Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][N:22]([C:31](=[O:33])[CH3:32])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CC3CCOCC3)c2C1
Yield: 15.3 %

Procedure:
1-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (27.0 mg, 15.3%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 61a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 447.2 (M+H)+
Reaction SMILES: S([O-])([O:4][CH3:5])(=O)=O.[CH3:7][N:8]1[C:13](=[O:14])[NH:12][C:11](=O)[O:10][C:9]1=[O:16]>O.C(Cl)(Cl)(Cl)Cl>[CH3:11][N:12]1[C:13](=[O:14])[N:8]([CH3:7])[C:9](=[O:10])[O:16][C:5]1=[O:4]
Reactant: COS(=O)(=O)[O-]
Reactant: Cn1c(=O)[nH]c(=O)oc1=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)oc(=O)n(C)c1=O
Yield: 92 %

Procedure:
The process disclosed in example 1 is used, except that the solvent is not distilled. 15.1 g of methyl sulfate (0.12 mole) are added to the solution of 3-methyl-1,3,5-oxadiazine-2,4,6-trione. The solvent is evaporated after 10 minutes of reaction at a temperature of 25° C. After washing with water and carbon tetrachloride, 14.6 g of 3,5-dimethyl-1,3,5-oxadiazine-2,4,6-trione (yield: 92%) which is a symmetrical disubstituted 1,3,5-oxadiazine trione are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:4][CH2:3][CH2:2][CH2:9][CH2:8][CH3:7])[CH:9]=1)[CH:5]=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: O=Cc1cc(O)cc(O)c1
Product: CCCCCCOc1cc(C=O)cc(OCCCCCC)c1

Procedure:
The title compound was prepared according to the method described in Example 9 above from 3,5-dihydroxy-benzaldehyde and 1-bromohexane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.N>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(O)c1C
Agent: N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COc1c(C)ccc(C)c1C
Yield: 92.1 %

Procedure:
A mixture of 50 g (0.367 mol) of 2,3,6-trimethylphenol, 55 g (0.4 mol) of potassium carbonate and 36 ml (0.38 mol) of dimethylsulphate in 500 ml of acetonitrile was heated under reflux overnight. 35 ml of conc. aqueous ammonia was then added, and the mixture refluxed for 1 hour. After filtration and evaporation, the residue was taken up in ether and washed twice with NaOH-solution and twice with NaHCO3 -solution. Drying (MgSO4) and evaporation gave 50.8 g (92%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: BrCc1ccccn1
Agent: Br
Product: CCOC(=O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
440 mg (1.22 mmol) of ethyl {4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate and 464 mg (1.84 mmol) of 2-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 371 mg (purity 65%, 44% of theory) of the title compound and 270 mg (50% of theory) of the product which is already hydrolysed (Example 8.1D)
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:24][N:25]([CH3:27])[CH3:26])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 75 °C
Yield: 91.7 %

Procedure:
A suspension of ethyl 3-(2-chloro-6,7-difluoro-3-quinolyl)-3-oxopropionate (6.17 g) in N,N-dimethylformamide dimethyl acetal (7.15 g) and ethyl acetate (60 cc) is heated to a temperature in the region of 75° C. for 1 hour 15 minutes. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. The residue is taken up with isopropyl ether (50 cc), drained and washed with the same solvent (3×25 cc). Ethyl 2-(2-chloro-6,7-difluoro-3-quinolinecarbonyl)-3-(dimethyl amino)acrylate (6.65 g) is obtained in the form of an orange-colored solid, m.p. 140° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH2:23]>>[C:24]1([C:22](=[CH2:21])[CH2:23][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4][C:3]2([CH3:20])[CH3:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: C=C(C)c1ccccc1
Product: C=C(CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1.0 g (3.6 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine and 10 g (85 mmol) of α-methylstyrene under a nitrogen atmosphere is heated at 120° C. for 36 hours. The reaction mixture is concentrated in vacuo and the title compound is isolated as a pale yellow oil after column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][CH2:19]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:11]1([CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of 68.1 g (0.5 mole) of 4'-hydroxyacetophenone, 100.3 g (0.5 mole) of 3-phenylpropyl bromide, 69.0 g (0.5 mole) of potassium carbonate and 500 ml of anhydrous acetone is refluxed with stirring for 8 hours. After adding 1 liter of water the product is extracted into ether, the extract is washed with water and 2 N sodium carbonate solution and dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting oil (125.8 g) begins to crystallize and yields after two recrystallizations from ether-hexane and ether, respectively, 73.9 g (58% yield) of the desired product, M.P. 80°-81°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8](OC=C)(=[O:11])[CH2:9][CH3:10].[O-][Mn](=O)(=O)=O.[K+]>CO.ClCCl>[C:8]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])(=[O:11])[CH2:9][CH3:10]
Reactant: CC(O)CN(C)C
Reactant: C=COC(=O)CC
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)OC(C)CN(C)C
Reaction time: 70 h
Yield: 38.1 %

