Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18](O)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42]1(=[O:52])[NH:46][C:45](=[O:47])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:18]([N:46]1[C:42](=[O:52])[C:43]2[C:44](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:45]1=[O:47])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(c1cc2cc(Cl)ccc2n1Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-(1-benzyl-5-chloro-1H-indole-2-yl)-2-methylpropan-1-ol (0.6 mmol), Ph3P, (1 mmol), phthalimide (1.8 mmol) in 5 mL of dry THF at 0° C., was added DIAD (1 mmol) drop wise. The mixture was warmed up to room temperature gradually and stirred overnight. The solution was poured into water, and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography (10% EtOAc:hexane) to yield 170 mg of title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.Cl.[F:13][C:14]1([F:18])[CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:13][C:14]1([F:18])[CH2:17][N:16]([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc([N+](=O)[O-])cc1CN1CC(F)(F)C1
Temperature: 65 °C

Procedure:
A sealed tube with a magnetic stirrer was charged with DMF (5 mL), 5-(Bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (0.39 g, 1.78 mmol), 3,3-difluoroazetidine hydrochloride (276 mg, 2.13 mmol) and DIPEA (0.8 mL, 4.45 mmol). The reaction mixture was heated at 65° C. for 3-5 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting residue was diluted with a mixture of Ethyl Acetate (15 mL) and water (15 mL). The aqueous layer was separated and extracted with Ethyl Acetate (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield of 156e as yellow oil, which was used without further purification for the next step. MS (ESI+) m/z 233.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1.[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[N:6][C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1N
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Cl)nc1C(=O)O

Procedure:
One of the intermediates, 2-amino-5-chloropyrazine is prepared following the general procedure of Palamidessi and Bernardi, J. Org. Chem. 29, 2491 (1964), wherein methyl 2-amino-3-pyrazinylcarboxylate is allowed to react with chlorine in acetic acid to yield methyl 2-amino-5-chloro-3-pyrazinylcarboxylate. This ester is hydrolyzed with aqueous sodium hydroxide to yield 2-amino-3-carboxy-5-chloropyrazine, which is then heated in tetrahydronaphthalene and decarboxylated to yield the desired 2-amino-5-chloropyrazine.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=O)[S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>CCCCCC>[C:1]([C:9]1[CH:10]=[C:11](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])[S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC#Cc1csc(C=O)c1
Solvent: CCCCCC
Product: CCCCCCC#Cc1csc(/C=C/C(=O)O)c1
Yield: 91 %

Procedure:
Reaction of 4-(1-octynyl)-2-thiophenecarboxaldehyde (1.1 g, 5 mmole) with malonic acid by the method described in Example 2 yielded the title compound 1.19 g, (91%) as a fawn solid, mp 81° (hexane) νmax (mull) 2600(vb) 1695, 1680, 1625, 965, 940, 830, 760; δ(CDCl3) 0.90(3H, t, J=6 Hz), 1.4(8H, m), 2.37(t, 2H, J=6 Hz), 6.22(H, d, 15 Hz), 7.25(1H, s), 7.40(1H, s), 7.80(d, 1H, J=15 Hz), 11.5(1H, bs).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:16]1([S:22]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:16]1([S:22][C:11]2[S:10][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=3)=[CH:13][CH:12]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc(-c2cccs2)c1
Reactant: ClSc1ccccc1
Agent: [Fe]
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccc(Sc3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.9 %

Procedure:
A mixture of 29.7 g (0.13 mole) of 2-(m-trifluoromethylphenyl)thiophene, 200 ml of reagent carbon tetrachloride, 15.5 ml (18.8 g 0.13 mole) of benzene sulfenyl chloride and 0.05 g of iron powder was allowed to stand 4 days at room temperature. The reaction mixture was found by vapor phase chromatography to contain approximately equal amounts of 2-(m-trifluoromethylphenyl)thiophene, diphenyl disulfide and the desired disubstituted thiophene. An additional 12.7 ml (0.11 mole) of benzenesulfenyl chloride and 0.05 g of iron powder were added. The mixture was stirred 2 hours at room temperature and then 1 hour at reflux. The carbon tetrachloride solvent was removed by distillation. The residue was distilled at reduced pressure to give 17 g (39%) of 2-phenylthio-5-(m-trifluoromethylphenyl)thiophene b.p. 172°-210° C. (0.04 mm), nD21 =1.6329-1.6330.
Reaction SMILES: [C:1]([C:4]1[C:5]([O-])=[N:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)=[N:8][CH:9]=1)(=O)[NH2:2].[Na+].P(Cl)(Cl)([Cl:31])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:31][C:5]1[C:4]([C:1]#[N:2])=[CH:9][N:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:6]=1
Reactant: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: N#Cc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Cl
Temperature: 90 °C
Reaction time: 24 h

