Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]2[CH:13]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 80 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a stirred solution of 4-(benzyloxy)-2-hydroxybenzaldehyde (10 g, 43.9 mmol) in DMF (60 mL), was added methyl bromoacetate (48.3 mmol, 4.57 mL), and potassium carbonate (24.2 g, 175.6 mmol). The solution was heated to 80° C. and stirred for 16 h. The reaction was quenched with water (100 mL) and aqueous extraction was performed with AcOEt (2×50 mL). The organic phase was dried with sodium sulfate and concentrated. Purification was achieved via silica gel chromatography employing 0-30% AcOEt in hexane gradient. This afforded 393 as a light yellow solid (4.5 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][CH2:11][C:12]([NH2:22])=[O:14]
Reactant: Cc1ccccc1CCOCC(=O)O
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1CCOCC(N)=O

Procedure:
The subtitle compound (5.02 g) was prepared according to the procedure in example 5 part b using 2-[2-(2-methylphenyl)ethoxy]acetic acid (6.726 g), oxalyl chloride (6.22 ml), concentrated ammonium hydroxide (60 ml), and toluene (60 ml).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][OH:30])[CH:10]=[CH:11][C:12]=3[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][OH:23])[C:7](=[O:31])[C:6]=2[C:5]([OH:32])=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O>C1C=CC=CC=1>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]1[N:27]([CH2:26][CH2:25][NH:24][C:9]2[C:8]3[C:7](=[O:31])[C:6]4[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][C:5]=4[OH:32])[C:14](=[O:16])[C:13]=3[C:12]([NH:17][CH2:18][CH2:19][N:20]3[CH2:3][CH2:2][O:1][CH:21]3[C:22]3[O:23][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[CH2:28][CH2:29][O:30]1
Reactant: O=Cc1ccco1
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21
Solvent: c1ccccc1
Product: O=C1c2c(O)ccc(O)c2C(=O)c2c(NCCN3CCOC3c3ccco3)ccc(NCCN3CCOC3c3ccco3)c21

Procedure:
A suspension of 3.11 g. of 1,4-dihydroxy-5,8-bis[[2-(2-hydroxyethylamino)ethyl]amino]anthraquinone [prepared as described in Example 1(A)] in 55.0 ml. of benzene containing 2.02 g. of 2-furaldehyde is stirred and heated under reflux using a Dean-Stark trap. A total of 0.2 ml. of water is collected as distillate over a 3 hour period, with no additional water after a total of 7 hours of refluxing. The hot solution is filtered, removing a small amount of blue-black solid. The filtrate is concentrated and petroleum ether is added to give a gum which slowly solidifies. The solid is collected and washed with benzene to give 2.05 g. of a blue-black solid.
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[C:9]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])(=[S:11])[NH2:10].C([O-])([O-])=O.[K+].[K+]>CO>[C:6]([C:2]1[S:11][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:10][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: NC(=S)NC(=O)c1c(F)cccc1F
Reactant: CC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)c1sc(NC(=O)c2c(F)cccc2F)nc1C
Temperature: 25 °C
Yield: 69.2 %

Procedure:
The solution of 3-chloro-2,4-pentanedione (670 mg, 4.88 mmol), N-carbamothioyl-2,6-difluorobenzamide (1.08 g, 5.0 mmol) and K2CO3 (0.8 g) in 20 mL of MeOH was stirred at reflux for 5 hours. The reaction was cooled to room temperature, and concentrated under reduced pressure. The residue was taken up with EtOAc. The solution was washed with water, dried (Na2SO4), filtered and concentrated. Purification on silica gel gave N-(5-Acetyl-4-methylthiazol-2-yl)-2,6-difluorobenzamide (1.0 g, 71%) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15](OC)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([CH3:23])[O-:22].[Li+].O>CC(O)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([O:22][CH:21]([CH3:23])[CH3:20])=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:19])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Reactant: CC(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc2c(C3CCCC3)cn(C)c2c1
Temperature: 65 °C
Yield: 95.2 %

