Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:9]3[N:19]=[C:20]([C:22]([OH:24])=O)[CH:21]=[C:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:38][NH:39][O:40][CH3:41].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:41][O:40][N:39]([CH3:38])[C:22]([C:20]1[CH:21]=[C:8]2[N:7]=[C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:11]=[C:10]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:9]2[N:19]=1)=[O:24]
Reactant: O=C(O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2nc(N3CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.15 g, 5.26 mmol) in dichloromethane (60 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.27 g, 13.0 mmol), N,O-dimethylhydroxylamine hydrochloride (2.49 g, 13.0 mmol), and triethylamine (2.30 g, 22.7 mmol) at 0° C. After being stirred for 17 h at room temperature, the reaction mixture was poured into saturated sodium bicarbonate. The mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) to give N-methoxy-N-methyl-5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxamide. MS (APCI): m/z 375 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:21]([O:23]CC)=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:21]([OH:23])=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nc(-c2ccccc2)c(C(=O)O)s1)c1ccccc1
Yield: 59.7 %

Procedure:
A mixture of ethyl 2-benzamido-4-phenylthiazole-5-carboxylate (1.62 g, 4.60 mmol) and lithium hydroxide (0.96 g, 23.00 mmol) was stirred at 50° C. in tetrahydrofuran/water mixture for 96 h. The organic solvent was removed in vacuo and the water layer was washed with ethyl acetate and then acidified by the addition of 15% hydrochloric acid solution to pH 5. The white precipitate obtained was collected by filtration and dried to afford 0.89 g of the title compound in 59% yield; 1H NMR (CDCl3, 300 MHz) δ 13.05 (s, 1H), 8.09 (d, J=7.1 Hz, 2H), 7.80-7.35 (m, 8H); MS (ES+) m/z 325.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:12]2[NH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2nc(C(F)(F)F)[nH]c12
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2nc(C(F)(F)F)[nH]c12
Yield: 92.8 %

Procedure:
To a solution of 4-nitro-2-trifluoromethylbenzimidazole (700 mg, 3.0 mmol) in methanol(50 ml)and was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (10%MeOH/CH2Cl2) gave the desired product (560 mg, 93%). 1H NMR (CD3SO2CD3): δ10.49 (s, 1H), 7.09 (t, 1H), 6.72 (d, 1H), 6.30 (d, 1H), 5.52 (bs, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17]([O:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].C(N(CC)CC)C>CCOCC.CCOC(C)=O>[C:17]([O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:11]=1)=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1C(=O)Oc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of Compound 3 in Et2O (120 ml) were added acetylsalicyloyl chloride (Compound 4) (5.9 g, 0.028 mol) and triethylamine (Et3N) (6.6 ml, 0.047 mol) in sequence at RT. The reaction mixture was stirred at RT under argon for 3 days. The reaction mixture was diluted with EtOAc (100 ml) and washed with aqueous saturated NaHCO3 (3×100 ml), brine (1×100 ml), and dried over anhydrous Na2SO4. The crude product obtained upon concentration was purified by column chromatography (elution solvent: 5% EtOAc in hexanes) to produce 9.4 g of Compound 5 in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C=O.[C:35](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([CH3:35])[CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([I:11])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCNC5)s4)c(Cl)cnc32)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCN(C)C5)s4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ambient solution of 3-(5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)pyrrolidin-3-ol (Example 117D) (410 mg, 0.682 mmol) in tetrahydrofuran (10 mL) was added formaldehyde (0.254 mL, 3.41 mmol, 37 wt % in water) and acetic acid (0.195 mL, 3.41 mmol). The reaction was stirred at room temperature for 20 minutes, and sodium triacetoxyborohydride (0.723 g, 3.41 mmol) was added in a single portion. The reaction was stirred at room temperature for 1 hour and was quenched by the addition of water and chloroform. The layers were separated, and the aqueous layer was extracted with additional chloroform (2×). The combined organics were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purifed by flash column chromatography on silica gel, wluting with a gradient of 0 to 8% methanol (containing 1% v/v ammonium hydroxide) in dichloromethane, to give the title compound. MS APCI(+) m/z 614.9 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].[H-].[Na+].Cl[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>CS(C)=O>[CH3:6][NH:5][CH2:4][CH2:3][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:1][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CNCCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCCC(Oc1ccc2ccccc2n1)c1ccccc1

