Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21](Br)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.C(NC(C)C)(C)C.[C:50]1([C:56]#[CH:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:36])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([C:57]#[C:56][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]([F:35])([F:34])[F:33])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2Br)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(trans-4-{[5-Bromo-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (100 mg, 0.174 mmol), CuI (0.97 mg, 0.005 mmol), and Pd(PhCN)2Cl2 (1.96 mg, 0.005 mmol) were dissolved in degassed dioxane (0.5 mmol). To this solution was added tri-(tert)-butylphosphine tetrafluoroborate (2.4 mg, 0.010 mmol) followed by diisopropylamine (0.029 mL, 0.2 mmol) and phenylacetylene (0.022 mL, 0.2 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was worked up by the addition of EtOAc and filtered through a plug of SiO2. The filtrate was concentrated and purified via flash chromatography (SiO2, 25% EtOAc-Hexanes) to yield (4-{[5-phenylethynyl-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester. (4-{[5-Phenylethynyl-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester was dissolved in CH2Cl2 (0.5 mL) and TFA (0.5 mL) was added. The solution was stirred for 2 h and the volatiles were removed and the crude residue was purified via preparative thin layer chromatography (SiO2, 2000 micron thickness, 1:9:90 NH4OH:CH3OH:CH2Cl2) to afford 49 mg (57%) of N4-[(trans-4-aminocyclohexyl)methyl]-5-(phenylethynyl)-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine, m/z 496.58 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH:10]C(=O)C(C)(C)C>OS(O)(=O)=O>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10]
Reactant: COc1cc(I)c(NC(=O)C(C)(C)C)cn1
Agent: O=S(=O)(O)O
Product: COc1cc(I)c(N)cn1
Temperature: 120 °C

Procedure:
A solution of N-(4-iodo-6-methoxypyridin-3-yl)pivalamide (Compound 2, 2.33 g, 7.0 mmol) in 10% H2SO4 (70 ml) was heated to reflux at 120° C. for 5 h. The mixture was cooled to 0° C. and was quenched cautiously with solid NaOH (10 g), extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) to yield the title compound as off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][NH2:21])[CH3:19].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:21][O:20][CH2:18][CH3:19])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5 g, 93%) was isolated as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:30]([C:31](=[O:42])[NH:32][C:33]3[CH:41]=[C:40]4[C:36]([CH:37]=[N:38][NH:39]4)=[CH:35][CH:34]=3)=[CH:29][C:17]3[N:18]=[C:19]([NH:21][C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([NH:32][C:31]([C:30]3[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=5)=[N:18][C:17]=4[CH:29]=3)=[O:42])[CH:41]=2)[CH:37]=[N:38]1
Reactant: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCNCC3)cc2[nH]1

Procedure:
The product from Example 89 was treated with 4M HCl in dioxane employing the procedure described for Example 80 to afford of 2-(3-methylpyridin-2-ylamino)-6-piperazin-1-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 468 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the 4-(tert-butyldiphenylsilyloxy)butan-1-ol (0.5 g, 1.5 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (775 mg, 1.83 mmol). The mixture was stirred for 1 h. The reaction mixture was poured into hexanes and the resulting white precipitant was removed via filtration. The solution was concentrated to give form a slurry, which was dissolved in dichloromethane (5 mL) and again poured into hexanes resulting in the precipitation of white solid. The solids were removed via filtration and the resulting solution was concentrated. This gave 475 mg (97%) of a clear oil: 1H NMR (CDCl3); δ1.04 (s, 9H), 1.89 (m, 2H), 2.55 (m, 2H), 3.69 (t, 2H, J=6.1 Hz)), 7.38 (m, 6H), 7.63 (d, 4H, J=1.7 Hz), 9.79 (t, 1H, J=1.8 Hz).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 71 %

Procedure:
A mixture of 12 parts of trans-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-3-(trifluoromethyl)benzamide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was solidified on scratching in 2,2'-oxybispropane. The precipitated product was filtered off and dissolved in 135 parts of methylbenzene and 105 parts of 1,1'-oxybisethane. The supernatant liquid was decanted, washed twice with a dilute ammonium hydroxide solution and the product was extracted with methylbenzene. The aqueous phase was saturated with potassium carbonate and the product was extracted with methylbenzene. The combined organic layers were dried, filtered and evaporated in vacuo, yielding 6.43 parts (71%) of trans-N-(3-methoxy-4-piperidinyl)-3-(trifluoromethyl)benzamide; mp. 100.3° C. (interm. 9).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:5][C:14](=[O:15])[O:16][CH3:17])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Yield: 63 %