Procedure:
88 mg of sodium 5-carbamoyl-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-4-olate (1-13-1, 0.228 mmol, 1 eq.) were suspended in 0.915 ml of phosphoric trichloride (9.82 mmol, 43 eq.) and 69 μl of N,N-diethylaniline (0.457 mmol, 2 eq.). The suspension was stirred at 90° C. bath temperature for 24 hours and then dropped to an ice cooled saturated aqueous sodium hydrogen carbonate solution. The resulting suspension was filtered off and dried in vacuo to yield 82 mg (0.21 mmol, 93.77%) of the analytically pure target compound.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(CO)COC2)c1OC(F)F
Temperature: 80 °C
Yield: 19.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (89 mg, 0.493 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 19%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH:35]=[O:36])=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:13]=2[C:23]([F:26])([F:25])[F:24])=[N:10][O:11]3)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]23[C:34]4[CH:33]=[CH:32][C:31]([CH2:35][OH:36])=[CH:30][C:29]=4[O:28][CH2:27][CH:8]2[C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:13]=2[C:23]([F:25])([F:26])[F:24])=[N:10][O:11]3)[CH2:5][CH2:6]1
Reactant: O=Cc1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2c(c1)OCC1C(c3onc(-c4ccccc4)c3C(F)(F)F)=NOC21N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazole-7-carbaldehyde (Preparation 60F, 0.070 g, 0.140 mmol) in methanol (1.0 mL) at room temperature was added sodium borohydride (1.43 mg, 0.038 mmol). The reaction mixture was stirred at room temperature for 30 min. Methanol was removed under reduce pressure, and the residue was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (9b-morpholino-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,9b-dihydro-3aH-chromeno[3,4-d]isoxazol-7-yl)methanol as a yellow oil. The product had an HPLC ret. time=2.83 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=502.0.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=[C:6]([CH2:8][Br:9])[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Br:9][CH2:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=1
Reactant: FC(F)Oc1ncc(CBr)cc1Br
Reactant: OB(O)c1cccc(Cl)c1
Product: FC(F)Oc1ncc(CBr)cc1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 10, using Intermediate 4 and 3-chlorophenyl boronic acid in Step 1, followed by bromination according to Step 3. [M+H]=348.17/350.15
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=2)=[N:2]1.S(Cl)(Cl)=O.CN(C=O)C.[BH4-].[Na+]>C(Cl)Cl.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=2)=[N:2]1
Reactant: O=C(O)c1nc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: OCc1nc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
(E)-3-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}[1,2,4]oxadiazole-5-carboxylic acid (14 mg, 0.04 mmol) obtained in Step 2 of Example 175 was dissolved in methylene chloride (1.0 mL), and thionyl chloride (5 μL, 239-0.06 mmol) and DMF (few drops) were added thereto, followed by stirring for 30 minutes. Then the mixture was concentrated and the residue was dissolved in dioxane (1.0 mL). Sodium borohydride (16 mg, 0.42 mmol) was added to the solution and the mixture was stirred at room temperature for 1 hour. Water was added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by preparative thin-layer chromatography (chloroform/acetone=4/1) to obtain Compound 179 (3.5 mg, 26%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](N)=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:15][B-](F)(F)F.N#[O+]>ClCCl>[F:15][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13]2)=[CH:8][CH:9]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Agent: N#[O+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccc(F)cc2c1
Temperature: 25 °C

Procedure:
A mixture 7-nitro-2-aminonaphthalene (1 g, 5.31 mmol) and nitrosonium tetrafluoroborate (931 mg, 7.97 mmol) in dichloromethane (10 mL) is stirred at room temperature for 12 hours and at 110° C. for 1 hour. After cooling to room temperature, the reaction mixture is concentrated by rotary evaporator under high vacuum. The residual oil is purified by flash chromatography on silica gel (3:1 hexanes/EtOAc) to give 7-fluoro-2-nitronaphthalene as a dark red solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[Cl:18][C:4]1[N:3]=[C:2]([NH:28][C@H:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[CH3:27])[CH:7]=[C:6]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)[CH:5]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CS(=O)(=O)N1CC=C(c2cc(Cl)nc(Cl)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(C2=CCN(S(C)(=O)=O)CC2)cc(Cl)n1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
225 mg of 2,6-dichloro-4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridine, 104 μl of (S)-(−)-1-(4-fluorophenyl)ethylamine, 68 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 359 mg of cesium carbonate and 17 mg of palladium acetate were added in turn to 5 ml of degassed tetrahydrofuran, and the mixture was stirred at 60° C. for 10 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate, and filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 118 mg of the objective compound as pale yellow powder.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=O)#[N:2].[ClH:18].Cl.[NH2:20][O:21][CH2:22][CH2:23][NH2:24].N1C=CC=CC=1.Cl>C(O)C>[ClH:18].[NH2:24][CH2:23][CH2:22][O:21][N:20]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: NCCON
Reactant: N#CCCCC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1

