iodide (1.09 g, 6.53 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed in vacuo and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated in vacuo and the resulting residue was purified on a silica gel column (0-100% ethyl acetate:hexanes over 19 min) to afford the desired product (253 mg, 19% yield). LCMS>98% at 254 nm, RT=1.33 min, m/z=258 (M+1).
Reaction SMILES: [Mg].II.Cl[CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].BrCCBr.[C:19](=[O:21])=[O:20].Cl>O1CCCC1.O>[CH3:7][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH2:5][C:19]([OH:21])=[O:20]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
While stirring powdery magnesium (9.56 g, 393 mmol) and iodine (one crumb) in tetrahydrofuran (10 ml), a solution of 1-chloro-2-methyl-2-phenylpropane (26.53 g, 157.3 mmol) and 1,2-dibromoethane (29.6 g, 157 mmol) in tetrahydrofuran (100 ml) was dropwise added at a rate permitting the reaction solution to gently reflux. After completion of the dropwise addition, the mixture was stirred at 60° C. for 4 hrs. The reaction solution was cooled to −78° C., and pulverized dry ice (50 g) was carefully added. After completion of the dropwise addition, the reaction solution was gradually warmed to room temperature with stirring. The reaction solution was diluted with water, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the recovered organic layer was evaporated under reduced pressure. The obtained residue was mixed with sodium hydroxide (6 g) and water (200 ml). The obtained aqueous solution was washed with diethyl ether-hexane, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the objective substance.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=1[O:35][CH2:36][CH3:37]>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:22][CH2:23][N:24]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[O:35][CH2:36][CH3:37])[CH2:25][CH2:26]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1c(N)ncnc1Cl
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CCOc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-isopropyl-pyridine and 6-chloro-5-ethoxy-pyrimidin-4-ylamine as the starting materials. LC-MS (M+H=491, obsd=491).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19][NH2:20])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[S:19]([NH2:20])=[O:27])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NSc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCO
Product: NS(=O)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 31.7 %

Procedure:
To an ice cooled stirred solution of 10 (1.5 g, 5 mmol) in ethanol:H2O (525 mL, 20:1, v/v), m-chloroperoxybenzoic acid (1 g, 1 eq.) in ethanol (50 mL) was added dropwise during 20 min. After 4 h the separated crystals were filtered off, the filtrate was evaporated to dryness, triturated with methanol, filtered, washed with methanol and dried at room temperature to yield 11, (0.5 g, 31% yield), m.p. >120° C. The filtrate was evaporated and purified by chromatography as described for 6 to yield another crop of 11, (0.25 g, 15%: overall yield 46%). IR (KBr): 1060 (vs, br, S=O), 1330 (s, S=O), 3000-3600 (NH2, OH) cm-1 : UV: λmax (pH 1) 272 nm (ε 3,000): λmax (pH 7) 275 nm (ε7,100): λ max (pH 11) 272 nm (ε 1,700): 1H NMR (DMSO-d6): δ 6.46 (d, 1, J =5.16 Hz, C1'H), 6.71 (s, 2, SONH2, exchanged with D2O), 8.83 (s, 1, C2H), 9.06 (s, 1, C8H), and other sugar protons. Anal. Calcd for C10H13N5O5S·0.3H2O (321.32): C, 37.38: H, 4.24: N, 21,80: S, 9.97. Found: C, 37.03: H, 4.19: N, 21.42: S, 10.37.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:10].[NH2:11][CH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[ClH:10].[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]#[N:11])[CH:8]=[CH:9][CH:2]=1
Reactant: N#Cc1ccccc1Br
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(CN)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A solution of 2-bromobenzonitrile (1.10 g), 3-aminomethylphenylboronic acid hydrochloride (1.13 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g), and tripotassium phosphate (5.20 g) in a 4:1 dimethoxyethane-water mixed solvent (60 mL) was stirred at 70° C. for 3 hours. 2-Bromobenzonitrile (0.070 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g) were added thereto, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and then separated into organic and aqueous layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: dichloromethane/methanol), and a fraction containing the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to the solution. The resulting suspension was filtered, and the product collected by filtration was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (0.483 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23](=[S:25])[NH2:24])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH:29](OCC)OCC>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]3[S:25][CH:28]=[CH:29][N:24]=3)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=S
Reactant: CCOC(CBr)OCC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1-c1nccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution (3 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carbothioamide (120 mg) in N,N-dimethylacetamide was added 2-bromo-1,1-diethoxyethane (125 mg), and the mixture was stirred at 60° C. for 2 hr, then at 100° C. for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60 mg, yield 47%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 415 (MH+).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].C(N(CC)CC)C.C1(C)C=CC=CC=1>CCCCCC>[CH3:3][Si:2]([CH3:5])([CH3:4])[N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: O=C1CCCN1
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N1CCCC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Chlorotrimethylsilane (TMSCl, 56.0 mL, 441 mmol) is added dropwise to a solution of 2-pyrrolidinone (30.4 mL, 400 mmol), triethylamine (70.0 mL, 502 mmol) and toluene (400 mL) at room temperature. After stirring at room temperature with a mechanical stirrer for 20 minutes, the mixture is heated at 50° C. for 4 hours. After cooling, the mixture is diluted with hexane (300 mL) and stirred for 30 minutes at room temperature. The mixture is filtered and the filtrate concentrated. Distillation of the residue (1 mm, 68+-74° C.) gives 50.0 g (94%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.FC(F)(F)S(O)(=O)=O.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=[C:30]2[N:37]([CH3:41])[N:38]=[C:39]([CH3:40])[C:29]=12.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[CH3:41][N:37]1[C:30]2=[N:31][CH:32]=[C:33]([C:34]([NH2:36])=[O:35])[C:28]([NH:27][CH2:26][CH2:25][NH:24][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])=[C:29]2[C:39]([CH3:40])=[N:38]1
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1nn(C)c2ncc(C(N)=O)c(NCCN)c12
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c2ncc(C(N)=O)c(NCCNC(=O)/C=C/C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) was dissolved in DCM (2 ml containing one drop of dimethyl formamide), oxalyl chloride was added (19 mg, 0.15 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-(2-aminoethylamino)-1,3-dimethyl-pyrazolo[3,4-b]pyridine-5-carboxamide trifluoromethanesulfonate (40 mg, 0.1 mmol) and diisopropylethylamine (60 μl, 0.35 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.1 mg (0.005 mmol, 5.7%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:24]#[N:25].[K+].O>CS(C)=O>[C:24]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1)#[N:25]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCC1CCc2ccccc2O1
Reaction time: 2 h

