Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].COC1C=CC(O)=CC=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>C(#N)C>[OH:2][CH2:1][CH2:3][NH:4][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCO
Agent: COc1ccc(O)cc1
Solvent: CC#N
Product: C=C(C)C(=O)NCCO
Reaction time: 1 h

Procedure:
To a 500 mL, four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, a 200 mL dropping funnel, and a nitrogen inlet/outlet, 48.8 g of ethanolamine (0.8 moles), 80 mg of 4-methoxyphenol and 100 mL of acetonitrile were added. The mixture was cooled below 0° C. with an ice/water salt bath. To this solution, 41.8 g of freshly distilled methacryloyl chloride (0.4 mole) in 100 mL of acetonitrile was added through the dropping funnel. The addition rate was controlled so that the reaction temperature was kept below 0° C. At the end of addition, the pH of the reaction mixture was adjusted to 7 with either methacryloyl chloride or ethanolamine solution. While keeping the reaction solution cold (below 5° C.), the ethanolamine HCl salts were filtered out. To the filtrate, 200 mL of deionized water and 40 g of Dowex MR-3C resin, which was pre-washed with two bed volumes of 1/1 ratio acetonitrile/water mixture for three times, were added. The resin was removed by filtration after agitating for one hour. The filtrate was concentrated to about 160 g by vacuum distillation. The final solution has the following properties: HPLC and FT-IR analysis indicates there is no ester formation; HEMAA concentration: 23.5% (wt/wt); pH=6.9 at 250° C.; Conductivity=3.9 μS/cm at 25° C.; Viscosity=1.9 cPs at 25° C. The yield of HEMAA was about 73%.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:12]=2[O:11][CH2:10][C:9]1=[O:13]
Reactant: ClCCCI
Reactant: CCc1cccc2c1OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1cccc2c1OCC(=O)N2CCCCl
Yield: 74.9 %

Procedure:
8-Ethyl-4H-benzo[1,4]oxazin-3-one (0.35 g, 2.0 mmol), Cs2CO3 (0.96 g, 2.9 mmol), and 1-chloro-3-iodopropane (0.45 g, 2.2 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.38 g, 74%). Rf=0.64 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 7.01-6.89 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.21-2.12 (m, 2H), 1.20 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 164.9, 143.3, 133.4, 128.4, 124.3, 122.6, 112.6, 67.2, 42.5, 39.2, 30.3, 23.0, 14.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[CH:6]2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:14])[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(C)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C)cc2c1

Procedure:
The isoquinoline of step 2 was dissolved in phosphorus oxychloride (2.5 mL) and heated at reflux for 1 hour. The excess phosphorus oxychloride was removed under reduced pressure and the residue was dissolved in chloroform. The resulting solution was washed with 1N aq. sodium hydroxide, water and brine. Evaporation of the solvent under reduced pressure gave crude 1-chloro-6-methoxy-3-methylisoquinoline, which was used directly in the next step.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH2:14])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:36][CH3:37])[CH:28]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([NH:14][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][C:29]=2[O:36][CH3:37])[C:11]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N)C1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Cl)cc2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of 0.060 g (0.18 mmol) of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) dissolved in 1.80 mL of dimethylformamide was added 0.037 g (0.20 mmol) of 4-chloro-2-methoxy-benzoic acid. To the resulting mixture was added 40 μL (0.22 mmol) of diethyl cyanophosphonate and 30 μl (0.20 mmol) of triethylamine at 0° C. The resulting mixture was stirred at room temperature for 2 hours and evaporated to dryness. Water was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium carbonate, saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride dried and evaporated. The residue was triturated with a mixture of diethyl ether/ethyl acetate and filtered to afford 0.048 g (53%) of the pure product as a powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.Cl.Cl.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH2:35])=[C:28]2[CH:27]=[CH:26]1>>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[NH:35][CH2:34][C:33]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:25][CH:26]=[CH:27][C:28]=34)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Reactant: NCc1ccnc2[nH]ccc12
Agent: Cl
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 427 (M+H). Calc'd. for C25H26N6O—426.52.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:34][OH:35])CC(C3C=CC(F)=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:8](=[N:34][OH:35])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2
Reactant: CCc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: CCc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1)C2