Procedure:
5.6 Mmol (1.35 g) of 4-cyano-4'-trifluoromethylbutyrophenone, 5.6 mmol (0.84 g) of 2 aminooxyethylamine dihydrochloride and 0.8 ml of pyridine were refluxed in 20 ml of absolute ethanol for 2.5 hours. The processing was equal to that of example 1. The resulting free base was dissolved in absolute ethanol and an equivalent quantity of 2N alcoholic hydrochloric acid was added. The ethanol was then removed in vacuo and the residue was crystallized twice from ethanol/ether (1:5). The melting point of the resulting title compound was 136°-136.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]([F:19])([F:18])[C:12]([O:14][CH2:15][CH2:16]Cl)=[O:13].O>CS(C)=O>[O:7]([C:12]1([C:11]([F:19])([F:18])[F:10])[O:14][CH2:15][CH2:16][O:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(OCCCl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)C1(Oc2ccccc2)OCCO1
Yield: 47.1 %

Procedure:
A solution of 23.5 g (0.25 mol) of phenol in 50 mL of DMSO was added dropwise to a stirred suspension of 12.0 g (0.25 mol) of 50% NaH in mineral oil in 100 mL of DMSO maintained at 15°-20° by cooling. After evolution of gas had slowed, cooling and stirring were continued while 44.3 g (0.25 mol) of 2-chloroethyl trifluoroacetate were added. The temperature of the reaction mixture was kept below 30° while the exotherm which occurred subsided, then the resulting mixture was stirred overnight, poured into 1 L of water, and extracted with 200 mL, then two 100 mL portions, of ether. The resulting ether solutions were washed with water, dried over CaSO4, and distilled to give 27.6 g (47% yield) of 2-phenoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 52°-54° at 80 Pa (0.6 mm). IR (neat) and NMR (CCl4) spectra were consistent with the assigned structure
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:27]=[C:28]=[S:29])=[CH:21][CH:20]=1>CN1C(=O)CCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][NH:27][C:28]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]3[C:14]([F:17])([F:15])[F:16])=[S:29])=[CH:23][CH:24]=1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Reactant: S=C=NCCc1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(NC(=S)NCCc3ccc(Cl)cc3)ccc21
Yield: 40 %

Procedure:
Reaction of 6-amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 200 μL of a 0.2 M solution in NMP, 40 μmol) with 2-(4-chlorophenyl)ethyl isothiocyanate (240 μL of a 0.2 M solution in NMP, 48 μmol), by the procedure outlined for Example 492, furnished the title compound (7.1 mg, 40%): RT=1.95 min; m/z (ES+)=440.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:23][C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3[nH]1)cn2C
Yield: 145.8 %

Procedure:
The product is prepared by following the procedure described in example 34, stage (k), starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34, stage (k) and 0.82 cm3 of 5N potassium hydroxide. 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde is obtained with the following characteristics:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.CN(C)[CH:17]=[O:18].Cl>CCCCCC.C(OCC)C>[Br:14][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([Br:13])[CH:10]=1)[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc(Br)cc(Br)c1
Temperature: -80 °C
Reaction time: 1 h

Procedure:
0.222 mol of a solution of n-butyllithium in hexane is added dropwise at −80° C. to 0.222 mol of 1,3,5-tribromobenzene in 1.8 liters of ethyl ether. The reaction mixture is stirred at −80° C. for one hour. A solution of 0.222 mol of N,N-dimethylformamide in 50 ml of ethyl ether is slowly added. The temperature is maintained at −80° C. for one hour, before being brought to ambient temperature. Stirring is carried out for one night. 450 ml of 1N hydrochloric acid are added. The reaction mixture is extracted with ether. The organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 95/5).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[N:9]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:8]2[N:9]=[C:5]([CH2:4][NH2:1])[O:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2coc(CN=[N+]=[N-])n2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2coc(CN)n2)OCCO1
Temperature: 55 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[C:21]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])=[N:20][NH:19][N:18]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)#[N:2].CS(C)=[O:32].C(=O)([O-])[O-].[K+].[K+].O.OO.S(=O)(O)[O-].[Na+]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[C:21]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])=[N:20][NH:19][N:18]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)(=[O:32])[NH2:2]
Reactant: N#Cc1ccc2c(n1)-c1sc(-c3n[nH]nc3-c3ccc(F)cc3F)cc1CCO2
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: OO
Solvent: O
Product: NC(=O)c1ccc2c(n1)-c1sc(-c3n[nH]nc3-c3ccc(F)cc3F)cc1CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a solution of 367 (70.0 mg, 0.172 mmol) in dimethyl sulfoxide (0.439 mL, 6.18 mmol) and treated with a solution of potassium carbonate (65.5 mg, 0.474 mmol;) in water (0.433 mL, 24.0 mmol;). After cooling at 0° C., hydrogen peroxide (0.540 mL, 7.04 mmol) was added slowly. The reaction was complete by LCMS at 15 min. Saturated sodium bisulfite (0.894 g, 8.59 mmol) was added and the reaction mixture extracted into ethyl acetate. The organics were washed with brine, dried over sodium sulfate and concentrated to give crude C which was submitted to reverse-phase HPLC to give 379 (27% yield). MS: (ESI+)=426.1