Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([C:29]6[N:33]=[C:32]([CH3:34])[NH:31][N:30]=6)[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.Br[CH2:38][CH2:39][O:40][CH3:41].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:36][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:35])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([C:29]6[N:33]=[C:32]([CH3:34])[N:31]([CH2:38][CH2:39][O:40][CH3:41])[N:30]=6)[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: Cc1nc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4C)n3c2)n[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1nc(-c2ccc3ncc(C(=O)Nc4cc(-c5noc(C6CC(F)(F)C6)n5)ccc4C)n3c2)nc1C

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F79) (6.0 mg, 0.012 mmol), 1-bromo-2-methoxyethane (1.7 mg, 0.012 mmol) and K2CO3(5.0 mg, 0.036 mmol) in DMF (0.5 mL) was heated at 120° C. for 30 minutes. The reaction mixture was purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(1-(2-methoxyethyl)-5-methyl-1H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (F99). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 10.11 (m, 1H), 8.65 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 8.06 (dd, J=2.0, 9.2 Hz, 1H), 7.88 (dd, J=0.8, 9.2 Hz, 1H), 7.85 (dd, J=2.0, 8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 4.34 (t, J=5.2 Hz, 2H), 3.89 (m, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.24 (s, 3H), 3.02-3.20 (m, 4H), 2.47 (s, 3H), 2.39 (s, 3H). MS m/z 549.1 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.I[CH2:14][CH2:15][CH3:16].C([O-])(O)=O.[Na+].[C:22]1(C)[CH:27]=CC=C[CH:23]=1>O>[CH2:14]([N:1]([CH2:23][CH2:22][CH3:27])[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH2:15][CH3:16]
Reactant: Cc1ccccc1
Reactant: CCCI
Reactant: NCCc1cccc2[nH]ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCN(CCC)CCc1cccc2[nH]ccc12
Yield: 83 %

Procedure:
A mixture of 4-[(2-amino)ethyl]indole (III) (2.0 g, 12.48 mmol), 1-iodopropane (8.5 g, 50 mmol), NaHCO3 (2.3 g, 27.4 mmol) in toluene (40 mL) was stirred at reflux temperature for 21 h. NaHCO3 (1.15 g, 13.7 mmol) in water (20 mL) and 1-iodopropane (2.12 g, 12.47 mmol) were added to the resultant mixture and was stirred at the same temperature for 6 h. When the mixture reached room temperature, it was filtered and layers were separated. The organic layer was washed with water (15 mL), dried, filtered and evaporated to obtain 2.53 g (83%) of 4-[2-(dipropylamino)ethyl]indole (IV).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10]C(C)(C)C)=[CH:6][CH:5]=1.C(O)C.S(=O)(=O)(O)O>O>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)Oc1ccc(OC(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Oc1ccc(OC(F)F)cc1
Yield: 72 %

Procedure:
30 g of 1-(difluoromethoxy)-4-(tert.-butoxy)benzene from Example 4a), 200 ml of ethanol, 50 ml of water and 10 ml of concentrated sulfuric acid were stirred at 80° C. for 2 hours. The reaction mixture was extracted with ether, the organic phase was dried and filtered, and the filtrate was concentrated to give 16 g of 4-difluoromethoxyphenol.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=1>CN(C=O)C>[NH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)=[C:6]([F:12])[CH:5]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1cc(F)c(O)cc1F
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of potassium hydride (30-35% dispersion in mineral oil, 1.9 g, 13.9 mmol) in DMF (30 mL) was added 4-amino-2,5-difluorophenol (1.7 g, 11.6 mmol) as a solution in DMF (5 mL). After one hour of stirring at ambient temperature, 4-chloropicolinamide (1.8 g, 11.6 mmol) was added and the reaction mixture was heated to 100° C. for 135 h. The mixture was cooled to room temperature, quenched with 10% aqueous lithium chloride and then extracted three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was partitioned between chloroform and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to a solid (3.0 g, 98%). 1H NMR (DMSO-d6) δ 8.51-8.57 (m, 1H), 8.14 (br s, 1H), 7.74 (br s, 1H), 7.37-7.38 (m, 1H), 7.17-7.30 (m, 2H), 6.74-6.80 (m, 1H), 5.62 (s, 2H); MS(ESI+) m/z 266 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:27]=[CH:26][NH:25][C:5]=2[N:6]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]2[CH:27]=[CH:26][NH:25][C:5]=2[N:6]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[N:8]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2)nc2[nH]ccc12
