Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14]CC)=[O:13])[CH:6]=[CH:7][CH:8]=1>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][CH:10]2[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C2CC2C(=O)O)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of ethyl 2-(3-methoxyphenyl)cyclopropanecarboxylate (1.63 g, 7.4 mmol) in 3N NaOH (35 mL) and MeOH (35 mL) was heated at 60° C. for 1 h. After cooling to rt, the reaction mixture was concentrated. The residue was dissolved in 1N HCl and extracted with DCM. The organic solutions were dried over Na2SO4, filtered, and concentrated to give the desired product (1.23 g, 87%) which was used without further fication. The cis and trans isomers were separated at a later stage of analog synthesis. LCMS: (FA) ES− 191.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.N1C=CC=CC=1>CO>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(C(=O)O)c(Nc2ccc3cn[nH]c3c2)n1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To the solution of 2-chloro-6-methylnicotinic acid 10 g and 6-aminoindazole 8.6 g in methanol 100 ml was added pyridine 9.5 ml, and then the solution was refluxed for 3 days. The reaction mixture was cooled, added H20 30 ml slowly at 20° C., and then stirred for 2 hr. The reaction mixture was filtered and the obtained solid was washed with methaol 20 ml. The desired compound (13.3 g, yield 85%) was obtained by drying of the solid product at 40˜50° C. in vacuo.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:22][C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:37]([O:41][C:42](=[O:47])[NH:43][CH2:44][CH2:45]O)([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH2:15]([O:22][C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:45][CH2:44][NH:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:47])=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Diisopropylazodicarboxylate (132 mL) was added dropwise over 45 minutes to a stirring mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (50 g, 0.167 mol), (2-hydroxyethyl)carbamic acid tert-butyl ester (103.4 mL, 0.668 mol), and THF (150 mL) with ice-methanol bath cooling from 15 to 35° C. When the exothermic reaction ceased, the cooling bath was removed, and the reaction was allowed to stir at room temperature overnight. The solvent was evaporated at reduced pressure, and the residue was applied to a 1 kg column of silica gel and eluted with methylene chloride. The chromatography was repeated twice. The residue after evaporation was washed with hexanes (1.5 L), and the resulting solid was re-crystallized from a mixture of hexanes and methylene chloride (4:1, 1 L) to afford 54 g (73%) of the pure product as a white solid. A second crop yielded an additional 10 g (13%) of the product. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.56 (m, 4H), 2.56 (t, 2H), 3.20 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:22](=[O:24])[CH3:23])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccncc1
Product: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)C1=CCC2=O
Reaction time: 16 h

Procedure:
Dissolve 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (2.45 g) in pyridine (7 cc) and acetic anhydride (4 cc) and allow to stand at room temperature for 16 hours. Remove the solvent under reduced pressure, add ethanol (20 cc) and again evaporate the solvent. Recrystallize the residue from ethanol to give a red crystalline solid, m.p. 122°-124°. Filter the solid through `Florisil` (100 g) with benzene, evaporate the solvent and recrystallize the product from ethanol to obtain 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 129°-130°C; ultraviolet absorption peak at 306 mμ (ε25,500), infrared absorption peaks at 5.78 μ, 8.27 μ, and 9.85 μ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C1C=CC=CC=1.O>[C:28]([O:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCc1ccc(OCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(OCCCc2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
A mixture of 2.0 g (0.007 mole) of 4-[3-(4-chlorophenyl)propoxy)-phenylmethanol and 4.0 g triethylamine is added to 3.6 g (0.02 mole) of hydrochloride of nicotinoyl chloride in 50 ml of anhydrous benzene with stirring and the mixture is refluxed for 4 hrs. After cooling, water is added to the reaction mixture. The product is extracted with benzene and the extract is washed with water and dried over sodiun sulfate. Benzene is removed, the residual solid is recrystallized from ethanol to give a title compound in yield of 1.8 g (67.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-])=O.S>N.C(O)C>[NH2:1][C:4]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N
