Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([O:36][CH3:37])=[C:29]([OH:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:35][C:29]1[C:30]([O:33][CH3:34])=[C:31]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])[CH:32]=[CH:27][C:28]=1[O:36][CH3:37]
Reactant: COc1ccc(Br)c(OC)c1O
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Temperature: 85 °C
Yield: 41 %

Procedure:
A stirring solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (3 g, 12.87 mmol) in dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (12.58 g, 38.61 mmol), Pd (PPh3)4 (743 mg, 0.64 mmol) and 3-bromo-2,6-dimethoxyphenol (3.32 g, 12.87 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (1.5 g, 41%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH2:12][CH2:13][NH2:14])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[S:11][C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1ncc(-c2ccccc2)s1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1ncc(-c2ccccc2)s1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 5 %

Procedure:
This compound was synthesized from 2-(5-phenylthiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 5%). 1H NMR (400 MHz, MeOD) δ 8.60-8.59 (t, J=1.4 Hz, 1H), 8.31-8.28 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.08-8.05 (dt, J=7.9 Hz, 1.3 Hz, 1H), 7.96 (s, 1H), 7.72-7.68 (t, J=7.9 Hz, 1H), 7.61-7.59 (m, 2H), 7.43-7.39 (m, 2H), 7.36-7.32 (m, 1H), 3.85-3.82 (t, J=6.9 Hz, 2H), 3.40-3.36 (t, J=6.8 Hz, 2H). MS (ESI) m/z: Calculated for C21H15F3N4O2S: 444.09. found: 445.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][C@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:25][C@H:20]1[O:21][C@@H:22]([CH3:24])[CH2:23][N:18]([CH2:17][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([C:31]4[CH:32]=[C:33]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:28]([O:27][CH3:26])=[N:29][CH:30]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[N:16][N:15]=2)[CH2:19]1
Reactant: C[C@@H]1CN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)C[C@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(C)c3c2)cc1NS(C)(=O)=O
Temperature: 110 °C
Yield: 17.1 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-methyl-1H-indazole (45 mg, 0.111 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (36.4 mg, 0.111 mmol), sodium carbonate (35.2 mg, 0.332 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (8.10 mg, 0.011 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was passed through a 2 g silica cartridge that was then washed with methanol. The solvent was evaporated under a stream of nitrogen and the residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a white solid (10 mg).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:45])[C@H:39]1[CH2:43][NH:42][CH2:41][C@@H:40]1[OH:44].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[CH3:37][N:38]([CH3:45])[C@@H:39]1[C@@H:40]([OH:44])[CH2:41][N:42]([C:2]2[C:21]([C:22]3[CH:27]=[N:26][CH:25]=[N:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:43]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C[C@@H]1O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 60 mg, 0.149 mmol) and DIPEA (0.182 mL, 1.043 mmol) were added to a vial containing iPrOH (1 mL). (3S,4S)-4-(Dimethylamino)pyrrolidin-3-ol (50 mg, 0.246 mmol) was added. The mixture was stirred at 110° C. for 16 h. The RM was treated with sat. aq. Na2CO3 (20 mL) and was extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 13% to 18% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=5.62 min, UPLC-MS (Condition 3) tR=0.73 min, m/z=489.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.15 (s, 6H) 2.52-2.59 (m, 1H) 2.87 (dd, J=10.95, 5.08 Hz, 1H) 3.19 (dd, J=11.34, 5.90 Hz, 1H) 3.28 (m, J=11.30, 6.30 Hz, 1H) 3.45 (dd, J=11.34, 6.65 Hz, 1H) 4.08 (quin, J=5.08 Hz, 1H) 5.09 (d, J=5.08 Hz, 1H) 7.36 (d, J=8.60 Hz, 2H) 7.85 (m, J=9.00 Hz, 2H) 8.11 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.35 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.CS([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[C:10](=[N+:27]=[N-:28])[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)N=[N+]=[N-]
Reactant: COC(=O)CC(=O)c1c(F)cccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of 5.80 g (25.1 mmol) of methyl 3-(2-chloro-6-fluorophenyl)-3-oxopropionate in 60 mL acetonitrile was added 3.9 mL (28 mmol) of triethylamine followed by 3.05 g (25.2 mmol) of methanesulfonyl azide. The mixture was stirred at room temperature for 18 h and concentrated by rotary evaporation. The resulting solid mass was washed with ethyl acetate/hexanes and the washings were filtered through a plug of silica gel. The filtrate was concentrated to give 4.90 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH2:1][O:8][C:17](=[O:18])[CH:16]([CH3:15])[CH2:20][CH:21]=[CH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CCC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of 4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylene chloride is added, dropwise, a solution of 29.5 g of racemic 2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. The mixture is stirred at room temperature for 4 hours, followed by successive washing with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation to give 35.2 g of the desired product as a colorless oil; bp 70°-75° C. at 0.10 mm Hg.