Procedure:
3,5-Dichloro-2-nitroaniline (600 mg, 2.90 mmol) was added with methyl chloroformate (25 mL, 0.12 M), and the mixture was subjected to a reaction for 18 hours under reflux. Methyl chloroformate was removed under reduced pressure, and the compound thus obtained was purified by column chromatography using 10% EtOAc/hexane to obtain the title compound (480 mg, yield: 63%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH:15]=O.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)N>C(O)C.C(O)(=O)C.O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[NH:18][CH:15]=1
Reactant: NNc1ccc(CC(=O)O)cc1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A solution of 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal, diethyl acetal (36 g) in absolute ethanol (125 ml) was added to a solution of 4-hydrazinobenzene acetic acid, hydrochloride (25 g) in 25% aqueous acetic acid (640 ml) heated to 80° under nitrogen. The mixture was heated at 70°-80° for 2.75 h and the solvent was removed under reduced pressure to give a red oil. This was diluted with water and extracted with ethyl acetate (5×250 ml). A gummy solid insoluble in either phase was collected and triturated with ethanol to give the title compound as a beige solid (7.4 g). The organic extracts were dried (MgSO4) and concentrated to an oil which was taken up in chloroform and treated with diethyl ether to give a second crop as a yellow solid (13.1 g). A sample (0.5 g) of this material was purified by column chromatography (Whatman MFC silica, 25 g) and elution with ethyl acetate--light petroleum (1:1) gave the title compound as a yellow solid (0.35 g) m.p. 189°-191.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](F)=[CH:8][CH:9]=1)[C:5]#[N:6].CC[N:13]([CH:17]([CH3:19])[CH3:18])C(C)C.C1(N)CC1>CN1CCCC1=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([NH:13][CH:17]2[CH2:19][CH2:18]2)=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)ccc1NC1CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 3-chloro-6-fluorobenzonitrile (5 g), Hunig's base (5.60 mL, 1 eq), and cyclopropylamine (3.34 mL, 1.5 eq) in anhydrous N-methylpyrrolidinone (16 mL) was heated to 110° C. for 18 h in a sealed tube. The mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed once with water, then brine, then concentrated and the residue was washed with hexanes delivering the product as a crystalline white solid (4.66 g, 75% yield). 1H-NMR (300 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.46 (dd, 1H), 7.02 (d, 1H), 6.70 (s, 1H), 2.40 (m, 1H), 0.75 (m, 2H), 0.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]=1[NH2:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:26]([O:29][CH2:30]C)(=O)C.CCCCCC>C(OC)(OC)OC>[CH3:26][O:29][CH:30]=[N:13][C:3]1[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CS(=O)(=O)Cc1cccc(Cl)c1N
Reactant: CCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: COC(OC)OC
Solvent: O
Product: COC=Nc1c(Cl)cccc1CS(C)(=O)=O

Procedure:
The 2-chloro-6-methanesulfonylmethyl-phenylamine (2.04 g, 0.019 mole) of Step 4 was suspended in 15 ml trimethyl orthoformate and p-toluenesulfonic acid hydrate (0.21 g) was added. The reaction mixture was brought to reflux and heated at this temperature for 3 h. The reaction was monitored by tlc (3:7 ethyl acetate:hexane, silica gel) which showed the appearance of a new slightly less polar spot. At the end of 3 h, the reaction was cooled and evaporated to dryness to afford N-(2-Chloro-6-methanesulfonylmethyl-phenyl)-formimidic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CC(C)=O>[CH2:28]([O:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][C:2]=1[Br:1])[CH:27]=[CH2:26]
Reactant: CCOc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Temperature: 65 °C
Yield: 94.5 %

Procedure:
To a solution of 2-Bromo-5-chloro-4-(4-ethoxybenzyl)phenol (7, 55 mmol) in acetone (180 mL) were added potassium carbonate (15.2 g, 110 mmol) and allyl bromide (7 mL, 83 mmol) and heated at 65° C. for 3 h. The insoluble material was removed by filter and the filtrate was evaporated under reduced pressure. The crude residue was purified on Biotage® purification apparatus (silica gel, 3 to 10% ethyl acetate in hexanes) to yield the title compound (21 g, 52 mmol, 95%) as colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16]CCCCCC.O1CCCCC1OCC#C.C(Br)CCCCC.[NH2-].[Li+]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC#CCC#CCC#CCOC1CCCCO1
Agent: C#CCOC1CCCCO1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCBr
Product: CCCCCCC#CCOC1CCCCO1

