Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)n(-c2ncccn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NaH (0.594 g, 14.84 mmol) was suspended in THF (10 mL), and 3,5-dimethylpyrazole (1.091 g, 11.35 mmol) was slowly added and stirred for one hour at room temperature. 2-Chloropyrimidine (1 g, 8.73 mmol) was slowly added to the mixture and refluxed for three hours. Completion of the reaction was confirmed by TLC, and then water (5 mL) was added to the mixture. The solvent was distilled off and the residue was extracted with ethyl acetate twice. The organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate) to give 1.05 g of the title compound (yield 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21](Cl)=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[N:22][C:21]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][C:32]=4[Cl:34])=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(Cl)cn3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cnc(-c4ccc(Cl)cc4Cl)cn3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using 5-chloro-pyrazine-2-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.077 g, 0.20 mmol) and 2,4-dichloro-phenyl boronic acid. (0.045 g, 0.24 mmol) to afford the product. LC/MS, Retention time=5.12 min; (m/z): calcd for C23H22Cl2N6O2S: 501.4; found: 501.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:28]3[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=3)=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1nn(C)cc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1,3-dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.71 min; [M+H]+=455.2.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2c(Cl)cccc2Cl)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2c(Cl)cccc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,6-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,6-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 65%, with a melting point of 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([O:30][CH2:29][CH2:28][O:27][C:26]1[C:19]2[C:20](=[N:21][CH:22]=[N:23][C:18]=2[NH:17][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:24][N:25]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Solvent: c1ccncc1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 7/500 mg, 1.22 mmol) was dissolved in dry pyridine (12 ml) and methanesulfonyl chloride (142 μl, 1.84 mmol) was added drop-wise under argon. The mixture was stirred for 1 hour at room temperature then partitioned between water and methylene chloride. The organic layer was washed with water, dried over MgSO4 and evaporated under vacuum. The residue was triturated in ether, filtered and dried to give the title compound as a tan solid (462 mg, 78%); NMR Spectrum: 3.28 (s, 3H), 3.80 (s, 3H), 4.58 (d, 2H), 4.69 (d, 2H), 5.16 (s, 2H), 7.03 (d, 2H), 7.37 (m, 3H), 7.55 (d, 1H), 7.85 (td, 1H), 8.13 (s, 1H), 8.29 (s, 1H), 8.58 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[Br:1])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(S(N)(=O)=O)cc1Br
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Br)c1
Yield: 78.6 %

Procedure:
2-Bromo-4-sulphamoylaniline (20.0 g) and α-chloroacetyl chloride (25.0 g) were refluxed together for 60 min. and the product worked up as in Example 2(a) to yield 20.5 g white needles, m.p. 174°-175°
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[N:43]=[C:44]=[O:45]>CCCCCC>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44](=[O:45])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 28 %

Procedure:
Part C. To a solution of 8-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptyl-1-octanamine (0.5 g, 0.001 mol) in hexane (25 mL) was added, dropwise, a solution of 2,4-difluorophenylisocyanate (0.15 mL, 0.194 g, 0.00125 mol) in hexane (10 mL), and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed using 8:2 hexane-ethyl acetate to give a solid which was triturated with cold ethyl acetate and then hexane to give the title compound (0.18 g, 0.00028 mol) as a white solid, mp 89°-91°. 1H NMR (DMSO-d6) δ 12.5(s,1H), 7.9(s,1H), 7.5-7.1 (m,10H), 3.3-3.1(m,5H), 1.8-1.2(m,17H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]([S:42](Cl)(=[O:44])=[O:43])=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N1CCOCC1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:42](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:44])=[O:43])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Agent: NC(CO)(CO)CO
Solvent: C1COCCN1
Solvent: ClCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A solution of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}-acetate (42 mg, 0.10 mmol) and β-styrene sulfonyl chloride (Aldrich, 23 mg, 0.11 mmol) in DCM (2 mL) was stirred at rt overnight in presence of a morpholine resin (1.5 eq., Novabiochem HL, 3.8 mmol/g) (1.5 eq). Trisamine resin (1 eq, Novabiochem, 3.5 mmol/g) was then added and the mixture stirred at rt for an additional 2 hrs. The reaction mixture was then filtrated and the solvent was removed under reduced pressure to give 55 mg (95%) of the title compound. HPLC, Rt: 5.8 min (purity: 83%). M+(ESI): 608.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>CN(C)C=O>[C:16]1([C:14]2[N:1]=[C:2]3[N:6]([CH:13]=2)[C:5]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[S:3]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc2c(s1)C(=O)CCC2
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21
Temperature: 25 °C
Yield: 74 %

