Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:12]([OH:16])(=[O:19])[CH3:13].[C:12]([OH:16])(=[O:19])[CH3:13].[CH:3]1[C:4]2[C:5](=[O:17])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13]=2[CH:14]=[CH:15][C:2]=1[CH:1]=[O:19]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a solution of 2-methylanthraquinone (16.0 g, 72.0 mmol) in a mixture of acetic acid (400 ml) and acetic anhydride (400 ml) was added concentrated sulfuric acid (16 ml) at 5° C. Chromium trioxide (18.0 g, 0.18 mmol) was added over a period of 1 hour at 5° C. The reaction mixture was then stirred at 5° C. for 4 hours, poured into ice water, and extracted with chloroform. The organic extract was dried over MgSO4 and concentrated under vacuum to give anthraquinone-2-aldehyde diacetate (16.0 g, 65%.) To a solution of the anthraquinone-2-aldehyde diacetate (16.0 g, 47.3 mmol) in acetic acid (400 ml) was added dropwise 35% aqueous hydrochloric acid (170 ml) at room temperature. The reaction mixture had been stirred while refluxing for 15 min. cooled to room temperature, filtered off with suction, and washed with water. After drying, anthraquinone-2-aldehyde (10.0 g, 89%) was obtained.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.[NH:36]1[CH2:40][CH2:39][C@@H:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O.O>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([C:24]([N:36]5[CH2:40][CH2:39][C@@H:38]([NH2:41])[CH2:37]5)=[O:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N[C@@H]1CCN(C(=O)c2cn3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccc3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-{[(1-adamantylmethyl)amino]carbonyl}imidazo[1,2-a]pyridine-2-carboxylic acid (25 mg, 0.071 mmol) in DMF (2 mL) is sequentially added 0.05 mL of DIEA, 15.8 mg of tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.085 mmol) and 37.6 mg of BOP (0.085 mmol). After stirring for 2 h at RT, the reaction mixture is diluted with EtOAc and water. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by PTLC (8% MeOH, 1% NH4OH in DCM) affords the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.CCOCC.[CH3:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.CC(C)([O-])C.[K+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:32]4[O:31][C:30]([CH3:29])([C:11]=3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH:34]=[CH:33]4)[CH2:4][CH2:3]1
Reactant: Cc1ccco1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC(=C2c3ccccc3C3=C(c4ccccc42)C2(C)C=CC3O2)CC1

Procedure:
To a solution of 10.0 g. (0.0273 mole) of 1-methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 50 ml. of dry ether is added 25 ml. of 2-methylfuran and 3.4 g. of potassium t-butoxide. The mixture is stirred and refluxed for 10 days. After the addition of water (1.0 1.), the mixture is extracted with an ether-benzene mixture (4:1). This organic phase is removed, washed with water, dried over magnesium sulfate, filtered, and the solvent is removed on a rotary evaporator. The residue that remains crystallizes readily to give 4.0 g. of product. The material is recrystallized from acetonitrile to give pure 1-methyl-4-(1-methyl-1,4-dihydro-1,4-epoxy-9H-tribenzo[a,c,e]cyclohepten-9-ylidene)piperidine, m.p. 175°-177°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](Br)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.Cl.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:33]2[CH:34]=[CH:35][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][CH:32]=2)=[C:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(Br)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 65 °C
Yield: 89.8 %