Procedure:
The title compound was prepared from 2-amino-4-ethyl-7-(4-fluoro-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 3, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 3/a stage 4).
Reaction SMILES: [C:1]([NH:4][C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2].[H][H].[C:19](NC(C1CCC(C(O)=O)CC1)(C)C)(=O)C.Cl.CO>N.[C].[Ru].CO>[C:1]([NH:4][C:5]([CH:8]1[CH2:9][CH2:10][CH:11]([C:12]([O:14][CH3:19])=[O:13])[CH2:15][CH2:16]1)([CH3:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)(C)C1CCC(C(=O)O)CC1
Reactant: CC(=O)NC(C)(C)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Ru]
Agent: Cl
Agent: N
Solvent: CO
Product: COC(=O)C1CCC(C(C)(C)NC(C)=O)CC1

Procedure:
A solution (200 ml) of 4-(1-acetamido-1-methylethyl)benzoic acid (17.9 g) and 5% ruthenium carbon (60 g) in 10% aqueous ammonia was stirred in an autoclave at initial hydrogen pressure of 70 atm and at 150°-170° C. for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a cis- and trans- mixture of 4-(1-acetamido-1-methylethyl)cyclohexanecarboxylic acid. Then, 31% hydrochloric acid-methanol (15 ml ) and methanol (100 ml ) were added thereto and the mixture was refluxed for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 14.0 g of a cis- and trans-mixture (3:1) of methyl 4-(1-acetamido-1-methylethyl)cyclohexanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:35][C:30]1([CH3:36])[C:31]([CH3:34])([CH3:33])[O:32][B:28]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: CC(C)c1cccc2nc(Nc3ccc(Br)cc3)oc12
Product: CC(C)c1cccc2nc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)oc12

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-7-isopropyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.412 g, 1.24 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white solid (0.346 g, 74%). RP-HPLC Rt 18.964 min, 79% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 379 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[O:10])[S:6][CH:7]=1.ClC1C=C(C=CC=1Cl)[CH2:25][NH:26]C(NC1SC=C(CNC)N=1)=O>>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][NH:26][CH3:25])[N:4]=1)=[O:10]
Reactant: O=C(NCc1cc(F)cc(F)c1)Nc1nc(CCl)cs1
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Product: CNCc1csc(NC(=O)NCc2cc(F)cc(F)c2)n1

Procedure:
The title compound was prepared from the above 1-(4-Chloromethyl-thiazol-2-yl)-3-(3,5-difluoro-benzyl)-urea following the procedure described for Intermediate 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:30][C:31]1([F:38])[CH2:37][CH2:36][CH2:35][CH2:34][NH2+:33][CH2:32]1>>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:31]([F:38])([F:30])[CH2:32]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCCC[NH2+]C1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCCC(F)(F)C4)C3)c2CC1

Procedure:
Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 3,3-Difluoro-perhydro-azepinium chloride.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:21][NH:20][CH2:19]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:14])([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:21][N:20]([CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:19]1)[CH3:2]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CNC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)C1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 3-[2-ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-azetidine (D131) (295 mg, 0.735 mmol) in Acetonitrile (10 mL) was added potassium carbonate (305 mg, 2.206 mmol) and ethyl 4-bromobutanoate (0.158 mL, 1.103 mmol). The reaction solution was heated to 60° C. overnight. The solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with water, dried and concentrated to afford ethyl 4-{3-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-azetidinyl}butanoate (D132) (295 mg) as an oil. MS (ES): C23H36BNO4 requires 401.3. found 402.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)(O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.N1C=CN=C1.S(Cl)([Cl:39])=O>C(#N)C>[F:1][C:2]([F:31])([F:30])[C:3]([Cl:39])([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (0.65 g) and imidazole (0.612 g) were dissolved in dry acetonitrile (30 cm3), and the solution cooled to ca. 0° C. Thionyl chloride (1.21 g) was added dropwise, with stirring. The reaction mixture was allowed to warm to the ambient temperature (ca. 22° C.) and was stirred for a further three hours. Analysis of the reaction mixture by thin layer chromatography and gas liquid chromatography at that time showed no starting tertiary alcohol to be present. The reaction mixture was quenched with water, and a small volume of saturated sodium chloride solution was added. The aqueous mixture was extracted four times with diethyl ether and, finally, once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation of the solvent under reduced pressure to give an oil. The product was purified by column chromatography on a silica gel support, using n-hexane containing 6% by volume ethyl acetate as eluent, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.48 g) as a colourless oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([O:19]CC3C=CC=CC=3)[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2.C1COCC1.C([O-])=O.[NH4+]>[Pd].CO>[Cl:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([OH:19])[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2
Reactant: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)O

