Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[C:6]([C:7]2[N:8]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[C:9]3[C:14]([CH:15]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH:12]=[CH:11][CH:10]=3)=CC(O)=N1.[N-:38]=[N+:39]=[N-:40].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[C:7]([C:6]1[NH:2][N:40]=[N:39][N:38]=1)[N:8]2[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccccc1-c1cccc2c1cc(-c1cc(O)nn1C)n2CCCOc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1cccc2c1cc(-c1nnn[nH]1)n2CCCOc1cccc2ccccc12

Procedure:
To a mixture of EXAMPLE 168B (416 mg) in N,N-dimethylformamide (10 ml) was added NaN3 (281 mg) and NH4Cl (231 mg). The mixture was stirred at reflux overnight. After this time the mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (200 ml) and water (60 ml). The organic phase was washed with brine and dried over Na2SO4. After concentration of solvent, the residue was dissolved in dimethylsulfoxide/methanol(1:1, 2 ml) and purified via RPHPLC. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (m, 1H), 7.88 (m, 1H), 7.54 (m, 3H), 7.47 (d, 1H), 7.40 (d, 1H), 7.30 (m, 5H), 7.14 (t, 1H), 6.88 (d, 2H), 6.23 (s, 1H), 5.70 (s, 1H), 4.91 (m, 2H), 4.21 (m, 2H), 3.51 (m, 3H), 2.36 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)[CH:16]=[O:17]>C1COCC1>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:16]=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2ccccc2)c1
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
A solution of 3-bromobiphenyl (Aldrich; 1 molar eq.) in dry THF was cooled to −78° C. and treated with tert-butyl]ithium (Aldrich; 1.7 M in hexanes, 2 molar eq.) in a dropwise manner. The reaction was allowed to stir at −78° C. for 40 minutes. Dimethylformamide (Aldrich; 2.5 molar eq.) was added and stirring continued an additional 20 minutes. The mixture was partitioned in a separatory funnel between methylene chloride and water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 5% ethyl acetate/hexanes. The desired aldehyde was obtained in 71% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12](Br)[CH:13]=[CH2:14]>C(O)C>[CH2:14]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH:13]=[CH2:12]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: C=CCBr
Solvent: CCO
Product: C=CCN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 78.5 parts of 2,2,6,6-tetramethylpiperidine-4-ol and 30.25 parts of allyl bromide in 250 parts of ethyl alcohol was heated under reflux conditions for 48 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide formed during the reaction and the ethyl alcohol solvent was removed by distillation under reduced pressure. The residue was triturated with cold petroleum ether (b.p. 40°-60°C) to remove a small amount of unreacted 2,2,6,6-tetramethylpiperidin-4-ol. Crystallisation of the residue from 40°-60°C petroleum ether gave 1-allyl-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 84°-5°C and the following elemental analysis by weight.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([OH:13])=O)(=[O:8])[CH3:7].[NH2:22][CH2:23][CH:24]([OH:31])[CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:6]([NH:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([NH:22][CH2:23][CH:24]([OH:31])[CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])=[O:13])(=[O:8])[CH3:7]
Reactant: CCC(C)(C)CC(O)CN
Reactant: CC(=O)NC(Cc1ccc(Br)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium bicarbonate (7.05 g, 83.8 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)propanoic acid (3 g, 10.5 mmol), 1-amino-4,4-dimethylhexan-2-ol (3.04 g, 21.0 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol) and 1-hydroxybenzotriazole (2.83 g, 21.0 mmol) in methylene chloride (105 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded 2-(acetylamino)-3-(4-bromophenyl)-N-(2-hydroxy-4,4-dimethylhexyl)propanamide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([N:6]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCCCN1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
Methanesulfonyl chloride (4.0 g, 35 mmol) was slowly added to a stirring solution of ethyl pipecolinate, (5.5 g, 35 mmol) and triethylamine (4.9 mL, 35 mmol) in anhydrous methylene chloride (88 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic layer was successively washed with water, twice with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (6.9 g, 84%). 1H NMR (CDCl3, 300 MHz) δ 4.72-4.71 (br d, 1H, J=3.6 Hz), 4.24-4.16 (qd, 2H, J=6.9, 2.6 Hz), 3.74-3.68 (m, 1H), 3.22-3.13 (td, 1H, J=12.3, 3.0 Hz), 2.93 (s, 3H), 2.31-2.25 (m, 1H), 1.83-1.51 (m, 5H), 1.32-1.27 (td, 3H, J=7.0, 0.6 Hz), 3.52-3.42 (m, 1H), 3.01 (s, 3H), 2.32-2.22 (m, 1H), 2.11-1.98 (m, 3H). ESI (m/z): 235.9 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:16][F:17])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11](/[CH:13]=[N:14]/[OH:15])=[CH:12][C:4]1=2.C1C(=O)N(Cl)C(=O)C1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[CH:30]=[C:29]([Cl:39])[C:28]=1[Cl:40].Cl>CN(C=O)C.O>[F:17][CH2:16][C:3]1([CH2:2][F:1])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([C:13]3[CH2:34][C:33]([C:31]4[CH:30]=[C:29]([Cl:39])[C:28]([Cl:40])=[C:27]([Cl:26])[CH:32]=4)([C:35]([F:38])([F:37])[F:36])[O:15][N:14]=3)=[CH:12][C:4]1=2