Procedure:
Following the method of Example 4, reaction of 3-hydroxy-N-methyl-3-phenylpropylamine, sodium hydride and 2-chloroquinoline in DMSO gives the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:7]3[O:8][CH:6]3[CH2:5][C:4]=2[CH:3]=1.[CH3:12][C:13]1([N:26]2[CH2:31][CH2:30][NH:29][C@@H:28]([CH3:32])[CH2:27]2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:7]([N:29]1[CH2:30][CH2:31][N:26]([C:13]3([CH3:12])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:27][C@@H:28]1[CH3:32])[C@H:6]([OH:8])[CH2:5]2
Reactant: Brc1ccc2c(c1)CC1OC21
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1
Solvent: CCO
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1[C@@H]1c2ccc(Br)cc2C[C@H]1O
Yield: 49.4 %

Procedure:
To a solution of 4-bromo-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (247.9 mg, 1.1746 mmol) in ethanol (10.00 mL) was added tert-butyl 4-methyl-4-[(3S)-3-methylpiperazin-1-yl]piperidine-1-carboxylate (349.36 mg, 1.1746 mmol). The reaction mixture was heated to reflux overnight. After cooling down, the mixture was evaporated under reduced pressure. Purification on silica gel with 50% ethyl acetate (1% NH4OH) and hexane afforded the fast moving product as the desired compound (295 mg; 49.4%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:24])[C:14]3[CH:21]=[C:20]([CH2:22]Cl)[O:19][C:15]=3[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:6][CH:5]=1.C(=O)(O)[O-:28].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:24])[C:14]3[CH:21]=[C:20]([CH2:22][OH:28])[O:19][C:15]=3[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)oc21
Temperature: 25 °C

Procedure:
A solution of 2 N aq. sodium hydroxide (2.5 mL) was added to a solution of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 2, 1.83 g) in DMF (40 mL). The mixture was heated and a sat. aq. sodium bicarbonate solution (10 mL) was added. The reaction mixture was allowed to cool to room temperature, was poured into water, and extracted with EtOAc (3×100 mL). The combined organic layers were concentrated. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 20/1; 15/1) to afford 0.258 g of the title compound as a yellow solid. Physical characteristics. M.p. 229-230° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.63, 8.56, 7.42-7.32, 6.85, 5.53, 4.54, 4.51, 3.94; MS (EI) m/z 346 (M+).
Reaction SMILES: CC([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:6]=1[Cl:23])=O.Cl.ClC1C(OC2C=CC(Cl)=CC=2Cl)=CC=C([N+]([O-])=O)C=1N.[OH-].[K+].Cl[O-].[Na+]>>[Cl:23][C:6]1[C:5]2[C:10](=[N+:11]([O-:13])[O:12][N:4]=2)[CH:9]=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(Oc2ccc(Cl)cc2Cl)c1Cl
Agent: Cl
Agent: Nc1c([N+](=O)[O-])ccc(Oc2ccc(Cl)cc2Cl)c1Cl
Agent: [K+]
Product: [O-][n+]1onc2c(Cl)c(Oc3ccc(Cl)cc3Cl)ccc21

