Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH:13]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH3:16])[CH:11]=1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(OC(C)C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OC(C)C)cc1OC
Reaction time: 12 h

Procedure:
A 1.60 g portion of methyl 2-hydroxy-4-isopropoxybenzoate was dissolved in 30 ml of 2-butanone, 1.60 g of potassium carbonate and 1.1 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, insoluble matter was removed by filtration through celite, and the solvent was again evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to give 1.70 g of methyl 4-isopropoxy-2-methoxybenzoate.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>Cl>[CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)C3CCCCC3)c(C)o2)cc1
Agent: Cl
Solvent: O
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoate (1.0 g, 2.65 mmol, 1.00 equiv) in 6N hydrochloric acid (20 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and 30 mL of water and ice were added. The precipitate ws collected by filtration, washed with 3×20 mL of hexane and dried in a vacuum oven to give 0.85 g (88%) of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid as a white solid. LC-MS: (ES, m/z): 365 [M+H]+, 341, 257, 216, 189, 146, 115.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Cl[C:13](=[N:18]O)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:5][C:3]1[O:4][N:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:2]=1[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(Cl)=NO
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1noc(C)c1C(=O)OC
Reaction time: 3 h
Yield: 37.9 %

Procedure:
23.2 g (0.2 mol) of methyl acetoacetate in 50 ml of absolute methanol are added to a solution of 10.8 g (0.2 mol) of sodium methylate (cryst.) in 150 ml of dry methanol at 0°-10° C., and the mixture is stirred at this temperature for 3 h. Subsequently, at 0°-10° C., 27.5 g (0.2 mol) of methyl α-chloro-α-hydroximinoacetate in 100 ml of absolute methanol are slowly added dropwise, and the mixture is stirred at room temperature for 12 h. The solution is worked up by evaporation to a small volume and addition of 800 ml of water, when the product separates out as oil. The organic phase is separated off, the aqueous phase is extracted with dichloromethane, the combined organic phases are dried, and the solvent is stripped off in a rotary evaporator. The residue is purified by column chromatography on silica gel (solvent cyclohexane/ethyl acetate 3:1). 15.1 g (38% of theory) of dimethyl 5-methylisoxazole- 3,4-dicarboxylate are obtained.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([CH3:11])[CH3:10].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[C:14]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: CC(C)N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3.3 ml (23.8 mmol) of triethylamine and 2.0 ml (23.3 mmol) of 2-aminopropane are added to a solution of 4.87 g (21.4 mmol) of 5-bromo-2,4-dichloropyrimidine in 23 ml of acetonitrile at 0° C. The reaction mixture is stirred at room temperature overnight and then the solvent is stripped off. The resulting residue is purified by chromatography (dichloromethane/ethanol 8:2). 4.09 g (16.4 mmol; yield: 76%) of the product are obtained.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([C:35]2[S:36][C:37](Br)=[CH:38][CH:39]=2)(=[O:34])=[O:33])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([C:35]2[S:36][C:37]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:38][CH:39]=2)(=[O:33])=[O:34])=[CH:27][CH:26]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Nc1ccncc1)c1ccc(Br)s1
Product: O=S(=O)(Nc1ccncc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid pyridin-4-ylamide (example B.57) (160 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (140 mg, 49%). MS (ISN) 574.1 [(M−H)−]; mp 215° C.
Reaction SMILES: [N:1]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:5][CH:4]([N:7]2[C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:23]1([C:28]([N:20]2[CH2:21][CH2:22][CH:17]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C@@H:11]5[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:18][CH2:19]2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCN(C2CCNCC2)CC1
Reactant: O=C(O)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCCC1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the solution of (3aR,7aR)-1-(1,4′-bipiperidin-4-yl)octahydro-2H-benzimidazol-2-one, 0.25 mmol) in dry DMF (3 mL) was added cyclopentanecarboxylic acid (34 mg, 0.3 mmol) followed by HATU (114 mg, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.5 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (5 mL) and the solvent was removed in vacuo. Dichloromethane (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The crude product was purified with high pH prep-LCMS to yield (3aR,7aR)-1-[1′-(cyclopentylcarbonyl)-1,4′-bipiperidin-4-yl]octahydro-2H-benzimidazol-2-one (64 mg, 63%) as white powder. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.25-1.49 (m, 6H), 1.53-1.73 (m, 8H), 1.76-2.03 (m, 9H), 2.18-2.36 (m, 3H), 2.51-2.62 (m, 2H), 2.91-3.11 (m, 6H), 3.56-3.68 (m, 1H), 4.13 (d, J=13.28 Hz, 1H), 4.58 (d, J=13.28 Hz, 1H). MS (M+1): 403.3
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:40])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:22]#[C:23][C@:24]2([O:32][CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:33][O:32][C@@:24]1([C:23]#[C:22][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[OH:40])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1
