Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]#[CH:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]#[CH:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Reactant: CN=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C#CCN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[Cl:6][CH2:5][CH:7]([OH:9])[CH2:8][O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCO
Reactant: ClCC1CO1
Product: CCCOCC(O)CCl
Yield: 73.7 %

Procedure:
A mixture of 300 g 1-propanol (5.0 mol), 231 g epichlorohydrin and 10 g ion exchange resin was refluxed for 22 hours. The reaction mixture was then cooled, filtered and distilled to give 281 g of 1-chloro-3-propoxy-2-propanol (74% yield). Reaction of this product with paraformaldehyde (2.8 mol) gave 202 g of product (69% yield) having the following structure: ##STR23## b.p.: 132° C. at 2 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]2[CH:16]=[C:17]([F:27])[C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:28])[C:9]([C:15]3[CH:16]=[C:17]([F:27])[C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:29])[CH:3]=2)=[CH:32][C:31]=1[F:30])=[O:38]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cc(F)c2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cc(F)c4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-8-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=570.3 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:18][C:17]1[C:9]([Br:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=[CH:11]2)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(O)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Triethylamine (0.29 g, 2.8 mmol) was added to a solution of 4-bromo-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 21, 0.67 g, 1.9 mmol) and acetyl chloride (0.22 g, 2.8 mmol) in THF (10 mL). The mixture was stirred for 10 minutes at room temperature and evaporated. The residue was partitioned between DCM and saturated aqueous NaHCO3. The reaction mixture was washed with saturated aqueous NaHCO3, and the organic phase was dried (MgSO4) and evaporated to give the title compound (0.6 g) as a red solid. MS m/z 394/396 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1>>[Br:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[N:12]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)c1=O
Yield: 73.4 %

Procedure:
Using the same general procedure as described for the preparation of 103l, reaction of 119b (400 mg, 1.66 mmol) with 3,5-dibromo-1-methylpyridin-2(1H)-one (441 mg, 1.66 mmol) gave a 76% yield (521 mg) of 119c as a yellow solid: mp 96-97° C.; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J=2.5 Hz), 7.42 (s, 1H), 5.31 (d, 1H, J=2.5 Hz), 6.87 (d, 1H, J=2.5 Hz), 5.84 (d, 1H, J=2.5 Hz), 4.16 (t, 2H, J=5.0 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.58 (s, 3H), 0.85 (s, 9H), −0.04 (s, 6H). MS (APCI+) m/z 427.4 (M+H).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([O:18][OH:19])([C:11]#[C:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14])[CH3:10].S(=O)(=O)(O)O>CCOCC>[O:1]=[C:2]([CH2:4][C:5]([CH3:7])([CH3:6])[O:16][O:15][C:13]([CH3:17])([CH3:14])[C:12]#[C:11][C:9]([CH3:8])([CH3:10])[O:18][O:19][C:5]([CH3:7])([CH3:6])[CH2:4][C:2](=[O:1])[CH3:3])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)(C#CC(C)(C)OO)OO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(=O)CC(C)(C)OOC(C)(C)C#CC(C)(C)OOC(C)(C)CC(C)=O
Temperature: 30 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
A mixture of 19.6 g. (0.2 mole) of mesityl oxide, 74.4 g. (0.083 mole) of 2,5-dimethyl-2,5-dihydroperoxy-3-hexyne and 60 ml. of ether was stirred at 0° C. while 1.3 g. of 77% sulfuric acid solution was slowly added. The reaction mixture was allowed to warm slowly to 30° C. and stirred for a total of 16 hours. The organic layer was separated, washed with water, 5% sodium hydroxide solution and again with water to pH 8. The mixture was then subjected to steam distillation in the presence of sodium bicarbonate solution at 20 torr for 2 hours to remove unreacted mesityl oxide and hydroperoxide. The product was taken up in ether, dried over anhydrous magnesium sulfate and the ether removed under reduced pressure leaving 20.52 g. of product (66.7% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN(C)C=O>[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Yield: 99 %

