Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27]1([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41]Br)=[C:37]([C:43]([F:46])([F:45])[F:44])[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:36][C:37]=2[C:43]([F:44])([F:45])[F:46])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.05 g, 4.70 mmol) in anhydrous THF (30 ml) was added 1.0 M lithium bis(trimethylsilyl)amide in THF (4.7 ml, 4.70 mmol) at ambient temperature under nitrogen. The solution was stirred at ambient temperature for 20 min. To the solution was added a solution of 4-(bromomethyl)-3-(trifluoromethyl)phenyl phenylmethyl ether (1.47 g, 4.26 mmol) in THF (15 ml). The mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (120 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the aqueous phase washed with ethyl acetate (30 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave a pale yellow oil (˜2.5 g). The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.61 g); LCMS: (System 4) MH+=488, tRET=3.37 min.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]([OH:15])=[O:14])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C(Cl)Cl>[C:24](=[O:25])([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[O:14][C:13](=[O:15])[CH:3]([O:2][CH3:1])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(NC(=O)Cc1cccs1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(NC(=O)Cc1cccs1)C(=O)OC(=O)OCC(C)C

Procedure:
One millimole of α-methoxy-N-(2-thienylacetyl)glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming α-methoxy-N-(2-thienylacetyl)glycyl i-butyl carbonate. To this solution at -78° is added p-methoxybenzyl-5-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl 6H-1,3-thiazine-4-carboxylate, and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-methoxybenzyl 7-methoxy-7-(2-thienylacetamido)-3-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroformethyl acetate.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](OC)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl (+−)-trans4-methylene-2-phenylcyclopentanoate (26.0 g, 128 mmol) prepared as in Step A in THF (600 mL) under nitrogen and cooled to −10° C. was added dropwise over 15 min 1M lithium aluminum hydride (LAH) in THF (193 mL). After 1 h, the bath was removed and the reaction was stirred at rt for 16 h. The reaction was cooled in an ice/methanol bath and the excess LAH was quenched by dropwise addition of acetone. The reaction was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (20-30% ethyl acetate in hexanes) to afford the title product (23.8 g).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: Cc1ccc(CCl)cc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(C)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-methylbenzyl chloride to form 1-(4-methylbenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 238°-239° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)O1.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[C:11]([O:10][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH:51]3[CH2:56][CH2:55][CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[N:3][C:4]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 65 °C
Yield: 109.6 %

Procedure:
tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (750 mg, 1.393 mmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (691.5 mg, 1.532 mmol) were suspended in MeCN (7.500 mL)/water (7.500 mL) and Na2CO3 (1.393 mL of 2 M, 2.786 mmol) was added. The reaction mixture was degassed with 3× nitrogen/vacuum cycles. Pd(tBu3P)2 (71.19 mg, 0.1393 mmol) was added and the reaction mixture again degassed 3 times then heated to 65° C. (Dry Syn Temp) for 1.5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethylacetate/water. The aqueous layer was extracted with ethylacetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 30% Petroleum/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-(5-((tert-butoxycarbonyl)amino)-6-(3-phenylisoxazol-5-yl)pyrazin-2-yl)phenyl)sulfonyl)piperidine-1-carboxylate as a yellow solid (1.01 g, 93% Yield). H NMR (400.0 MHz, DMSO) δ 9.53 (s, 1H), 8.67 (d, 2H), 8.12 (d, 2H), 8.05-8.03 (m, 3H), 7.60-7.57 (m, 3H), 3.76 (br d, 1H), 3.47-3.41 (m, 1H), 3.02-2.95 (m, 1H), 2.81-2.77 (m, 1H), 2.09-2.04 (m, 1H), 1.77-1.63 (m, 2H) and 1.42-1.21 (m, 29H) ppm
Reaction SMILES: ClCCl.C([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:25][C:26](=[O:40])[C:27]4[N:32]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[N:31]=[C:30]([CH3:39])[C:28]=4[N:29]=3)=[C:20]([O:41][CH3:42])[CH:19]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH:33]1([N:32]2[C:27]3[C:26](=[O:40])[NH:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([NH:17][CH:14]5[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]5)=[CH:19][C:20]=4[O:41][CH3:42])=[N:29][C:28]=3[C:30]([CH3:39])=[N:31]2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: COc1cc(NC2CCN(Cc3ccccc3)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(NC2CCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To a 3 ml dichloromethane solution of 120 mg (0.228 mmol) of the compound obtained in Example 223, 50 μl (0.456 mmol) of 1-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Further, 50 μl (0.456 mmol) of 1-chloroethyl chloroformate and 3 ml of 1,2-dichloroethane were added, and the mixture was heated under reflux for 5 hours. Then, the reaction mixture was distilled under reduced pressure, 3 ml of methanol was added to the residue, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane/methanol=20/1) to obtain 62 mg (62%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[N+:9]([C:12]1[N:13]=[C:14]2[N:19]([CH:20]=1)[CH2:18][CH2:17][CH:16]([CH2:21][OH:22])[O:15]2)([O-:11])=[O:10].[H-].[Na+].C(=O)=O.CC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:21][CH:16]2[O:15][C:14]3=[N:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][N:19]3[CH2:18][CH2:17]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CO)CC2
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(Br)cn1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.3 %

