Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)cc2)cn1
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100 mL) was added 4-methyl-1H-imidazole (0.82 g, 10 mmol) and K2CO3 (11 g, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL×2). The organic layer was dried and concentrated. The solid was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd—C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[CH2:16]([OH:29])[CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>CN(C=O)C>[OH:29][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCCCCCCBr
Reactant: OCCCCC#CC#CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCCCCC#CC#CCCCCO
Reaction time: 15 h
Yield: 33.4 %

Procedure:
In a glass reaction vessel, a suspension of 120 milligrams of sodium hydride was prepared in 10 milliliters dry DMF and 972 milligrams of 5,7-dodecadiyn-1,12-diol (HO(CH2)4C≡C—C≡C(CH2)4OH), was added. After stirring for 5 minutes 1.31 grams of CH3(CH2)11Br was added and the resulting mixture was stirred for 15 hours. The mixture was then quenched by addition of saturated NH4Cl solution and diluted with 100 milliliters of diethyl ether. The organic layer was separated and washed 3 times with brine, dried over MgSO4, filtered and the solvent was removed to yield a yellow oil. The oil was purified over silica gel (25%-35% by volume of ethyl acetate in hexanes gradient) to yield 606 milligrams of HO(CH2)4C≡C—C≡C(CH2)4O(CH2)11CH3 as a white solid.
Reaction SMILES: I[CH:2]([CH:8]([CH3:16])[C:9]([Cl:15])([F:14])[C:10]([Cl:13])([F:12])[F:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>C(O)C>[N:17]([CH:2]([CH:8]([CH3:16])[C:9]([Cl:15])([F:14])[C:10]([Cl:13])([F:12])[F:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(I)C(C)C(F)(Cl)C(F)(F)Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(N=[N+]=[N-])C(C)C(F)(Cl)C(F)(F)Cl
Yield: 122.5 %

Procedure:
Then in 350 ml of 80% ethanol, 31 g (0.0080 mol) of ethyl 2-iodo-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate and 26 g (0.040 mol) of sodium azide were refluxed at an elevated temperature for 22 hours. By treating the product by following the procedure of Example 1, there was obtained 3.03 g (0.0098 mol, yield of 12%) of ethyl 2-azido-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate having b.p. 94° C./4 mm, nD20 1.4420, νN3 2113 cm-1 and νC=O 1748 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: Br[Mg]CCCc1ccccc1
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)c1cccnc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Bromo-pyridine-3-carbaldehyde (1.25 g, 6.72 mmol) was dissolved in THF (10 mL) and cooled to 0° C. 3-phenyl-propyl magnesium bromide (0.5 M in THF, 20.2 mL, 10.08 mmol) was slowly added and the reaction stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The reaction was monitored by TLC and when complete was quenched with 10 mL of NH4Cl (sat'd, aq.). The volume of THF was reduced and the reaction was submitted to EtOAc/H2O workup. The crude material was purified on silica gel (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][CH:9](O)[CH:10]=[CH2:11]>Br>[Br:2][CH2:11][CH:10]=[CH:9][C:8]#[C:7][C:6]([CH3:14])([CH3:13])[CH3:5]
Reactant: C=CC(O)C#CC(C)(C)C
Reactant: BrP(Br)Br
Agent: Br
Product: CC(C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 ml 48% HBr and 10 g PBr3 are stirred to homogeneity at 40°. An alcoholic solution of 13.5 g of 6,6-dimethyl-hept-1-en-4-yn-3-ol is then added dropwise at 10° and the resulting mixture stirred at room temperature for 11/2 hours. The reaction mixture is poured onto ice-water and repeatedly extracted with hexane. The organic phase is separated, washed repeatedly with aqueous NaCl, dried and concentrated on a rotary evaporator. NMR spectroscopy reveals that the resulting oily reaction product comprises a 3:1 mixture of trans- and cis-1-bromo-6,6-dimethyl-hept-2-en-4-yne which is employed directly in further alkylation.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:64][CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:71])([CH3:73])[CH3:72])=[O:74])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][CH:27]([CH3:28])[CH3:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 48) (82 mg, 0.2 mmol) and HATU (0.091 g, 0.240 mmol) was added DMF (2 mL) and the mixture treated with DIPEA (0.105 mL, 0.600 mmol) at room temperature. After 5 min, 1,1-dimethylethyl (2-aminoethyl)carbamate (0.047 mL, 0.300 mmol) was added and the mixture stirred at room temperature for 1 h. The reaction mixture was partitioned between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography eluting with a MeOH/DCM gradient to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}carbonyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (95 mg, 0.172 mmol, 86% yield) as a pale brown foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=553.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of methyl-o-toluate (0.93 mL, 6.6 mmol), N-bromosuccinimide (1.25 g, 7.0 mmol) and azaisobutryonitrile (11 mg, 0.07 mmol) in chloroform (10 mL) was heated at 65° for 16 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with H2O and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give methyl 2-(bromomethyl)benzoate.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl>[CH:1]([N:14]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:11][CH2:12][CH2:13]1)=[O:2]
Reactant: c1ccc2c(c1)CNCCO2
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 15 ml of formic acid was added dropwise 5 ml of acetic anhydride, and the mixture was stirred for 20 minutes at room temperature. To the mixture was added dropwise a solution of 2.2 g of 2,3,4,5-tetrahydro-1,4-benzoxazepine in 10 ml of dichloromethane, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, then the mixture was subjected to extraction with dichloromethane. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, and water. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.6 g of 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as an oily anhydrous substance.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[S:3]1.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([CH:2]3[C:7](=[O:8])[NH:6][C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[S:3]3)[CH2:22][CH2:21]2)[CH:15]=1
Reactant: O=C1Nc2ccccc2SC1Cl
Reactant: Cc1ccnc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(N2CCN(C3Sc4ccccc4NC3=O)CC2)c1
Yield: 16.8 %