Procedure:
Pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether can be prepared by coupling propargyl alcohol tetrahydropyranyl ether with n-hexyl bromide in the presence of lithium amide, to produce 2-nonyn-1-ol tetrahydropyranyl ether, then hydrolysing of the tetrahydropyranyloxy function with Pyr/PTS in ethanol solution followed by esterification of the hydroxy compound with methanesulfonyl chloride in the presence of triethylamine. The mesylate is then reacted with lithium bromide in acetone solution to produce 1-bromo-2-nonyne. Finally the latter compound is coupled with hexa-2,5-diyn-1-ol-tetrahydropyranyl ether in the presence of ethylmagnesium bromide and cuprous chloride. The sequence of reaction conditions are essentially the same as those described hereinafter in detail.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH:20]=3)[CH:16]([CH2:15][CH2:14]2)[CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C2C3CCC2CN(C(=O)OCc2ccccc2)C3)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C2C3CCC2CN(C(=O)OCc2ccccc2)C3)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
8-(3-Amino-phenyl)-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (185 mg, 0.55 mmol) was dissolved in pyridine (3 mL), cooled to 0° C. then charged with methanesulfonylchloride (0.064 mL, 0.825 mmol) dropwise, causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by APCI MS after 1 h. Following a 1N HCl quench (10 mL), the product was extracted with EtOAc (2×30 mL), washed with saturated aqueous NaHCO3 solution (1×30 mL), saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4, filtered and concentrated to give an orange liquid (153 mg, 67%). (TLC 30% EtOAc/hexanes Rf 0.15); 1H NMR (400 MHz, CDCl3) δ 7.33–7.19 (m, 5H), 7.21 (t, J=7.9 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 5.24 (s, 2H), 4.03 (d, J=12.5 Hz, 1H), 3.94 (d, J=12.6 Hz, 1H), 3.07 (d, J=12.5 Hz, 1H), 3.03 (d, J=12.5 Hz, 1H), 2.90 (s, 3H), 2.86 (s, 1H), 2.50 (br s, 1H), 2.44 (br s, 1H), 1.60 (m, 2H), 1.47 (m, 2H); APCI MS m/z 415.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Nc1nc2cc(F)ccc2s1
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(F)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-fluoro-benzothiazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH:19](I)([CH3:21])[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:7]([O:6][P:4]([CH:9]([CH:19]([CH3:21])[CH3:20])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CC(C)I
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5.5 ml of tert-butyl diethylphosphonoacetate are dissolved in 20 ml of dimethylformamide, and 820 mg of sodium hydride (60% strength in paraffin oil) are added a little at a time at 0° C. The suspension is stirred at 0° C. for 15 minutes, and 2.4 ml of isopropyl iodide are then added. The mixture is stirred at room temperature for 12 hours. 250 ml of ethyl acetate are then added, and the reaction mixture is washed three times with in each case 150 ml of water. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=5:1. This gives 4.2 g of tert-butyl 2-(diethoxyphosphoryl)-3-methylbutyrate as an oil. C13H27O5P (294.33), MS(ESI): 239 (M-C4H8+H+), Rf(n-heptane:ethyl acetate=1:1)=0.34.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9]([S:21][CH3:22])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[C:9]([S:21]([CH3:22])=[O:34])=[C:8]2[CH3:23])=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2c(c1)c(SC)c(C)n2Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)c(S(C)=O)c(C)n2Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
A 300 mg portion of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylthio)-1H-indole-5-carboxylate was dissolved in 3 ml of chloroform, and 203 mg of 3-chloroperbenzoic acid was added under ice-cooling, followed by stirring at the same temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:hexane=1:0:1 to 1:0:0 to 100:1:0 to 50:1:0 to 30:1:0) to obtain 279 mg of ethyl 1-(4-fluorobenzyl)-2-methyl-3-(methylsulfinyl)-1H-indole-5-carboxylate as a colorless solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([C:13]2[C:24]([CH2:25]O)=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([C:13]2[C:24]([CH2:25][C:5]#[N:6])=[C:16]3[C:17]4[CH:23]=[CH:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1c(-c2ccccc2)nn2ccc3occc3c12
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1c(-c2ccccc2)nn2ccc3occc3c12
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (460 μL, 3.63 mmol) and trimethylsilyl cyanide (645 μL, 4.84 mmol) in dichloromethane (12 mL) was added a solution of (2-phenylfuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)methanol (320 mg, 1.21 mmol) in dichloromethane (12 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred for 2 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→50/50) to give the title compound (240 mg, yield 73%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:24]=[CH:23][C:22]3[C@@H:21]4[C@H:12]([C@H:13]5[C@@:17]([CH2:19][C@@H:20]4[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])=[O:38])=[CH:27][CH:26]=4)([CH3:18])[C@@H:16]([OH:49])[CH2:15][CH2:14]5)[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:58])C=1>>[CH:1]1([O:6][C:7]2[CH:24]=[CH:23][C:22]3[C@@H:21]4[C@H:12]([C@H:13]5[C@@:17]([CH2:19][C@@H:20]4[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:39][CH2:40][CH2:41][C:42]([F:47])([F:48])[C:43]([F:44])([F:45])[F:46])(=[O:58])=[O:38])=[CH:27][CH:26]=4)([CH3:18])[C@@H:16]([OH:49])[CH2:15][CH2:14]5)[CH2:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 79.4 %

Procedure:
By operating as in Example 56 using at the start 698 mg of the product obtained in Example 68 and 228 mg of metachloro perbenzoic acid, 567 mg of expected product is obtained. M.p.=166° C.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)(=O)C>[OH-].[Na+]>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=1[SH:3]
Reactant: Nc1nc2ccc(F)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(F)cc1S
Temperature: 120 °C
Reaction time: 2 h
Yield: 129.3 %

Procedure:
2-Amino-6-fluorobenzothiazole (5.0 g, 29.7 mmol) was stirred in 10N NaOH (120 mL) and heated to 120° C. After 2 hours the mixture was allowed to cool and treated with acetic acid (˜70 mL) to adjust the pH of the mixture to 4.0. The resulting precipitate was collected and washed with 3 volumes (30 mL) of water and dried in vacuo to give 5.5 g of 2-amino-5-fluorothiophenol suitable for use in the subsequent step.