Procedure:
The mixture of methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (50.0 g, 0.194 mol) and lithium isopropoxide (16.2 g, 95%, 0.233 mol) in 2-propanol was stirred at 65±5° C. for at least 30 min for complete trans-esterification. The batch was cooled to 40±5° C. and water (600 g) was added at a rate to maintain the batch temperature at 40±5° C. After addition, the mixture was cooled to 20-25° C. over 2±0.5 h and held at 20-25° C. for at least 1 h. The batch was filtered and rinsed with 28 wt % 2-propanol in water (186 g), and water (500 g). The wet cake was dried in vacuo (≦200 Torr) at 40-45° C. until the water content was ≦0.5% to give isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A % (240 nm).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9]([Mg]Br)[CH:10]=[CH2:11].C(Br)C=C.[NH4+].[Cl-].Cl>C(OCC)C>[OH:8][C:4]([CH2:9][CH2:10][CH3:11])([CH2:5][CH2:6][CH3:7])[CH2:3][CH:2]=[CH2:1]
Reactant: CCCC(=O)CCC
Reactant: C=CC[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(O)(CCC)CCC
Temperature: 0 °C

Procedure:
113 g of 4-heptanone in 1000 ml of dry diethyl ether was slowly added to a solution of allylmagnesium bromide, prepared from 36.5 g of Mg and 178 g of allyl bromide in 500 ml dry diethyl ether. After the addition the mixture was refluxed for 10 hrs. The reaction mixture was poured on a mixture of 150 g ice, 450 ml of 20% NH4Cl and 350 ml of 5M HCl. The ether phase was separated and the water phase extracted with diethyl ether (3×100 ml). The combined organic phases were then washed with a Na2CO3 -solution and water, dried with Na2SO4 and evaporated. The residue was distilled. Yield: 142 g (b.p. 38°-40° C./0.1 torr) 1H-NMR(CDCl3): δ0.9(6H,CH3), 1.3-1.6(9H,CH2,OH), 2.1-2.3 (CH2C=C), 5.0-5.2(CH2 =C), 5.6-6.1 (CH=C)
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:8])[O:3]1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:38])[O:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1>C(Cl)Cl>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:27]([O:28][CH2:29][C:30]3[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=3)=[O:38])[CH2:14][CH2:13]2)=[O:8])[O:3]1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(NCCC1CCNCC1)c1c[nH]c(=O)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-oxo-N-(2-(piperidin-4-yl)ethyl)-2,3-dihydrooxazole-5-carboxamide (step 3) (210 mg, 0.76 mmol) was suspended in DCM (2 ml). DIPEA (265 μl, 1.52 mmol) was added and the reaction mixture sonicated to aid dissolution. 3,5-dichlorobenzyl carbonochloridate (182 mg, 0.76 mmol) in DCM (2 ml) was added and the mixture was left stirring vigorously at RT overnight. The resulting mixture was diluted with DCM and washed with citric acid (emulsion formed). Brine was added and organics were separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica eluting with 75-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:29][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: [NH4+]
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
A mixture of 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.00 g, 3.14 mmol), prepared in the previous step, ammonium acetate (12.1 g, 157 mmol) and acetic acid (100 mL) was heated to 100° C. under a nitrogen atmosphere for three hours. The mixture was cooled to ambient temperature, and the precipitate was isolated by filtration to give 2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole as a white solid (0.86 g, 91%), mp 208.5–209.5° C. Elemental Analysis for C21H17NO Calc'd: C, 84.25; H, 5.72; N, 4.68. Found: C, 84.25; H, 5.77; N, 4.56.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(#N)C>[CH2:4]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:33]2=[O:34])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In this reference example, 4.04 g of 1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine trihydrochloride, 3.04 g of triethylamine, 2.03 g of 1,1'-carbonyldiimidazole and 50 ml of acetonitrile are mixed and stirred at room temperature for 4 hours. Then, 0.8 g of 1,1'-carbonyldiimidazole is further added to the mixture and the resultant mixture is refluxed with heating for 20 minutes. The solution is cooled to room temperature. The crystals deposited are separated by filtration, washed with water and dried to obtain 2.50 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 1.75 g of the desired product.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>C(#N)C>[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C@@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH3:28])([CH3:27])[CH3:29]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 13.1 %

