Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH3:17])[C:11]=2[O:14][CH3:15])[CH2:6][C:5]1=O)C=C.[CH3:19][NH2:20].[CH3:21][C:22]([OH:24])=O>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[C:12]2[CH2:13][CH:4]3[C:5](=[CH:6][C:7]=2[CH:8]=[CH:9][C:10]=1[O:16][CH3:17])[N:20]([CH3:19])[C:22](=[O:24])[CH2:21]3
Reactant: CC(=O)O
Reactant: CN
Reactant: C=CCC1Cc2c(ccc(OC)c2OC)CC1=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CC1CC(=O)N(C)C1=C2
Temperature: 120 °C

Procedure:
To a stirred solution of Intermediate I (830 mg) in toluene (7 mL) in a microwave reactor vial was added a solution of methylamine (0.75 mL, 8 M in EtOH) and AcOH (0.34 mL) was added. The reactor was sealed and the mixture was heated at 120° C. for 15 min under microwave irradiation. The solution was concentrated in vacuo and the residue was dried in vacuo. The crude product was purified by silica gel chromatography (EtOAc/heptane). Yield: 210 mg of compound 12 as an oil.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:43]=[CH:42][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[F:41])=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[F:41][C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[NH:30][C:28]([C:27]1[CH:42]=[CH:43][C:24]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[N:25][CH:26]=1)=[O:29]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1F)c1ccc(Cl)nc1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C(F)(F)F)cc4F)cn3)CC2)cc1

Procedure:
4-{4-[5-(2-Fluoro-4-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(2-fluoro-4-trifluoromethyl-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C24H20N4O3F4 [M+H]+: 489.1545. Found: 489.1543.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]1([NH2:20])[CH2:19][O:18][CH2:17]1.[S:21]1(=[O:32])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][NH:24][CH2:23][CH2:22]1>>[NH2:20][C:16]1([CH2:15][NH:14][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([N:24]3[CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:21](=[O:32])[CH2:22][CH2:23]3)[N:11]=2)[CH2:19][O:18][CH2:17]1
Reactant: NCC1(N)COC1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: O=S1CCNCc2ccccc21
Product: NC1(CNc2nc(N3CCS(=O)c4ccccc4C3)nc3ccc(Cl)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4,6-trichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, CD3OD) δ ppm 8.57 (s, 1 H), 8.01-7.73 (m, 2 H), 7.52-7.40 (m, 4 H), 5.31-5.28 (d, J=15.2 Hz, 1 H), 4.66-4.53 (m, 6 H), 4.08 (s, 2 H), 3.51-3.50 (m, 2 H), 1.36-1.31 (m, 1 H).
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]3[O:32][C:31]([C:33]4[S:34][CH:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[N:37]=4)=[CH:30][C:29]=3[CH:42]=1)[CH:19]=[C:18]2[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:10])C1C=CC=CC=1.O1CCCC1>CO>[C:38]([C:36]1[N:37]=[C:33]([C:31]2[O:32][C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:20]4[C:21]5[C:17](=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][C:9]([OH:10])=[O:8])=[CH:23][CH:22]=5)[C:18]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:19]4)=[CH:42][C:29]=3[CH:30]=2)[S:34][CH:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCCCC(=O)OCc3ccccc3)cc12
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCCCC(=O)O)cc12

Procedure:
A solution of methyl 5-[3-(benzyloxycarbonyl)propoxy]-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetate in a mixed solvent of tetrahydrofuran (2 ml) and methanol (2 ml) was hydrogenated over 10% Pd--C (60 mg) at room temperature under atmosphere pressure. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(3-carboxypropoxy)indole-3-acetate (0.16 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([CH2:37][O:38][CH2:39][CH3:40])[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[CH2:39]([O:38][CH2:37][CH:5]([CH2:4][O:3][CH2:1][CH3:2])[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:40]
Reactant: CCOCC(COCC)Oc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOCC(COCC)Oc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
To a mixed solution of ethyl 3-[4-({4′-[2-ethoxy-1-(ethoxymethyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.665 g, 1.20 mmol) in ethanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 72 hrs. Water was added to the reaction mixture and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (0.588 g, yield 93%) as a colorless viscous oil.
Reaction SMILES: [H-].[Na+].SCCCS.Br[CH2:9][CH2:10][P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12]>CCCCCC>[CH:10]([P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH2:9]
Reactant: CCOP(=O)(CCBr)OCC
Agent: SCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: C=CP(=O)(OCC)OCC
Temperature: 0 °C
Yield: 90 %