Agent: S
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C

Procedure:
Ethyl 2-(2,4-dinitroanilino)-5-ethyl-thiophene-3-carboxylate (0.5 g) in 6N ammonia (25 ml) and ethanol (10 ml) was stirred at reflux temperature and hydrogen sulphide gas passed in over a period of 2 hours. The reaction mixture was cooled to room temperature and the title compound obtained as a yellow precipitate filtered off, washed with water, and dried in vacuo, m.p. 174°-176° C. (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1([Si:16]2([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH2:21][CH2:20][CH:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)C=CC=CC=1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Si@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:27])=[CH:29][CH:30]=2)[CH2:20][CH2:21]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COCCCCC[Si]1(c2ccccc2)CCC(c2ccc(C(=O)O)cc2)CC1
Product: COCCCCC[Si@H]1CC[C@H](c2ccc(C(=O)Oc3ccc(Cl)c(Cl)c3)cc2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-dichlorophenol and 4-(4-phenyl-4-(5-methoxypentyl)-4-silacyclohexyl)benzoic acid, thereby obtaining the intended product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C:17]2[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:16]1=2)=[O:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][C:17]3[N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:22]=[CH:23][C:16]2=3)=[O:14])[CH:6]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Cl)c(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Yield: 87.3 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)pyrazole (0.026 g, 0.15 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.045 g, 0.15 mmol) and K2CO3 (0.043 g, 0.31 mmol) in THF (0.6 mL) and DMF (0.3 mL) was heated at 60° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on SiO2 with a gradient elution of 0-60% EtOAc/hexanes to afford the desired product (0.056 g, 87%). 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.70 (s, 1H), 7.45 (m, 2H), 7.16 (dd, J=8.4, 8.4 Hz, 2H), 5.17 (s, 2H), 3.81 (m, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.12 (m, 2H); MS: (ES) m/z calculated for C18H14ClF4N5O [M+H]+ 428.1, found 428.1.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:26]#[C:27][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 3.6 %

Procedure:
Copper (I) iodide (0.03 g) was added to a mixture of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (1.05 g, Example 40a), phenylacetylene (0.33 g) and bis(triphenylphosphine)palladium(II) chloride (0.23 g) in triethylamine (10 ml), and the reaction mixture heated to 90° C. with stirring under nitrogen for 4 hours. The reaction mixture was allowed to cool to room temperature and then poured into water (150 ml). The product was extracted with ethyl acetate which was washed with brine and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure and the residue purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give the title compound as a white solid (0.040 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](=[O:8])[C:5]([C:9](=O)[CH2:10][CH3:11])=[C:4]([OH:13])[CH2:3]1.[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][NH2:23])=[CH:18][CH:17]=1>C(O)C.C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][N:23]=[C:9]([C:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=2[OH:13])[CH2:10][CH3:11])=[CH:18][CH:17]=1
Reactant: NOCc1ccc(Cl)s1
Reactant: CCC(=O)C1=C(O)CC(C)(C)CC1=O
Solvent: ClCCl
Solvent: CCO
Product: CCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
