Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (22.7 mL, 2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture was allowed to stir at 0° C. for 30 min, and concentrated in vacuo to dryness. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, and quenched with saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (19.60 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.49-7.43 (m, 1H), 7.42-7.25 (m, 13H), 7.23-7.17 (m, 2H), 7.12-7.04 (m, 2H), 6.91 (s, 1H), 6.72-6.62 (m, 2H), 6.51-6.44 (m, 1H), 6.39 (dd, J=8.6, 2.4 Hz, 1H), 4.99 (s, 2H); MS (ES+) m/z 536.3 (M+23).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=1.[C:17]([OH:21])(=[O:20])[CH:18]=O>>[OH:12][C:10]1([CH3:11])[O:21][C:17](=[O:20])[CH:18]=[C:9]1[C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=[CH:5][C:6]=1[O:13][CH3:14]
Reactant: O=CC(=O)O
Reactant: COc1ccc(C(F)(F)F)cc1CC(C)=O
Product: COc1ccc(C(F)(F)F)cc1C1=CC(=O)OC1(C)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
5-(Trifluoromethyl)-2-methoxyphenylacetone (2800 mg, 12 mmol) was mixed with glyoxylic acid (2.7 mL 18 mmol) and stirred at 100° C. for 16 hours. The reaction mixture was then concentrated in vacuo and azeotroped with toluene to afford the title compound (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Ca+2].[Br-:24].[Br-:25].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[NH2:1][C:2]1[C:7]([Br:24])=[CH:6][C:5]([Br:25])=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: [Br-]
Reactant: CCOC(=O)N(CCN(C)C)c1ccccc1N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N(CCN(C)C)c1cc(Br)cc(Br)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a solution of N-(2-aminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (1.60 g) in methanol (20 ml) and dichloromethane (30 ml) were added calcium carbonate (1.29 g) and benzyltrimethylammonium tribromide (5.05 g), and the reaction mixture was stirred at room temperature for 24 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. To the residue were added 5% aqueous sodium hydrogen sulfite solution and 1N aqueous sodium hydroxide solution to make the solution alkaline and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.87 g of N-(2-amino-3,5-dibromophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])C.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>CC#N>[OH:27][CH:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:8]2[C:9](=[O:10])[N:5]([CH:1]([CH3:3])[CH3:4])[S:6](=[O:18])(=[O:19])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCC(O)CC1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCC(O)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.53 mmol), 4-aminocyclohexanol (0.092 g, 0.80 mmol) and TEA (0.081 g, 0.80 mmol) was dissolved in dry MeCN (3 ml). The reaction was heated in a microwave reactor at 120° C. for 10 mins. A few extra drops of 4-aminocyclohexanol was added and the reaction was heated in a microwave reactor at 140° C. for 20 mins. The residue was purified by silica gel column chromatography using a 25:75 mixture of hexane and EtOAc, to give a 50:50 mixture of cis and trans isomers (0.130 g, 67%). The mixture was separated by HPLC (C8, 0.05M NH4OAc (pH=4.1):MeCN 1:1) to give cis (Example 38) and trans (Example 48) isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Reactant: COc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Yield: 41 %

Procedure:
The product of Example 29, step B and sodium 4-methoxybenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 4:1 hexane/ethyl acetate) provided tert-butyl 8-(4-methoxyphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (221 mg, 41%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.90-7.86 (m, 2H), 7.79 (d, J=9.0 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 6.98-6.91 (m, 2H), 4.56 (s, 2H), 3.83 (m, 5H), 2.86 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH3:28][C:29]1([CH3:42])[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34](B(O)O)[CH:35]=2)[O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:29]1([CH3:42])[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH3:27])[CH:35]=2)[O:30]1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CCc2cc(B(O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(C)c(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.73 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.58 g, 49%) as a colorless solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[C:10]1[C:11](=[O:22])[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18](=[O:21])[C:19]=1[Br:20]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:11](=[O:22])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:18](=[O:21])[C:19]=2[Br:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1C(Br)=C(Br)C(=O)c2ncccc21
