Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=O)[CH2:10][N:11]([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:12][N:11]([CH3:13])[CH2:10][CH2:9][NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CN(C)CC(=O)N[C@H]1CC[C@H](C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCN[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.5 g of N-(trans-4-methylcyclohexyl)-2-dimethylaminoacetamide was dissolved in 100 ml of THF. Under an argon stream, the solution was added dropwise to a solution of 3.6 g of lithium aluminum hydride suspended in 200 ml of THF under ice-cooling. After the addition, the solution was reacted for 8 hours, while it was refluxed. After reaction, the solution was allowed to cool to room temperature. Then, 10 g of sodium sulfate decahydrate was added to the solution under ice-cooling. The solution was stirred for 1 hour, and the precipitate was filtered out. The solvent was removed in vacuo to obtaine an oily substance. This substance was refined by vacuum distillation, yielding 3.8 g of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[CH2:35][O:36]C(=O)C)[C@H:12]([CH3:27])[CH2:13][O:14][C:15](OC2C=CC([N+]([O-])=O)=CC=2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:40]([NH2:42])[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[CH2:35][OH:36])[C@H:12]([CH3:27])[CH2:13][O:14][C:15]([NH:42][CH2:40][CH3:41])=[O:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)COC(=O)Oc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNC(=O)OC[C@@H](C)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[2[[[[4-nitrophenyl]oxy]carbonyl]oxy]-(R)-methylethyl]benzenesulfonamide (0.85 g, 0.14 mmol) was added ethylamine (0.13 g, 0.28 mmol) in DMF (2 mL). The resulting mixture was allowed to stir at 22° C. for 12 h and concentrated under reduced pressure. The mixture was diluted with methanol/H2O (2 mL), followed by the addition of K2CO3. The mixture was filtered and the solvent was removed. Silica gel chromatography (30% ethyl acetate/hexanes) of the concentrate afforded the title compound. Yield=900/o colorless oil: MS (ESI+), 462 (M+H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH3:15])=[N:12][C:11]=1[CH3:16])(=[O:9])[CH3:8]>>[CH3:15][C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:16])[N:12]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: Brc1ccsc1
Product: Cc1nc(C)c(C(C)(O)c2ccsc2)o1

Procedure:
Starting with 3-bromothiophene and 5-acetyl-2,4-dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 132°-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([OH:40])=O)[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH:66]1([NH:70][C:71]([C@@H:73]2[CH2:77][CH2:76][CH2:75][NH:74]2)=[O:72])[CH2:69][CH2:68][CH2:67]1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:74]3[CH2:75][CH2:76][CH2:77][C@H:73]3[C:71](=[O:72])[NH:70][CH:66]3[CH2:67][CH2:68][CH2:69]3)=[O:40])[C:33]3[C:28](=[CH:29][C:30]([CH3:41])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)c3ccc(C)cc3n2)CC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Temperature: 40 °C

Procedure:
To a solution of 3.5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-carboxymethoxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 30 ml of DMF, 1.1 g of EDC, 1.1 g of pentafluorophenol and 1.8 g of NEM was added and the reaction mixture was warmed to 40° C. for 4 h. Then, after cooling to RT 2.6 g of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 1 g of NEM in 10 ml of DMF was added. After 4 h the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.8 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:31])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].I[CH:39]1[CH2:42][O:41][CH2:40]1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:29][S:26]([C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=1)[C:15]([N:14]([CH3:31])[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:39]1[CH2:42][O:41][CH2:40]1)=[O:30])(=[O:28])=[O:27]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1O
Reactant: IC1COC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC1COC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution N-(4-(2-hydroxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (100 mg, 222 μmol, example 263, intermediate a) in DMF (2 ml) was added K2CO3 (61.4 mg, 444 μmol) and 3-iodooxetane (44.9 mg, 244 μmol). The reaction mixture was stirred for 18 hours at 80° C. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (52 mg, 46%). MS (ESI): m/z=507.120 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[NH2:7][C@@H:8]1[CH2:9][C@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:11]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: NCCN
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4C[C@@H](N)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, (cis-3-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclobutyl)carbamic acid tert-butyl ester (144 mg, 0.236 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.73 ml, 9.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was suspended in dichloromethane (1.2 ml) and ethylenediamine (0.96 ml, 14.2 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h then water and ethyl acetate were added. The suspension was filtered and washed with hot water and ethyl acetate. The product was dried under high vacuum to provide 86 mg (91%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-amino-cyclobutyl)-amide as a light yellow powder. MS: (M+H)+=380; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.09 (s, 1H), 8.54 (dd, J=8.7, 5.3 Hz, 1H), 8.41 (s, 1H), 8.28 (d, J=7.6 Hz, 1H), 7.71 (dd, J=9.8, 1.9 Hz, 1H), 7.28 (td, J=9.1, 1.9 Hz, 1H), 5.54 (br. s., 2H), 4.15 (s, 3H), 4.04-4.18 (m, 1H), 3.07-3.22 (m, 1H), 2.65-2.80 (m, 2H), 1.66-1.80 (m, 2H).
Reaction SMILES: C(OCC([C:13]1[O:14][C:15]2[C:16](=[C:18]([C:37]#[N:38])[C:19]([CH3:36])=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=2N2CC[C@H](N(C)C)C2)[N:17]=1)(C)C)C1C=CC=CC=1.O1CCOCC1.[ClH:45]>C(OCC)C>[ClH:45].[CH3:36][C:19]1[C:18]([C:37]#[N:38])=[C:16]2[N:17]=[CH:13][O:14][C:15]2=[CH:21][C:20]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)cc2ocnc2c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 161.5 %