Procedure:
A 110 mg quantity (0.26 mM) of the product of Step 4A, 1,1-dimethylethyl ester of 1-(chloromethyl)-1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid, is stirred at room temperature under nitrogen in 2 ml freshly distilled THF and 2 ml methanol. 120 mg 10% Pd/C (palladium on charcoal) and 130 mg ammonium formate is added. After TLC shows the reaction mixture to be complete, the reaction mixture is filtered, and the solid washed with freshly distilled THF. The combined filtrate and wash is partitioned between ethyl acetate and brine (saturated aqueous sodium chloride solution), the layers separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated yield (BOC)CPI hydrochloride, 1,1-dimethylethyl ester of 1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methyl-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:25])[CH3:24])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[N:20]=[C:19]([N:23]([CH3:24])[CH3:25])[N:18]([CH3:26])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: CN(C)c1nc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c(=O)n1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Yield: 89.2 %

Procedure:
A mixture of 4.62 g (11.4 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione and 460 mg of 10% palladium on charcoal in 50 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 14 hour period. It was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel eluting with a 1:1 v:v mixture of ethyl acetate and hexane to give 3.2 g of the title compound as a pale grey solid, m.p.: 247°-249° C. (dec); 1 -NMR (DMSO-d6) ppm 7.45 (d, 1H), 6.95 (d, 1H), 3.3 (s, 3H), 3.0 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(Cl)ccc2Cl)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2,5-dichloroaniline (1.6 g.) in dry dimethylformamide (10 ml.) potassium hydroxide (1.0 g.) was added in small portions over 5 minutes, and stirring continued for a further 15 minutes. To the resultant solution was added 2-chloro-3,5-dinitrobenzotrifluoride (2.7 g.) in small portions over 5 minutes. When the addition was complete the mixture was stirred for 30 minutes at 20° C, after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (10 ml.) was then added, the mixture stirred for further 15 minutes and then poured into water (150 ml.) The solid precipitate was collected by filtration, washed with water and dried to yield 2(2,5-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 125°-126° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6](Cl)=[O:7])[CH2:3][CH2:2]1.[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:4][CH2:5][C:6]([NH:21][C:13]2[C:12]([CH:9]([CH3:11])[CH3:10])=[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(Cl)CCC1CC1
Reactant: CC(C)c1c(N)nn2cccnc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CCC2CC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product from Example 114D (100 mg, 0.754 mmol) in CH2Cl2 (0.5 mL) was added to a stirring solution of the product from Example 112C (109 mg, 0.62 mmol) in pyridine (1.0 mL) at room temperature. The solution was stirred at room temperature for 2 hours, and then quenched by addition of methanol (0.5 mL). After 30 minutes, the solution was concentrated under vacuum, and the residue was purified by flash chromatography (silica gel, eluted with EtOAc), followed by crystallization from 80% EtOH-water to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 0.07-0.18 (m, 2H) 0.40-0.53 (m, 2H) 0.71-0.89 (m, 1H) 1.41 (d, J=7.1 Hz, 6H) 1.63 (q, J=7.2 Hz, 2H) 2.55 (t, J=7.5 Hz, 2H) 3.14 (hept, J=7.1 Hz, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 1.7 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H) MS (ESI) m/z 273 (M+H)+; Anal. Calculated for C15H20N4O: C, 66.15; H, 7.40; N, 20.57. Found: C, 66.39; H, 7.28; N, 20.26.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].N1C=CC=CC=1.ClCCl.[CH3:25][CH:26]([CH3:33])[C:27]([O:29][CH2:30][CH2:31][OH:32])=[O:28]>O>[C:27]([O:29][CH2:30][CH2:31][O:32][C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)(=[O:28])[CH:26]([CH3:33])[CH3:25]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
83 g ((0.36 mol) of 3,5-dinitrobenzoyl chloride (compound 2) and 28 g (0.36 mol) of pyridine were placed in a 1-l four-necked flask equipped with a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added 100 ml of dichloromethane for dissolution. The flask was cooled to 10° C. with ice water. Thereto was dropwise added, in 20 minutes with the temperature (10° C.) being maintained, 62 g (0.47 mol) of 2-hydroxyethyl 2-methylpropionate. After the dropwise addition, the flask was immersed in an oil bath of 50° C. and the flask contents were stirred for 1 hour. The flask was cooled to room temperature and 50 ml of water was added, followed by stirring for several minutes. All the flask contents were transferred into a separating funnel and the aqueous layer was separated to remove. The organic layer taken out was returned to the separating funnel. Thereto was added a 5% aqueous sodium carbonate solution, followed by mixing. The lower layer (organic layer) was taken out and dried over anhydrous magnesium sulfate. From the dried solution was removed dichloromethane by distillation by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from a mixed solvent consisting of 200 ml of methanol and 100 ml of water to obtain 2-(3,5-dinitrobenzoyloxy)ethyl isobutyrate (compound 3). Yield: 100 g (86%) Melting point: 55-58° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]1[CH2:10]OC[CH2:7]1.[CH3:11][C:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=1>C(O)(=O)C>[CH3:3][C:2]1[CH2:1][CH:11]=[C:12]([CH2:13][CH2:14][CH3:15])[CH:16]=1.[CH2:7]([C:14]1([OH:17])[CH2:15][CH2:16][C:12]([CH3:11])=[CH:13]1)[CH2:6][CH3:10]
Reactant: C1CCOC1
Reactant: CCC[Mg]Cl
Reactant: CC1=CC(=O)CC1
Solvent: CC(=O)O
Product: CCCC1(O)C=C(C)CC1
Product: CCCC1=CCC(C)=C1
Temperature: -10 °C