Procedure:
A sample of 60% NaH in mineral oil (95 mmol) was placed in a 2-neck round bottom flask and charged with dry hexane (20 mL). This solution was allowed to stir for ten minutes, after which the hexane-mineral oil layer was completely removed. The flask was then charged with dry tetrahydrofuran (100 mL), followed by dropwise addition of HS(CH2)3SH (46 mmol) with constant stirring. The resulting solution was cooled at 0° C. and BrCH2CH2P(O)(OC2H5)2 (95 mmol) was added dropwise with constant stirring over a period of 30 minutes. Excess NaH was quenched by addition of 50 mL of deionized water. The solution was extracted from ethyl acetate (3×50 mL) and washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. Upon filtering, the solvent was removed in vacuo to afford compound 5 in 90% yield along with a trace amount of diethyl vinylphosphonate. The compounds were separated on a silica gel column (20 cm; 60 mesh) using 90:10 ethyl acetate to hexane solvent mixture. Removal of the solvent in vacuo, afforded compound 5 as a viscous, yellow-green oil with an overall yield of 88%. High resolution FAB/MS Anal. Calcd. for C15H34O6P2S2 : 436.1272; Found: [M+H+ ], m/z=437.1350. 1H NMR (CDCl3): δ 1.34 (t, 3JHH =9.0 Hz, 12H, OCH2CH3), 1.87 (qn, 2H, CH2CH2CH2), 2.03 (m, 4H, PCH2CH2), 2.65 (t, 3JHH =9.0 Hz, 4H, CHCH2CH2), 2.74 (m, 4H, PCH2CH2), 4.11 (m, 8H, OCH2CH3). 13C NMR (CHCl3): δ 16.3 (d, 3JPC =4.5 Hz, OCH2CH3), 24.8 (d, 2JPC =3.0 Hz, PCH2CH2), 26.6 (d, 1JPC =136.6 Hz, PCH2CH2), 28.5 (s, CH2CH2CH2), 30.5 (s, CH2CH2CH2), 61.6 (d, 2JPC= 6.0 Hz OCH2CH3). 31P NMR (CDCl3): δ 29.1 (s).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=[O:10].[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10]
Reactant: CN(C)c1ccncc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccncc1CO
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A solution of 4-dimethylaminopyridine-3-carboxaldehyde (J. Het. Chem, 25, 81) (1.5 g) in ethanol (25 ml) was treated with sodium borohydride (200 mg) and the mixture was stirred for 4 hours. Concentrated hydrochloric acid (1 ml) was added and the mixture was concentrated. The residue was treated with saturated aqueous sodium chloride (40m) and concentrated aqueous sodium hydroxide (2 ml) and the mixture was extracted with dichloromethane (4×20 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (40 ml), dried (PS paper) and concentrated. The residue was dissolved in methanol, treated with decolourising charcoal, filtered and concentrated to give 4-dimethylaminopyridine-3-methanol (1.1 g) as a pale yellow oil. NMR: (d6DMSO): δ2.9 (6H,s); 4.5(2H,s); 4.0-4.8(1H, br.s); 6.7(1H,d); 8.15(1H,d); 8.3(1H,s); m/e 153 (M+H)+ ; 135(M+H-H2O)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][O:17][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
Methyl(4S)-4-[(tert-butoxy)carbonylamino]-5-hydroxypentanoate (9.11 mmol, 2.25 g) was dissolved in 30 mL of methylene chloride. p-Toluenesulfonyl chloride (9.1 mmol, 1.7 g) and triethylamine (27.33 mmol, 3.8 mL) were added and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and crude was purified by column chromatography (SiO2, 4:1 n-hexanes/ethyl acetate to 7:3 n-hexanes/ethyl acetate) to yield the title compound (1.98 g, 54% yield). ES-MS: 402 (M+1).
Reaction SMILES: [OH-].[Na+].CN(C)[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=1)=O.[N+]([O-])(O)=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH2:31])=[NH:30])[CH:25]=[CH:26][CH:27]=1>CC(O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[N:31]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([Cl:15])[CH:10]=3)[CH:6]=[CH:5][N:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: N=C(N)Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
31 mg (0.78 mmol) of sodium hydroxide are added to a suspension of 150 mg (0.7 mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 165 mg (0.71 mmol) of 3-chloro-phenyl-guanidine nitrate in 1.5 ml of 2-propanol. After stirring under reflux for 18 hours, the reaction mixture is cooled and filtered and the material retained on the filter is washed thoroughly with water. After drying (60°, HV), N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 196°-198°, Rf =0.67 (methylene chloride:methanol=95:5), FAB-MS: 317 (M+ +1).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1.Cl.CCCCCC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:23][CH:24]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc(CC(Cc2ccc(Cl)cc2)=C2C=CC=C2)cc1
Temperature: -78 °C
Yield: 22.2 %

