Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18]Cl)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH2:18][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2c(-c3ccccc3)cc(CCl)cc2c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(-c3ccccc3)cc(CSc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the halide from Step 2 (600 mg, 0.22 mmoL) in dry DMF (5 mL) was added at r.t. NaH (90 mg, 2.2 mmoL), followed by thiophenol (114 mL, 1.1 mmoL). The reaction mixture was stirred at r.t. for 18 hr., then transferred to H2O and extracted with EtOAc. The combined organic phases were washed with brine, and dried over MgSO4. After evaporation of the solvent and purification by flash chromatography on silica gel (hexanes:EtOAc; 7:3) the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][S:13][C:14]2[S:15][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:18]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].CS(O)(=O)=[O:27].OOS([O-])=O.[K+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][S:13]([C:14]2[S:15][C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:18]=2)=[O:27])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CCOC(=O)c1ccc(CSc2nnc(-c3cccnc3)s2)nc1
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(CS(=O)c2nnc(-c3cccnc3)s2)nc1
Reaction time: 3 h

Procedure:
A mixed solution of 4.92 g of 2-[(5-ethoxycarbonylpyridin-2-yl)methylthio]-5-(3-pyridyl)-1,3,4-thiadiazole, 2.7 ml of methane-sulfonic acid, 18 ml of acetic acid, and 45 ml of water was cooled to 0° C., oxone (4.65 g) was added to the solution, and the mixture was stirred for 3 hours. The reaction mixture was neutralized with an aqueous solution of sodium hydrogencarbonate so that the pH value was 5, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography (chloroform/methanol=30/1), and a fraction having an Rf value of 0.25 was recrystallized from ethanol to obtain 2.45 g of 2-[(5-ethoxycarbonylpyridin-2-yl)methylsulfinyl]-5-(3-pyridyl)-1,3,4-thiadiazole.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>>[O:12]=[C:11]1[C:6]2[C:7](=[C:2]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[N:3]=[CH:4][CH:5]=2)[O:8][C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:10]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)nccc4c3=O)cc2)CCC1
Yield: 37 %

Procedure:
Following the procedure used to prepare tert-butyl 1-(4-(8-(1-isobutyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl carbamate, tert-butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted with pyridine-3-boronic acid to give the title compound (20 mg, 37%). LCMS (Method I): RT=7.45 min, [M+H]+=546.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[C:12]([N:14]([CH3:16])[CH3:15])=O>CN(C=O)C>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1/[CH:1]=[CH:12]/[N:14]([CH3:16])[CH3:15]
Reactant: Cc1nc2ccccc2o1
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1nc2ccccc2o1
Temperature: 145 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 2-methylbenzo[d]oxazole (3 g, 22.6 mmol) in DMF (3.2 g) and dimethyl acetamide (3.5 g, 29.3 mmol) was stirred under N2 at 145° C. overnight. Then the solution was poured into ice-water and extracted with EtOAc (100 mL×2). The organic phase was washed, dried and concentrated. The residue was purified by column chromatography to get the title compound (2.2 g). MS (ESI) m/z 134 (M+H+).
Reaction SMILES: C([CH:4]1[CH2:7][CH:6]([CH2:8][CH3:9])[CH2:5]1)(=O)C.ClC1C=CC=[C:13]([C:17]([O:19]O)=[O:18])C=1>C(Cl)(Cl)Cl>[C:17]([O:19][CH:4]1[CH2:5][CH:6]([CH2:8][CH3:9])[CH2:7]1)(=[O:18])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1CC(C(C)=O)C1
Solvent: ClC(Cl)Cl
Product: CCC1CC(OC(C)=O)C1
Reaction time: 120 h
Yield: 57.3 %

Procedure:
A solution of 5.5 g of the 1-acetyl-3-ethylcyclobutane, and 10.7 g of m-chloroperbenzoic acid in 107 ml chloroform was allowed to stand for five days in the dark. The reaction mixture was cooled via external ice cooling and filtered. The filtrate was diluted with CHCl3 and washed with 10 percent aqueous sodium thiosulfate, 10 percent aqueous sodium carbonate and brine, dried over Na2SO4, and filtered. The solution was subjected to distillation (aspirator vacuum) to afford 3.55 g of 1-acetoxy-3-ethylcyclobutane, as a clear oil (bp 65°-67°). The material had the following spectral chracteristics: nmr (CDCl3) δ 0.82 (3H, t, J=7.0 Hz) 1.10 and 1.12, (same side product noted in the 1-acetyl compound spectra), 1.0-2.5 l (7H, m), 2.01 (3H, s) and 4.9 (1H, m); ir (CHCl3) 950, 1040, 1085, 1205, 1250, 1375, 1460, 1720, 2870, 2925 and 2960 cm-1 along with trace of 3200-3600 (broad) and 3600 cm-1 for the same side product noted in the 1-acetyl the compound spectra.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:11]2[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCC1CO1
Product: Brc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-bromophenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]2=[O:13].[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl>O1CCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[CH:4]([OH:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:6]2[OH:13]
Reactant: Cc1c(O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1c(O)cc2c(c1Cl)C(O)C1(CCCC1)C2O
Temperature: 25 °C