Procedure:
n-PrMgCl (2.0M in Et2O, 20 ml, 40 mmol) and THF (10 ml) were charged under nitrogen into a 100 ml, 3-necked, round-bottom flask equipped with a thermometer, magnetic stirring bar, and an addition funnel. The mixture was cooled to -10° C. in an ice/acetone bath. 3-Methyl-2-cyclopentenone (97%, 3.6 g, 36.4 mmol) was added into the PrMgCl at -10° to -5° C. over a period of 20 minutes. The reaction mixture was slowly warmed to 22° C. over a period of one hour. GC analysis of a small acidified sample (added into excess aqueous acetic acid at 5° to 15° C., pH=4.5) showed a >97% conversion of 3-methyl-2-cyclopentenone. The reaction mixture was then slowly added at <5° C. into aqueous acetic acid (4.66 g, 77.6 mmol of acetic acid in 14.0 g of water) over a period of 30 minutes to form 1-methyl-3-n-propylcyclopentadiene via the dehydration of the 1-propyl-3-methyl-2-cyclopenten-1-ol intermediate. The pH of the aqueous layer was 4.5. The reaction mixture was stirred at 36° C. for 1 hour to complete the dehydration reaction. GC analysis indicated a >97% conversion of 1-propyl-3-methyl-2-cyclopenten-1-ol and the formation of 1-methyl-3-n-propylcyclopentadiene (with 28% exo isomers). The aqueous layer was phase cut. The organic layer, which weighed 29.2 g, was washed at 5° C. with aqueous Na2CO3 solution (2.42 g, 22.8 mmol of Na2CO3 in 10.0 g of water). The pH of the aqueous layer was 9.0. After phase cutting the aqueous layer, the organic layer weighed 25.4 g. Proton NMR (with CH2Br2 as internal standard) indicated that the yield of 1-methyl-3-n-propylcyclopentadiene was 77±4%. The structure of 1-methyl-3-n-propylcyclopentadiene was confirmed by GC/MS.