Procedure:
5-Bromo-2-fluoropyridine (91) (0.52 mL, 5.05 mmol) was added to a solution of oxazine alcohol 134 (see Example 2BB) (500 mg, 2.51 mmol) in anhydrous DMF (10 mL) under N2 at 0° C. The resulting mixture was treated with 60% NaH (151 mg, 3.78 mmol), then quickly degassed and resealed under N2. Further 5-bromo-2-fluoropyridine (91) (0.52 mL, 5.05 mmol) was added and the mixture was stirred at room temperature for 2.5 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (30 mL), added to brine (100 mL) and extracted with CH2Cl2 (8×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% EtOAc/CH2Cl2 firstly gave foreruns, and then further elution with 2-4% EtOAc/CH2Cl2 gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (136) (778 mg, 87%) as a white solid: mp (MeOH/CH2Cl2/hexane) 182-184° C.; 1H NMR [(CD3)2SO] δ 8.30 (dd, J=2.6, 0.5 Hz, 1H), 8.07 (s, 1H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 6.91 (dd, J=8.8, 0.6 Hz, 1H), 4.90 (m, 1H), 4.58 (dd, J=12.0, 3.3 Hz, 1H), 4.52 (dd, J=12.0, 6.0 Hz, 1H), 4.17 (ddd, J=12.6, 5.8, 2.8 Hz, 1H), 4.09 (ddd, J=12.5, 11.0, 5.2 Hz, 1H), 2.34-2.26 (m, 1H), 2.23-2.11 (m, 1H). Anal. (C12H11BrN4O4) C, H, N.
Reaction SMILES: NC1C(C=[N:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=NC(Cl)=C(Cl)N=1.BrC1C=CC(S(Cl)(=O)=O)=CC=1.NN>>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([NH:12][NH2:11])(=[O:14])=[O:15])=[CH:21][CH:20]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=NNS(=O)(=O)c1ccc(Br)cc1
Agent: NN
Agent: O=S(=O)(Cl)c1ccc(Br)cc1
Product: NNS(=O)(=O)c1ccc(Br)cc1

Procedure:
p-Bromobenzenesulfonic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of p-bromobenzenesulfonyl chloride with hydrazine to form p-bromobenzenesulfonylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH4-].[Na+]>C(O)C>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCOCC2)c1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 15 g. (0.123 mole) of 3-hydroxybenzaldehyde in 150 ml of ethanol is added 26.5 g (0.304 mole) of morpholine. Then 4.7 g (0.124 mole) of sodium borohydride is added portionwise over 1 hour. The solution is stirred for 1 hour and allowed to sit overnight. The solvent is then evaporated via a rotary evaporator and the residue triturated with 200 ml cold water. After acidification with concentrated HCl, the solution is extracted with ethyl acetate. The aqueous layer is basified with ammonium hydroxide and extracted again with 100 ml ethyl acetate. The organic layer is dried over MgSO4, filtered and evaporated. The residue is recrystallized twice from acetonitrile to give 6.3 g of product m.p. 113°-15° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)#[N:39]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:43]2[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[CH:41][CH:42]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C#N)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 57 %