Procedure:
A solution of ethyl 2-bromo-9-phthalimidononanoate [prepared according to Chem. Pharm. Bull. 34, 2078 (1986)] (3 g), L-alanyl-L-proline tertiary butylester (1 g) and triethylamine (0.8 ml) in acetonitrile (200 ml) is subjected to 60 hours' reflux. Acetonitrile is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The solution is dehydrated with anhydrous sodium sulfate, and thereafter is concentrated to obtain an oily residue. When this substance is applied to a silica gel chromatography (ethyl acetate:n-hexane=3:1) for separative purification, 310 mg of N-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]-L-alanyl-L-proline tertiary butylester is obtained as a colorless oil from the first effluence.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:19]=[CH2:20].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:18]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:19]=[CH2:20]
Reactant: C=CCNc1ccccc1
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCN(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a round bottom flask was added 2-(tert-butoxycarbonylamino)-3,3-dimethylpent-4-enoic acid (120 mg, 0.493 mmol), N-allylaniline (0.134 mL, 0.986 mmol), EtOAc (5 mL) and Hunig's Base (0.258 mL, 1.48 mmol). The reaction mixture was cooled to 0° C. 1-propanephosphonic acid cyclic anhydride (314 mg, 0.986 mmol) was added and the reaction was stirred at 0° C. for 5 min and then at rt for 3 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give tert-butyl 1-(allyl(phenyl)amino)-3,3-dimethyl-1-oxopent-4-en-2-ylcarbamate (70 mg, 0.20 mmol, 40% yield) as clear oil. Anal. Calcd. for C21H30N2O3 m/z 358.2. found: 359.2 (M+H)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])(C)(C)C.Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=[CH:26][C:17]=1[NH:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([OH:5])=[O:7]
Reactant: Clc1cnc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: O=C(O)N1CCCCC1CNc1cnc2ccccc2n1

Procedure:
The title compound (0.73 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and 2-chloroquinoxaline (0.5 g) according to the procedure of D8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)Oc1cc(=O)[nH]cc1Cl
Yield: 39.7 %

Procedure:
The general procedure of Example 3 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 2.75 g of hexanoyl chloride, thereby producing 1.33 g of the title compound in a yield of 40%.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:15]=[N:14][S:13][N:12]=1)[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:11]1[CH:15]=[N:14][S:13][N:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cnsn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1cnsn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
An aqueous solution of 1N sodium hydroxide (5.4 ml.) was added with stirring at ambient temperature to a solution of methyl 2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (syn isomer) (0.9 g.) in methanol (10 ml.) and the mixture was stirred for 1 hour at ambient temperature. Methanol was distilled off and water was added to the residue, after which the mixture was washed with ether. The aqueous layer was adjusted to pH 1.5 with 10% hydrochloric acid, subjected to salting-out and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. Ether was distilled off. Benzene was added to the residue and removed to give crystals of 2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (0.67 g.), mp 99° to 100° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[O:3])[NH2:2].Cl[CH:24]([C:30]([CH3:32])=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:30]([CH3:32])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH3:22])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C
Yield: 31.1 %

Procedure:
cis(±)-Benzyl (1-carbamoyl-3-methoxypiperidin-4-yl)carbamate obtained in Example (103b) (0.92 g, 3 mmol), ethyl α-chloroacetoacetate (3.29 g, 20 mmol) and sodium bicarbonate (0.84 g, 10 mmol) were stirred at 120° C. for three hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/1, 4/1) to obtain 0.39 g of the title compound as a light brown solid (27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1.[C:16]1([C:22]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:23]2[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:23]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[CH2:15][N:12]([CH2:13][CH2:14]4)[CH2:11][CH:10]=[CH:9]5)=[CH:4][N:3]=3)[N:25]=[CH:24]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C1=CC2(c3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)nc3)CCN(C1)C2
Temperature: 85 °C