Procedure:
2-[2-(Benzyloxy)-1,1-dimethylethyl]-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#13) (150 mg, 0.295 mmol) was dissolved in diethyl ether (5 ml), a 1,4-dioxane solution of 4 N hydrogen chloride (111 μl, 0.442 mmol) was added, followed by stirring at room temperature for 10 minutes. The reaction liquid was concentrated under reduced pressure to obtain a pale pink, amorphous 2-[2-(benzyloxy)-1,1-dimethylethyl]-7-(3-dimethylamino)pyrrolidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile hydrochloride (129 mg). The hydrochloride (118 mg, 0.216 mmol) was dissolved in methanol (7 ml), and catalytically hydrogenated at room temperature under 5 atmospheres on 10%-palladium carbon (50% wet, 75 mg), for 30 minutes. The catalyst was separated by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried on anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the entitled compound (48 mg, 53%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:40])[CH:23]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:34]CC=C)=[C:29]([Cl:38])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:41])[O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:40])[CH:23]([NH:25][C:26](=[O:39])[C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([OH:34])=[C:29]([Cl:38])[CH:28]=2)[CH3:24])=[O:16])[CH2:12][C:11](=[O:41])[O:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: ClCCl
Product: CC(NC(=O)c1cc(Cl)c(O)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A 140 mg sample of 82 (0.23 mmol) was dissolved in CH2Cl2 (4 mL) and treated with DMBA (35.4 mg, 0.26 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol). The solution was stirred at 0° C. for 15 mins, warmed to room temperature for 2 hours, then diluted with CH2Cl2 and washed with water (2×) and brine. The solvent was concentrated in vacuo and the residue purified by flash chromatography on silica gel using MeOH/CH2Cl2 (1/99 to 3/97) to give the title compound (93.2 mg, 71% yield). 1H-NMR (500 MHz, CD3OD) δ 1.16 (d, 0.25H), 1.28-1.49 (m, 2.75H), 1.63-2.33 (m, 4H), 2.48 (dd, 0.4H), 3.39-3.59 (m, 0.2H), 3.60-3.73 (m, 0.8H), 3.73-3.96 (m, 1H), 4.24-4.48 (m, 2H), 4.57-4.92 (m, 7H), 5.44 (s, 0.4H), 5.50 (d, 0.4H), 5.64 (d, 0.8H), 5.75 (d, 0.5H), 7.16-7.43 (m, 5H), 7.78-7.8.9 (m, 1.6H), 8.40-8.63 (m, 0.4H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 11.57, 11.82 min. LC-MS (ES+) m/e=564.1 (M+H)
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([NH2:12])[CH:10]=[CH2:11]>O1CCCC1>[CH2:9]([NH:12][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: CCCCCC(=O)Cl
Solvent: C1CCOC1
Product: C=CCNC(=O)CCCCC
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
Hexanoyl chloride (33 g, 0.25 mol) in 250 mL of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (28.6 g 0.5 mol) in 200 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtration was concentrated under vacuum to yield 37 g of N-allyl hexanamide as a colorless viscous liquid.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:28][CH2:27][NH:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:29]([N:26]1[CH2:27][CH2:28][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A suspension of 3-(naphthalene-1-sulfonyl)-5-(pyrrolidin-3-yloxy)-1H-indazole (52.8 mg, 0.134 mmol) in 1,2-dichloroethane was treated sequentially with butyraldehyde (0.1 mL, 1 mmol) and acetic acid (0.1 mL, 2 mmol), stirred at ambient temperatures, under nitrogen, for 20 minutes, treated with additional acetic acid (0.2 mL, 3 mmol) and 1,2-dichloroethane, stirred at ambient temperature for 1 hour, 40 minutes, treated with sodium triacetoxyborohydride (96.7 mg, 0.457 mmol), stirred for 3 hours at ambient temperatures, diluted with chloroform and poured into excess 2.5 N sodium hydroxide. The phases were separated; the organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.25% ammonium hydroxide/2.5% methanol in chloroform to afford 5-(1-butyl-pyrrolidin-3-yloxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light yellow foam, 30.0 mg (49.8% yield). The foam was dissolved in chloroform and methanol, treated with ethereal HCl and concentrated in vacuo at 83° C. for 13 hours to give the title product as a pale yellow foam, 26.9 mg, Mass spectrum (+EI, [M+H]+) m/z 450. 1HNMR (500 MHz, DMSO-d6): δ14.19 (s, 1H), 10.25-10.65 (m*, 1H), 8.75 (d, 1H, J=8.54 Hz), 8.56 (d, 1H, J=6.83 Hz), 8.28 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.56-7.65 (m, 3H), 7.27 (s, 1H), 7.12 (dd, 1H, J=9.15 Hz and 2.32 Hz), 5.19-5.24 (m, 1H), 3.39-3.96 (m*, 3H), 3.08-3.24 (m*, 3H), 2.00-2.63 (m*, 2H), 1.56-1.64 (m, 2H), 1.21-1.34 (m, 2H), 0.80-0.90 ppm (m, 3H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2[C:15]=1[CH:14]=[CH:13][NH:12][CH:11]=2)(=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[OH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2[C:15]=1[CH:14]=[CH:13][NH:12][CH:11]=2
Reactant: CC(=O)OC1=C2C=CNC=C2C=CC=C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC1=C2C=CNC=C2C=CC=C1