Procedure:
The title compound was prepared in 57% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 4-cyanophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]3)=[O:14])=[CH:8][C:7]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C.[CH3:50][C:51]([CH3:53])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:51]([N:27]1[CH2:26][CH2:25][N:24]([CH:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH3:5])=[C:7]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[CH:34]=[CH:33][N:32]=5)[CH:8]=4)=[O:14])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:29][CH2:28]1)([CH3:53])[CH3:50]
Reactant: CC(C)=O
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C(C)C)CC2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.33 h
Yield: 70.6 %

Procedure:
N-(4-Methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 mL), and triethylamine (101 mg, 1 mmol) was added followed by acetone (35 mg, 0.6 mmol). After the solution was stirred for 20 minutes, sodium triacetoxyborohydride (128 mg, 0.6 mmol) was added. The solution obtained was stirred overnight at room temperature and then purified by high performance liquid chromatography at pH=10 to obtain 58 mg (71% yield) of the title compound. MS (M+1)=548.31. 1HNMR (DMSO-d6, ppm): δ 10.14 (s, 1H); 9.26 (s, 1H); 8.98 (s, 1H); 8.67 (d, J=4.8 Hz, 1H); 8.49 (d, J=4.8 Hz, 1H); 8.46 (d, J=8.4 Hz); 8.05 (s, 1H); 7.77 (s, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.51 (dd, J=8.0 & 4.8 Hz, 4.8 Hz, 1H); 7.46 (d, J=8.2 Hz, 1H); 7.41 (d, J=5.2 Hz, 1H); 7.35 (d, J=7.6 Hz, 1H); 7.17 (d, J=8.4 Hz, 1H); 4.30 (t, J=7.0 Hz, 1H); 2.91 (m, 12H); 2.81 (s, 3H); 2.3-2.6 (m, 9H); 2.02 (m, 2H); 0.92 (t, J=6.4 Hz, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(CCCCCCc5ccccc5)c4=O)cc3)CC2)cc1
Agent: Br
Product: O=c1n(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)cnn1CCCCCCc1ccccc1
Yield: 73 %

Procedure:
This compound was synthesized as a white amorphous solid from 4n (27.4 mg, 0.054 mmol) in 48% aqueous HBr (1.0 mL) in 73% yield by following general procedure 1.4: MALDI-MS: 498.3 (M+H+), 520.3 (M+Na+).
Reaction SMILES: C(N)(=O)C(C)C.[CH:7]1([C:10]2[N:14]([CH3:15])[C:13]([CH:16]=[O:17])=[CH:12][N:11]=2)[CH2:9][CH2:8]1>>[CH:7]([C:10]1[N:14]([CH3:15])[C:13]([CH:16]=[O:17])=[CH:12][N:11]=1)([CH3:9])[CH3:8]
Reactant: Cn1c(C=O)cnc1C1CC1
Agent: CC(C)C(N)=O
Product: CC(C)c1ncc(C=O)n1C

Procedure:
2-Isopropyl-3-methyl-3H-imidazole-4-carbaldehyde was prepared from isobutyramide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:14][Si:15]([CH3:29])([CH3:28])[CH2:16][CH2:17]N=C(O)N(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([OH:11])[C:8]([O:10][CH2:17][CH2:16][Si:15]([CH3:29])([CH3:28])[CH3:14])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(O)C(=O)O)cc1
Reactant: CC(C)N(C(O)=NCC[Si](C)(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(O)C(=O)OCC[Si](C)(C)C)cc1
Yield: 72 %