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: O/N=C/c1ccc2c(c1)C(CF)(CF)OB2O
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: OB1OC(CF)(CF)c2cc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
To a solution of (E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (440 mg, 1.83 mmol) in DMF (10 mL) at rt was added NCS (294 mg, 2.19 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (577 mg, 2.10 mmol) and TEA (403 mg, 4.0 mmol) in DMF (10 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, then stirred at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, 16%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.74 (s, 1H), 7.96-7.80 (m, 5H), 4.89-4.80 (m, 2H), 4.73-4.64 (m, 2H), 4.46 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H) ppm; HPLC purity: 95.3% at 214 nm; MS: m/z=516 (M+1, ESI+).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9].CC1(C)COB([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])OC1>>[CH2:11]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([C:3]1[N:4]=[CH:5][N:6]([CH3:7])[C:2]=1[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)c1ccc(B2OCC(C)(C)CO2)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1ncn(C)c1Br
Product: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)OC)cc1C(=O)N1CCc2ccccc2C1
Yield: 39.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264I, 5-bromo-N,N-dibutyl-1-methyl-1H-imidazole-4-carboxamide (600 mg, 1.9 mmol) and methyl 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 264H, 1.55 g, 3.8 mmol) were converted to the title compound (400 mg, 40%). MS(ESI+) m/z 531.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[Cl-].[Zn+2]>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(C#N)cc1
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a stirred solution of ethyl prop-2-ynoate (5.98 g, 60.96 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (60 mL) maintained under nitrogen at −65° C. was added dropwise a 2.5M solution of n-BuLi (28 mL, 1.50 equiv) in hexanes. The reaction mixture was stirred at −65-40° C. for 1 h then a 0.7M solution of ZnCl2 (170 mL, 2.00 equiv) in THF was added. The resulting solution was stirred at room temperature for 30 min. 4-iodobenzonitrile (6.87 g, 30.00 mmol, 0.50 equiv) was then added in portions followed by the addition of Pd(PPh3)Cl2 (1.05 g, 1.00 equiv). The resulting mixture was stirred at 50° C. for 5 h and then quenched by the addition of 150 mL of saturated NH4Cl solution. The mixture was extracted with 3×100 mL of ether. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of methanol in dichloromethane to give 3.25 g (27%) of ethyl 3-(4-cyanophenyl)propiolate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]>CO.Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:36])[CH3:35])=[CH:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Yield: 60 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (1.0 g) is suspended in a mixture of 25 ml methanol and 3.4 ml of concentrated hydrogen chloride acid and refluxed overnight. After evaporation to dryness under reduced pressure the remanens is triturated with methanol and thereafter recrystallized with methanol/water to give the title compound (0.47 g). Melting point: 156-157° C. 1H-NMR (CDCl3, 400 MHz): δ=5.36 (1H, s) 3.67 (3H, s); 3.23 (1H, m). MS (abbreviation for mass spectroscopy): Calculated: 414.6. Found 414.3.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[N:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][CH:19]=[N:20][N:21]=2)=[O:11])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Nc1nncs1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74.7 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 94 mg of 2-amino-1,3,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, the resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 185 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 16) represented by the formula:
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:13]=2[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33]Cl.C(=O)([O-])O.[Na+]>CS(C)=O>[CH2:3]([N:10]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([O:22][CH2:33][CH2:32][O:31][CH3:30])=[CH:21][C:13]=2[CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCCl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOc1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Reaction time: 0.67 h