Reaction SMILES: [N+](C1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.C([O-])(=O)C([O-])=[O:20].[K+].[K+].[OH-].[Na+].O>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:17](=[O:20])[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11]=12
Reactant: O=[N+]([O-])c1cc2cccnc2c2ncccc12
Reactant: O=C([O-])C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2cccnc2-c2ncccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a 1 L one-necked flask was added a mixture of 30 g (0.13 mol, 68%) 5-nitro-1,10-phenanthroline, 51 g (0.61 mol) potassium oxalate, 12.5% NaOH(aq) 150 ml and 450 ml water. The mixture was then heated to reflux (100° C.) and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was added with 1 L ethyl acetate, stirred for 30 minutes, and filtered to collect the filtrate. The residual solids were added into 300 ml ethyl acetate, stirred for 30 minutes and filtered to collect the filtrate. The combined filtrates were extracted to separate the organic layer, dehydrated by MgSO4, concentrated, and recrystallized from 200 ml methanol, so as to obtain light yellow solids cyclopenta[2,1-b;3,4-b′]dipyridin-5-one 13.3 g (0.07 mol, yield 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.[C:24]1([S:30]([N:33]2[C:37]3=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]3[C:35]([CH:43]=[O:44])=[CH:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:43]([C:35]2[C:36]3[C:37](=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=3)[N:33]([S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:32])=[O:31])[CH:34]=2)[OH:44])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under an atmosphere of nitrogen at −78° C., a solution n-butyllithium (2.50 M in hexane, 7.10 mL) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed to warm to room temperature for 1 hour. The reaction was cooled to −78° C. followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was cooled to −78° C., followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.50 mL) slowly. After 60 minutes, 1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (597, 1.90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound (598, 1.25 g, 50.9%). MS (ESI) [M+H+]+=415.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19](Cl)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)C(=O)CC2C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2c3c(c(N4CCNCC4)c(F)cc3c1=O)C(=O)CC2C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
6.75 g (0.02 mole) of 8-chloro-9-fluoro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 120 ml of chloroform, 6.89 g (0.08 mole) of piperazine was added thereto, and this mixture was stirred at 20°-25° C. for 6 hours. The resulting reaction solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 10.1) as the developing solvent]. The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 4.79 g (61.8% yield) of 9-fluoro-5-methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester in the form of yellow crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[NH2:23].C(=O)([O-])O.[Na+]>C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)=[C:20]([Cl:19])[CH:21]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 3.5 hrs. The reaction mixture was allowed to cool to room temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (293 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[N:5]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:3]=1.Cl.C(O)(C)C.C(OCC)(OCC)OCC.C([O-])(O)=O.[Na+].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[CH:45]1([NH:48][C:2]2[N:3]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]3[C:7]=2[N:8]=[CH:9][N:11]3[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[CH2:47][CH2:46]1
Reactant: NC1CC1
Reactant: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 41 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