Reactant: CO[C@]1(C#CC(O)(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)CN2CCC1CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCNCC2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Neat TFA (130 μL, 1.67 mmol) was added in one portion to a solution of tert-butyl-4-(1-hydroxy-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propynyl}-1-piperidinecarboxylate 170 (190 mg, 0.42 mmol) in CH2Cl2 (5 ml) at 0° C. After 3 hours at the same temperature, the cooling bath was removed and the reaction warmed up at room temperature. After 10 hours, the reaction was diluted with ether and cooled at 0° C. A solution of NaHCO3 was slowly added till pH was made basic. After separation, the organic layer was dried over Na2CO3 and evaporated in vacuum. The white solid was chromatographied on silica gel (elution: CH2Cl2/MeOH/NH4OH 94/6/0.1) and 3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-1-(4-piperidinyl)-2-propyn-1-ol 136 was obtained as a colorless semi-solid oil (mixture of diastereomers, 57 mg, 38%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17])[C:6]([NH:8][CH2:9][CH2:10][OH:11])=O)#[N:2].S(Cl)(Cl)=O>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]=[C:6]1[C:5]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:18])[CH3:17])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(C2=NCCO2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide was dissolved in DCM (30 mL) and thionyl chloride (1.43 g, 12 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 1 h and then quenched at 0° C. with water (200 μL) and 6N NaOH solution (1 mL). The mixture was stirred for 30 min. The aqueous layers were extracted with DCM and the combined organic extracts were washed with brine and dried over MgSO4 to afford 570 mg (61% for two steps) of 5-(4,5-dihydrooxazol-2-yl)-2-isopropoxybenzonitrile INT-31. LCMS-ESI (m/z) calculated for C13H14N2O2: 230.3; found 231.0 [M+H]+, tR=2.50 min. 1H NMR (400 MHz, CDCl3) δ 8.17-7.86 (m, 2H), 6.91 (d, J=8.9 Hz, 1H), 4.65 (dt, J=12.2, 6.1 Hz, 1H), 4.37 (dd, J=14.3, 4.9 Hz, 2H), 3.98 (t, J=9.5 Hz, 2H), 1.36 (t, J=5.5 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]3)[N:7]=2)[CH2:2]1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Br:12][C:11]1[C:6]([O:5][CH:3]2[CH2:2][N:1]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:4]2)=[N:7][C:8]([NH:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]2)=[N:9][CH:10]=1
Reactant: C[C@H]1CC[C@@H](Nc2ncc(Br)c(OC3CNC3)n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(azetidin-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)-pyrimidin-2-amine (1.24 g, 3.64 mmol) and Et3N (0.6 mL, 3.64 mmol) in DCM (20 mL) at 0° C. was added methanesulfonyl chloride (417 mg, 3.64 mmol). The mixture was stirred at 0° C. for 5 h, diluted by DCM, washed with saturated aqueous sodium carbonate solution and water, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, eluted by 1% methanol in DCM) to give the title compound as a white solid (1.3 g, 85% yield). MS (ESI) m/z: Calc. 418.1 (M+). Found: 420.1 (M++2).
Reaction SMILES: COC(C1C=C(OC2C=CC(Cl)=CC=2[Cl:21])C=CC=1[N+]([O-])=O)=O.[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:21][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([Cl:31])=[O:30]
Reactant: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Cl)c1cccc(Cl)c1

Procedure:
In the commercial process for producing herbicidal bifenox, i.e., methyl 2-nitro-5-(2'4'-dichlorophenoxy)-benzoate, preparation of a reaction precursor involves the chlorination of benzoyl chloride to obtain m-chlorobenzoyl chloride. This material is then reacted with methanol to produce the corresponding methyl chlorobenzoate.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]1)[C:4](=[O:10])[CH2:3][C:2]2=[O:11].C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:39][CH3:40])=[C:36]([Pb+3])[CH:37]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:39][CH3:40])=[C:34]([CH:3]2[C:2](=[O:11])[CH:1]3[CH2:9][CH2:8][CH:5]([CH:6]=[CH:7]3)[C:4]2=[O:10])[CH:33]=1
Reactant: O=C1CC(=O)C2C=CC1CC2
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Br)cc1C1C(=O)C2C=CC(CC2)C1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A solution of bicyclo[3.2.2]non-6-ene-2,4-dione (0.835 g, 5.58 mmol), prepared by the method of R. Beaudegnies et al., WO2005/123667, in dry chloroform (30 ml) is stirred at room temperature then thoroughly flushed with nitrogen. To this mixture is added 4-dimethylaminopyridine (3.41 g, 28 mmol) and anhydrous toluene (5 ml), followed by heating to 80° C. 5-Bromo-2-ethylphenyllead triacetate (4.75 g, 8.36 mmol) is added portionwise over 20 minutes, and the mixture is further heated at this temperature for a further 4 hours then left to stand overnight. 2M hydrochloric acid (40 ml) is added, and the suspension is vigorously stirred for 30 minutes then filtered through diatomaceous earth (washing with additional dichloromethane, 40 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (40 ml×2). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown oil. The crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio) to afford 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione (0.400 g, 22%) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:5]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
52.5 g (0.3 mol) of 2-chlorobenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. During the dropwise addition, the mixture was cooled to 60° C., and the temperature was then kept at 60°-70° C. When the reaction was complete, 40 ml of toluene were added at 45° C. 92 g (89% of theory) of the abovementioned compound of melting point 108° to 110° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>>[Cl:17][C:6]1[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=[C:2]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:33][N:32]=2)(=[O:36])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