Procedure:
A solution of 4'-chloro-5'-methyl-6'-hydroxyspiro(cyclopentane-1,2'-indan)-1',3'-dione (4.0 g., 0.015 mole) in tetrahydrofuran (100 ml.) is cooled to 15° C. and treated over 5 minutes with a solution of sodium bis-(2-methoxyethoxy)aluminum hydride (10 ml. of a 70% solution in benzene). The reaction is stirred one-half hour at 25° C., cooled to 10° C. and slowly treated with 20% aqueous hydrochloric acid until acidic. The organic phase is evaporated to an oil, dissolved in ether, washed with water, dried over magnesium sulfate and the solvent evaporated affording 4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-1',3',6'-triol.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:43][CH:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:43][CH:44]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:50])[CH3:51])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(Br)s1)c1ccccc1
Reaction time: 16 h
Yield: 299.5 %

Procedure:
To a solution of 5-bromo-2-thiophenecarboxylic acid (3.2 g, 15.2 mmol), PyBrOP (8.5 g, 18.2 mmol) and diisopropylethyl amine (10.6 mL, 60.9 mmol) in DCM (76 mL) at 25° C. was added 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (3.6 g, 3.14 mmol)[prepared in Preparation 1]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (4 g, 62%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]1[O:21][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni].O1CCOCC1>[OH:21][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)C1OC1c1ccc(OCc2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Yield: 80 %

Procedure:
A mixture of ethyl-2,3-epoxy-3-(4-benzyloxyphenyl)propionate of the formula (9) (125 g) obtained according to the procedure described in step (ii) above, Raney Nickel catalyst (12.5 g) and 1,4-dioxane (750 ml) was hydrogenated at room temperature at 30-40 psi of hydrogen pressure for a period of 8-10 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the solvent was removed under reduced pressure to afford the title compound of the formula (10) (100-105 g, 80-83%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][N:8]=2)=[C:4]([CH3:17])[CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].ClC1C=CC=C(Cl)C=1C(N(C1C=NC(OC2C=CC(Cl)=CC=2C)=CC=1)C)=O>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([N:13]([C:10]1[CH:9]=[N:8][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:17])=[CH:12][CH:11]=1)[CH3:14])=[O:22]
Reactant: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2ccccc2C)cn1

Procedure:
2-Methyl-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared from 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino) pyridine and 2-methylbenzoyl chloride in the same manner as 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.[Si:29]([O:36][C@H:37]1[C@H:41]2[O:42][CH2:43][C@@H:44]([OH:45])[C@H:40]2[O:39][CH2:38]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Si:29]([O:36][C@H:37]1[C@H:41]2[O:42][CH2:43][C@H:44]([OH:45])[C@H:40]2[O:39][CH2:38]1)([C:32]([CH3:35])([CH3:33])[CH3:34])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of triphenylphosphine (542 mg, 2.066 mmol), benzoic acid (252 mg, 2.066 mmol), and (3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (538 mg, 2.066 mmol) in anhydrous THF (8.0 mL) under nitrogen at room temperature was added DIAD (0.40 mL, 418 mg, 2.066 mmol), dropwise, over 10 min. After stirring for 16 h at room temperature, the mixture was concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 50 g (2×25 g in series) silica gel cartridge eluting with 0-50% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The fractions containing desired product were combined and concentrated under reduced pressure. The resultant colorless oil was dissolved in MeOH (10 mL), and 5N aqueous NaOH (2.0 mL, 10.0 mmol) was added. After stirring for 20 h at room temperature, the mixture was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, and then concentrated under reduced pressure to afford the title compound as a white solid. LC-MS: calculated for C12H24O4Si 260.14, observed m/e: 261.17 (M+H)+ (Rt 0.42/4 min)1H NMR (500 MHz, CDCl3): δ 4.49 (t, J=4.5 Hz, 1H), 4.34 (d, J=4.3 Hz, 1H), 4.25 (m, 2H), 3.92 (dd, J=10.0, 3.5 Hz, 1H), 3.84 (d, J=10.0 Hz, 1H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 3.50 (t, J=8.0 Hz, 1H), 2.84 (s, 1H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([OH:23])=O)=[CH:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C(Cl)(=O)C(Cl)=O.[NH:40]1[CH2:45][CH2:44][CH:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][C:47]2=[O:55])[CH2:42][CH2:41]1>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[C:13]([C:21]([N:40]2[CH2:45][CH2:44][CH:43]([N:46]3[C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:48][C:47]3=[O:55])[CH2:42][CH2:41]2)=[O:23])=[CH:12]1)[CH3:24])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCn1cc(C(=O)O)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of 0.20 g (0.57 mmol) 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-6-chloro-1H-indole-3-carboxylic acid, 0.11 ml (0.63 mmol) N,N-diisopropylethylamine and 2 drops of N,N-dimethylformamide in 4 ml dicholormethane were added 0.060 ml (0.74 mmol) oxalyl chloride at 0-5° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 3 h. A solution of 0.15 g (0.68 mmol) 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and 0.11 ml (0.63 mmol) N,N-diisopropylethylamine in 2 ml dicholormethane was added. After stirring for 15 min at room temperature silica gel was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was transferred to a silica gel column. Elution gave 0.26 g (82%) of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]2[CH:9]=[N:11][NH:8][C:7]=12
Reactant: Cc1cc(C)c(N)c(Br)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cn[nH]c2c(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-4,6-dimethylpyridin-3-amine [104829-98-3] (4.00 g, 19.9 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g, 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 min and was then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at RT for 16 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The precipitate was filtered off, washed and discarded. The combined filtrates were washed with water and brine, then dried (Phase separator) and concentrated under vacuum to give 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 212 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:47])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:46])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:45])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:44])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:43])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:42])[C:39]([OH:41])=[O:40]>>[C:39]([C:38]([CH3:42])=[CH:37][CH2:36][CH2:35][C:34]([CH3:43])=[CH:33][CH2:32][CH2:31][C:30]([CH3:44])=[CH:29][CH2:28][CH2:27][C:26]([CH3:45])=[CH:25][CH2:24][CH2:23][C:22]([CH3:46])=[CH:21][CH2:20][CH2:19][C:18]([CH3:47])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:41])=[O:40]
Reactant: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: COc1c(C)cc(O)c(OC)c1OC
Product: COc1c(C)c(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Yield: 51.2 %

