Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[NH:28][N:27]=[N:26][N:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nnn[nH]3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3nnn[nH]3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.47 g, 1 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the obtained crystals crystallized from methanol-diethyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1H-tetrazol-5-yl)-1(2H)-isoquinolinone hydrochloride (0.38 g, 92.7%) as crystals.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(F)c3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Yield: 81.4 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(5-ethanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (137 mg, 0.198 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethanesulfonyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (102 mg, 82%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H38F2O8S (M+H)+ 633.2328, found 633.2327.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](O)=[O:53])=[CH:47][CH:46]=1>C(#N)C>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:53])=[CH:47][CH:46]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(Cl)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.4 mmol) and 4-chlorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminlpropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was filtered. The solid was slurried with hot acetone (15 mL) to afford 2-(4-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 82%) as a white solid: mp 243-245° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.04 min. (86%); 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.54 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 7.29-7.38 (m, 4H), 7.61-7.67 (m, 1H), 7.71-7.83 (m, 2H), 8.68 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.86, 41.31, 48.83, 121.90, 127.13, 128.14, 130.94, 131.14, 131.52, 133.22, 134.69, 135.11, 139.95, 166.89, 167.42, 169.78, 170.24, 172.73; Anal. Calcd. for C22H18N3O5Cl: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 60.06; H, 3.85; N, 9.67; Cl, 8.07.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.O1CCC(C=O)C1.O1CCCC1C[CH2:21][CH2:22][NH2:23].[Cl-].C(C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CCOCC.C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH:3]([CH:6]=[CH:21][C:22]#[N:23])[CH2:2]1
Reactant: OCC1CCOC1
Reactant: NCCCC1CCCO1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: N#CC=CC1CCOC1

Procedure:
Tetrahydro-3-furanmethanol (0.96 mL, 10 mmol) was oxidized to tetrahydrofuran-3-carbaldehyde (assume 50%) via the TPAP/MNO oxidation procedure described for 3-(tetrahydro-furan-2-yl)-propylamine. Wittig reaction of the crude aldehyde with (cyanomethyl)triphenylphosphonium chloride as described for 3-(tetrahydrofuran-2-yl)propylaamine gave 3-(tetrahydrofuran-3-yl)acrylonitrile (3.3 mmol) as a 2:1 mixture (1H NMR) of the E/Z isomers after column chromatography (10% Et2O/CH2Cl2 elutant). Hydrogenation of 3-(tetrahydrofuran-3-yl)acrylonitrile in the presence of Raney Ni as detailed for 3-(tetrahydro-furan-2-yl)-propylamine gave 3-(tetrahydrofuran-3-yl) propylamine. (33% yield). ESI-MS (m/z) 130 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:25]=[O:26].[OH-].[Na+]>O1CCCC1.O>[OH:1][C:2]1[C:3]([C:11]2([CH2:25][OH:26])[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:24])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1c1cc2c(cc1O)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2c(C(F)(F)F)cccc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a suspension of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (5.64 g, 16.7 mmol), para-formaldehyde (1.78 g, 59.4 mmol) in tetrahydrofuran (20.0 mL) and water (50.0 mL) was added the aqueous solution of sodium hydroxide (2.68 g, 66.9 mmol) in water (30.0 mL). The reaction mixture was stirred at 0° C. for 1 h and quenched with 10% hydrochloric acid (50.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic solution was washed with saturated ammonium chloride (3×50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (4.56 g, 73%) as a fluffy solid: 1H NMR (300 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.16 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.01 (s, 1H), 6.94 (dd, J=7.7, 7.7 Hz, 1H), 6.18 (s, 1H), 5.88 (s, 2H), 5.03 (br, 1H), 3.97 (ABq, J=9.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 180.5, 150.3, 146.8, 141.5, 140.0, 136.0, 127.5, 123.8, 121.0, 117.7, 109.7, 108.4, 101.2, 97.9, 60.2, 55.2; MS (ES+) m/z 390.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>CN(C)C=O>[CH2:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)[CH:9]=[CH:10][CH3:11]
Reactant: CC=CCCl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCNc1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 65.5 %

