Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[OH-].[Na+].[C:15](#[N:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[OH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]=1[CH2:17][CH2:16][C:15]#[N:18]
Reactant: C=CC#N
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCc1c(O)ccc2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To 44.8 g of 6-bromo-2-naphthol were added 120 ml of toluene and 8.8 g of sodium hydroxide, followed by stirring at 65° C. for 30 minutes. Then, thereto was added dropwise 11.4 g of acrylonitrile at 80° C., followed by stirring at the same temperature for 3.5 hours. After left for cooling, the toluene layer was decanted, and to the residue was added 240 ml of water. A small amount of insoluble matter was filtered off, and to the filtrate was added 140 ml of 5% hydrochloric acid. The precipitate was collected by filtration and sufficiently washed with water. The resulting crude product was recrystallized from ethanol to obtain 30.7 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][CH2:15]CCCN>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:15][Cl:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCl
Reactant: NCCCCCl
Agent: Cl
Product: CC(C)(C)OC(=O)NCCCCCl

Procedure:
This compound, employed as the starting material in example 2, is prepared by following substantially the same procedure described above under (a) but using 4-chloro-butylamine hydrochloride instead of 3-chloro-propylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:1][C:2]1[C:3](=[O:12])[O:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc2ccccc2oc1=O
Product: CCOC(=O)C(=CNc1cc2ccccc2oc1=O)C(=O)OCC
Temperature: 120 °C
Yield: 89.2 %

Procedure:
A mixture of 3-aminocoumarin (30.0 g, 0.186 mole) and diethyl ethoxymethylenemalonate (75.0 g, 0.347 mole) is heated at 120° C. for 4 hours under nitrogen. The reaction mixture is cooled and triturated with hexane. The product is filtered off and washed with hexane. Recrystallization from ethyl acetate gives white crystals (55.0 g, 89%), mp. 134-135.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH3:23][S:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]#[N:30].C1CCN2C(=NCCC2)CC1.C(#N)C>>[CH3:23][S:24][CH2:25][CH2:26][CH:27]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:28][C:29]#[N:30]
Reactant: CSCC/C=C/C#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CSCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 83.2 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(methylthio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU (45 μL, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 30-70 ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.CN(C)[N:15]=[CH:16][C:17]([F:19])=[CH2:18]>C(Cl)(Cl)Cl>[F:19][C:17]1[CH2:18][C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[NH:15][CH:16]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=C(F)C=NN(C)C
Solvent: ClC(Cl)Cl
Product: O=C1C2=C(NC=C(F)C2)C(=O)c2ccccc21
Yield: 5 %

Procedure:
A solution of naphthoquinone (632 mg, 4 mmol) and 2-fluoro-2-propenal N,N-dimethylhydrazone was refluxed for 22 hours in dry chloroform (15 ml.) Another portion of naphthoquinone (0.41 g, 2.59 mmol) was added and the reflux continued for 3 more hours. After the solvent was evaporated at reduced pressure, silica gel column chromatography with elution with ethyl-ether-petroleum ether (1:1) yielded 187 mg (21%) of compound (I-1) and 42 mg (5%) of 3-fluoro-1,4-dihydro-1-azaanthracen-9,10-dione. m.p. 214° C. (MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](=[O:44])[CH2:33][CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:35]2)=[CH:30][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][C:28]2[CH:37]=[C:36]3[C:31]([C:32](=[O:44])[CH2:33][CH:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35]3)=[CH:30][CH:29]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=C1CC(c2ccccc2)Oc2cc(O)ccc21
Product: O=C1CC(c2ccccc2)Oc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21

Procedure:
7-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 150 mg of 7-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.67 (dd, 1H, J 9.0, 2.8 Hz), 7.89 (d, 1H, 8.6 Hz), 7.60-7.35 (m, 6H), 7.04 (d, 1H, 2.1 Hz), 6.97 (dd, 1 H, 8.6, 2.1 HZ), 5.75 (dd, 1H, J 13.0, 2.7 Hz), 3.32 (dd, 1H, 16.9, 13.0 Hz), 2.85 (d, −16.9, 2.7 Hz).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC(Cl)=CC=1>O>[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Product: CON=C(C1=NCCO1)c1ccccc1O
Yield: 56 %

Procedure:
Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1.5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56%) as an oil.
Reaction SMILES: [F:1][C:2]1([F:47])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34](/[CH:39]=C/C3C=CC=CC=3)[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3]1.C[N+]1([O-])CC[O:52]CC1>C(Cl)Cl>[F:1][C:2]1([F:47])[CH2:5][CH:4]([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH:39]=[O:52])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:3]1
Reactant: O=C(NC1CC(F)(F)C1)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(/C=C/c2ccccc2)c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CC(F)(F)C2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Yield: 22.6 %

