Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>C(O)C>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10](=[O:19])[C:11]4=[C:12]([C:13]4[S:14][CH:15]=[C:16]([CH3:18])[N:17]=4)[N:4]3[CH2:3][CH:2]([CH2:23][OH:24])[O:1]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(O)CO)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CO)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 6-(2,3-dihydroxypropyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (450 mg, 1.284 mmol), 5-chlorofuran-2-carbaldehyde (184 mg, 1.413 mmol) and bismuth triflate (169 mg, 0.257 mmol) in ethanol (9.584 ml) was stirred at room temperature for 2.5 hours. TFA (310 μl) was added and the mixture heated under microwave radiation at 80° C. for 20 mins, then further heated under microwave radiation at 80° C. for 10 hours. The reaction was then concentrated to half-volume under vacuum, a further portion of bismuth triflate (169 mg, 0.257 mmol) and powdered molecular sieves (200 mg) were added and the mixture heated under microwave radiation at 80° C. for 10 hours. The mixture was evaporated under vacuum and the residue partitioned between EtOAc (100 ml) and saturated K2CO3(aq) (100 ml) The phases were separated and the aqueous phase was extracted with EtOAc (3×100 ml). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-50% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:17]=[C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])[O:15][N:14]=3)=[CH:11][N:12]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(Oc2ncc(-c3cc(C(C)NC(C)=O)on3)s2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC(C)c1cc(-c2cnc(Oc3ccc(O)cc3)s2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of Example 53B (726 mg, 2.02 mmol) in dichloromethane (20 mL) was added boron tribromide (763 μL, 8.08 mmol) at −78° C. Upon addition, the mixture was allowed to stir at 25° C. for 16 hours. The reaction was then cooled to 0° C., treated with methanol (10 mL) and diluted with dichloromethane (80 mL). The resulting mixture was washed with water (120 mL) and brine (150 mL). The organic layer was dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 40% to 90% ethyl acetate in hexanes to provide 384 mg of the title compound (55%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.99 Hz, 3H) 1.87 (s, 3H) 4.93-5.24 (m, 1H) 6.55 (s, 1H) 6.82-6.95 (m, 2H) 7.16-7.34 (m, 2H) 7.95 (s, 1H) 8.53 (d, J=8.09 Hz, 1H) 11.78 (s, 1H); MS (ESI) m/z 346.0 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(O)CCC.C(O)C.CCOCC>[ClH:1].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[O:10][C:9](=[O:11])[N:8]([CH:12]([CH3:14])[CH3:13])[CH2:7]2)[CH2:25][CH2:24]1
Reactant: CC(C)N1CC(CCCCCl)OC1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CCCCO
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CCCCC2CN(C(C)C)C(=O)O2)CC1
Yield: 69 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-(1-methylethyl)-2-oxazolidinone (5.2 g, 0.0237 mol), 1-(2-methoxyphenyl)piperazine (4.56 g, 0.0237 mol), potassium carbonate (9.84 g, 0.0712 mol) and potassium iodide (1.0 g) in n-butanol (200 mL) gave an oil. The oil was dissolved in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ether gave a solid which was collected by filtration and dried under high vacuum at 70° C. to give 7.36 g (69% yield), mp 206°-213° C.