Procedure:
The procedures of Example 1 were repeated except that 5 g of 2,3,4-trimethoxy-5-methylphenol and 3.5 g of 24-hydroxy-2,6,10,14,18,22-hexamethyl-2,6,10,14,18,22-tetracosahexaenoic acid were employed as the starting materials to give 2.5 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH:31]([CH2:33][CH3:34])[CH3:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH:31]([CH2:33][CH3:34])[CH3:32])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)NS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCC(C)NS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-sec-butyl-4-methyl-benzenesulfonamide (Intermediate 146), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][C@@H:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C@H:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](O)Cn1ccc2cc(F)ccc21
Reaction time: 1 h
Yield: 80 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g (7 mmol) of 5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 7 ml of water. The mixture was diluted with 180 ml of ether, washed twice with 90 ml of water each time and with 50 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 28 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.09 g (80%) of (R)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a light brown oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:27])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[ClH:27].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCSc1ccncc1
Yield: 84.3 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.61 ml (4.96 mmol) of pivaloyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.01 g of the desired compound (free base) (96.4%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cl)ccc1OCc1ccccc1

Procedure:
Phenylmethyl 5-chloro-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 43; 4.16 g, 11.8 mmol), in ethanol (40 ml) and 2M NaOH (20 ml) was heated at reflux for two hours. The mixture was cooled, concentrated in vacuo, acidified with 2M HCl and extracted with ethyl acetate (×3). The organics were washed with brine, dried (MgSO4), and concentrated to give a yellow oil. Purified using biotage chromatography (C18 cartridge, CH3CN/H2O) to give the title compound as a white solid. 1.9 g.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>CC1CCCO1.CCOC(C)=O>[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[C:28]([C:33]#[C:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Reactant: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CN(C)CC#Cc1cc(N2C3CCC2CC3)ccc1NC(=O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid 17 (19 mg, 0.07 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)aniline 27 (20 mg, 0.07 mmol) in 2-methyltetrahydrofuran (190.9 μL) was added T3P (118 mg, 0.19 mmol) and pyridine (12 mg, 12 μL, 0.15 mmol). The reaction was heated at 100° C. for 30 min under microwave irradiation. The reaction was diluted with EtOAc and quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organics were washed once with water, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC (0-99% CH3CN/0.05% TFA) to give N-[4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(3-dimethylaminoprop-1-ynyl)phenyl]-4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxamide (8 mg, 17% yield). LC/MS m/z 509.7 [M+H]+, retention time 1.06 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 13.23 (d, J=6.8 Hz, 1H), 12.40 (s, 1H), 10.31 (s, 1H), 8.96 (d, J=6.6 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.08-8.06 (m, H), 8.07 (dd, J=1.5 Hz, 8.1 Hz, 1H), 8.00-7.95 (m, 2H), 7.15-7.09 (m, 2H), 4.49 (s, 2H), 4.29 (s, 2H), 2.94 (s, 6H), 1.67 (d, J=7.2 Hz, 4H), 1.44 (d, J=7.0 Hz, 4H).