Procedure:
1.4 g of anhydrous potassium carbonate and 1.0 g of 1-chloro-2-butene were added to 1.6 g of 3-aminobenzotrifluoride in 30 ml of dimethylformamide, followed by stirring at 70°-90° C. for 2 hours. Potassium carbonate was then removed by filtration, and 100 ml of an aqueous saturated sodium chloride solution were added and extraction was then carried out with toluene. After drying over anhydrous sodium sulfate, the solvent was distilled off, and silica gel chromatography was then done to obtain 1.4 g of the desired compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C)C=O.O.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH3:22])[C:13]=2[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2oc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)oc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a cooled (0° C.) solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.45 g, 5.4 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (0.26 g, 60% dispersion in mineral oil, 6.6 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by the addition of iodomethane (1.0 mL, 16 mmol). The reaction mixture was stirred at ambient temperature for 16 h and diluted with water (20 mL) and ethyl acetate (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic solution was washed with water (5×20 mL) and brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0 to 25% gradient) to afford 5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one (1.26 g, 83%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ7.02 (d, J=8.6 Hz, 1H), 6.55 (dd, J=8.6, 2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 3.35 (s, 3H), 0.99 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:42])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(CC2(O)CCNCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate (0.090 g, 0.00016 mol) in dichloromethane (2 mL) was slowly added a 20% solution of trifluoroacetic acid in dichloromethane (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature and stirred for four hours. The solvent was removed under reduced pressure. An aqueous solution of 5 N sodium hydroxide was added to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-piperidinol (0.045 g, 0.000096 mol).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:15](Cl)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:15]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][Br:1])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(CO)CBr
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(CBr)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-2,2-dimethyl-1-propanol (26.9 mL), 4-(dimethylamino)pyridine (2.67 g), and triethylamine (33.5 mL) were dissolved in toluene (250 mL) and cooled to 0° C. Pivaloyl chloride was added dropwise over 30 min (temperature rose to 15° C.) and upon completion the reaction was allowed to warm to 23° C. and stirred for 1 h. The reaction was filtered and the filtrate washed with 2N aqueous HCl (250 mL), aqueous sodium hydrogencarbonate solution (250 mL) and aqueous brine (250 mL). The organic layer was separated and the solvent evaporated to give the subtitle compound (53.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[CH3:13][O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[N:2]=1)=[O:11]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Next, a mixture of methyl indazole-3-carboxylate (2.05 g, 11.4 mmol), 2,4-dichlorobenzyl chloride (3.35 mL, 12.54 mml), and K2CO3 (7.0 g, 50 mmol) in acetone (22 mL) was refluxed overnight at a temperature of 70° C. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with acetone. The combined filtrate was concentrated under vacuum (rotovapor). The solid thus obtained was dissolved in CH2Cl2 and filtered to remove any undissolved solid. The solution was then concentrated, diluted with hexane and left in the refrigerator overnight. The precipitated solid was then filtered, washed with a mixture of hexane/ethyl acetate (9:1) to yield the pure product as a white solid. Yield=3.5 g (89%); m.p.=144°-146° C.; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.8 Hz, 1H), 7.39-7.47 (m, 4H), 7.12 (d, J=8.8 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 5.81 (s, 2H), 4.11 (s, 3H).
Reaction SMILES: C([O:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:7]1=[O:28])(C)(C)C.C(O)(C(F)(F)F)=O>O>[OH:5][N:6]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[C:11]3[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:7]1=[O:28]
Reactant: CC(C)(C)ON1C(=O)c2ccc(N3CCCC3)c3cc([N+](=O)[O-])cc(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1c2ccc(N3CCCC3)c3cc([N+](=O)[O-])cc(c23)C(=O)N1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A mixture of 2-t-butyloxy-5-nitro-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.09 g, 0.23 mmol, from Example D3-B) and TFA was stirred at room temperature for 4 hours and poured into water. The solid was filtered and washed with acetone to give (0.06 g, 80%) of the title compound, mp 290-291° C.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[N:13][CH:12]=[C:11]2O.C(Cl)(Cl)Cl.C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[N:13][CH:12]=1
Reactant: COc1cc2nncc(O)c2cc1OC
Reactant: O=P(Br)(Br)Br
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2nncc(Br)c2cc1OC
Temperature: 65 °C
Reaction time: 18 h