Procedure:
2-Amino-4,5-dihydrobenzothiazole-7(6H)-one (18 g) prepared in the above (A) was dissolved into dimethylformamide (250 ml), and 2-bromoacetophenone (21,83 g) was added thereto followed by heating to reflux for 12-15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and placed into distilled water. The resulting precipitates were filtered, neutralized with sodium hydroxide solution, filtered, washed with ethyl acetate (100 ml), and dried to give the titled compound (21.25 g, 76%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.[CH3:26]O>>[CH3:26][O:1][C:2]1[C:3]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:13][C:4]=2[CH2:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1
Reactant: CO
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2c(c1)C(OC)=Cc1ccccc1C2

Procedure:
In 50 ml of dry methanol was dissolved 6.3 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 10. Thionyl chloride (7 g) was added, and the solution was heated under reflux for 2 hours with stirring. After the reaction, the reaction mixture was cooled, and methanol was distilled off. The residue was dissolved in 200 ml of benzene. The benzene solution was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The benzene was then distilled off. The residue was chromatographed on a silica gel column using benzene as an eluent. A slightly yellow solid was obtained from the eluate. Recrystallization from n-hexane afforded 4.6 g of methyl 11-methoxy-5H-dibenzo[a,d]cycloheptene-2-acetate as colorless needle-like crystals having a melting point of 72° to 73° C.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1
Reactant: COc1ccc(Oc2cnc3ccccc3c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Oc2cnc3ccccc3c2)cc1
Yield: 97.8 %

Procedure:
A mixture of 3-(4-methoxyphenoxy)quinoline (2.6 g), acetic acid (20 ml) and hydrobromic acid (20 ml of 48%) was boiled under reflux for 5 hours. The solution was concentrated under reduced pressure, poured onto ice and the resultant precipitate was collected by filtration to give 3-(4-hydroxyphenoxy)quinoline as a dark brown solid (2.4 g), mp 250° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([S:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([F:23])[F:22]>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([S:24][C:21]([F:23])([F:20])[F:22])[CH:26]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(SC(F)(F)F)c1
Product: FC(F)(F)Sc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethylsulfanyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethylsulfanyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5]
Reactant: CCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyoctanoic acid (1.90 g) and triethylamine (1.65 ml) in DMF (20 ml) was added benzyl bromide (1.41 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.71 g of benzyl 3-hydroxyoctanoate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH:5]2[O:4][CH:3]([CH2:2][O:1][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:7][CH2:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC(CO)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.0 g (261 mmol) of 2,5-bis(hydroxymethyl)tetrahydrofuran are dissolved in 260 ml of dichloromethane. A solution of 99.0 g (521 mmol) of p-toluenesulfonyl chloride in 52 ml of pyridine and 130 ml of dichloromethane is added dropwise thereto. After stirring at room temperature for 24 hours, the precipitate is filtered off with suction and washed with dichloromethane. The filtrate and the washing phases are combined, washed with dilute hydrochloric acid and then with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness. The crude product is recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:42])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=[O:69])N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:42])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([C:18]([F:20])([F:21])[F:19])[CH:9]=2)[C:4](=[O:22])[N:3]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][S:31]([CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:37])([F:38])[F:39])=[O:69]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CC(=O)Nc1ccc(N2C(=O)N(CCOCCOCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(N2C(=O)N(CCOCCOCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Yield: 75 %

