Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:16][O:17][NH3+:18]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:18][O:17][CH3:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Product: CON=C1CCN(Cc2ccccc2)CC1

Procedure:
The starting material is prepared as follows: The solution of 94.5 g of 1-benzyl-4-piperidone and 46 g of methoxyammonium chloride in 600 ml of ethanol-pyridine (1:1) is refluxed overnight and evaporated. The residue is dissolved in water, the solution made basic with 12.5% aqueous sodium hydroxide and extracted with diethyl ether. The extract is washed with water and saturated aqueous sodium hydroxide, dried and evaporated, to yield the 1-benzyl-4-methoxyiminopiperidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5]O)[CH3:2].[BrH:14]>>[CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5][Br:14])[CH3:2]
Reactant: Br
Reactant: CCc1cc(C)cc(CC)c1CO
Product: CCc1cc(C)cc(CC)c1CBr
Yield: 89 %

Procedure:
14.7 g (82.5 mmol) of 2,6-diethyl-4-methylbenzyl alcohol in 150 ml of hydrobromic acid are stirred at 100° C. for 4 h. After cooling, the mixture is extracted with dichloromethane and the extract is washed with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. Distillation (110° C. bath temperature, 0.3 mbar) gives 17.82 g (89%) of 2,6-diethyl-4-methylbenzyl bromide as a colourless oil. 1H-NMR (400 MHz, CDCl3): δ=1.28 (t, 6H), 2.30 (s, 3H), 2.73 (q, 4H), 4.61 (s, 2H), 6.90 (s,
Reaction SMILES: [C:1](OC)(=[O:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6].[CH:10]1([CH:13]([CH3:15])[OH:14])[CH2:12][CH2:11]1>>[C:1]([O:14][CH:13]([CH:10]1[CH2:12][CH2:11]1)[CH3:15])(=[O:7])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CC(O)C1CC1
Reactant: CC/C=C\CC(=O)OC
Product: CC/C=C\CC(=O)OC(C)C1CC1

Procedure:
Prepared from methyl (3Z)-3-hexenoate and cyclopropyl methyl carbinol according to the ester preparation method B described above.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13](=[O:21])(=[O:20])[CH2:12][CH2:11]1>O>[N+:6]([C:18]1[CH:17]=[CH:16][C:15]2[O:10][CH2:11][CH2:12][S:13](=[O:20])(=[O:21])[C:14]=2[CH:19]=1)([O-:9])=[O:7]
Reactant: O=S1(=O)CCOc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)CCO2
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
2.554 g 66% H2SO4 and 1.454 g 65% nitric acid were mixed at 0° C. 2.395 g 2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide were added in portions at 0° C. After stirring for 30 min. the mixture was diluted with water and the product isolated by filtration. Chromatography on silica yielded 1.6 g of the title compound and 0.37 g 0.58 g of the 8-nitro isomer.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (2.54 mL, 24 mmol) and N-methylpiperazine (2.22 mL, 20 mmol) was dissolved in DMSO (25 mL) and irradiated in a microwave oven (max power 250 W, 160° C.) for 10 min, then cooled to room temperature. The solvent was removed under high vacuum, and the residue was dissolved in EtOAc and extracted with 0.5M aqueous HCl. The aqueous extracts were combined, basified to pH 8, and extracted with EtOAc. The organic layer was washed with brine, and then dried over MgSO4. Evaporation of the solvent provided the crude 1-methyl-4-(4-nitrophenyl)piperazine as an brown oil.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[NH:40][C:39]2=[O:48])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCOCC.O.CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:7][CH2:6][CH:5]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=5[NH:40][C:39]4=[O:48])[CH2:36][CH2:37]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reaction time: 64 h

Procedure:
A mixture of 11 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 6 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 3.5 g of potassium carbonate, 4.1 g of potassium iodide and 80 ml of dimethylformamide is stirred at 70°-80° C for 64 hours. The reaction mixture is poured into water, ether is added to the separated semi-solid, and the whole is stirred for 30 minutes. The substance insoluble in water and ether is collected by filtration, washed with ether and dried. The obtained crystals are dissolved in a mixture of chloroform and methanol (9:1), and the solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystals, melting at 279°-284° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[N:43]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(5-trifluoromethyl(2-pyridyl))amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-trifluoromethylpyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([Cl:16])[C:10]([Cl:15])=[C:11]([CH2:13][O:14][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=1
Reactant: OCc1cc(Br)cc(Cl)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.34 M) solution of (5-bromo-2,3-dichlorophenyl)methanol (1 eq.) from the previous step was added chloro(1,1-dimethylethyl)dimethylsilane (1.1 eq.) and imidazole (1.5 eq.). The resulting yellow solution was stirred at RT for 16 h. The reaction mixture was then diluted with ether and washed sequentially with 10% aq. HCl, water and brine. The ether extract was dried Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:17]([O-])=O)[C:3]1=[O:20].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:15][C:14]1[NH:17][C:4]2[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(C)=O)c1ccn(C)c(=O)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c2c(=O)n(C)ccc12
Yield: 72.8 %