Procedure:
Under nitrogen, to dimethylsulfoxide (5 ml) was added potassium hydroxide (34 mg) at room temperature, and the suspension was stirred at the same temperature for 40 minutes. To this one were added N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (200 mg) and 2-chloroethyl methyl ether (55 μl), and the mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=10:1 to 5:1) to give N-benzyl-N-[3-(2-methoxyethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (213 mg).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CN=3)=NOC=2C)=NC=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2C)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)cn1
Yield: 91.7 %

Procedure:
As described for example 283, 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (175 mg, 0.51 mmol) was converted, instead of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (154 mg, 92%) which was obtained as a white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19](=[O:29])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:12]=1>CN(C=O)C.[Cl-].[NH4+].C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19](=[O:29])[N:20]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([Cl:3])[N:9]=2)[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:12]=1
Reactant: COc1ccc(NC(=O)OCc2cccnc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)OCc2cccnc2)c2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% dispersion, 0.30 g, 0.75 mmol) was added to a solution of 2,4-dichloropyrimidine (0.75 g, 0.50 mmol) and (4-methoxyphenyl)-carbamic acid pyridin-3-ylmethyl ester (1.3 g, 0.50 mmol) in DMF (5 mL). The mixture was allowed to stir at room temperature for 2 h. The resulting solution was diluted with sat. aqueous ammonium chloride and ethyl acetate. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford a colorless oil. This oil was purified via column chromatography on silica gel (gradient elution with 0-5% methanol-dichloro-methane) to afford (2-chloropyrimidin-4-yl)-(4-methoxyphenyl)carbamic acid pyridin-3-ylmethyl ester as a tan solid. MS (MH+) 371; Calculated 370.8 for C18H15ClN4O3.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[NH:13][N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1.[H-].[Na+].[CH2:26](Br)[CH3:27].Cl>CN(C=O)C.O>[F:23][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[N:13]([CH2:26][CH3:27])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)[nH]ncc3c12
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(CC)ncc3c12
Temperature: 5 °C
Yield: 46 %

Procedure:
To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (261 mg, 0.803 mmol) in n,n-dimethyl formamide, sodium hydride (33 mg, 0.803 mmol) was added at 20-30° C. under nitrogen. Ethyl bromide (95.4 mg, 0.88 mmol) was added to the reaction mixture. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10° C. Water (100 ml) was added dropwise to the reaction mixture at 0-10° C. and acidified with dilute hydrochloric acid. The precipitate obtained was filtered and dried in oven. It was purified by silica gel column chromatography using 10% ethyl acetate in chloroform. White colored solid (130 mg) was obtained.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+].Br[C:26]1[C:31]([O:32][CH2:33][CH2:34][CH:35]=[CH2:36])=[CH:30][CH:29]=[C:28]([Br:37])[N:27]=1>CN(C=O)C.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:37][C:28]1[N:27]=[C:26]2[C:35](=[CH2:36])[CH2:34][CH2:33][O:32][C:31]2=[CH:30][CH:29]=1
Reactant: C=CCCOc1ccc(Br)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C1CCOc2ccc(Br)nc21
Temperature: 105 °C
Yield: 22.4 %

Procedure:
To a stirred mixture of PPh3 (67.6 g, 0.258 mol), KOAc (42 g, 0.43 mol), Pd(OAc)2 (1.94 g, 8.6 mmol) and Et4NCI (28.6 g, 0.172 mmol), was added 2,6-dibromo-3-(but-3-enyloxy) pyridine (26.4 g, 0.086 mol) in anhydrous DMF (300 mL). The mixture was heated at 105° C. for 18 hours. After cooling to ambient temperature, the mixture was dissolved in Ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum) to afford the title compound as oil (4.35 g, 22%). 1H NMR (400 Mz, DMSO-d6): δ 2.74 (t, J=5.4, 2H); 4.20 (t, J=6, 2H); 5.12 (s, 1H); 5.98 (s, 1H); 7.24 (d, J=7.5, 1H); 7.40 (d, J=7.5, 1H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)[CH:4]([CH3:6])[CH3:5].[OH:20][C@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](O)=[O:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:20][C@H:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([N:17]1[CH2:18][CH2:19][N:14]([C:12]2[CH:13]=[C:8]([O:7][CH2:3][CH:4]([CH3:6])[CH3:5])[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)=[O:23]
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)COc1cc(N2CCN(C(=O)[C@H](O)c3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-isobutoxy-6-(piperazin-1-yl)pyrimidine dihydrochloride (30 mg, 0.097 mmol), (R)-2-hydroxy-2-phenylacetic acid (15 mg, 0.097 mmol), and triethylamine (0.07 mL, 0.49 mmol) in DMF was added HBTU (48 mg, 0.13 mmol), and the mixture was stirred at rt for 1 h. Then the mixture was poured onto water (3 mL), and the aqueous layer was extracted with dichloromethane (three times). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 7.2 mg (15% yields) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[N:15]1([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:31])([F:32])[F:33])=[N:28][N:29]=3)[N:26]=2)[CH2:20][CH2:19]1)(=[O:13])=[O:12]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
Naphthalene-2-sulfonyl chloride (175 mg, 0.77 mmol) was added to 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.55 mmol) in pyridine (2 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated to remove the pyridine. The crude product was purified by preparative HPLC (Phenomenex Gemini C18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(naphthalen-2-ylsulfonyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (168 mg, 66%) as a solid.