Procedure:
Racemic 1-dimethylamino-2-propanol (100 g, 0.97 mol) was stirred with vinyl propionate (106 ml, 0.97 mol) at ambient temperature and Novozym 435 (6 g) was added. The reaction mixture was stirred slowly for 70 hours and after this time tlc (10% methanol/dichloromethane--visualise KMnO4 solution) indicated that the reaction had gone to 50% conversion. The enzyme was removed by filtration and the filter bed was washed with ethyl acetate (2×100 ml). The organic layer was then washed with water (4×100 ml) and the combined washes were back extracted with ethyl acetate (400 ml). The organic layer was then washed with brine (200 ml) and dried (MgSO4). The ethyl acetate was removed in vacuo to leave 58.7 g (0.37 mol, 70% based on maximum yield of 84.5 g) of (-)-1-dimethylamino-2-propyl propanoate as a yellow oil. δH (220 MHz; CDCl3) 1.13 (3H, t, 7 Hz, CH3CH2CO), 1.21 (3H, d, 6 Hz, H-3), 2.25 (6H, s, N(CH3)2),2.10-2.60 (4H, m, H-1 & CH3CH2CO), 5.09 (1H, m, H-2). The optical purity was not measured at this stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([Cl:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(Cl)c3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 52.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (35 mL), 3-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (525 mg, 53%) as a pale yellow solid: mp 156-159° C. Anal Calc'd. for C22H16N2SO2Cl2: C, 59.60, H, 3.69, N, 6.32, S, 7.23. Found: C, 59.43, H, 3.59, N, 6.15, S, 7.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:23]2([O:25][CH2:24]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:23]([OH:25])([CH2:24][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC2(CO2)C1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3(O)CCN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 70 °C
Yield: 47 %

Procedure:
A solution of 7-methoxy-1H-quinolin-2-one (650 mg, 3.7 mmol) and 1-oxa-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1 eq., commercial) in DMF (10 mL) was treated with Cs2CO3 (1 eq.) and heated at 70° C. overnight. The mixture was partitioned between EA and water, the org. phase washed with water and brine, dried over MgSO4 and concentrated. The product was purified by CC (EA/Hept 1:1, EA) to give the desired intermediate as a yellowish oil (650 mg, 47% yield).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C@:27]([OH:31])([C:29]#[CH:30])[CH3:28]>N1CCCCC1.[Cu]I.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>[OH:31][C@:27]([C:22]1[N:21]=[CH:26][CH:25]=[CH:24][N:23]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
Reactant: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(I)cc1-2
Reactant: C#C[C@@](C)(O)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(C#C[C@@](C)(O)c3ncccn3)cc1-2
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol (156 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.8 mL). The solid was collected by filtration to furnish the title compound (51 mg, 0.13 mmol, 50%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 1.69 (d, J=10.72 Hz, 2H), 2.06 (br. s., 2H), 2.93 (qd, J=7.99, 3.15 Hz, 2H), 3.46 (td, J=7.25, 3.78 Hz, 1H), 3.62 (td, J=8.12, 3.63 Hz, 1H), 3.99 (s, 3H), 5.16-5.44 (m, 2H), 6.99 (d, J=7.57 Hz, 1H), 7.15 (d, J=7.57 Hz, 1H), 7.33 (br. s., 1H), 7.52 (br. s., 1H), 8.49 (s, 1H), 8.85 (br. s., 2H); M+H=400.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)=[CH:34][C:33]=1[C:48]([F:51])([F:50])[F:49]>CN(C)C1C=CN=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:24]=2)=[O:40])=[CH:34][C:33]=1[C:48]([F:49])([F:50])[F:51]
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Agent: CN(C)c1ccncc1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4ccc(OC)c(C(F)(F)F)c4)c3)ncnc2cc1OCCN1CCOCC1
Yield: 27 %