Procedure:
To a solution of ethyl 2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxobutanoate (2.5 g, 8.8 mmol) in ethanol (50 mL) was added ammonium chloride (0.5 g, 9 mmol) in water (5 mL) at room temperature. The mixture was stirred and heated to reflux. Then iron powder (0.5 g, 8.9 mmol) was added in one portion. The mixture was stirred at reflux for 2 hours. Once starting material was consumed, the resultant mixture was filtered when it was hot, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give ethyl 2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 75%) as a brown solid. LRMS (M+H+) m/z: calcd 234.1. found 234. 1H NMR (400 MHz, d6-DMSO): δ 12.54 (s, 1H), 7.30 (d, J=5.1 Hz, 1H), 6.78 (d, J=5.1 Hz, 1H), 4.24 (q, J=5.1 Hz, 2H), 3.51 (s, 3H), 2.56 (s, 3H), 1.32 (t, J=5.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1ccc(C=CC(=O)O)cc1F
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1F

Procedure:
Using 2.0 g of 3-fluoro-4-methoxycinnamic acid (Example 99), 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that performed in Example 81 was carried out. As a result, 2.21 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3-fluoro-4-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[C:22]([CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:24])=[O:23]>C1COCC1.O>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:26]/[CH2:25][C:22]([OH:24])=[O:23]
Reactant: Cc1cccc(C=O)c1C
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(/C=C/CC(=O)O)c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of 2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40 mL) was added NaHMDS (41.1 mL, 82.1 mmol) at −20° C., and the reaction was stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide (5.0 g, 37.3 mmol) was added to the reaction at −78° C., and reaction was stirred while warming to rt overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (50×3 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated to give 7.00 g (99%) of the crude title compound as a yellow solid. [M+H] calc'd for C12H14O2, 191. Found 191.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:33]
Reactant: O=C=NCCCl
Reactant: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NCCCl)CS[C@H]12
Yield: 35.4 %

Procedure:
A solution of 3-hydroxymethyl-7β-(2-methoxyiminophenylacetamido)ceph-3-em-4-carboxylic acid (synisomer) (0.35 g.), 2-chloroethylisocyanate (0.097 g.) and triethylamine (1.79 g.) in dimethylformamide (10 ml.) was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution, and the aqueous phase washed with ethyl acetate, acidified and extracted with ethyl acetate. The combined extracts were dried, concentrated to ca. 5 ml. and dropped dropwise with stirring to petroleum spirit (250 ml.). The resulting solid was filtered and dried to give the title acid (0.157 g., 35%) λmax (pH 6 buffer) 258 nm (ε 6,800), λmax (Nujol) 3250 (NH), 2600 and 1715 (CO2H), 1700 and 1530 (NHCO2R), 1660 and 1540 cm.-1 (CONH), τ (DMSO-d6) values include 0.22 (doublet J 9 Hz; 7β-NH), 2.3 to 2.6 (multiplet; aromatic protons), 6.05 (singlet; OCH3), 6.40 (multiplet; C-2 CH2 and --CH2Cl), 6.65 (multiplet; --NHCH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: ClCCBr
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH was treated with 1-bromo-2-chloroethane (3 equiv) and cesium carbonate (2 equiv). The reaction was heated to 60° C. and stirred overnight. As described above, the desired product was then obtained upon chromatographic purification (EtOAc, followed by MeOH, then 2 M NH3 in MeOH). Yield; 30% overall from Prep. 90. MS ES+ m/e 401.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (2.0 g, 12.1 mmol) and 1-(2-bromo-phenyl)-ethanone (1.63 mL, 12.1 mmol) in dry acetonitrile (60 mL) was added a 0.4 M aqueous sodium carbonate solution (60 mL) and the reaction mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.433 mmol) was then added and the reaction mixture heated to 90° C. for 22 hours. The hot reaction mixture was filtered through celite and then concentrated in vacuo to remove acetonitrile. The resulting aqueous suspension was diluted with water to 75 mL then washed with diethyl ether (75 mL). The aqueous phase was acidified to pH 1 by the addition of concentrated hydrochloric acid and the resulting white suspension cooled to 4° C. for 1 hour. The solid product was filtered, washed with water and then dried in vacuo at 50° C. overnight to afford the title compound (2.62 g, 91%) as a white solid, m.p. 199-201° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C)[CH:30]=[O:31]>O1CCCC1>[Cl:21][C:22]1[C:27]([CH:30]=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN(C)C=O
Reactant: Clc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cccnc1Cl
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
Form a solution of lithium diisopropylamide by the adding n-butyl lithium (37.5 mL, 0.06 mol, 1.6 M in hexanes) to diisopropylamine (8.39 mL, 0.06 mol) in tetrahydrofuran (200 mL) at −10 to −20° C. under a nitrogen atmosphere. After stirring for 20 min., cool the mixture to −70° C. and add 2-chloropyridine (4.96 mL, 0.05 mol) dropwise via syringe and stir the mixture for 1 hour at this temperature. Add N,N-dimethylformamide (7.73 mL, 0.10 mol) dropwise via syringe and stir for 1 hour near −70° C. after which time remove the cooling bath and add a solution of aqueous 5N hydrochloric acid/tetrahydrofuran (5 ml125 mL) in a dropwise manner. Add water (200 mL) and warm the mixture to −10° C. Extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using 10% ethyl acetate/hexanes allowing for isolation of the desired aldehyde (2.86 g, 40%) as a solid. MS(EI): (M)+ 140.2, 141.3, 143.3 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[O:23]=[CH:24][CH2:25][C:26](O)=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[C:26]([OH:27])[CH2:25][CH:24]=[O:23]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Reactant: O=CCC(=O)O
Product: CC1=C(CCON=C(O)CC=O)c2cc(F)ccc2/C1=C\c1ccncc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-oxopropionic acid by the method of Example 1.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.[ClH:29].CCOCC>CO>[ClH:29].[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.6 %