Solvent: CCO
Product: O=C1C(Nc2ccc(Cl)cc2)=C(Br)C(=O)c2ncccc21

Procedure:
CeCl3 (0.1 mmol) as a catalyst and 4 equivalents of 4-chloroaniline (10 mmol) were added to 6,7-dibromo-5,8-quinolindion (10 mmol) dissolved in ethanol (100 ml). The reaction mixture was heated at reflux for 8 hrs. After reading the completion of reaction by TLC, it was cooled, filtered, and recrystallized with ethanol to give redish powder of 6-[(N-4-chlorophenyl)amino]-7-bromo-5,8-quinolidione.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=O)[O:23]C(C)(C)C)[CH3:20])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2].Cl.[C:32](OCC)(=O)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]2[N:8]=[C:9]([C:11]3[N:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:23])[CH3:32])[CH3:20])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOc1ccc2nc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn3)oc2c1
Agent: Cl
Product: CCOc1ccc2nc(-c3ccc(OC[C@H](C)NC(C)=O)cn3)oc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-{[6-(6-ethoxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (5.53 g), 4M hydrogen chloride/ethyl acetate (100 mL) and ethyl acetate (100 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with acetic anhydride (50 mL) and pyridine (50 mL). The obtained mixture was stirred at room temperature overnight. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (ethanol/hexane) to give the title compound as white crystals (3.48 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][N:12]=[C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[N:10]=1.B(Br)(Br)Br>C([O-])(O)=O.[Na+]>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][N:12]=[C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[N:10]=1
Reactant: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)ns1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)COC(=O)N1CCN(c2nsc(-c3ccccc3O)n2)CC1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
To isobutyl 4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate from above was added boron tribromide solution (1 M in CH2Cl2, 1.7 mL, 1.7 mmol) at −30° C. The reaction mixture was stirred at −30° C. for 1 h and at room temperature for 3 h. To this mixture was added boron tribromide (1 M in CH2Cl2, 1.4 mL, 1.4 mmol), and the reaction was stirred for another hour. The reaction mixture was diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to give a residue which was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 4-(5-(2-hydroxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate. LC/MS: m/z 363.3 (M+H)+ at 3.52 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][C:17](F)([F:19])[C:16](F)([F:21])[CH2:15]2)[CH:11]=[CH:10][C:9]=1[N:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26](=[O:31])[C:25]([C:32]2[N:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:35]=[CH:34][CH:33]=2)=[N:24]1.O>CS(C)=O>[F:21][C:16]1[C:17]([F:19])=[CH:18][N:14]([C:12]2[CH:11]=[CH:10][C:9]([N:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26](=[O:31])[C:25]([C:32]4[N:36]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:35]=[CH:34][CH:33]=4)=[N:24]3)=[C:8]([F:7])[CH:13]=2)[CH:15]=1
Reactant: COc1cn(-c2ccc(N3CC(F)(F)C(F)(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
KOtBu (236 mg, 2.1 mmol) was added portionwise at room temperature to a solution of 1-[2-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (352 mg, 0.7 mmol) in DMSO (3.5 mL). After stirring for 30 min, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with hexane/AcOEt (1/1-0/1) followed by purification by preparative HPLC. Recrystallization from MeOH/H2O afforded the title compound (105 mg, 32% yield) as a white solid: mp 212-214° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 6.42 (1H, t, J=9.0 Hz), 6.68-6.78 (2H, m), 6.87 (1H, ddd, J=1.1, 2.6, 9.0 Hz), 7.07 (1H, dd, J=2.6, 12.4 Hz), 7.33 (1H, d, J=2.3 Hz), 7.36-7.48 (5H, m), 7.78-7.79 (2H, m). LC-MS (ESI) m/z 464 [M+H]+. Anal. Calcd for C24H16F3N5O2: C, 62.20; H, 3.48; N, 15.11. Found: C, 62.20; H, 3.51; N, 15.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13]OS(C)(=O)=O)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][N:26](C)[CH2:27]CN>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:26]([CH3:27])[CH3:25])[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cn(CCOS(C)(=O)=O)c2ncc(Br)cc2c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCN(C)C)c2ncc(Br)cc2c1=O