Procedure:
Phosphorus oxybromide (125 g, 0.436 mol) was added to a suspension of 6,7-dimethoxycinnolin-4-ol (65 g, 0.32 mol) in chloroform (550 mL, 6.9 mol). The reaction mixture was stirred at 65° C. for 18 hours. Formation of a fine yellow solid was observed. The reaction mixture was poured onto crushed ice (200 g), and the pH was adjusted to 6-7 with sodium acetate (285 g) and sat. NaHCO3. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide a light tan oil. DCM (40 mL) and hexanes (250 mL) were added, and the resulting solid was filtered to provide 4-bromo-6,7-dimethoxycinnoline as an off-white solid.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][N:36](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C:19]([CH:21]1[CH2:22][CH2:23]1)=[O:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)C1CC1

Procedure:
In an analogous manner to that described in Example 29, starting from (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-oxopropyl]-1-(2,4-dinitrophenyl)imidazole-4-propionamide by treatment with potassium carbonate in methanol there is obtained (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R)-1-(cyclohexylmethyl)-3-cyclopropyl-2-hydroxy-3-oxopropyl]imidazole-4-propionamide as an amorphous solid; MS: 629 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31][CH2:32]C3C=CC=CC=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].[Br-]>C(Cl)Cl>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31][CH2:32][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCCc2ccccc2)O1

Procedure:
was prepared by a similar method as compound 213e to afford a mixture of diastereoisomers (75/25) as a white solid (258 mg, 83%): mp. 101° C.; [α]D25 −96° (c 0.2, CH2Cl2); IR (KBr) 3328, 2935, 2978, 1732, 1669, 1603, 1483, 1450, 1414, 1237, 1155, 1082, 989, 755; 1H NMR (CDCl3) δ7.84-7.80 (2H, m), 7.54-7.17 (8H, m), 7.06-6.99 (1H, m), 6.25 (1H, d, J=7.9H), 5.41 (0.75H, d, J=5.4H), 5.31 (0.25H, bs), 5.23-5.09 (1H, m), 4.93-4.87, (1H, m), 4.68-4.51 (2H, m), 4.40-4.33 (0.25H, m), 4.24-4.14 (0.75H, m), 3.95-3.70 (1H, m), 3.30-3.13 (1H, m), 3.14-2.78 (5H, m), 2.47-2.21 (2H, m), 2.05-1.50 (5H, m). Anal. Calcd for C29H32N4O7.0.5H2O: C, 62.47; H, 5.97; N, 10.05. Found: C, 62.17; H, 5.83; N, 9.97. MS (ES+) 549.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH2:18][CH2:19][CH3:20])[C:15]([CH3:17])=[N:16][C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(Cl)(Cl)Cl>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:22]=[CH:21][C:13]4[N:14]([CH2:18][CH2:19][CH3:20])[C:15]([CH3:17])=[N:16][C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:23]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCCn1c(C)nc2cc(-c3nc4cc(N)ccc4o3)ccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCn1c(C)nc2cc(-c3nc4cc(NC(C)=O)ccc4o3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.4 %

Procedure:
To a solution of 5-(5-aminobenzoxazol-2-yl)-2-methyl-1-n-propylbenzimidazole (see Working Example 82-4) (200 mg, 0.653 mmol) in chloroform (5 mL) was added triethylamine (132 mg, 1.31 mmol) and acetic anhydride (100 mg, 0.979 mmol), and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, the precipitated crystals were filtered, and after washing with water were dried to yield the title compound (176 mg, 77% yield) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3].S(Cl)([Cl:20])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[O:16][CH3:17])[C:2]#[CH:3]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Yield: 85.6 %

Procedure:
To 100 ml of toluene were added 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid, 9.5 g of thionyl chloride and 50 mg of DMF and the mixture obtained was heated under reflux for 3 hours. Then, the reaction mixture was concentrated. The solid obtained was washed with hexane to obtain 12.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:34][CH3:35])[CH2:9][C:10]2[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:34][CH3:35])[CH2:9][C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(Cc1ncc[nH]1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a stirred suspension of 2-[2-(3-chloro-phenyl)-2-methoxy-ethyl]-1-trityl-1H-imidazole (0.24 g) at room temperature in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux. Stirring was continued for 3 hours. The mixture was cooled to room temperature and concentrated to leave a light yellow solid. This was taken up in H2O and brought to pH=12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/methanol 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:CH2Cl2→CH2Cl2/methanol 9:1) to give 2-[2-(3-chloro-phenyl)-2-methoxy-ethyl]-1H-imidazole (0.11 mg) as light yellow gum. MS 237.1 ([M+H]+)