Procedure:
Under a nitrogen atmosphere, a 100-mL three-necked flask was charged with 0.66 g (9.22 mmol) of lithium cyclopentadiene and 10 mL of dehydrated THF, and the mixture was stirred. This solution was cooled (to −78° C.) in a dry ice/methanol bath, and 2.50 g (8.96 mmol) of bis(4-chlorobenzyl)ketone dissolved in 15 mL of dehydrated THF was added dropwise. Subsequently, the mixture was stirred for 17 hours while gradually warming to room temperature. Then, 1 N hydrochloric acid was added to the resulting brown-black solution to terminate the reaction. Thereafter, hexane was added to perform liquid-liquid phase separation, and the aqueous layer was subjected to extraction with hexane twice. The resultant was combined with the organic layer obtained previously. The resultant liquid was then washed two times with a saturated aqueous solution of sodium hydrogen carbonate, two times with water, and once with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain a target product as a yellow powder (yield 0.65 g (22%)). The target product was identified by 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1ccc(NNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
10 g of 4-methoxyphenylhydrazine hydrochloride are dissolved in water and then triethylamine is added until the salt has been neutralized. Extraction is carried out with AcOEt and then the extract is evaporated to dryness to produce 8 g of precipitate composed of 4-methoxyphenyl-hydrazine. This compound is dissolved in 30 ml of ether and then a solution of 13 ml of acetic anhydride dissolved in 30 ml of ether is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then the white precipitate formed is filtered off to produce 7.4 g of the expected compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)O
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Product: C=C(C)C(=O)OCCCCOc1ccc(C(=O)O)cc1

Procedure:
4-(4-Hydroxybutoxy)benzoic acid was first prepared by the method described in Whitcombe et al., Polymer Comm. 32, 380-381 (1991). This acid was then esterified with methacrylic acid by the method described in Portugall et al., Makromol. Chem. 183, 2311 (1982) to give an oil, which was precipitated into water, filtered, dried and recrystallized from 2-propanol to give 4-(4-methacryloxybutoxy)benzoic acid, melting point 103°-106° C. this acid was converted to the desired acid chloride using the method described in the aforementioned Portugall et al. paper; the acid chloride was obtained as a clear, colorless oil, which was recrystallized from dry hexanes to give the final product (84% yield) as fluffy white needles, melting point 30°-31° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=2)[C:42]2=[N:41][CH:40]=[CH:39][CH:38]=[C:37]2[CH:36]=[CH:35]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3cccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 7-azaindole (16.76 mg, 0.142 mmol, Alfa Aesar, Ward Hill, Mass.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. Purification by silica gel chromatography, eluting with 50% EtOAc in hexanes gave 2-(4-((S)-2-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (28 mg) as a mixture of two isomers.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[C:22](C)=[CH:21][CH:20]=[CH:19][C:18]=3C)[CH:12]=2)[C:7]1=[O:25].[CH2:27](O)[CH2:28][CH2:29]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:14]([OH:15])[C:13]2[C:8]([C:7]=1[OH:25])=[CH:9][CH:10]=[C:11]([O:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:12]=2)=[O:26])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCO
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Agent: [Na]
Product: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Reaction time: 3 h