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3nc(S(C)=O)c4cc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a solution of 1-(4-(4-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (451 mg, 1.18 mmol) in CH2Cl2 (12 mL), mCPBA (320 mg, 65%, 1.20 mmol) was added. The mixture was stirred at room temperature for 1 h. It was then concentrated in vacuo, the residue was purified by HPLC to give 1-(4-(4-(4-(methylsulfinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (136 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:11][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 1 h
Yield: 21.3 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.23 mL, 1M inTHF, 0.23 mmol) was added to a solution of 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole (Example 4e, 25.0 mg, 0.12 mmol) in THF (1.5 mL) at -78° C. and the mixture was stirred for 1 h. Phenylsulfonyl chloride (30 uL, 0.24 mmol) was added and the mixture stirred at room temperature for 2 h. prior to quenching with water (4 drops) and silica gel (~1g). Purification using solid phase extraction tubes (1000 mg silica, eluting with 0-10% 2M methanolic ammonia in dichloromethane) yielded 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-phenylsulfonylindole (9.0 mg, 22%, HRMS-FAB+ for C20H20N2O2S: calculated MH+ : 353.13239; found: 353.13235).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]1([CH3:37])[CH:25]=[CH:24][C:23](S(OCC2CCCCC2)(=O)=O)=[CH:22][CH:21]=1>>[CH:20]1([CH2:37][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 51.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (185 mg, yield: 51.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=1.O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:35]=[C:26]1[C:27]2[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:30])[N:25]1[O:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:13]([N:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCCO)c1)C1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
A mixture of alcohol 17 (8.8 g, 26 mmol), tetrahydrofuran (100 mL), N-hydroxyphthalimide (3.8 g, 23 mmol) and triphenylphosphine (5.2 g, 20 mmol) was stirred at 0° C. for 5 min. To the mixture was added DEAD (3.4 mL. 20 mmol) dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 12 h prior to concentration in vacuo. The residue was purified by chromatography to provide phthalimide 18 (3.7 g) contaminated with Mitsunobu by-products. This material was used directly in subsequent experiments. 1H NMR (300 MHz, CDCl3) δ 7.78-7.85 (m, 2H), 7.73-7.77 (m, 2H), 6.94 (t, 2H), 6.38 (d, 1H), 5.95 (bs, 1H), 5.18 (d, 2H), 4.40 (t, 2H), 3.8-4.4 (m, 4H), 2.20-2.28 (m, 2H), 1.4-1.9 (m, 1H). Mass spectrum (CI) calcd. for C26H27N2O5Cl: 483 (M+H). Found: 483.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[N:4]=[N:3][NH:2][N:1]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1nn[nH]n1
Product: COc1ccc(N2CCN(C(=O)Cc3nn[nH]n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (2H-tetrazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.57 min, [M+1]+ 463. Potency class A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:19])=[C:7]2[C:15]=1[C:14](=[CH:16][O:17]C)[CH:13]1[CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.O>[CH:16]([CH:14]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[C:7]2[C:15]1=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH3:19])=[O:17]