Procedure:
To a solution of 4-methoxymandelic acid (2.00 g, 10.978 mmol) in 55 mL of dioxane at 90° C. is added 2-trimethylsilylethyl-N,N-diisopropyl-pseudourea. The resulting solution is refluxed for about 8 hours. After cooling the mixture is diluted with 50 mL of ethyl acetate, filtered, washed with saturated aqueous sodium bicarbonate followed by brine, dried over magnesium sulfate, and concentrated. The resulting residue is chromatographed on silica gel (9/1 hexanes/ethyl acetate) to give the title compound as an oil: 2.24 g, 72% yield. 1H NMR (300 MHz, CDCl3): 7.32 (d, J=8.8, 2 H), 6.89 (d, J=8.8, 2 H), 5.08 (d, J=5.6, 1 H), 4.38-4.17 (m, 2 H), 3.81 (s, 3 H), 3.41 (d, J=5.6, 1 H), 0.96 (m, 2 H), 0.01 (s, 9 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([CH2:25][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:27]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C(=O)OCc2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g of benzyl indole-2-carboxlate in solution in 20 ml of dimethylformamide are introduced slowly into 30 ml of a suspension of 1 g of NaOH NaH in 30 ml of dimethylformamide and 3.1 g of methyl bromoacetate are then introduced. After 12 hours at ambient temperature, with stirring, the mixture is poured into a volume of ice-water and then extracted with ethyl acetate. The dried organic phase is concentrated and the residue is recrystallised from aqueous ethanol (95%, V/V). m.p.=94° C.; yield 87%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=1[Cl:18].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:18][C:10]1[C:11]([Cl:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[C:8](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccccc2F)c(Cl)c1Cl

Procedure:
To a solution of 10 g (0.033 m) of 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone of Example 1a in 100 ml of pyridine, 3.17 g of hydroxylamine HCl is added. The mixture is refluxed for about 64 hours. The pyridine is evaporated and the residue partitioned between 5% HCl and ethylacetate. The ethylacetate extract is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-methoxy-2'-fluorobenzophenone oxime, mp 195°-197° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:12]1[C:6]2[O:5][C:4]([C:1]3([CH3:2])[O:17][CH2:16][CH2:15][O:3]3)=[CH:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: OCCO
Reactant: CCc1cccc2cc(C(C)=O)oc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc2cc(C3(C)OCCO3)oc12
Yield: 78.8 %

Procedure:
A stirred mixture of 50 g of 2-acetyl-7-ethylbenzofuran, 3.0 g of paratoluenesulphonic acid and 45.0 g of ethyleneglycol in 1200 ml of toluene was heated under reflux for 12 hours with azeotropic removal of water. The cooled solution was washed successively with dilute sodium hydroxide solution, water and brine and then dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated to dryness. The residual yellow oil was distilled under nitrogen to give 48.6 g of 7-ethyl-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran of boiling point 86°-88°C/0.05 mm Hg.
Reaction SMILES: C(N1C2C(=O)[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](C#N)=[CH:18][CH:17]=3)C([Cl:24])=NC=2N=C1N1CCCC(NC(=O)OC(C)(C)C)C1)C#CC.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]2[N:55]([CH2:56][C:57]#[C:58][CH3:59])[C:54]3[C:53](=[O:60])[N:52]([CH2:61]C4C=CC=CC=4C#N)[C:51]([C:70]#[N:71])=[N:50][C:49]=3[N:48]=2)[CH2:42]1>>[ClH:24].[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]2[N:55]([CH2:56][C:57]#[C:58][CH3:59])[C:54]3[C:53](=[O:60])[N:52]([CH2:61][C:19]4[CH:20]=[CH:21][C:16]([C:15]#[N:11])=[CH:17][CH:18]=4)[C:51]([C:70]#[N:71])=[N:50][C:49]=3[N:48]=2)[CH2:42]1
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccc(C#N)cc3)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccc(C#N)cc3)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl [1-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Examples 242 (f) and (g).