Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]21[CH2:19][CH2:18][CH2:17][CH2:16]2.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]3[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:12]=32)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
A solution of 2.58 g of (RS)-2'-(2-oxoethyl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 1.98 g (67%) of (R)-1-[7'-methoxy-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccncc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2ccncc2c1
Temperature: -75 °C
Yield: 80.6 %

Procedure:
To a 2-liter, 3-necked round bottom flask equipped with a magnetic stir bar and addition funnel is added 19.7 g (0.124 mole) 7-methoxyisoquinoline and 800 ml of dry dichloromethane. This solution is stirred and cooled to -75° C. with a dry ice/acetone bath, 628 ml (0.628 mole) of 1.0M boron tribromide in dichloromethane is added dropwise maintaining the temperature at -75° C. Thereafter the slurry is stirred for 18 hours allowing the temperature to rise to room temperature. The reaction slurry is poured into 1 liter of ice water and stirred for an hour. The layers are separated and the aqueous layer is then adjusted from acidic to neutral (pH 7) with 1N NaOH. A yellow solid precipitates and is filtered off, then air dried to yield 14.5 g of a yellow solid, 81%.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:19]1([CH3:27])[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:27])=[CH:20][CH:21]=1)[C:2]#[C:1][C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (15.0 g, 82.3 mmol) in tetrahydrofuran (165 mL), 2.77 M n-butyllithium (solution in n-hexane, 62.4 mL, 172.9 mmol) was added dropwise at −72° C. for 25 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. Thereafter, p-tolualdehyde (10.2 mL, 86.4 mmol) was added dropwise at −72° C. for 5 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (17.7 g, 58.5 mmol, 71%) as an amorphous product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C(=O)C>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
38 mg of 2-methylphenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(2-methylphenyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[S:20][C:21](=[S:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added rhodanine (24 mg, 0.184 mmol) and piperidine (18 μL, 0.184 mmol). The mixture was heated in microwave (200 W) for 10 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one. LCMS (M+1=388)
Reaction SMILES: Cl.[NH:2]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][NH:11][C:12]=3[CH:13]=[C:5]2[CH2:4][CH2:3]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[N:11]1[C:12]2=[CH:13][C:5]3[CH:4]=[CH:3][NH:2][C:6]=3[CH:7]=[C:8]2[CH2:9][CH2:10]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1cc2cc3c(cc2[nH]1)CCN3
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4cc5[nH]ccc5cc43)c2cc1OC
Yield: 67 %

Procedure:
Utilizing a procedure analogous to that described in Example 24 (with conversion to its HCl salt using a procedure analogous to that described in Example 2), this product was prepared in 67% yield from 1,2,3,5-tetrahydro-pyrrolo[2,3-f]indole (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 245°-252° C.; LC-MS: 347 (MH+); RP18-HPLC RT: 3.67 min)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH:18]#[C:19][CH3:20]>C(NCC)C.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.[Cu]I>[CH3:17][N:8]1[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:5]2[CH:4]=[N:3][C:2]([C:18]#[C:19][CH3:20])=[C:6]2[CH2:7]1
Reactant: C#CC
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC#Cc1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
6.78 g (20 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 100° in a pressure tube overnight with 80 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 30 mg of copper(I) iodide and about 2 ml of propyne in 60 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on 300 g of silica gel while eluting with ethyl acetate. By recrystallization of the crude product from ethanol there was obtained 4,5-dihydro-5-methyl-3-(1-propynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 206°-207°.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC4C=CC=CC=4)[CH:20]=3)[C:15]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][C:2]([CH3:49])([CH3:48])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[C:15]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:35][CH:34]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: CC(C)(C)COS(=O)(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)COS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 73.8 %