Reaction SMILES: [CH:1]1([CH:7]([N+:14]([O-:16])=[O:15])[CH:8](O)[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1C=CC=CC=1>[F:10][C:9]([F:11])([F:12])[CH:8]=[C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])C(C1CCCCC1)C(O)C(F)(F)F
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: c1ccccc1
Product: O=[N+]([O-])C(=CC(F)(F)F)C1CCCCC1
Temperature: 70 °C
Yield: 66 %

Procedure:
A mixture of 3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ol (2) (1.015 gm) and ([methoxycarbonylsulfamoyl]triethylammonium hydroxide, inner salt) (Burgess reagent) (2.2 gm) in benzene (10 mL) was heated to 70° C. for 1.5 hours. After cooling the reaction mixture to room temperature, the organic layer was decanted away from the solids and evaporated to dryness under reduced pressure. Purification of the crude product on silica gel chromatography (eluting with 2% ethyl acetate/hexane) gave (3,3,3-trifluoro-1-nitroprop-1-enyl)cyclohexane (0.62 gm, 66%).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:19]([N:21]1CCOC[CH2:22]1)C.C(OC(Cl)=O)C(C)C.O>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=1
Reactant: CCN1CCOCC1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(c1ccc(C(=O)N(C)C)cc1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.2 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is dissolved in 10 ml of dimethylformamide, mixed at 0° C. with 1 ml of N-ethylmorpholine and 1 ml of chloroformic acid isobutyl ester. It is stirred for 30 minutes at 0° C., 2 ml of dimethylamino solution is instilled and stirred for 2 hours at 0° C. It is stirred into 500 ml of water, extracted with ethyl acetate and the organic phase is concentrated by evaporation in a vacuum. The remaining residue is distilled on a bulb tube. Boiling point: 260° C./0.03 mbar. 0.9 g of 4-[1-(1-imidazolyl)butyl]-benzoic acid dimethylamide is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([F:23])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C@H:10]1[C@H:11]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N[C@@H]1CCNC[C@H]1F)c1ccccc1
Yield: 95.5 %

Procedure:
Using a similar procedure to that described in Example 1, step 4, trans-1-tert-butoxycarbonyl-3-fluoro-4-[(1R)-1-phenylethylamino]piperidine (0.1147 g, 0.356 mmol) was reacted with trifluoroacetic acid (0.5 mL) in dichloromethane (1.0 mL) to give 75.6 mg (96%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.19 (1H, m), 1.35 (3H, d, J=6.6 Hz), 1.68 (1H, m), 2.40-2.73 (3H, m), 2.85 (1H, m), 3.26 (1H, m), 3.99 (1H, q, J=6.6 Hz), 4.28 (1H, two m, J=49.8 Hz), 7.20-7.35 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([OH:18])=O)[C:5]2=1.[CH3:26][NH:27][CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([N:27]([CH3:28])[CH3:26])=[O:18])[C:5]2=1
Reactant: CNC
Reactant: Cn1c2ccc(F)cc2c2c(C(=O)O)cn(-c3ccccn3)c(=O)c21
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cn(-c2ccccn2)c(=O)c2c1c1cc(F)ccc1n2C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g (7.4 mmol) of 6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 2.4 g (14.8 mmol) of N,N'-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added. The mixture is stirred for 48 h at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from ethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([NH:14][C:15](=[O:26])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]2)=[C:12](Cl)[CH:11]=[C:10]([CH3:28])[N:9]=1>>[OH:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:15]([NH:14][C:13]2[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:9][C:10]([CH3:28])=[CH:11][C:12]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:26])[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
Morpholine (9.0 mL) was added to N-(2,4-dichloro-6- methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (1.0 g, 2.88 mmol), and the mixture was stirred for 24 hours at 100° C. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (developer: chloroform/ammonia-saturated methanol=50/1), to thereby yield 826 mg of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide in a yellow amorphous state (yield: 63.9%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1.[C:24]([NH:32][NH2:33])(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11]3[N:12]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:32][N:33]=3)[C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2=NCC(=S)Nc3c(Cl)ccc(Cl)c32)cc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Product: CC(C)c1ccc(C2=NCc3nnc(-c4ccccc4)n3-c3c(Cl)ccc(Cl)c32)cc1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,9-dichloro-1,3-dihydro-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 7,10-dichloro-1-phenyl-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COc1ccc(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)cc1
Yield: 2.7 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(4-methoxy-phenoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (50 mmol) in toluene to give the title compound as a white solid (160 mg).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=2[N:25]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][C:21]([CH3:20])=[N:25][C:24]=3[CH:26]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc3sc(C)nc3c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C21H23NO5S [M+H]+: 402.1.