Yield: 49 %

Procedure:
A solution of ethyl 6-bromo-1-{2-[(methylsulfonyl)oxy]ethyl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 20, 700 mg, 1.67 mmol) in dichloromethane was purged with N,N-dimethylethane-1,2-diamine gas until the starting material disappeared. The reaction mixture was washed with water, and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford ethyl 6-bromo-1-[2-(dimethylamino)ethyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 300 mg, (49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13].[C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])(=[O:22])[CH:20]=[CH2:21].[OH-].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]2[C:8](=[O:13])[N:9]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])[C:10](=[O:12])[NH:11]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=C2NC(=O)NC2=O)cc1OC
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COC(=O)CCN1C(=O)NC(=Cc2ccc(OC)c(OC)c2)C1=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
20 g (80.6 mmol) of 5-(3,4-dimethoxybenzylidene) -hydantoin, 17.8 g (96 mmol) of 2-ethylhexyl acrylate and 0.90 g (1 6 mmol) of potassium hydroxide were added to 150 ml of dimethylformamide, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 200 ml of water and extracted with 500 ml of ethyl acetate.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[OH:20].CI.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[O:20][CH3:23]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(OC)c1Br)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a solution of 4-bromo-2,7-dimethoxy-3-hydroxy-10H-phenothiazine (3.54 g) and methyliodide (2.5 ml) in DMF (20 ml) there was added pulverized potassium carbonate (1.3 g). The reaction mixture was stirred at room temperature. After 15 minutes, another addition of potassium carbonate (1 gram) was made, followed by two other such additions at 15-minute intervals. The final mixture was stirred for a further 15 minutes, then it was diluted with water (100 ml) and ethyl acetate (100 ml). The organic layer was washed twice with water, dried and evaporated down to a solid residue. Crystallization from acetone followed by column chromatography on silica gel eluting with 1:19 ethyl acetate-dichloromethane afforded the pure title compound (1.27 g). m.p. 223°-225° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])([O:3]CC)=[O:2].[OH-].[Li+]>C(O)C>[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc2[nH]cc(CCN(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A solution of 2-[5-Carboethoxy-1H-indol-3-yl]N,N-dimethylethylamine (1.4 g, 5.4 mmol) and lithium hydroxide (0.45 g, 10.8 mmol) in ethanol (40 ml) was heated at 60° C. for 8 hours, then stirred overnight at room temperature. The ethanol was removed in vacuo and the crude residue chromatographed (eluant 20:15:5:1 ether:ethanol:water:ammonia). The acid (0.94 g, 75%) was isolated as a white solid, after precipitation with ether. δ(360 MHz, D6 -DMSO) 2.86 (6H, s), 3.09 (2H, t, J=7 Hz), 3.33 (2H, t, J=7 Hz), 7.22 (1H, s), 7.46 (1H, d, J=9 Hz), 7.78 (1H, dd, J=9 and 2 Hz), 8.12 (1H, s).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH:6]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:9]=[C:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[C:11]([OH:10])=[O:12]
Reactant: O=C1CC(NC(=O)C(F)(F)F)C(=O)O1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CC(NC(=O)C(F)(F)F)C(=O)O)c1ccccc1

Procedure:
A solution of 3-[(trifluoroacetyl)amino]succinic anhydride (4.00 g, 19.0 mmol) and aluminum chloride (5.56 g, 41.7 mmol) in benzene (80 mL) was refluxed for 5 h, then cooled in an ice bath and quenched by the slow addition of water. The reaction mixture was worked up with ethyl acetate and 10% hydrochloric acid. The residue was purified by chromatography (silica gel, 100% methylene chloride to 90/10/1/1 methylene chloride/methanol/acetic acid/water gradient elution). Recrystallization of the resulting oil from methylene chloride/hexanes produced the title compound as a white solid (3.00 g). 1H NMR (500 MHz, (d6-acetone) □ 11.56 (bs, 1H), 8.63 (bs, 1H), 8.06 (dd, J=8.3, 1.2 Hz, 2H), 7.70-7.67 (m, 1H), 7.57 (t, J=7.7 Hz, 2H), 5.14-5.10 (m, 1H), 3.84 (dd, J=18.3, 6.8 Hz, 1H), 3.77 (dd, J=18.1, 4.6 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ncccc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccnc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light-yellow gum. MS(m/e): 408.3 (MH+).