Procedure:
A solution of 5-acetyloxycyclohepta[1,2-c]pyridine in hydrochloric acid (75 ml, ca. 5 N) was heated and stirred at its reflux temperature for 61/2 hrs. The resulting red-colored solution was stirred overnight, then neutralized with solid K2CO3 (pH=8) and the oily precipitate extracted with methylene chloride. The organic phase was separated, washed with brine, and dried (MgSO4). Filtration through celite gave a light yellow filtrate which on concentration gave a gummy brown solid. The solid was triturated with hexane and collected by filtration. The yield of light tan solid was 5.10 g (59%), m.p. 127°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:15][CH:16]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethanol (0.568 g) in THF (10 mL) was added NaH (0.270 g, 60% in oil). The mixture was stirred at room temperature for 2 hours, before 2,5-dibromopyridine (0.8 g) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column (Hex/EtOAc=100:5) to give 5-bromo-2-(4-fluorophenethoxy)pyridine (0.3 g). LCMS (M+H)=296.0.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11](=[S:15])[NH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:19](O)C.CI>O>[CH2:1]([C:8]1[C:9](=[O:16])[NH:10][C:11]([S:15][CH3:19])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(=S)[nH]c(=O)c1Cc1ccccc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 60 °C

Procedure:
5-Benzyl-6-methylthiouracil (6.0 gms) and sodium hydroxide (1.06 gms) were dissolved in water (30 mls). The solution was cooled and ethanol (60 mls) and methyl iodide (3.67 gms) added with stirring. The mixture was heated at 60° C for 178 hour, cooled and the resulting solid collected and water-washed. A second crop of solid was obtained by acidification of the filtrate to pH=4 with acetic acid. Recrystallisation from ethanol produced 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (5.53 gms) m.p. = 220°-221.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]([N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH2:54])[CH:51]=[CH:50][C:48]=2[N:49]=1)([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH:41]([N:44]([CH3:55])[C:45]1[S:46][C:47]2[CH:53]=[C:52]([NH:54][C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH:51]=[CH:50][C:48]=2[N:49]=1)([CH3:43])[CH3:42]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Yield: 51.7 %

Procedure:
Prepare according to Method A, using 4-(4-fluorophenyl)benzoic acid (253 mg, 1.17 mmol), HATU (451 mg, 1.19 mmol), N2-Isopropyl-N2-methyl-benzothiazole-2,6-diamine (200 mg, 0.904 mmol), DIEA (520 μL, 2.99 mmol), and a chromatography gradient of MeOH in CH2Cl2 (0-5%) to afford the title compound (196 mg, 52%). mass spectrum (m/e): 420.0 [M+H], 418.0 [M−H]. 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 8.27 (d, 1H, J=2.2 Hz), 8.06 (d, 2H, J=8.4 Hz), 7.85-7.78 (m, 4H), 7.56 (dd, 1H, J=8.8, 2.2 Hz), 7.40 (d, 1H, J=8.2 Hz), 7.37-7.31 (m, 2H), 4.34 (m, 1H), 2.98 (s, 3H), 1.23 (d, 6H, J=6.6 Hz).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[C:1]([C:4]1[O:5][C:6]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(=O)c1ccco1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2ccc(F)cc2)o1
Yield: 42 %

Procedure:
To a solution of 19.71 g (0.18 mol) of 2-acetylfuran in 120 ml of methylene chloride were added 42.9 ml (2.0 eq) of 4-fluorobenzylchloride and 36.6 g (1.5 eq) of zinc chloride. The mixture was refluxed for 12 hours. The precipitated crystal was filtered and washed with methylene chloride. The obtained solid was dissolved in water and extracted with ethylacetate. The organic layer was washed with water and a diluted aqueous solution of sodium hydrogencarbonate and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from n-hexane to give 16.4 g of 2-acetyl-5-(4-fluorobenzyl)furan. Yield: 42%. Mp: 27-29° C.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofluran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91M, 3 ml) (Louw et. al. Tetrahedron 48:6087-6104, (1992), prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (±)1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc. 1) in tetrahydrofuran (3 ml). The solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%). Evaporation of the fractions gave the title compound. m/z (CI+)424 (M+H), 324 (M+2H--t-BuOCO--), 368 (M+2H--t-Bu).