Reactant: COC=C1c2c(OC)ccc(C)c2C2CCCCC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)c2c1C(C=O)C1CCCCC21

Procedure:
4.54 Grams of 8-methoxy-9-methoxymethylene-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene was dissolved in 200 ml of 1,4-dioxane and 50 ml of water. To the solution was added 0.90 g of p-toluenesulfonic acid monohydrate and this was refluxed for 18 hours. To the reaction mixture was added 200 ml of water and extraction was carried out with diethyl ether. The organic layer was dried with magnesium sulfate, filtered and concentrated and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) and recrystallized from ethanol to obtain 3.94 g of 9-formyl-8-methoxy-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 92°-93° C. and of colorless needle-like crystal.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].Br[CH2:14][C:15]([OH:17])=O.P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)Cl.C([O-])(=O)C[C:29]([CH2:34][C:35]([O-:37])=O)([C:31]([O-:33])=O)O.[Na+].[Na+].[Na+]>[Fe](Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:35](=[O:37])[C:34](=[C:29]3[C:31](=[O:33])[C:7]4[CH:8]=[CH:9][C:4]([N:3]([CH2:11][CH3:12])[CH2:1][CH3:2])=[CH:14][C:15]=4[O:17]3)[O:10][C:6]=2[CH:5]=1)[CH3:12]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: O=C(O)CBr
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc2c(c1)OC(=C1Oc3cc(N(CC)CC)ccc3C1=O)C2=O

Procedure:
10.0 g (60.5 mmol) of 3-diethylaminophenol are mixed with 12.5 g (90.1 mmol) of bromoacetic acid at a reaction temperature of 60° C., with exclusion of moisture and vigorous stirring with a precision glass stirrer. 7.0 g (46 mmol) of phosphoryl chloride, 6.3 g (46 mmol) of phosphorus trichloride and 24.6 g (152 mmol) of anhydrous iron trichloride are added. After a reaction time of 24 hours, 3 parts of ice are added to the dark violet mixture and the solid mixture is dissolved with cautious heating and stirring. After addition of sodium citrate (as a complexing agent for Fe3+ -ions), the mixture is extracted by shaking three times with 80 ml of chloroform each time. The dark red organic phase is dried over MgSO4. After the solvent has been stripped off on a rotary evaporator, 55.66 g of dark violet, highly viscous crude product are obtained. 0.7 g of crude product are worked up by column chromatography over silica gel using chloroform as the mobile phase. The trans colorant isomer can be separated off as a red-violet fraction in the first runnings. After the solvent has been stripped off on a rotary evaporator, the resulting dark red solid is dried under an oil pump vacuum at 95° C. for 7 hours.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[CH3:18]/[C:19](/[CH:27]=O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:18][C:19](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:27]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: C/C(C=O)=C\c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Butyllithium (135 mL of 2.5 N solution) was added to 600 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (30.5 g) in 220 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. over a period of 60 minutes. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of α-methyl-trans-cinnamaldehyde (23.2 g) in 100 mL of anhydrous THF was added to the reaction at −65° C. over a period of 70 minutes. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. The reaction was then acidified with 5% hydrochloric acid (125 mL) to a pH of 2.8. The aqueous layer was extracted with 100 mL of ether twice and with 100 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 100 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 25.8 g of the desired 4-methyl-5-phenyl-2,4-pentadienoic acid. 1H NMR (acetone-d6, 300 MHz), δ(ppm) 7.53 (d, 1H), 7.43 (m, 4H), 7.37 (dd, 1H), 6.97 (broad s, 1H), 6.02 (d, 1H), 2.07 (s, 3H).