In this example, a mixture containing 4.0 gms (0.02 mol) of 5,5-dimethyl-3-hydroxy-2-propionylcyclohex-2-en-1-one and 3.6 gms (0.022 mol) of O-[(5-chlorothien-2-yl)methyl]hydroxylamine in 75 mls of ethanol was stirred at room temperature for about 12 hours. The mixture was then evaporated to remove the ethanol, affording a thick syrup. The syrup was then dissolved in methylene chloride and extracted twice with aqueous 5% wt. sodium hydroxide. The aqueous layer was separated and acidified with concentrated hydrochloric acid and then extracted twice with methylene chloride. The methylene chloride layer was separated, dried with magnesium sulfate, and filtered. The filtrate was evaporated under vacuum, affording a viscous liquid which was then purified via column chromatography eluting with tetrahydrofuran-hexane (1:2 vol. ratio) affording 4.8 gms of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]propyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([O:17][CH:18]1[CH2:21][C:20]2([CH2:25][C:24]([C:26]3[CH:31]=[N:30][C:29]4[NH:32][N:33]=[CH:34][C:28]=4[C:27]=3[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:23][O:22]2)[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O.O>[CH2:10]([O:17][CH:18]1[CH2:21][C:20]2([CH2:25][C:24]([C:26]3[CH:31]=[N:30][C:29]4[N:32]([CH2:1][CH3:2])[N:33]=[CH:34][C:28]=4[C:27]=3[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:23][O:22]2)[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCI
Reactant: c1ccc(COC2CC3(CC(c4cnc5[nH]ncc5c4NC4CCOCC4)=NO3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C3=NOC4(C3)CC(OCc3ccccc3)C4)cnc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Ethyl iodide (0.227 gm, 1.45 mmol) and potassium carbonate (0.2 gm, 1.45 mmol) were added to the solution of 5-[2-(benzyloxy)-5-oxa-6-azaspiro[3.4]oct-6-en-7-yl]-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.21 gm, 0.48 mmol) (step b) in dimethylformamide and the reaction mixture was stirred at 60° C. for about 5 hours. It was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified over silica gel column.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:17]([S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])([CH3:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:17]([S:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:33])([CH3:19])[CH3:18]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CC(C)SCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
To a solution of (4) (0.25 g, 1.14 mM) and (6) (0.274 g, 1.0 mM) in dry methylene chloride (10 mL) at room temperature was added 4-dimethylaminopyridine (0.122 g, 1.0 mM) followed within one minute by a solution of N,N'-dicyclohexylcarbodiimide (0.22 g, 1.06 mM) in methylene chloride (1 mL), 3×1 mL rinses with methylene chloride. After 2 days, the filtered mixture was concentrated in vacuo and the residue flash chromatographed on silica gel using 15-20% ethyl acetate in hexane as eluant to give product 7 (0.22 g) as an oil that solidified readily in a short time.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Br:41])[CH:35]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Br:41])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(O)c(Br)c1
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Br)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled to 4-(2-amino-ethyl)-2-bromo-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 634. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 8.1 (m, 1H) 8.0 (d, 1H) 7.5 (m, 3H) 7.4 (s, 1H) 7.1 (m, 2H) 6.9 (d, 1H) 4.9 (m, 1H) 4.5 (s, 2H) 3.8 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
To a stirred solution of 30 mg of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one in 1 ml of DMF were added 1.1 eq. of NaH (55% in oil). The reaction mixture was stirred for 30 min. before the addition of 1.2 eq. of 2-chloro-N,N-dimethyl-acetamide. The crude reaction mixture was purified by preparative HPLC to afforded 10 mg of the title compound as a white powder.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([OH:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[N:15]=[N:14]C(C(OC)=O)=[CH:12][CH:11]=1.Cl>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[N:14][C:4]([C:5]([OH:8])([CH3:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)O
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: C[Mg]Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Cl)nn1
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