Procedure:
To a solution of (3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4c (1.09 g, 2.82 mmol) in Methanol (6 mL) was treated with 1.0 M HCl/ether (28.2 mL, 28.2 mmol). The reaction mixture was stirred at ambient temperature for 19 h and concentrated in vacuo. The residue was repulped overnight in a mixture of Methanol (5 mL) and Ether (40 mL). The resulting tan solid was filtered and dried under high vacuum to afford the title compound 4-L (745 mg).
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)(=O)=[O:13])=[CH:7][C:6]=1[C:23]#[N:24]>C(O)C>[NH2:24][C:23]1[C:6]2[C:5](=[N:10][CH:9]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:13])=[O:1])[CH:7]=2)[NH:3][N:2]=1
Reactant: N#Cc1cc(NS(=O)(=O)c2cc(F)cc(F)c2)cnc1Cl
Reactant: NN
Reactant: O
Solvent: CCO
Product: Nc1n[nH]c2ncc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Temperature: 100 °C
Yield: 104.6 %

Procedure:
1.786 g (35.7 mmol) of hydrazine hydrate is added under argon to a solution of 784 mg (2.38 mmol) of N-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-sulfonamide in 6 mL of ethanol. The solution is heated to 100° C. for 20 hours and then cooled to room temperature. The solvent is evaporated to yield 810 mg of N-(3-amino-1H-pyrazolo[3,4-b]pyridin-5-yl)-3,5-difluorobenzene-sulfonamide (100%) which is used without further purification in the following steps.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.Cl[CH2:10][CH:11]=O.C(N(C(C)C)CC)(C)C.O>C(O)CCC>[CH3:8][S:7][C:4]1[S:3][C:2]2=[N:1][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CSc1nnc(N)s1
Reactant: O=CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCCCO
Product: CSc1nn2ccnc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.2 %

Procedure:
2-Amino-5-methylthio-1,3,4-thiadiazole (10.00 g; 67.92 mmol; 1.00 eq.) was reluxed in 1-butanol (100.00 ml) until complete dissolution of starting material. Then, chloroacetaldehyde (21.91 ml; 169.81 mmol; 2.50 eq.) was slowly added and the reaction was refluxed for 2 h. Diisopropyethylamine (11.63 ml) was slowly added over 2 h using a syringe pump. After 18 h, the reaction was allowed to cool to room temperature. Then, water was added and the aqueous phase was extracted 4 times with EtOAc. The combined organics were washed with brine, dried over MgSO4 to give 17 g of a viscous brown oil. The crude was purified by flash chromatography (preabsorption using MeOH an silica) using 95/5 dichloromethane/methanol. The combined fractions gave 3.05 g of the desired product as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([O:25]C)=O)=[CH:13][C:12]=2[N:11]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])=[CH:13][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)c(C(F)(F)F)c1)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 19.4 %

Procedure:
Under inert atmosphere to a solution of methyl 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (Step-3 of Intermediate-56, 0.100 g, 0.297 mmol) in dry toluene was added 4-fluoro-3-trifluoromethyl aniline (0.080 g, 0.446 mmol) and trimethyl aluminium (2.0 M solution in toluene) (0.037 g, 0.516 mmol). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 0.75-1% DCM: MeOH to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.40-7.57 (m, 4H), 7.65 (s, 1H), 8.06 (m, 1H), 8.30 (s, 1H), 9.37 (s, 1H), 10.40 (s, 1H), 11.68 (s, 1H); MS [M+H]+: 522.14.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8]O)(=[O:5])[C:2](C)=[CH2:3].CC(CC)=[N:12]O>>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:3].[NH2:12][C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCC(C)=NO
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
Into a four-necked flask provided with a stirrer, a condenser and a thermometer are charged 1500 parts of 3-methylpentane adipate having a molecular weight of 500, 134 parts of trimethylol propane and 1464 parts of tetramethylxylylene isocyanate. Thereafter, they are warmed to 100° C. and reacted for 5 hours to obtain polyfunctional terminal isocyanate prepolymer (ratio of NCO content 4.1%). Then, the temperature of the product is rendered into 60° C. and 174 parts of β-hydroxyethyl methacrylate is added to conduct the reaction for 2 hours. Thereafter, 130 parts of methylethyl ketoxime is further added to conduct the reaction for 2 hours, whereby there is obtained urethane acrylate.