Procedure:
0.79 g of sodium (34 mmol) were dissolved in 100 ml of n-butanol with stirring. Then the temperature was raised to 95° C. to 100° C., 5.70 g of [5-(2,6-dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (16.8 mmol) were added in one portion and stirring was continued at 95° C. to 100° C. for 3 h. Subsequently, the solvent was evaporated in vacuo, 25 ml of aqueous 2N HCl and 100 ml of ethyl acetate were added and the mixture was stirred vigorously for 30 min before it was filtered by suction. The organic phase was separated from the filtrate, dried over MgSO4 and was evaporated in vacuo to give a brown gum that was triturated with methanol. The resulting precipitate was filtered by suction and dried in vacuo to give 870 mg of a yellowish solid (A). The filtrate was evaporated in vacuo, dissolved in a small amount of methanol and stored overnight in a refrigerator. The resulting precipitate was filtered by suction and dried in vacuo to give 246 mg of a yellowish solid (B). A and B were pooled and purified by flash column chromatography on silica gel eluting with dichloromethane:ethyl acetate (98:2). Evaporation of the first fraction yielded 762 mg of the title compound; 1H NMR (CDCl3): δ=8.31 (bs, 1H), 8.12 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.09 (bs, 3H), 4.39 (t, 2H), 2.11 (s, 6H), 1.77 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[NH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)C>[O:39]1[CH2:40][CH2:41][N:36]([NH:35][C:5]2[O:6][CH2:7][C:8](=[O:16])[C:9]=2[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:37][CH2:38]1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: NN1CCOCC1
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: CCO
Product: CC(C)OC(=O)C1=C(NN2CCOCC2)OCC1=O
Reaction time: 18 h

Procedure:
To a solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (12.2 g, 53.6 mmol), which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, in ethanol (45 mL), 4-aminomorpholine (5.7 mL, 59.2 mmol) was added at ambient temperature. The mixture was stirred for 18 h. The solvent was removed under reduced pressure, and the crude product was suspended in methyl tert-butyl ether, then the precipitate was collected by filtration, washed with methyl tert-butyl ether and hexane then dried to afford isopropyl 2-(morpholinoamino)-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (11.2 g, y. 75%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Product: CS(=O)(=O)c1ccc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1

Procedure:
This compound is prepared according to synthesis 229, from 200 mg (0.49 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 110 mg (0.55 mmol) of 4-methanesulfonylphenylboronic acid to give, after purification by chromatography on silica (eluent dichloromethane/methanol 95/5), 49 mg (32%) of 8-(4-methanesulfonyl-phenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Mn]([O-])(=O)(=O)=[O:15].[Na+].[OH2:20]>C(O)(C)(C)C>[Cl:1][C:2]1[C:6]([C:7]([OH:15])=[O:20])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: O
Reactant: CC1CN(c2cccnc2)N=C1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a mixture of 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2.0 g, 10 mmol) in water (10.0 mL) and tert-butanol (5.0 mL) was added a solution of sodium permanganate (NaMnO4) (5.0 g, 35 mmol) in water (15 mL) over 20 minutes. The mixture was heated to 80° C. and stirred overnight. Additional sodium permanganate (0.711 g, 5.0 mmol) in water (2.0 mL) was added after 16 hours and the mixture was stirred for another 4 hours. The dark mixture was filtered through Celite®, washed with water (5.0 mL) and ethyl acetate (3×15 mL). The aqueous layer was extracted with ethyl acetate (25 mL) and acidified with concentrated hydrochloric acid to pH 5 leading to white precipitate which was collected by filtration. The filtrate was concentrated leading to white precipitate which was collected by filtration and washed with water (2.0 mL). The solid products were combined and dried under high vacuum to afford the title compound as a white solid (1.0 g, 46%): 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.59 (d, J=4.7, 1H), 8.28 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.58 (dd, J=8.0, 4.4 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 162.24, 148.35, 141.46, 140.21, 135.01, 134.01, 126.45, 124.23, 115.34; ESIMS m/z 224 ([M+H]+).