Procedure:
A mixture of 15.8 g (47 mmol) of 2-p-toluenesulfonyloxyethyl-3,4-dihydro-2H-1-benzopyran and 3.4 g (52 mmol) of potassium cyanide in 320 ml of dimethyl sulfoxide is stirred for 2 hours. After addition of water, the product is extracted with chloroform containing a little methanol and then the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 10% ethyl acetate, 7.8 g of compound are obtained in oil form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:13])=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(C)s1
Yield: 99.8 %

Procedure:
5-Methyl-4-nitro-thiophene-2-carboxylic acid methyl ester [15.09 g., 75.0 mM, Intermediate (23)] is dissolved in ethyl acetate (200 mL) to which 10% palladium on charcoal (1.03 g) is added and the mixture is shaken under 50 psi of hydrogen. The catalyst is removed by filtration and the solvent is removed leaving 4-amino-5-methyl-thiophene-2-carboxylic acid methyl ester [12.82 g., 99.8%, Intermediate (24)] as a yellow solid; MS 171.9 (100%, M+1).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=O>>[CH2:42]([N:41]([CH2:44][CH3:45])[CH2:39][CH2:38][O:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[CH:4][CH:3]=1)[CH3:43]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 28.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-diethylacetamide (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.1 mg) was obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[OH:22][C@@H:20]([C:9]1[N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:3]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)C1
Yield: 34 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.044 mmol) and triethylamine (18.5 μL, 0.133 mmol) in methylene chloride (0.3 mL) was added ethyl chloroformate (5.1 μL, 0.0531 mmol). The resulting mixture was stirred until completion then the solvent evaporated. The crude residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 5.6 mg (34%) of the desired product. LCMS calculated for C18H23N4O3S (M+H)+: m/z=375.1. Found: 375.0. 1H NMR (300 MHz, CDCl3) δ 9.08 (d, J=1.3 Hz, 1H), 7.69 (dd, J=5.5 and 1.3 Hz, 1H), 7.62 (d, J=5.5 Hz, 1H), 5.21 (d, J=6.7 Hz, 1H), 4.83-4.68 (m, 1H), 4.43-4.23 (m, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.93-3.66 (m, 1H), 3.18-3.01 (m, 1H), 2.76-2.60 (m, 1H), 2.20-2.10 (m, 1H), 2.00 (d, J=13.8 Hz, 1H), 1.79 (d, J=6.4 Hz, 3H), 1.70-1.61 (m, 2H), 1.30-1.16 (m, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].[F:27][C:28]([F:45])([F:44])[C:29]1[CH:30]=[CH:31][C:32]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[N:33][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN1CCCC1=O>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:45])([F:27])[F:44])=[CH:34][N:33]=5)=[CH:43][CH:42]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2]
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCN(Cc4ccc(Oc5ccc(C(F)(F)F)cn5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
(R)-2-Nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.50 g), 4-(5-trifluoromethylpyridin-2-yloxy)benzaldehyde (0.41 g), N-methylpyrrolidone (10 ml), and sodium triacetoxyborohydride (0.44 g) were mixed and stirred at room temperature for 16 hours. The reaction mixture was added to a 1 N sodium hydroxide aqueous solution. The precipitated crystal was collected by filtration. The crude crystal was purified by silica gel column chromatography (methylene chloride:ethyl acetate=8:2→methylene chloride:ethyl acetate=2:8) and recrystallized from acetone-ether to afford the title compound as a pale yellow powder (0.55 g).