Procedure:
A mixture of ethyl 1-benzyl-3-bromo-5-nitro-1H-indole-2-carboxylate (0.40 g, 1 mmol), 4-tert-butylbenzeneboronic acid (0.36 g, 2 mmol), 2 M aqueous sodium carbonate (5 mL), tetrakis(triphenylphosphine)palladium (0) (0.20 g, 0.17 mmol) in ethanol (5 mL) and toluene (5 ml) was heated at 65° C. for 16 h and then cooled. The reaction mixture was diluted with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate and concentrated. Flash silica gel chromatography using 5˜25% ethyl acetate/hexane gave 0.41 g (90%) of ethyl 1-benzyl-3-(4-tert-butylphenyl)-5-nitro-1H-indole-2-carboxylate as a yellowish solid: 1H NMR (DMSO-d6) δ 0.92 (t, J=7.0 Hz, 3H, 1.36 (s, 9H, 4.10 (q, J=7.0 Hz, 2H, 5.89 (s, 2H, 7.09 (d, J=8.4 Hz, 2H, 7.22-7.45 (m, 3H, 7.95 (d, J=7.6 Hz, 2H, 7.54 (d, J=8.5 Hz, 2H, 7.91 (d, J=11.2 Hz, 1H, 8.22 (dd, J=11.2, 2.1 Hz, 1H, 8.37 (d, J=2.1 Hz, 1H; MS (ESI) m/z 457 (MH+); HRMS calcd for C28H29N2O4: 457.2128; found (ESI+): 457.2114; Anal. calcd for C28H28N2O4: C, 73.66; H, 6.18; N, 6.14. Found: C, 73.48; H, 6.30; N, 5.97.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[S:13][C:12]([C:14](OCC)=[O:15])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:8][C:9]1[S:13][C:12]([C:14](=[O:15])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 4-methylpyridine (32.3 mmol) and ethyl 5-chlorothiophene-2-carboxylate (35.5 mmol) in anhydrous THF (58 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 64.5 mmol). The mixture was stirred 3 h at 5° C. The resulting precipitate was filtered and acidified with 6 molar HCl. The precipitate was then filtered and dried to afford 2.9 g (35% yield) of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[N:34]=[C:33]2[C:41]([N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])=[O:19])=O)(C)(C)C.CCCCCCC>ClCCl>[NH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[N:34]=[C:33]2[C:41]([N:43]1[CH2:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51]1)=[O:42])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of trifluoroacetic acid are added to 371 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-4,5-difluorobenzyl 2-tert-butoxycarbonylaminoethyl carboxylate in 4 ml of dichloromethane with ice-cooling. The mixture is subsequently stirred at 25° C. for a further 2 h, 5 ml of n-heptane are added, and the mixture is evaporated to dryness in vacuo. The residue is dissolved in 500 μl of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: [NH2-].[Na+].[Na].N.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: c1ccc(Cn2ccc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of sodium amide (prepared from 19.6 g, 0.85 mole of sodium and a few mg of Fe(NO3)3 -9H2O) and 800 mL of liquid NH3 (a dry ice condenser was used) was added a solution of 100 g (0.85 mole) of indole in 250 mL of dry ether during 15 minutes. The mixture was stirred for 30 minutes and then a solution of 107.8 g (0.85 mole) of benzyl chloride in 100 mL of dry ether was added during 30 minutes. The ammonia was allowed to evaporate overnight. The sides of the flask were washed down with MeOH and then 500 mL of H2O was added. The mixture was extracted with ether (2×500 mL). The combined ether extracts were washed with 250 mL of H2O and dried over MgSO4. The solvent was evaporated. The residue was distilled at 2 mm: fr 1, b.p. 172°- 183°, fr II, b.p. 183°-186°, 5 g; fr III, b.p. 186°-187°, 10.9 g; fr IV, b.p. 187°-191°, 121.8 g; fr V, b.p. 191°-197°, 13.9 g. Fractions III-V solidified upon standing several hours. Fraction IV had m.p. 42°-43°. Fraction III was crystallized from aqueous MeOH giving 9.9 g of colorless needles, m.p. 42.5°-43.5°. Fraction V was crystallized from aqueous MeOH giving 11.6 g of colorless needles, m.p. 43°-45.5°. The total yield was 143.3 g (81.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][NH2:20].C1COCC1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([NH:20][CH3:19])=[O:12]
Reactant: Cc1cc(Cl)c(C(=O)O)c(C)n1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1c(Cl)cc(C)nc1C
Temperature: 0 °C
Yield: 62 %