Procedure:
To a solution of (R,E)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-styrylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (509 mg, 0.8 mmol) in DCM (10 ml) at 0° C. was added 4-methylmorpholine N-oxide (104 mg, 0.8 mmol). Ozone was bubbled through the resulting yellow solution for 10 min. The reaction solvent was removed and the residue was purified by ISCO chromatography (12 g column, 0-30% EtOAc/hexane) to yield (R)-1-(3,3-difluorocyclobutyl)-3-(1-(4-fluoro-3-formylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea as a colorless oil (106 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ ppm 10.22 (s, 1H), 8.06 (m, 1H), 7.67 (dd, J=6.19, 2.65 Hz, 1H), 7.16 (m, 4H), 6.85 (m, 3H), 6.69 (m, 3H), 5.85 (m, 1H), 5.40 (d, J=6.57 Hz, 1H), 4.00 (m, 1H), 2.90 (m, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7]C([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](O)=O.S(Cl)(Cl)=O.[CH3:16]N(C)C=O>>[CH2:8]([N:1]([CH:2]([CH3:3])[CH3:9])[CH:6]([CH3:5])[CH3:16])[CH3:7]
Reactant: O=C(O)C1CC2CCN1CC2
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-azabicyclo[2.2.2]octane-2-carboxylic acid (488 mg), thionyl chloride (5 mL) and N,N-dimethylformamide (23 mg) was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). A mixture of methyl 3-amino-5-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate and methyl 3-amino-5-[1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-yl]thiophene-2-carboxylate (750 mg) produced above, and N-ethyl-N-(1-methylethyl)propan-2-amine (0.916 mL) were added, and the mixture was stirred at 60° C. for 2 hr. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (534 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.O>CCO.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:25])([CH3:1])[CH2:3][N:4]2[C:14](=[O:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CC(C)(C)c2ccc(N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)-2-(N-Boc-amino)-ethanone (3.9 g) was dissolved in EtOH (30 ml) and Fe powder (3.1 g) NH4Cl (299 mg) and H2O (5 ml) were added. The reaction was stirred at 80° C. overnight. The reaction was filtered through Celite® and evaporated off the MeOH. The residue was partitioned between CH2Cl2 and sat'd NaHCO3. The organic layer was removed, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 25% EtOAc/hexane.) The purified fractions were concentrated in vacuo to afford the compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]=[CH2:19])[C:13](=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:28]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:39]([N:28]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@@H:29]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:30]([CH:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH2:17][CH:18]=[CH2:19])[C:13]1=[O:20])[OH:31])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=CC(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C=CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
Add to a solution of 4-benzyloxycarbonyl-1-allylpiperazin-2-one (1.1 g, 4.0 mmol) in dry THF (4 mL/mmol) at −78° C. under nitrogen lithium bis(trimethylsilyl)amide (1.OM solution in THF, 4.0 mL, 4.0 mmol) dropwise and stir 30 min. Add 2-(dibenzylamino)-3-phenylpropanal (732 mg, 2.2 mmol) in dry THF (2 mL/mmol) and stir at −78° C. for 45 min. Quench with saturated aqueous ammonium chloride solution. Separate organic layer and wash with water, saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 100% hexanes to 1:1 hexanes:ethyl acetate) to give a mixture of four diastereoisomers (836 mg, 62%). Separate the isomers by normal phase HPLC (95:5 hexanes:isopropanol 95/5) to provide:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[S:38](Cl)([CH3:41])(=[O:40])=[O:39]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[C:17]3[C:18](=[CH:22][N:23]([CH:25]4[CH2:26][CH2:27][N:28]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:29][CH2:30]4)[N:24]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCNCC5)nc34)ccn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C5CCN(S(C)(=O)=O)CC5)nc34)ccn2)c1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a solution of N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (49 mg, 0.122 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (0.051 ml, 0.365 mmol) and mesyl chloride (10.41 μl, 0.134 mmol). The reaction was removed from the ice bath and briefly stirred at room temperature. The reaction mixture was concentrated and subjected to silica column chromatography eluted with 0-5% methanol in dichloromethane using a step gradient (over 24 minutes) to give N-(2-(2-fluoro-5-methylphenyl)pyridin-4-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (12 mg, 21%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31-2.49 (m, 7H) 2.83-2.95 (m, 3H) 2.95-3.10 (m, 2H) 4.03 (d, J=12.63 Hz, 2H) 4.42-4.66 (m, 1H) 7.03-7.24 (m, 4H) 7.34 (s, 1H) 7.75 (s, 1H) 7.83 (dd, J=7.58, 2.02 Hz, 1H) 8.18 (s, 1H) 8.44 (d, J=4.80 Hz, 1H) 8.65 (d, J=5.56 Hz, 1H). MS [M+H] found 481.4.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Clc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Reactant: C1CCNC1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCC5)cc4ccc3n12