Procedure:
Following the procedure of Example 4, N-methylcarbonyl 2-chloro-3-(2,4-dichlorophenoxy)-6-nitroaniline is converted, by reaction with HCl, to 2-chloro-3-(2,4-dichlorophenoxy)-6-nitroaniline, which is then reacted with potassium hydroxide and sodium hypochlorite, again following Example 4 procedures, to yield the final product, 4-chloro-5-(2,4-dichlorophenoxy)benzo-2,1,3-oxadiazole N-oxide.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].C[S+](C)C.[CH2:12]([C@:14]12[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][C@H:15]1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=12)[CH:24]=[N:23][N:22]3[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH3:13].[CH2:40]([C@@]12CCC(=O)C[C@@H]1CCCC1C=C3C(=CC=12)C=NN3C1C=CC(F)=CC=1)C>C1COCC1>[CH2:12]([C:14]12[CH2:38][CH2:37][C:36]3([CH2:40][O:39]3)[CH2:35][CH:15]1[CH2:16][CH2:17][CH2:18][C:19]1[C:27]2=[CH:26][C:25]2[CH:24]=[N:23][N:22]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:21]=2[CH:20]=1)[CH3:13]
Reactant: CC[C@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCC12CCC3(CO3)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C
Yield: 37.1 %

Procedure:
A flask with stir bar and nitrogen line was charged with sodium hydride (60 wt % in oil, 0.212 g, 5.31 mmol) and DMSO (9 mL) then the mixture was warmed in an oil bath heated to about 65° C. for about 1 h. The mixture was cooled to rt, diluted with THF (18 mL) then cooled to about 0° C. Trimethylsulfonium iodide (1.084 g, 5.31 mmol) was added then the mixture was stirred for about 15 min. rac-(4aR,12bR)-12b-Ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazole-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.800 g, 2.125 mmol) was added in one portion then the mixture was stirred and allowed to warm to rt. After stirring overnight the mixture was concentrated under reduced pressure to remove THF. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organics were washed with water (2×25 mL) then brine (25 mL), dried over MgSO4, then filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using 0-10% EtOAc in DCM. Product fractions containing the epoxide isomer with the higher Rf (TLC, 95:5 DCM/EtOAc, vis by UV) were collected and concentrated under reduced pressure to yield rac-(2′R,4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-2,4,4a,5,6,7,9,12b-octahydro-1H-spiro[benzo[6,7]cyclohepta[1,2-f]indazole-3,2′-oxirane] (154, R1=4-Fluorophenyl, R2=Ethyl) (0.308 g, 37.1%); LC/MS, method 3, Rt=2.94 min, MS m/z 391 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J=0.8 Hz, 1H), 7.89 (s, 1H), 7.84-7.77 (m, 2H), 7.56 (s, 1H), 7.45-7.36 (m, 2H), 3.26-3.18 (m, 1H), 2.97-2.92 (m, 1H), 2.61-2.54 (m, 2H), 2.24-2.15 (m, 1H), 2.03-1.71 (m, 8H), 1.62-1.58 (m, 1H), 1.39-1.21 (m, 2H), 1.06-1.01 (m, 1H), 0.40 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3ccncc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 4-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 121°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][N:23]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccncn1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccncn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 4-pyrimidinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:9]=1>CCO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:9]=1
Reactant: COCc1cc(C(=O)OC)ccc1-c1cc(F)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1cc(F)ccc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 5N aqueous solution of NaOH (3 mL, 15 mmol) was added into a solution of methyl 5′-fluoro-2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (2.88 g, 10.0 mmol) in EtOH (30 mL) and stirred at 60° C. for 1 hour. The reaction mixture was concentrated under vacuum. The residue was taken up with MTBE (100 mL), water (50 mL) and a 5N aqueous solution of HCl (4 mL). The layers were separated. The organic layer was washed with water (50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under vacuum. After purification by crystallization from a mixture of MTBE and heptane, the title compound was obtained as a white powder (2.31 g, 84%). HPLC (Method A) Rt 3.9 min (Purity: 100%). LC/MS (Method B): 273.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.05 (s, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.92 (dd, J=7.9, 1.7 Hz, 1H), 7.36 (dd, J=8.5, 6.0 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.16 (m, 1H), 6.98 (dd, J=9.5, 2.8 Hz, 1H), 4.16 (d, J=12.5 Hz, 1H), 4.10 (d, J=12.5 Hz, 1H), 3.19 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][CH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[C:11](=[O:15])[NH:10]1)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O>[OH:14][CH:12]1[C:11](=[O:15])[NH:10][CH:9]([CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:13]1
Reactant: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(O)CCC1CC(O)C(=O)N1