Procedure:
Using the procedure described in Example 230B 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline (90 mg, 0.23 mmol) was reacted with phenyl 4-methoxy-3-(trifluoromethyl)phenylcarbamate described in Example 138A (99 mg, 0.32 mmol) and 4-(dimethylamino)pyridine (28 mg, 0.23 mmol) to give 1-(4-methoxy-3-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (38.72 mg, 27%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.92 (bs, 1H), 8.85 (bs, 1H), 8.56 (s, 1H), 7.60-7.51 (m, 3H), 7.43-7.35 (m, 2H), 7.26-7.19 (m, 2H), 6.92 (d, 1H), 4.33 (bs, 2H), 3.99 (s, 3H), 3.84 (s, 2H), 3.61 (s, 4H), 2.90-2.69 (m, 2H), 2.65-2.55 (m, 2H); LC-MS (ESI) m/z 614 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].N(C(C)(C)C#N)=NC(C)(C)C#N.BrBr>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
2.0 g of cis-chrysanthemic acid and 23 mg of azobisisobutyronitrile were dissolved in 20 ml of toluene and thereto was added dropwise a solution of bromine (21 mg) in carbon tetrachloride with stirring at 80° C. over a period of 20 minutes. Thereafter, a treatment similar to Example 1 was carried out to obtain 1.91 g of chrysanthemic acid. Gas chromatographic assay thereof showed the composition: cis, 9.8% and trans, 90.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of N,N'-dicyclodicyclohexylcarbodiimide was added at room temperature while stirring to a solution of 1.0 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate was subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which were pure according to thin-layer chromatography gave 0.9 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]benzaldehyde; m.p. (C-I) 77°-78° C.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][NH:5]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-D-Dab(Fmoc)-OH (206 mg, 0.5 mmol, Oakwood Products) and piperidine (0.3 mL, 3.03 mmol) were dissolved in DMF (1.6 mL). The resulting mixture was stirred at room temperature for 30 minutes. The volatiles were removed in vacuo and the residue was used directly in the subsequent step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:17]([O:16][P:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12])[CH3:18]
Reactant: CCOC(=O)c1ccc(P(=O)(OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(diethoxyphosphoryl)-benzoic acid ethyl ester (2b) (2.46 g, 8.59 mmol) in methanol (86 mL) was slowly added lithium hydroxide (monohydrate, 0.36 g, 8.59 mmol) in water (86 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by crystallization from hexane/ethyl acetate (2.37 g), m.p. 101° C. 1H NMR (300 MHz, CDCl3) δ(ppm)): 1.27 (t, J=7.03 Hz, 6H), 4.03 (q, J=7.03 Hz, 4H), 7.85 (m, 2H), 8.09 (m, 2H), 12.65 (bs, 1H). 31P NMR (121 MHz, CDCl3) δ 21.611.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:10]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)COC
Temperature: -78 °C
Yield: 75 %

Procedure:
1.5 ml of triethylamine was added to 500 mg of amino-acetic acid ethylester hydrochloride dissolved in 5 ml of chloroform, and the solution was cooled to −78° C. 0.34 ml of methoxyacetylchloride diluted with 3 ml of chloroform was slowly added thereto, and the resulting solution was heated slowly to room temperature and reacted for 6 hours. The reacted solution was washed with distilled water, adjusted to pH 8 to 9 by adding saturated sodium bicarbonate solution, extracted with organic solvent, dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (595 mg, 75%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=O.[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])#[N:26]>O>[Cl:24][C:21]1[CH:20]=[C:7]2[C:6](=[CH:23][CH:22]=1)[N:5]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COC(=O)CC#N
Reactant: COc1ccc(C(=O)c2cc(Cl)ccc2N)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(Cl)ccc2n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Powdered aluminium chloride (0.21 g) was added to a mixture of 2-amino-5-chloro-3',4'-dimethoxybenzophenone (0.23 g) and methyl cyanoacetate (5 ml), and the resulting mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with hexane/ethyl acetate (4/1, v/v) gave methyl 6-chloro-4-(3,4-dimethoxyphenyl)quinazoline-2-acetate (0.161 g, 55%) which was then recrystallized from isopropyl ether. Colorless needles. mp. 144°-145° C.
Reaction SMILES: B.C1COCC1.O=[C:8]1[CH:13]([CH2:14][C:15](O)=[O:16])[S:12][C:11]2[S:18][C:19]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:20][C:10]=2[NH:9]1.CO>C1COCC1>[OH:16][CH2:15][CH2:14][CH:13]1[S:12][C:11]2[S:18][C:19]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:20][C:10]=2[NH:9][CH2:8]1
Reactant: NS(=O)(=O)c1cc2c(s1)SC(CC(=O)O)C(=O)N2
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1cc2c(s1)SC(CCO)CN2
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A solution of borane/THF (200 ml, 1M, 200 mmol) was added gradually to a solution of (2,3-dihydro-2-oxo-6-sulfamoyl-1H-thieno-[2,3-b]-[1,4]thiazin-3-yl)acetic acid (12.3 g, 40 mmol) in THF (200 ml). The mixture was stirred at ambient temperature until gas evolution ceased and the resulting clear solution was heated under reflux overnight. The reaction mixture was cooled to 25° C. and treated with methanol (200 ml). When gas evolution ceased, the mixture was evaporated to dryness under vacuum and the residue was restripped from methanol two additional times (2×50 ml). Recrystallization of the residue from water gave 6.4 g 3-(2-hydroxyethyl)-2,3-dihydro-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 145°-147° C. An additional 1.2 g of product was isolated from the filtrate on standing. Further recrystallization from water gave material of mp 149°-150° C.