A solution of THF (2.5 mL) and toluene (10 mL), and methylmagnesium chloride (3.0 M, 9.7 mL) were stirred at −20° C. under N2 atmosphere followed by the addition of t-BuOH (0.5 mL, 5.79 mmol) in THF (7 mL) dropwise. The solution was allowed to stir for 30 min and warmed to 3° C. and cooled backed down to −20° C. followed by the addition of the methyl 6-chloropyridazine-3-carboxylate (1.0 g, 5.79 mmol) in portions. The solution quickly turned dark violet and was stirred at 0° C. for 30 min. The solution was then poured into a flask containing 1 N aqueous hydrochloric acid at −5° C., diluted with ethyl acetate, and stirred for 10 min. The layers were then separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The acidic aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. Purification via flash chromatography (silica, 0-100% ethyl acetate/hexanes) provided the title compound. LRMS (ESI) calcd for C7H10ClN2O [M+H]+: 173.1, Found: 173.1
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:7]2[C@@H:3]1[C@H:4]([OH:9])[O:5][C:6]2=O.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+].Cl.[Cl-].[Na+]>O>[CH3:1][C:2]1([CH3:10])[C@H:3]2[C@@H:7]1[CH2:6][O:5][C:4]2=[O:9]
Reactant: CC1(C)[C@H]2[C@H](O)OC(=O)[C@H]21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Product: CC1(C)[C@@H]2C(=O)OC[C@@H]21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
170.6 g of (1R,5S) 6,6-dimethyl-4-(R)-hydroxy-3-oxa-bicyclo (3,1,0) hexane-2-one were added to 800 ml of water and a solution of 127.2 g of sodium carbonate in 400 ml of water was slowly added thereto at 0° C. The mixture was stirred at 0° C. for 15 minutes and 45.4 g of sodium borohydride were added thereto at 0° C. in small fractions. The mixture was stirred for 4 hours at 0° C. and adjusted to a pH of 2 addition of 2N hydrochloric acid. The mixture was saturated with sodium chloride and stood overnight and was extracted with methylene chloride. The extract was evaporated to dryness under reduced pressure and the residue was rectified under reduced pressure to obtain 130.2 g of (1R,5S) 6,6-dimethyl-3-oxa-bicyclo (3,1,0) hexane-2-one with a specific rotation of [α]D20 =- 92° (C=1% in ethanol).
Reaction SMILES: [N:1]1([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH:15]C(=O)OC(C)(C)C)=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>>[N:1]1([C:7]2[N:23]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: Cl
Product: Nc1ccc2nc(N3CCOCC3)nn2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A mixture of tert-butyl 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamate (363 mg, 1.14 mmol) and hydrochloric acid (5M in diethyl ether, 24.0 g, 20 ml, 100 mmol) was stirred for 5 hours at 25° C. and then the solvent was evaporated under reduced pressure. The light yellow residue was made alkaline using sodium hydroxide solution (2M in water). The mixture was extracted 2 times with ethyl acetate, the organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtrated and evaporated to dryness, affording 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (227 mg, 91%) as grey solid. Mp.: 165° C. MS: m/z=220.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])(C)(C)C.CCCCCC.Br[C:18]1[S:22][C:21]([C:23]2[N:27]3[N:28]=[C:29]([CH3:37])[CH:30]=[C:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:26]3=[N:25][C:24]=2[CH3:38])=[C:20]([CH3:39])[CH:19]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH2:33]([CH:32]([C:31]1[C:26]2[N:27]([C:23]([C:21]3[S:22][C:18]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[CH:19][C:20]=3[CH3:39])=[C:24]([CH3:38])[N:25]=2)[N:28]=[C:29]([CH3:37])[CH:30]=1)[CH2:35][CH3:36])[CH3:34]
Reactant: c1cocn1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncco4)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 5.2 %

Procedure:
To a −78° C. solution of oxazole (0.14 g, 2.04 mmol) and THF (3 mL) is added 1.6 M t-Bu-Li in hexane (1.32 mL, 2.14 mmol). The mixture is stirred at −78° C. for 15 minutes. 0.5 M ZnCl2 in THF (4.3 mL, 2.14 mmol) is added and the solution warmed to ambient temperature. 3-(5-Bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) is added and mixture is stirred at 65° C. overnight, diluted with EtOAc (30 mL), washed with 10% citric acid (20 mL), water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20% EtOAc/hexane gradient) and is chromatographed (50×250 C18 Symmetry column, 20-70% water: 0.1% TFA/ACN: 0.1% TFA gradient) to furnish the title compound (0.020 g, 0.053 mmol, 5%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.75-1.93 (m, 4H), 2.17 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 3.29-3.38 (m, 1H), 6.69 (s, 1H), 7.19 (s, 1H), 7.59 (s, 1H), 7.65 (s, 1H). LC/MS (m/z): calcd. for C21H24N4OS (M+H)+: 381.3; found: 381.1.