Reaction SMILES: Cl.N[CH2:3][CH:4]([CH3:8])[C:5]#[C:6][CH3:7].O.O[N:11]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:32][C:33]1[CH:34]=[C:35]([O:39][CH:40]([CH2:44][CH3:45])[C:41](O)=[O:42])[CH:36]=[N:37][CH:38]=1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:32][C:33]1[CH:34]=[C:35]([O:39][CH:40]([CH2:44][CH3:45])[C:41]([NH:11][C:4]([CH3:3])([C:5]#[C:6][CH3:7])[CH3:8])=[O:42])[CH:36]=[N:37][CH:38]=1
Reactant: CCC(Oc1cncc(Cl)c1)C(=O)O
Reactant: CC#CC(C)CN
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-aminomethyl-pent-2-yne hydrochloride (2.67 g; prepared as described below) in dry N,N-dimethyl formamide (150 ml) at ambient temperature was added dry triethylamine (4.2 ml). The mixture was stirred at ambient temperature for 5 minutes and 1-hydroxybenzotriazole hydrate (2.97 g), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (4.22 g) and 2-(5-chloro-3-pyridyloxy)butyric acid (4.53 g) were added sequentially. The mixture was stirred at ambient temperature for 2.75 hours, stored at ambient temperature for 18 hour and poured into water. The product was extracted into diethyl ether (three times) and the extracts were combined, washed with aqueous sodium o hydrogen carbonate (twice), water (twice) and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residual gum fractionated by chromatography (silica: diethyl ether) to give a pale yellow oil, which was triturated with hexane to give the required product as a colourless solid, 4.5 g, m.p. 87–89° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(O)CO.C(OCC)(=O)C>[CH2:18]([NH:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCCN
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (for example, as prepared for Intermediate 2) (10 g) in dry ethylene glycol (commercially available, for example, from Aldrich) (50 mL) at room temperature and under nitrogen was added n-butylamine (commercially available, for example, from Aldrich) (16 mL) in one go. The reaction was heated at 120° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with water (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. This afforded the title compound as a viscous green oil (10.2 g) that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[Cl:18][C:6]1[CH:5]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-amino-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (100 mg) in pyridine (1 mL) was added 4-fluorobenzenesulfonyl chloride (59 mg) and the resulting solution was allowed to stir at room temperature for 1 h. The reaction solution was poured over water, extracted with ethyl acetate, the organic layer washed with 1N hydrochloric acid, water, brine, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (40% acetone/hexanes) to afford the title compound of Step B as a light-yellow colored solid, 115 mg. m.p. 90-96° C., MS Calc.:553.4; Found:550.9.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]=2[C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:25][C:26](Br)=[O:27].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1.O>[CH:1]1([C:4]([C:6]2[S:10][C:9]([NH:11][C:26](=[O:27])[CH2:25][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:8][C:7]=2[C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CC2)s1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)Nc1nc(-c2ccco2)c(C(=O)C2CC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
Compound 419 (192 mg, 0.824 mmol) and triethylamine (0.379 mL, 2.72 mmol) were dissolved in THF (4 mL), and bromoacetyl bromide (0.215 mL, 2.47 mmol) was added thereto at 0° C., followed by stirring at room temperature for 1 hour. At 0° C., a solution (2 mL) of morpholine (1.08 mL, 12.4 mmol) in THF and triethylamine (1.73 mL, 12.4 mmol) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography to afford the entitled Compound 421 (229 mg, 77%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][C:13](=NO)[CH2:12][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1C[O:30]CC1>>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][C:13](=[O:30])[CH2:12][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: ON=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1
Agent: Cl
Product: O=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one oxime. A solution of 3.87 g of the compound from step G in 80 mL of THF with 5 mL of 1 M HCl was heated at reflux for 16 h. The volatiles were removed in vacuo and water was added (300 mL). The mixture was adjusted to pH 9 by the addition of 1 M NaOH and then was extracted with CH2Cl2. The combined extracts were washed with brine and the solvent was removed in vacuo to provide 1-benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one. This product (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in 20 mL of pyridine. The reaction mixture was stirred at RT for 14 h then was diluted with water (300 mL), and stirred an additional hour. The mixture was filtered on paper and the solids were washed with EtOAc and dried in vacuo to afford 2.48 g of the desired compound. 1H NMR (500 MHz, acetone-d6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H), 3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.Cl.[NH2:14][CH2:15][CH2:16][SH:17]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[NH:14][CH2:15][CH2:16][S:17]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: NCCS
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2NCCS2)cc1OC
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (2.19 g, 13.2 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 40 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2×25 ml), washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.77 g). The material was triturated with hexane (3×5 ml) to give 2-(3,4-dimethoxyphenyl)-1,3-thiazolane (8) as a friable white solid (0.65 g, 66%), mp 54-56°.