Procedure:
0.25 g (0.94 mmol) of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) dissolved in 3 ml of tetrahydrofuran, 1.24 g (2.07 mmol) of 1-triphenylmethyl-4-tributylstannylimidazole and 0.06 g (0.08 mmol) of bis(triphenylphosphine)dichloropalladium are successively introduced into a 10 ml three-necked round-bottomed flask. The mixture is then heated at 85° C. for 15 hours and then diluted in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:32])[C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1.[CH:33](OC)(OC)OC>>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:22]1[CH:21]=[C:11]([CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:3]3[N:32]=[CH:33][O:1][N:2]=3)=[CH:31][CH:30]=2)[CH:23]=1)[C:12]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:13]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=N)NO)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: COC(OC)OC
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3ncon3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 55 °C

Procedure:
3-{4-[(Hydroxyamino)(imino)methyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide was taken up in trimethyl orthoformate (3 mL) and 2 drops of borontrifluoroetherate added. The resulting solution was heated to 55° C. in a CEM explorer microwave for 80 mins. The volatiles were removed under reduced pressure and the resulting oil chromatographed on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the desired compound as a white foam (295 mg)
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][CH:42]1[CH:59]([C:60]([OH:62])=O)[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)=[O:40])([CH3:37])([CH3:36])[CH3:35].N1CCCC1>CN(C=O)C>[C:34]([O:38][C:39](=[O:40])[NH:41][CH:42]1[CH:59]([C:60]([N:3]2[CH2:4][CH2:6][CH2:9][CH2:7]2)=[O:62])[CH2:58][N:45]2[CH2:46][CH2:47][C:48]3[C:53]([CH:44]2[CH2:43]1)=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH3:57])[CH:49]=3)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)CN1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)N3CCCC3)CN1CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
N-Ethyldiisopropylamine (96 mg, 0.74 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 103 mg, 0.27 mmol) were added at r.t. to a suspension of (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid (100 mg, 0.25 mmol) in N,N,dimethylformamide (2 mL), then after 45 min pyrrolidine (19 mg, 0.27 mmol) was added. The homogeneous solution was stirred 90 min at r.t., then partitioned between hexane/ethyl acetate 1:1 and water. The organic layer was washed with brine, dried (MgSO4), and evaporated, and the residue chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 80:1:0.2) to produce the title compound (58 mg, 51%). Light yellow solid, MS (ISP) 460.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@@H:24]3[O:26][CH2:25]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@H:24]([OH:26])[CH2:25][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c23)c1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H](O)CN4CCN(C)CC4)cc(OC4CCOCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 22, 4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.07 g) was reacted with 1-methylpiperazine (0.05 ml) to give the title compound (0.04 g); NMR Spectrum: (DMSOd6) 1.8–1.9 (m, 2H), 2.2 (s, 3H), 2.2 (d, 2H), 2.25–2.6 (m, 10H), 3.55 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.05 (m, 2H), 4.2 (m, 1H), 4.9 (d, 1H), 5.1 (m, 1H), 6.8 (m, 1H), 6.85 (d, 1H), 6.95 (d, 1H), 7.5 (d, 1H), 8.12 (d, 1H), 8.5 (s, 1H), 9.9 (s, 1H); Mass Spectrum: M+H+ 558 and 560.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: Oc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(COc2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 2.0 g (13 mmol) 4-nitrobenzyl alcohol and 3.60 g (13.7 mmol) triphenylphosphine in 30 ml tetrahydrofurane is treated with 1.54 g (13.7 mmol) of 3-fluorophenol. The mixture is cooled in an ice-bath and 2.39 g (13.7 mmol) of diethyl-aza-dicarboxylate is slowly added. The ice-bath is removed and the reaction mixture stirred over night at room temperature. The tetrahydrofuran is evaporated, the oily residue triturated with diethyl ether, filtered and concentrated. Chromatography (silica gel, ethyl acetate/hexane 1:9) yields 2.52 g (78%) of the title compound as a slightly yellow solid. MS: m/e=247.1 (M++H).