Procedure:
4-Chloro-2,6-dimethyl-pyridine-3-carboxylic acid (925 mg, 5 mmol) was suspended in anhydrous dichloromethane (15 ml), the mixture was cooled to 0° C. and oxalyl chloride (560 μl, 6.5 mmol) was added dropwise with stirring followed by two drops of DMF. The mixture was stirred at room temperature for 90 minutes, the solvent was removed under reduced pressure, the residue was dissolved in anhydrous dichloromethane (15 ml), the solution was evaporated to dryness again, and the residue was dissolved in anhydrous dichloromethane (15 ml) and cooled to 0° C. TEA (2.1 ml, 15 mmol) was added dropwise followed by dropwise addition of a 2M solution of methylamine in THF (5 ml, 10 mmol). The mixture was stirred at 0° C. for 30 minutes, the solvent was removed under reduced pressure and the residue taken up in saturated sodium bicarbonate solution (40 ml). The mixture was extracted with dichloromethane (3×), the combined extracts were dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was triturated with diethylether to yield 610 mg of a crystalline solid (3.1 mmol, 62%). MS (APCI): m/z=198.8 [M+1]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([OH:44])(=[O:43])[CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C:23]1[CH:42]=[CH:41][C:26]([NH:27][CH2:28][C@@H:29]2[NH:40][C:39]3[C:37](=[O:38])[NH:36][C:34]([NH2:35])=[N:33][C:32]=3[NH:31][CH2:30]2)=[CH:25][CH:24]=1)=[O:22])[C:17]([OH:19])=[O:18].C(O)=O>CN(C)C=O>[CH:1]([N:40]1[C@@H:29]([CH2:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([C:21](=[O:22])[NH:20][C@H:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][C:13]([OH:44])=[O:43])=[CH:42][CH:41]=2)[CH2:30][NH:31][C:32]2[N:33]=[C:34]([NH2:35])[NH:36][C:37](=[O:38])[C:39]1=2)=[O:2]
Reactant: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O=CO
Product: Nc1nc2c(c(=O)[nH]1)N(C=O)[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2

Procedure:
The method of claim 1 wherein said treating comprises adding 1,1'-carbonyl-diimidazole to a solution of (6S)-tetrahydrofolic acid and formic acid in substantially dry N,N-dimethyl-formamide, whereby N5-Formyl-(6S)-tetrahydrofolic acid is produced.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1

Procedure:
A solution of 3-bromo-1-propanol (10 mmole) in dichloromethane (20 ml) containing pyridinium p-toluene sulfonate (150 mg) is stirred with dihydropyran (15 mmole) for 20 hours at ambient temperature. The solution is then washed with water, dried (MgSO4 anhydrous), evaporated and is chromatographed on silica gel to afford the title compound.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]([OH:20])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:22]O>B(F)(F)F.CCOCC.C(Cl)Cl>[OH:1][CH:2]([C:15]1[CH:19]([O:20][CH3:22])[O:18][C:17](=[O:21])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CO
Reactant: CCCCCCCCCCCCC(O)C1=CC(=O)OC1O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCC(O)C1=CC(=O)OC1OC

Procedure:
A mixture of 0.8 g. of 4-(1-hydroxytridecyl)-5-hydroxy-2(5H)-furanone and 43 ml of methanol with a catalytic amount of BF3.OEt2 (3 drops) is stirred under argon for 15 hours. The mixture is diluted with methylene chloride, washed with water and dried over magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The resulting oil is purified by flash chromatography to give 4-(1-hydroxytridecyl)-5-methoxy-2(5H)-furanone.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>CCOCC>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
step 2—To a solution of 1,3-dibromo-5-methoxy-benzene (60 g, 0.2256 mol) and anhydrous Et2O (1 L) cooled to −78° C. and maintained under an Ar atmosphere was added dropwise over 30 min n-BuLi (100 mL, 0.2482 mol, 2.5M in hexane). The yellow solution was stirred at −78° C. for 20 min. To the reaction mixture was added dropwise dry DMF (19 mL, 248.2 mmol) over 15 min and the reaction stirred at −78° C. for 10 min before the cooling bath was removed and the reaction allowed to warm to −30° C. over 30 min. The reaction vessel was placed in an ice-water bath and warmed to −10° C. The mixture was slowly added to an ice cold saturated aqueous NH4Cl solution (400 mL). The organic layer was separated and the aqueous phase thrice extracted with Et2O. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to afford an oil which solidified on standing. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (3 to 5% EtOAc) to afford 3-bromo-5-methoxy-benzaldehyde.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)#[N:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C(=O)C>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[N:7]=[C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:21]#[N:22])[CH:3]=[CH:4][CH:5]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: FC(F)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Reactant: N#Cc1ccccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Temperature: 80 °C
Yield: 12.3 %