4,6-Dichloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidine is treated with 5-isopropyl-pyridine-2-sulfonamide potassium salt to form 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide. This compound is then added to a solution of sodium in ethylene glycol. After heating, 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide is obtained and then added to a solution of pyridine-2-carbonyl azide in dioxane to form pyridin-2-yl-carbamic acid 2-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-ethyl ester (see EP 0713875A1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>C1COCC1>[C:28]1([C:25]2[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=2)[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:36])=[CH:32][CH:33]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 485.2 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[NH:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:30]([CH2:38][CH2:39]Br)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C(#N)C>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:39][CH2:38][CH:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:2]1[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)C(Br)CCBr
Reactant: O=C(NNC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Bis(phenylmethyl) 1,2-hydrazinedicarboxylate (5.91 g, 19.68 mmol) was placed in a 500 ml round bottomed flask and acetonitrile (150 ml) was added followed by cesium carbonate (14.11 g, 43.3 mmol). 1,1-Dimethylethyl 2,4-dibromobutanoate (4.00 ml, 19.68 mmol) was added dropwise and the reaction was heated to 60° C. and stirred overnight. The resulting solution was cooled to room temperature and passed through a pad of celite. The filtrate was concentrated and purified via combiflash silica gel chromatography (0-100% EtOAC in hex) yielding 3-(1,1-dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (5.3 g, 12.03 mmol, 61.1% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:19]1[O:21][CH2:20]1>C1COCC1.CCOCC>[CH:1]1[C:13]2[CH:12]([CH2:19][CH2:20][OH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a stirred, cooled (-78° C.) solution of 6.00 g (36.1 mmol) of fluorene in 75 mL of THF was added 15.4 mL (36.2 mmol) of 2.35 M n-BuLi in hexanes dropwise. The resulting dark orange mixture was stirred for 1.5 h and 26.0 mL (36.4 mmol) of 1.4 M ethylene oxide in Et2O was added. The resulting bright orange mixture was warmed slowly to room temperature over 3.5 h, quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The residue was poured into water and extracted twice with Et2O. The combined organic layers were washed with brine and dried over magnesium sulfate. Solvent was removed at reduced pressure and the crude product was chromatographed on 150 g of flash silica gel eluting with 25% EtOAc in hexane to afford 5.05 g (67%) of the desired alcohol as a white solid, mp 98°-99° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]Br>ClCCl>[Br:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(O)c(C=O)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Ex-29A: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0° C. using an ice-water bath. Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0° C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, m.p. 63–64° C. 1H-NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H). Anal. Calcd. for C8H7BrO3: C, 41.59; H, 3.05. Found: C, 41.86; H, 3.05.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Yield: 16.1 %

Procedure:
A mixture of 0.5 g of 4-(4-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.35 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. The residue was chromatographed on 60 g of Kieselgel 60 with diethyl ether/ethyl acetate (1:1) as the eluent. The product-containing fractions were concentrated and the residue was digested with a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. The product separated upon neutralization of the filtrate with concentrated hydrochloric acid. Recrystallization from 50 ml of 60% ethanol yielded 0.10 g of 4-methyl-N-[4-(4-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: C([NH:4][C@@H:5]1[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.Cl.[CH3:24][C:25]([CH:27]1[C:33](=[O:34])[CH2:32][C:31]([CH3:36])([CH3:35])[CH2:30][C:28]1=[O:29])=O.C(N(CC)C(C)C)(C)C>[OH-].[Na+]>[CH3:35][C:31]1([CH3:36])[CH2:32][C:33](=[O:34])[C:27](=[C:25]([NH:4][C@@H:5]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([CH2:21][OH:22])[O:15][C@@H:6]2[O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:24])[C:28](=[O:29])[CH2:30]1
Reactant: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(N[C@H]1[C@@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)CC(C)(C)CC1=O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A solution of Benzyl 2-Acetamido-2-deoxy-α-D-glucopyranoside (4.70 g, 15.11 mmol) in 1 M NaOH solution was refluxed at 120° C. for 15 h. The reaction mixture was cooled to room temperature, neutralised with 1 M HCl solution and concentrated. The residue was dissolved in dry ETOH (50 ml) and filtered. 2-Acetyldimedone (4.11 g, 22.6 mmol) and N,N-diisopropylethylamine (2 ml) were added to the filtrate, and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness, and the residue was taken up in EtOAc (50 ml), washed with 1M KHSO4 solution, brine, and evaporated to give Benzyl 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-α-D-glucopyranoside (7) (3.78 g, 58%).