Procedure:
7 g (=0.035 m) of 2-chloro-2H-1,4-benzothiazine-3(4H)-one, 6.2 g of N-(4-methylpyridin-2-yl)-piperazine, and 7 g of triethylamine were heated at reflux with stirring for 5 hours in 100 ml of toluene. The suspension was worked up by diluting it with 200 ml of toluene, and the resulting precipitate was filtered out and dissolved in 20% strength aqueous hydrochloric acid solution. The solution was rendered alkaline by adding an ammonium hydroxide solution, and the resulting precipitate was filtered out, washed with water and dried. 2 g of beige-colored crystalline 2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-2H-1,4-benzothiazine-3(4H)-one having a melting point of 245° C. were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc(N)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 500 g (4.2 moles) of 4-vinylaniline and 460 g (4.2 moles) of triethylamine in 1000 cc of anhydrous diethyl ether under a nitrogen atmosphere was added dropwise 478 g (4.2 moles) of methanesulfonyl chloride. The temperature of the reaction vessel was kept below 5° C. by an ice bath during the course of the reaction. When addition was complete (40 min.), the mixture was stirred for an additional 2 hours and the contents of the flask then brought to room temperature. The mixture was filtered and extracted with 500 cc of 1.0 M HCl solution. The etheral portion was separated, dried and the ether removed on a rotary evaporator. The resulting oily solid was extracted with 500 cc of ethanol and recrystallized from ethane/water and then from toluene. 70-75% yield after recrystallization. M.P. = 97° C.
Reaction SMILES: Cl[C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C(N(CC)CC)C>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]([C:4](=[C:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(C(=O)Cl)=C(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=C(C)C
Yield: 30 %