Reaction SMILES: [CH2:1]([O:5][P:6]([C:13]1[CH:17]=[C:16]([I:18])[S:15][C:14]=1I)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:2][CH2:3][CH3:4].C([Li])CCC.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C1COCC1>[CH2:9]([O:8][P:6]([C:13]1[CH:17]=[C:16]([I:18])[S:15][CH:14]=1)([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOP(=O)(OCCCC)c1cc(I)sc1I
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOP(=O)(OCCCC)c1csc(I)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In THF, 3.10 g (5.9 mmols) of 3-(dibutoxyphosphoryl)-2,5-diiodothiophene was dissolved and cooled down to −78° C. Commercially available n-butyl lithium (1.59 M hexane solution, 6.2 mmols) was slowly dropped, followed by stirring for 1 hour at a standing temperature. Thereafter, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a brown oil at a yield of 1.88 g (yield: 79%). The thus obtained substance was used as it is for reaction in Example 12(18).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[CH3:44][C:45]1[S:49][C:48]([NH2:50])=[N:47][CH:46]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:44][C:45]1[S:49][C:48]([NH:50][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:47][CH:46]=1
Reactant: Cc1cnc(N)s1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 5 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 5-methyl-thiazol-2-ylamine (166 mg, 1.45 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (25 mL) and ethyl acetate (25 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (5 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl)-amide (120 mg, 57%) as a pink solid: mp 216-219° C.; (ES)+-HRMS m/e calcd for C16H16ClN3OS (M+) 333.0703, found 333.0708.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:30]=3)[S:28][C:19]=12
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(C=O)c4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(CN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Morpholine (100 μL, 1.15 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (400 mg, 0.88 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (1.0 g, 4.73 mmol) is added. After stirring at 0° C. for 1 hour, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 154 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 205–207° C.; 1H NMR (DMSO-d6) δ 2.38 (m, 4H), 3.51 (s, 2H), 3.59 (m, 4H), 3.86 (s, 3H), 7.32–7.48 (m, 3H), 7.64–7.70 (m, 2H), 7.77 (s, 1H), 7.91 (s, 1H), 8.61 (s, 1H), 9.74 (s, 1H); MS 523.1, 525.0 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]#[CH:16])=[O:12])=[CH:4][CH:3]=1.[N:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=1)=[N+:22]=[N-:23].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(NCc1cn(Cc2cccc(Oc3ccccc3)c2)nn1)c1cccnc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80.9 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 138 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1b (220 mg 80%); mp: 160-162° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 495 [M+H]+. Yield: 80%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)=[N:8][N:7]=[CH:6]2.[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24].C(N(CC)CC)C.[ClH:35]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCOCC.O>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([N:15]1[CH2:16][CH2:17][CH:18]([O:21][C:26](=[O:27])[NH:25][CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20]1)=[N:8][N:7]=[CH:6]2
Reactant: CCCN=C=O
Reactant: COc1cc2cnnc(N3CCC(O)CC3)c2cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNC(=O)OC1CCN(c2nncc3cc(OC)c(OC)cc23)CC1

Procedure:
6,7-Dimethoxy-1-[4-hydroxypiperidino]phthalazine (0.81 g), n-propyl isocyanate (0.83 g), triethylamine (0.4 ml) and dry chloroform (20 ml) were heated together under reflux for 10 hours. The mixture was then cooled, treated with water (15 ml) and separated. The chloroform layer was shaken with 1 N sodium hydroxide (10 ml), dried (MgSO4) and evaporated in vacuo to give a yellow oil. The oil was dissolved in the minimum volume of chloroform and chromatographed on silica (bed size 3×27 cm). Elution was commenced with chloroform containing gradually increasing amounts of methanol (up to 10%). The first 800 mls of eluant were discarded then 14×70 ml fractions were collected. Appropriate fractions were selected by thin layer chromatography, combined and evaporated in vacuo to give a yellow oil. This oil was dissolved in the minimum volume of ethyl acetate, diluted with ether (30 ml), and acidified to pH 3 with saturated hydrogen chloride. The precipitated solid was collected and recrystallized from acetonitrile to give 6,7-dimethoxy-1-[4-(N-n-propylcarbamoyloxy)piperidino]phthalazine hydrochloride (0.32 g), m.p. 175°-180°.