Procedure:
A 3,000 ml two-necked flask equipped with a stirrer and a reflux condenser was charged with 500 ml of thionyl chloride and 277 g of 4-n-decyloxybenzoic acid obtained by a conventional method, and stirred together with 0.1 g of dimethylformamide at room temperature over one night. Thereafter, the mixture was heated for 1 hour under reflux. Then, unreacted thionyl chloride was removed under reduced pressure to obtain 293 g of 4-decyloxybenzoyl chloride as a colorless to yellow oily product (yield: 99%, boiling point: 175° to 180° C./0.5 mmHg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH3:30])([CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)[C:15]#[N:16]>C1COCC1>[C:15]([C:14]([NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:30])[CH2:17][N:18]1[CH:26]=[C:25]2[C:20]([C:21]([Cl:29])=[C:22]([Cl:28])[CH:23]=[C:24]2[Cl:27])=[N:19]1)#[N:16]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-nitrobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.7 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=452, RT=0.69 min.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH3:21])=[CH:15][CH:16]=2)[S:9]1(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(O)cc2S(=O)(=O)N1Cc1ccccc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc2c(c1)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 0 °C
Yield: 78 %

Procedure:
A mixture of 2-benzyl-6-hydroxysaccharin (0.86 g), 2-bromoethyl 2-methoxyethyl ether (d=1.347, 0.45 mL), potassium carbonate (1.24 g), methyl ethyl ketone (50 mL) and dimethylformamide (2 mL) was heated under reflux for five hours, then poured into ice-water (500 mL). The resulting solid was collected, washed with water and dried affording 2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.92 g, 78% yield, mp 86°-88° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[CH:20]1([CH2:19][O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)c(F)c1
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-4-nitrophenol (10.0 g) in DMF (100 mL) were added potassium carbonate (17.6 g) and (bromomethyl)cyclopropane (9.26 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated to give the title compound (13.8 g).
Reaction SMILES: [Na].[C:2]1([CH2:8][OH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1>O>[CH3:29][C:25]1[CH:24]=[C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[N:13]=[N:12][C:11]([O:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(OCc4ccccc4)nn3)CC2)c1
Temperature: 180 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a stirred solution of 0.7 parts of sodium in 20 parts of benzenemethanol were added 5.8 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and heated in an oil bath at 180° C. After standing overnight, water was added and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 2,2'-Oxybispropane was added to the residue. The product was filtered off and crystallized from a mixture of 2-propanol and methanol. The product was filtered off and dried, yielding 3.4 parts (47%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-(phenylmethoxy)pyridazine: mp. 159.4° C. (compound 267).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]#[N:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([NH:23][C:24]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([Cl:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:4]([C:11]#[N:12])=[C:5]2[CH2:10]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N=C=O
Reactant: N#Cc1c(-c2ccccc2)c(Cl)n2c1CNCC2
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C#N)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
To a solution of 34 g (119 mmol) of 6-chloro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile in 300 ml of dichloromethane are added 16.3 ml (143 mmol) of tert-butyl isocyanate (CAS1609-86-5). After stirring for 4 hours at room temperature, the solvent is evaporated off under reduced pressure to give an orange-coloured solid, which is crystallized from acetonitrile to give 40.0 g of N-tert-butyl-6-chloro-8-cyano-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide in the form of a yellow powder after filtering off and drying.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>[Ag]=O.CN(C=O)C>[C:15]([O:14][C:12](=[O:13])[CH2:11][O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][OH:1])[N:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=c1cccc(CO)[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of 1.38 g of 6-(hydroxymethyl)pyridin-2(1H)-one, 2.15 g of tert-butyl bromoacetate, 3.07 g of silver oxide, and 33 mL of DMF was stirred at room temperature for 12 hours, and then at 60° C. for 12 hours. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.92 g of tert-butyl{[6-(hydroxymethyl)pyridin-2-yl]oxy}acetate as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][C:44]#[N:45]>CN(C=O)C>[C:44]([CH2:43][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([N:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1)#[N:45]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)nccc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)nccc3c2)cc1
Temperature: 60 °C