Procedure:
Compound 39 described below was synthesized according to a similar method to that described in Example 2 using the compound of Example 38 as starting reagent replacing the compound of Example 1. The expected compound is obtained in the form of a pale yellow oil with a yield of 75%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22](O)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1.O.[NH3:27]>ClCCl>[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22]([NH2:27])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 50 °C
Yield: 69.8 %

Procedure:
Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 hr and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% ammonia water (10 mL) and a solid precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 hr. Water (20 mL) was added to the mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 44 mg 2-p-tolylbenzo[d]oxazole-4-carboxamide as a solid (yield 69.8%). 1H-NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 6.01 (s, 1H), 7.34-7.36 (d, J=7.6 Hz, 2H), 7.43-7.47 (t, J=8.0 Hz, 1H), 7.71-7.73 (d, J=8.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H); LC-MS (ESI) m/z 253 [M+1]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9])(=[O:4])[CH2:2][CH3:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([S:27](O)(=[O:29])=[O:28])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:9][S:27]([C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=2)(=[O:29])=[O:28])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1cc(N)ccc1OC
Reactant: COc1cc(S(=O)(=O)O)cc(OC)c1OC
Product: CCC(=O)Nc1cc(NS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)ccc1OC

Procedure:
Compound 91 is synthesized following a similar method as in Example 1 and using 3-propionamido-4-methoxyaniline and 3,4,5-trimethoxybenzenesulfonic acid as materials. Total yield of the two steps: 40%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 58%). MS (ISP) 582.2 [(M+H)+]; mp 193-194° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]([N:20]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:21][C:22]([C:24]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=[CH:33]3)[CH2:29][CH2:28][CH2:27][N:26]4[CH:25]=2)=O)=[O:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:19])[N:20]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:21][C:22]=2[C:24]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=[CH:33]3)[CH2:29][CH2:28][CH2:27][N:26]4[CH:25]=2)=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)c1cn2c3c(cccc13)CCC2)C(=O)Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(c2cn3c4c(cccc24)CCC3)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
A mixture of 3-(2-{tert-butoxycarbonyl-[2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-amino}-2-oxo-ethyl)-indole-1-carboxylic acid tert-butyl ester (1.04 g, 1.82 mmol) and DBU (0.27 mL, 1.91 mmol) in anhydrous DMF (20 mL) was stirred at 110° C. for 2 h. The mixture was cooled and evaporated. The residue was purified by silica gel column chromatography (eluent: 4/1 then 3/1 hexane/EtOAc) to give 3-[1-tert-butoxycarbonyl-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-indole-1-carboxylic acid tert-butyl ester as a yellow foamy solid (0.64 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ: 8.13 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.30 (m, 1H), 7.05 (m, 3H), 6.89 (m, 2H), 5.00 (s, 2H), 4.03 (t, J=5.6 Hz, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.03 (m, 2H), 1.65 (s, 9H), 1.54 (s, 9H). LCMS: m/e 554.21 [M+H].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)([CH3:14])[CH3:13])=[CH:16][C:17]=1[C:27]1[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccncc2)c1
Yield: 41.2 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (130 mg, 0.291 mmol), pyridine-4-boronic acid (54 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (46 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J=1.6, 4.5 Hz, 2H), 7.61-7.39 (m, 4H), 7.15 (dd, J=8.6, 10.2 Hz, 1H), 5.31 (s, 1H), 4.69-4.57 (m, 1H), 3.40-2.07 (m, 6H), 1.69 (d, J=10.8 Hz, 6H), 2.06-0.74 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.0, 157.6, 143.3, 141.6, 141.5, 126.7, 126.6, 124.9, 124.8, 120.1, 119.9, 116.1, 115.9, 115.4, 115.1, 109.2, 71.4, 55.9, 55.0, 47.6, 46.7, 29.9, 25.6, 24.8, 19.8 ppm. Purity: 97% UPLCMS (210 nm); retention time 0.82 min; (M+1) 384.6.