Procedure:
To a degassed solution of 3-(6-bromopyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (200 mg, 0.58 mmol), 2-cyanophenylboronic acid (172 mg, 1.16 mmol) and potassium phosphate (370 mg, 1.75 mmol) in N,N-dimethylacetamide (4 ml) was added tetrakis(triphenylphosphine)paladium(0) (33.8 mg, 29.2 μmol) and the reaction heated at 80° C. for 18 h. After cooling to ambient temperature the reaction was poured onto a cartridge of strong cation-exchange resin and non-basic impurities removed by elution with methanol. The product was then eluted with a 2M solution of ammonia in methanol and evaporated to give an orange oil. This residue was purified by silica gel chromatography eluting with isohexane on a gradient of ethyl acetate (20-60%) to give a solid. Crystallisation from ethyl acetate-dichloromethane gave 2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile (26 mg) as a white solid: δH (400 MHz, CDCl3) 7.38 (1H, d, J 7),7.61 (2H, m), 7.78 (2H, m), 7.91 (2H, m), 7.99 (1H, dd, J 9 and 9), 8.58 (1H, s), 10.62 (1H, d, J 9); m/z (ES+) 366 (M++H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.[Br:19]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:19][C:8]1[C:6]2[NH:7][C:2]([CH3:18])([CH3:1])[NH:3][C:4](=[O:17])[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[N:13][NH:14][C:15]=1[CH3:16]
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1[nH]ncc1-c1sc2c(c1Br)NC(C)(C)NC2=O
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a vigorously stirred solution of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.080 g, 0.305 mmol) in acetic acid (2 mL) was added slowly bromine (0.019 mL, 0.366 mmol). After 5 min, the mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with acetone (5 mL), PTSA (3 mg) and DMF (1 mL). The mixture was stirred for 30 min at 70° C. and poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give a yellow solid. This solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (65.4 mg, 63%) as a yellow solid:
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])C>[OH-].[Na+]>[C:4]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 8 by saponification of (Z)-3-[1-(3-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-2-indolinone in sodium hydroxide solution.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:4]=[CH:5][N:6]=1.[CH3:16][O:17][CH:18]([O:22][CH3:23])N(C)C>>[CH3:16][O:17][CH:18]([O:22][CH3:23])[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH2:15][CH2:14]1
Reactant: Cc1nccn1CCCC1CCNCC1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(CCCn2ccnc2C)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]piperidine (2.3 g, 0.0105M) and dimethylformamide dimethylacetal (20 ml) was heated at 100° C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetal gave 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde dimethylacetal. A solution of this piperidine carboxaldehyde dimethylacetal in methylene chloride (10 ml) was added to a mixture of 6-aminopenicillanic acid (2.16, 0.01M) and diisopropyl ethylamine (1.15 ml) in methylene chloride (50 ml) at 0° C. The reaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs. The solvent was removed and water (50 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.15 molar hydrochloride 1.75 molar hydrate (1.76 g, 33% yield).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccnc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccnc(OCc2ccc(CC[N+](=O)[O-])cc2)c1
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
To a dimethyl sulfoxide (50 mL) solution of 4-methyl-2-(4-((E)-2-nitro-vinyl)-benzyloxy)-pyridine (3.10 g, 11.5 mmol) described in Manufacturing Example 43-1-3 and acetic acid (3.10 mL) was added sodium borohydride (733 mg, 18.4 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 10 minutes. Water was then added dropwise into the reaction solution at room temperature while cooling appropriately, and the reaction mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5→1:2) to obtain the title compound (1.10 g, 35.1%).