Under nitrogen atmosphere, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamino]pyrimidin-2-yl}isobutyramide (20.0 g, 56.53 mmol) was dissolved in an anhydrous solution of HCl/isopropanol 2M (170 ml, 339.17 mmol). The mixture was heated at 40-42° C. for 2 h. The resulting solution was cooled to 8-10° C., then triethyl orthoformate (28.2 ml, 169.59 mmol) was added and the reaction mixture was stirred at the same temperature for 2 h. NaHCO3 (28.50 g, 339.17 mmol) was added slowly, stirred 30 min and the salts were filtered off. To the resulting clear solution, NaHCO3 (4.75 g, 56.53 mmol) and cyclopropylamine (19.6 ml, 282.65 mmol) were added, the mixture was refluxed for 1 h and the salts were filtered off. The solution was evaporated and the syrup was dissolved in hot isopropanol (200 ml). This mixture was cooled to 0-2° C. and the resulting slurry filtered off. The solid was dried under vacuum at 30° C. There was obtained 14.42 g (72%) of (−)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide as a white powder. HPLC analysis: 94.4%+4.0% Abacavir.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[F:21].C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:3]([F:21])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide (0.15 mmol) was added piperazine-1-carboxylic acid tert-butyl ester (0.195 mmol), NaOtBu (0.375 mmol), XantPhos (0.03 mmol), Pd2 dba2 (0.009 mmol) and 1,4 dioxane (0.2 mL). The reaction vial was purged with Ar, sealed, and heated at 85° C. overnight. The reaction was worked up by diluting with ethyl acetate (mL) washed with NH4Cl (1.5 M, 4 mL), and brine (4 mL), filtered through a plug of Na2SO4, and dried under a stream of nitrogen. To the intermediate was added DCM (1 ml) and TFA (0.2 mL) and stirred at room temperature for 1 hr. The reaction was diluted ethyl acetate (mL) washed with NaHCO3 (saturated, 4 mL, twice), and brine (4 mL), filtered through a plug of Na2SO4 and dried under a stream of nitrogen yielding the product, N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide. LCMS calcd for C21H26FN3O (m/e) 355, obsd 356 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C[N+]1([O-])CC[O:21]CC1>C(#N)C>[CH:2]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15])=[O:21]
Reactant: CCOC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 30 %

Procedure:
Ethyl 4-bromomethyl-3-nitrobenzoate (46.11 g) was dissolved in 500 ml of acetonitrile, then 20 g of 4-methylmorpholine-N-oxide was added and the mixture was stirred at room temperature for 80 minutes. The reaction solution was concentrated in vacuo, water was added and the mixture was extracted with chloroform. The organic layer was washed with a saturate aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluting solvent to give 10.723 g of ethyl 4-formyl-3-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:17]=[C:18]([CH3:22])[S:19][C:20]=1[CH3:21]
Reactant: Cc1nc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(C)s1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(C)s1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
0.40 g of 5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-methyl-2H-pyridazin-3-one and 2 ml of phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-partitioned. The organic layer was washed with brine three times, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 0.40 g 3-chloro-5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-m ethylpyridazine (hereinafter, described as compound (1) of the present invention.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[NH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Br:44])[CH:42]=2)[N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:36]=1>ClCCCl>[Br:44][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[N:36]=[C:35]2[NH:34][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (8.41 g, 39.1 mmol) and ethyl 2-ethoxyquinoline-1(2H)-carboxylate (EEDQ, 9.66 g, 39.1 mmol) in DCE (50 mL) was allowed to stir at rt for 10 min. To this solution was added a solution of tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate (6.1 g, 19.54 mmol) in DCE (50 mL) in one portion and the resulting mixture was heated at 70° C. overnight. The mixture was partitioned between sat NaHCO3 and EtOAc and the phases were separated. The aqueous layer was extracted (×2) with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified on flash chromatography (BIOTAGE® eluting with a gradient of 0 to 100% Ether/Hexanes) to afford the title compound as yellow solid contaminated with quinoline. The material was dissolved in ether and washed several times with HCl (1M). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (4.8 g, 48% yield) as yellow solid. The material was used as is in subsequent steps. 1H NMR (500 MHz, CD3OD) δ 8.19 (app d, J=11.3 Hz, 1H), 8.03 (unresolved dd, J=8.9, 11.0 Hz, 1H), 7.67-7.70 (m, 1H), 4.40-4.44 (m, 1H), 3.57-3.61 (m, 1H), 3.47-3.52 (m, 1H), 2.33-2.42 (m, 1H), 2.01-2.13 (m, 2H), 1.91-1.98 (m, 1H), 1.68 (s, 9H), 1.50, 1.42 (s, 9H, rotamers, 2:1 ratio). LCMS: Anal. Calcd. for C22H29BrN4O5: 508, 510; found: 509, 511 (M+H)+.