Procedure:
To a vial charged with 1-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (113 mg, 0.224 mmol) was added DMF (898 μl) and Cs2CO3 (219 mg, 0.673 mmol) and bromoacetonitrile (53.8 mg, 0.45 mmol) respectively. The mixture was heated to 60° C. overnight affording conversion to desired product fairly cleanly. m/z (ESI) 543.2 (M+H)+. The mixture was dried under reduced pressure and purified with a 25 g Interchim column (25 μm silica) ramping EtOAc in heptane (0-100%, 10% DCM throughout) affording product as a light brown solid. m/z (ESI) 543.2 (M+H)+
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:41]=[CH:40][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)\[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:22][CH:21]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO.Cl>O1CCCC1>[C:3]1([C:9]2[N:14]3[CH:15]=[C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:24][O:25]/[N:26]=[C:27](/[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)\[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:40][CH:41]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cn3c(-c4ccccc4)cccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate (400 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 E-4-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyric acid (365 mg, yield 94%) as colorless crystals. m.p. 160-161° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:31]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[C:11]3([CH2:31][O:10][C:8]=2[CH:9]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:12]3=[O:29]
Reactant: ClCI
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C3(COc4cc(F)c(C#N)cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.50 g, 27.03 mmol) and chloroiodomethane (5.00 mL, 68.7 mmol) in tetrahydrofuran (200 mL) and N,N-dimethylformamide (50 mL) was added cesium carbonate (26.40 g, 81.02 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 20 h and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford 6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (5.27 g, 48%): mp 142-143° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 3H), 7.11-7.02 (m, 2H), 6.89-6.85 (m, 4H), 6.77 (d, J=9.0 Hz, 1H), 5.12-4.75 (m, 4H), 3.78 (s, 3H); MS (ES+) m/z 400.7 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH3:14].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:11]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]#[N:1])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC=O
Reactant: N#Cc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g 4-Aminomethyl-benzonitrile and 3.75 ml Butyraldehyde were dissolved in 40 ml methanol. 3.0 g molecular sieves 4 Angström were added and the mixture was stirred at room temperature for two hours. Then 2.2 g sodium borohydride were added and the mixture was stirred for an additional hour at room temperature. 250 ml ethyl acetate were added, and the reaction was quenched by addition of 4 ml water. The reaction mixture was filtered through a pad of celite and MgSO4. The filtrate was evaporated in vacuo to provide 3.7 g crude 4-Butylaminomethyl-benzonitrile. This material was used without further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[CH3:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1>CCCCCC.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([CH3:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: Cc1ccc2c(=O)oc(=O)[nH]c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)Cc2nnnn2C)c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (2.5M, 20 ml) was added slowly to a stirred solution of 1,5-dimethyltetrazole (4.9 g) in dry tetrahydrofuran (100 ml) at -5° to 0° under nitrogen. After stirring for 0.5 hour, 7-methyl-1H-3,1-benzoxazine-2,4-dione (2.6 g) was added and stirring continued for 1.5 hours at room temperature and for 3 hours at 40°. The solvent was evaporated under reduced pressure at 40°-50°, water (100 ml) was added to the residue, followed by 5N hydrochloric acid dropwise until neutral to Universal pH paper. The mixture was extracted with ethyl acetate (3×50 ml) and the combined extracts were washed with 10% aqueous potassium carbonate solution (50 ml), dried over anhydrous magnesium sulphate and then evaporated under reduced pressure at 50°. The residue was triturated with ether to give a solid product which was collected by filtration and recrystallised from ethyl acetate to give the novel compound 1-(2-amino-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 155°-6°.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:5][N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:6]2[C:2]([C:29]3[CH:30]=[C:31]4[CH:37]=[CH:36][NH:35][C:32]4=[N:33][CH:34]=3)=[N:3][N:4]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:5]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CSc1nccc(-c2cn(C3CCCCO3)nc2I)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3[nH]ccc3c2)n1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a solution of 4-[3-Iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-2-methylsulfanyl-pyrimidine B (1.33 g, 3.3 mmol) and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (1 g, 4.1 mmol) in DMF (30 mL) was added a 2M solution of sodium carbonate (2 mL). The sodium carbonate appeared to come out of solution upon addition. The mixture was deoxygenated with a nitrogen bubbler for a few minutes. The palladium catalyst was added and nitrogen bubbling continued for a few minutes before the bubbler was removed. The mixture was heated at 85° C. for 18 hr. LCMS shows complete conversion to product. The mixture was dropped into saturated aqueous NaCl and the resulting solids collected by filtration and rinsed with water. The solids were dissolved in methanol/dichloromethane (1:9), dried over MgSO4 and reduced to minimum volume. The residue was purified on a short column of silica gel using a gradient of 0-50% ethyl acetate in dichloromethane as eluant to give 5-[4-(2-Methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-1) (0.89 g, 69%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (br. s., 1H), 8.69 (s, 1H), 8.43 (d, J=5.31 Hz, 1H), 8.29 (d, J=2.02 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.51 (t, J=3.03 Hz, 1H), 7.11 (d, J=5.31 Hz, 1H), 6.48 (dd, J=3.28, 1.77 Hz, 1H), 5.53 (dd, J=9.85, 2.27 Hz, 1H), 4.00 (br. d, J=13.39 Hz, 1H), 3.61-3.76 (br. m, 1H), 2.10-2.24 (br. m, 4H), 1.91-2.06 (br. m, 2H), 1.65-1.80 (br. m, 1H), 1.50-1.63 (br. m, 2H).