Procedure:
In a manner similar to the procedure described in Example I, ethyl 2-chlorocarbonyl-3-methyl-2-butenoate (9.6 grams, 0.05 mole) prepared in Example XXV, 4-bromo-2-methylaniline (5.3 grams, 0.03 mole) and triethylamine (4.0 milliliters, 0.03 mole) were reacted to give 2.9 grams (0.009 mole) of ethyl 2-[(4-bromo-2-methylphenyl)aminocarbonyl]-3-methyl-2-butenoate as a white solid having a melting point of 116° C.-119° C. NMR analysis of the product indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[Cl:25][C:26]1[CH:31]=[N:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:25][C:26]1[N:27]=[C:28]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[CH:29]=[N:30][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Temperature: 105 °C
Yield: 97.7 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 14 (1.00 g, 2.272 mmol) and 2-chloro-6-(tributylstannyl)pyrazine 1b (1.375 g, 3.41 mmol) in DMF (9 mL) followed by Pd(PPh3)4 (0.131 g, 0.114 mmol) and CuI (7.70 μL, 0.227 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 1 h. The resulting mixture was diluted with DCM. The organic layer was separated, washed with water, dried, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in Hexanes) to give 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.95 g, 2.22 mmol, 98% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 427.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[Li]CCCC.CN([CH:25]=[O:26])C.O>O1CCCC1>[CH3:15][C:5]1([CH3:16])[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CC(C)c1cc(Br)cc2c1OCCC2(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C=O)cc2c1OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-4,4-dimethyl-8-(propan-2-yl)-3,4-dihydro-2H-chromene (154 mg, 0.54 mmol) in tetrahydrofuran (5.44 mL) was cooled to −78° C. and n-BuLi (261 μL, 0.65 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (168 μL, 2.17 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature, and stirred for 30 minutes before water was added. It was then extracted with EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to obtain the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 180 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (20 mg, 0.06 mmol) in NMP was added 3-chloroaniline (38 μL, 0.36 mmol) and a few granules of p-toluenesulfonic acid. The reaction was heated in microwave at 180° C. 1.5 hours. The reaction mixture was filtered and purified by prep HPLC then prep TLC (1% MeOH/DCM) to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow solid. LCMS (M+1=427)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]
Reactant: Cc1cccc(C)c1CO
Reactant: N#Cc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (6.27 g, 46.1 mmol) and diisopropyl azodicarboxylate (DIAD, 9.24 g, 45.7 mmol) in dry THF (30 ml) was added drop wise to a solution of 3-Hydroxybenzonitrile (5 g, 37 mmol) and triphenylphosphine (TPP, 11.99 g, 45.7 mmol) in THF (100 ml) at 0° C. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[CH:23]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:35](=O)([O-])[OH:36].[Na+]>CN(C)C=O>[C:6]([C:10]1[N:11]=[C:12]([NH:15][C:16]([C:18]2[CH:34]=[CH:33][N:21]3[C:22](=[O:32])[C:23]([CH:35]=[O:36])=[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[N:25]=[C:20]3[CH:19]=2)=[O:17])[S:13][CH:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylformamide (1 ml) was added dropwise with phosphorus oxychloride (66 μl, 0.712 mmol) under ice cooling, then warmed to room temperature, and stirred for 15 minutes. The reaction solution was cooled to 0° C. with ice, added with N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide (147 mg, 0.356 mmol) dissolved in dimethylformamide (4 ml) under ice cooling, and stirred at 0° C. for 2 hours and 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate and concentrated under reduced pressure. The resulting residue was added with chloroform for extraction, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 98.2 mg of the title compound as yellow crystals in a mixture with dimethylformamide.
Reaction SMILES: FC(F)(F)S([Cl:6])(=O)=O.[C:9]1([C:15](=[O:27])[CH2:16][C:17](=[O:26])[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:6][C:18]1[C:17](=[O:26])[CH:16]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:27][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Cl
Reaction time: 2 h

Procedure:
Trifluoromethane sulphonyl chloride (3.95 ml) was added over 10 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (8.1 g) and triethylamine (6.5 ml) in dichloromethane (100 ml) at 0° to 5° C. The solution was stirred for 2 hours at 0° to 5° C., then made acidic by passing in hydrogen chloride gas. The mixture was stirred for 3 hours at room temperature, washed with water and evaporated to a brown oil which crystallised from ethanol-water. The product was recrystallised from ethanol-water and from ethyl acetate-petroleum ether 60°-80° C. to give ethyl 3-chloro-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 121° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9].I[CH2:21][CH2:22][OH:23].C(OCC)(=O)C.C(OC(=O)C)C.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][N:15]([CH2:21][CH2:22][OH:23])[CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: OCCI
Reactant: Clc1ccc(OC2CNCc3occc32)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4-(3,4-Dichlorophenyloxy)-4,5,6,7-tetrahydrofuro-[2,3-c]pyridine hydrochloride (Example 119) (50 mg) was dissolved in 5 mL of dehydrated ethanol and then 220 mg of 2-iodoethanol was dropped thereinto. The reaction solution was heated with stirring at 80° C. overnight and concentrated in vacuo to evaporate the solvent and excess 2-iodoethanol. The residue was purified by silica gel column chromatography and the resulting free substance of the objective compound was dissolved in 5 mL of ethyl acetate. Into this ethyl acetate solution was dropped a solution of one equivalent of hydrochloric acid ethyl acetate and the resulting mixed solution was concentrated to give 18 mg of the objective compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:30])[OH:26])=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCOc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, 3.03 mL, 21.2 mmol) in THF (30 mL) in 250 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 8.12 mL, 20.3 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was cooled to −78° C. and 2-fluoro-5-(2-methoxyethoxy)pyridine (1.58 g, 9.23 mmol) in a total of 5 mL THF was added slowly. The orange mixture was stirred at that temperature for 30 min then triisopropyl borate (Aldrich, 4.72 mL, 20.3 mmol) in a total of 5 mL of THF was added slowly. The mixture was stirred at −78° C. for 10 min, then the cold bath was removed and the mixture was stirred at room temperature for 1 h. 1N NaOH (about 70 mL) was added and the layers were separated. The aqueous phase was washed with EtOAc (50 mL) and acidified to about pH 5 with 5 N HCl. The aq phase was extracted with EtOAc (4×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.76 g, 89% yield) as a pale yellow residue. This material was used without further purification.