Procedure:
A mixture of 1.0 g. of 3-chloroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.0 ml. of pyrrolidine and 5 ml. of N-methyl-2-pyrrolidinone is stirred and heated at reflux for 17 hours, cooled and diluted with 100 ml. of ethyl acetate. The precipitate of 3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, stirred with 50 ml. of 1% aqueous triethylamine hydroiodide and recollected; m.p. 312°-320° C. after crystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:28][OH:29])[CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCC(=O)c1ccc(Sc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Reactant: NO
Agent: Cl
Product: CCC(=NO)c1ccc(Sc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Yield: 15 %

Procedure:
Using an analogous procedure that described in Example 66, 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}propiophenone was reacted with hydroxylamine hydrochloride to give 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}propiophenone oxime in 15% yield, m.p. 113°-114° C.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH2:12][O:11][CH:10]2[C@@H:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:28][CH:27]=4)=[CH:20][CH:19]=3)[CH2:14][O:15][CH:9]12.Cl>C(O)C>[OH:7][C@@H:8]1[CH2:12][O:11][CH:10]2[C@@H:13]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:30][CH:31]=4)=[CH:22][CH:23]=3)[CH2:14][O:15][CH:9]12
Reactant: CCCCCCOc1ccc(C=Cc2ccc(CO[C@H]3COC4C3OC[C@H]4OC3CCCCO3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCOc1ccc(C=Cc2ccc(CO[C@H]3COC4C3OC[C@H]4O)cc2)cc1
Yield: 80 %

Procedure:
The crude (E) 4-{3(R)-(tetrahydropyran-2-yloxy)-hexahydrofuro[3,2-b]furan-6(S)-yloxymethyl}-4′-hexyloxystilbene (19) was dissolved in 10 ml of ethanol and 0.5 ml of concentrated hydrochloric acid were added. Then the mixture was heated to reflux for 10 minutes. The product crystallized at room temperature. It was washed with ethanol and dried in the dessicator. 8.7 g of a white solid were obtained (overall yield 80%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OC2CCNC2)cc1
Yield: 82.2 %

Procedure:
To a solution of tert-butyl 3-(4-(trifluoromethoxy)phenoxy)pyrrolidine-1-carboxylate (325 mg, 0.936 mmol) in CH2Cl2 (3.7 mL) was added TFA (360 μL, 4.68 mmol). The colorless solution was dried under reduced pressure and the crude oil obtained purified with a 5 g SCX-2 column washing first with MeOH, then with 2M NH3 in MeOH leading to elution of basic materials to afford 3-(4-(trifluoromethoxy)-phenoxy)pyrrolidine (190 mg, 0.769 mmol, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C@:28]([OH:32])([C:30]#[CH:31])[CH3:29])[N:24]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C@@:28]([OH:32])([C:25]4[N:24]=[C:23]([CH3:22])[O:27][N:26]=4)[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)c(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)O)nn(-c4nc(N)ncc4Cl)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (400 mg, 0.96 mmol) in piperidine (4 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (111 mg, 0.10 mmol), copper(I) iodide (18.3 mg, 0.10 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (292 mg, 1.92 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). The partially purified compound was dissolved in DCM (20 mL) and washed with 2M aqueous citric acid (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound as a dark oil: 1H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.62 (3H, s), 6.80 (1H, s), 7.53-7.35 (3H, m), 8.09 (1H, s), 8.23 (1H, d, J=8.4 Hz), 8.56 (1H, s); LC-MS: m/z=+439.90 (M+H)+. This compound, with LC-MS purity=65% UV, was used in the next step without further purification.
Reaction SMILES: [CH:1]([CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)=O.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][N:27]([CH2:1][CH:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:17]([CH3:26])[S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH2:4]2)[CH2:28][CH2:29]1
Reactant: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)(=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1,1-dioxide (270 mg) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give pale-pink crystals from a fraction eluted with ethyl acetate:hexane=50:50. The obtained pale-pink crystals were purified by preparative HPLC to give the title compound (140 mg, yield 20%) as white crystals. melting point 242° C.