Procedure:
To a round bottom flask add the product from Example 66 (42 mg, 0.062 mmol), ammonium formate (29 mg, 0.464 mmol), 10% Pd/C (6 mg, 15% by weight) and MeOH (5 mL). Heat the mixture at reflux for 35 minutes. Cool the reaction to ambient temperature and filter it through a pad of Celite, then rinse the Celite with hot ethyl acetate and hot methanol. Evaporate the filtrate in vacuo and purify the resulting residue by radial chromatography over silica (2-5% MeOH gradient in CH2Cl2) to provide 27 mg of 4-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl}-benzenesulfonic acid 2,2-dimethyl-propyl ester (74%). Dissolve the free base (6.7 mg) in CH2Cl2 (3 mL) and add 0.023 mL (2 equivalents (eq.)) of a 1.0M solution of hydrochloric acid in diethyl ether. Shake this solution for 1-2 minutes at ambient temperature and evaporate it in vacuo to provide 7.1 mg of the title compound. MS (IS+) m/e 590 (M+1-HCl).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]([CH:50]2[CH2:52][CH2:51]2)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH:50]4[CH2:52][CH2:51]4)[N:48]=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1nnnn1C1CC1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nnnn3C3CC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as red gum. MS (m/e): 405.3 (MH+).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C(O)(C)C>[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:29]1[CH2:30][CH2:31][CH:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2cc(C(=O)CCN3CCC(Cc4ccccc4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 1.6 g of sodium iodide were mixed in 60 ml of isopropanol and stirred at 40°-50° C. for 2 hours. Then 2.2 g of 4-benzylpiperidine and 3.0 g of DBU were added to the reaction mixture and refluxed by heating for 6 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogen-carbonate aqueous solution and stirred at a room temperature for 1 hour. The insoluble matters fromed were collected by filtration washed with water and dried, then recrystallized from ethanol to obtain 1.8 g of 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[CH3:14][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C.C(O)C>[CH3:14][O:12][C:11]([C:10]1[C:2]([NH2:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH2:5][CH2:4]2)=[O:13]
Reactant: Nc1c(C(=O)O)ccc2c1CCC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1N)CCC2
Reaction time: 1 h
Yield: 75.6 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (5 mL) in water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol) and NaOH (5.03 g, 126 mmol) in water (97 mL) over a period of 30 minutes, stir the mixture at room temperature for 1 h. Acidulate with 1N hydrochloric acid, filter the solid, wash with water and dry to afford 4-amino-indan-5-carboxylic acid (3.13 g, 87%). Dissolve 4-amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2 M in hexanes) at room temperature and stir the solution for 1 h. Remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.50 g, 76%). 1H NMR (MeOD, 300 MHz) δ 2.12 (quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].CO.Cl>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCC(=O)O)c2ccco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (402 mg, yield 93%) as colorless crystals. m.p. 131-133° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCN(CC)CCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-diethylethane-1,2-diamine according to general procedure 1 providing the intermediate (160 mg, 80%) as a clear oil: Rf=0.22 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.52 (t, J=6.0 Hz, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.68 (quart, J=7.2 Hz, 4H), 1.12 (t, J=7.2 Hz, 6H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: [CH3:1][C:2]([NH:16]C(=O)OC(C)(C)C)([CH3:15])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1.[ClH:24]>C(OC)(C)(C)C>[ClH:24].[CH3:15][C:2]([NH2:16])([CH3:1])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: CC(C)(Cc1nc(-c2ccccc2)no1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COC(C)(C)C
Product: CC(C)(N)Cc1nc(-c2ccccc2)no1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of tert-butyl 2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-ylcarbamate (2.72 g, 8.57 mmol) and HCl (4M in dioxane; 21.4 mL, 85.7 mmol) was stirred at 25° C. for 3 h. The resulting white suspension was diluted with tert-butylmethylether (100 mL) and stirred for 1 h. The reaction mixture was filtered and the precipitate was dried in vacuo to give the product as white solid (2.01 g, 7.92 mmol, 92.4%). MS: M=218.1 (M+H−HCl)+
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].[NH2:9][C:10]1[C:15]([O:16][CH3:17])=[N:14][C:13]([CH3:18])=[CH:12][N:11]=1.N1C=CC=CC=1>ClCCl>[CH3:17][O:16][C:15]1[C:10]([NH:9][C:6](=[O:7])[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[N:11][CH:12]=[C:13]([CH3:18])[N:14]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1nc(C)cnc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(C)cnc1NC(=O)OCC(C)C

Procedure:
Isobutylchloroformate (4.79 ml) was added to a stirred solution of 2-amino-3-methoxy-5-methylpyrazine (5 g) and pyridine (2.91 ml) in dichloromethane-(10 ml) at ambient temperature. After 90 minutes the reaction mixture was diluted with dichloromethane (10 ml) and washed with 2M hydrochloric acid (3×20 ml), water (20 ml) and saturated sodium chloride solution (20 ml) and then dried (MgSO4). Volatile material was removed by evaporation to give a solid which was recrystallised from hexane to give isobutyl N-(3-methoxy-5-methylpyrazin-2-yl)carbamate (6.5 g); 1H NMR (CDCl3): 1.0 (d, 6H), 2.0 (m, 1H), 2.4 (s, 3H), 4.0 (d, 2H), 4.02 (s, 3H), 7.3 (s, 1H), 7.8 (s, 1H); mass spectrum (positive chemical ionisation (+ve CI)): 240 (M+H)+.
Reaction SMILES: C(O)(=[O:3])C.S(=O)(=O)(O)O.O.[C:11]([C:13]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:17])[CH:14]([CH3:16])[CH3:15])#N>C(OCC)(=O)C>[C:20]1([C:19]2[O:26][C:11](=[O:3])[C:13]([CH:14]([CH3:16])[CH3:15])([CH3:17])[N:18]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O
Reactant: CC(C)C(C)(C#N)NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C1(C)N=C(c2ccccc2)OC1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
40 ml of glacial acetic acid, 3.92 g (0.038 mole) of concentrated sulfuric acid and 0.36 g (0.02 mole) of water were added to 8.6 g (0.04 mole) of N-(1-cyano-1,2-dimethylpropyl)benzamide. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 100 ml of water and 100 ml of ethyl acetate for layer separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and concentrated to obtain 7.2 g (0.033 mole) of 2-phenyl-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)=[CH:38][C:37]=1[CH3:50].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH2:41][C:42]2([CH3:46])[CH2:45][O:44][CH2:43]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cc1cc(OCC2(C)COC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(C)COC6)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (500 mg), 3-((4-bromo-3,5-dimethylphenoxy)methyl)-3-methyloxetane (450 mg), K3PO4 (450 mg) are suspended in toluene (2.5 mL) and water (250 μL) and purged for 10 minutes with argon. Palladium-(II)-acetate (12 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (44 mg) are added, the vial is sealed and the mixture is stirred at 100° C. for 4 hours. After cooling to room temperature the mixture is partitioned between diethylether and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→60:40) to give the title compound. Yield: 420 mg; LC (method 4): tR=1.93 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.