Procedure:
4-Hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester (1.87 g) and trifluoroacetic acid (1.2 g) in 10 ml of N,N-dimethylformamide was heated at 100° C. until disappearance of starting material by thin layer chromatography. After concentration under reduced pressure, the resulting solid is washed with acetone and filtered to give 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid. NMR (DMSOD6) and 12.14 (s, 1H), 7.96 (d, J=5 Hz, 1H), 5.37 (m, 1H), 4.00 (m, 1H), 2.60-1.09 (m, 6H). IR (cm-1) 3420, 3080, 2030, 2920, 1698, 1494, 1387, 1284.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:26][CH3:27].[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[CH:20]5)=[N:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:26][CH3:27])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCBr
Reactant: CC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (200 mg, 0.47 mmol), (WO 00/47212 A1, Example 314), and 1-acetylpiperazine (180 mg, 1.40 mmol) in N,N-dimethylformamide (4 ml) was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with brine (×2), dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue (5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (109 mg, 49%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:16]([CH3:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]=3[CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Li])CCC.[Cl-:26].[Cr+3:27].[Cl-].[Cl-]>C1COCC1>[Cl-:26].[Cl-:26].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([Cr+2:27])[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]3[CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC1=C(C)C(C)C(c2cccc3ccc(C)nc23)=C1C
Reactant: [Cr+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Cr+2])(c2cccc3ccc(C)nc23)C(C)=C1C
Reaction time: 2 h
Yield: 50 %

Procedure:
0.3 g of 1-(2-methyl-8-quinolyl)-2,3,4,5-tetramethylcyclopentadiene (1.14 mmol) in 30 ml of THF was deprotonated using 0.45 ml of n-butyllithium (2.5 M in hexane, 1.14 mmol). After the mixture had been stirred for two hours, the red solution was added dropwise to a suspension of chromium(III) chloride in 20 ml of THF. After the mixture had been stirred at room temperature for 16 hours, the solvents were evaporated off, and the resultant residue was taken up in 20 ml of toluene. The green suspension was filtered, and the residue was extracted a number of times with hot toluene. Conventional work-up gave the product as a green powder (0.22 g) in a yield of 50%.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([NH:43][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.03 mmol) and 1-(3-dimethyl)aminopropyl)-3-ethylcarbodiimide hydrochloride (12.09 g, 63.04 mmol) in tetrahydrofuran (170 mL) under nitrogen atmosphere was added N,N-diisopropylethylamine (17.46 g, 135.0 mmol). After the mixture was stirred at ambient temperature for 30 minutes, 1-hydroxybenzotriazole (8.52 g, 63.04 mmol) and benzylamine (6.76 g, 6.88 mL, 63.04 mmol) were added. The mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL), washed with water (2×100 mL) and brine (2×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate:petroleum ether, 2:1) to afford the title compound (11.91 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (t, J=6.0 Hz, 1H), 7.34-7.25 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 298.1 (M+1), 300.1 (M+1).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH2:48][CH2:49][O:50][CH3:51])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[F:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH2:48][CH2:49][O:50][CH3:51])(=[O:47])=[O:46])[CH:44]=[CH:39][C:40]=1[F:52])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: COCCS(=O)(=O)c1ccc(F)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: COCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 80 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-Bromo-1-fluoro-4-(2-methoxy-ethanesulfonyl)-benzene (Intermediate 132), the title compound was obtained as a colorless oil in 80% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)O.[BH4-].[Na+].O>CC(O)C>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:8]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: OC(c1cnc2ccccc2c1)c1ccc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: c1c[nH]c(Cc2cnc3ccccc3c2)c1
Yield: 80.8 %

Procedure:
To a solution of (1H-pyrrol-2-yl)(3-quinolyl)methanol (40.0 mg) in 2-propanol (3 mL) was added sodium borohydride (33.9 mg), and the mixture was refluxed for one hour. To the mixture was added water, and the mixture was concentrated. The residue was separated using water and ethyl acetate, and the organic layer was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-(3-quinolylmethyl)-1H-pyrrole (30.0 mg, 75%).