Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14].[OH-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCOC(C)=NO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloronitrobenzene, 136.2 g, and 111.4 g ethyl N-hydroxyacetimidate are dissolved in 216 ml DMF. The temperature is adjusted to 30° C. and 41.6 g solid NaOH is added in 8 portions keeping the temperature at 30-35° C. After one hour the temperature is adjusted to 40-45° C. and the mixture stirred for 1.5 hours. Cooling is applied and 520 ml water is fed at such a rate as to keep the temperature at ca 40° C. The slurry formed is cooled to 17° C. and filtered. The filter cake is washed with 175 ml ethanol/water 90/10 (V/V) followed by 175 ml water. Wet product, 214.5 g, corresponding to 192 g dry ethyl N-(4-nitrophenoxy)acetimidate is isolated. Yield 98.5%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
To a suspension of 0.0262 g (0.000062 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methylbenzoic acid (I-60) in 3 mL of dimethylformamide was added 0.0144 g (0.000107 mole) of 1-hydroxybenzotriazole, 0.0365 g (0.000096 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.07 mL (0.000402 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.012 g (0.0001 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.021 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methyl-N-(1-methyl-4-piperidinyl)benzamide (I-61)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:42][CH2:43][OH:44].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:42][CH2:43][OH:44])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(CCO)C1
Yield: 10.8 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (100 mg, 0.19 mmol Example 74), diisopropylethylamine (100 μl, 0.58 mmol), 2-chloroethanol (60 μl, 0.58 mmol) and potassium iodide (32 mg, 0.19 mmol) in acetonitrile (1.5 ml) was heated in a microwave at 160° C. for 20 minutes. Purification of the resulting product on preparative HPLC (standard basic condition) gave the title product (10 mg, 11%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.75 (t, 2H), 3.47 (s, 2H), 3.61 (t, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 3.93 (s, 2H), 5.41 (brs, 1H), 6.79 (brs, 1H), 7.18 (m, 2H), 7.21 (s, 1H), 7.75 (brs, 1H), 7.86 (s, 1H), 8.52 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:20])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]=[O:19])[CH:4]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:22]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH3:20])[CH:8]=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[C:12]([CH:18]=[O:19])=[CH:13]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: Cc1cccc(-c2ccc3[nH]cc(C=O)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Reaction time: 3 h
Yield: 62 %

Procedure:
NaH (60% in mineral oil dispersion, 6 mmol, 1.2 equiv.) was added to a stirred solution of aldehyde 8 (5 mmol, 1 equiv.) in anhydrous dimethylsulfoxide (DMSO) at room temperature. After 1 h of stirring at the same temperature, 1-bromooctane was added and the mixture stirred for another 3 h. Distilled water was added to the reaction mixture which was then extracted with CH2Cl2. The organic layer was washed with brine, dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc/hexane as eluting solvents as described in Section 5.4.1. Yield: 62%; 1 H NMR (300 MHz, CDCl3): δ 9.98 (s, 1 H), 8.53 (s, 1 H), 7.66 (s, 1 H), 7.57-7.46 (m, 3 H), 7.39-7.29 (m, 2 H), 7.13 (d, J=7.2H, 1 H), 4.1 (t, J=8.7 Hz, 2 H), 2.42 (s, 3 H), 1.86 (t, J=3 H), 1.29-1.24 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 184.8, 143.7, 141.6, 138.9, 135.4, 135.1, 129.1, 128.9, 127.1, 119.3, 119.2, 118.5, 116.8, 111.6, 47.4, 32.7, 31.6, 29.6, 29.0, 26.7, 22.5, 14.0.
Reaction SMILES: [Li]CCCC.[CH:6]1([N:9]2[C:13]([CH3:14])=[N:12][N:11]=[C:10]2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.Br[CH:22]([C:24]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[O:26][N:25]=1)[CH3:23]>C1COCC1>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH:22]([CH3:23])[CH2:14][C:13]3[N:9]([CH:6]4[CH2:8][CH2:7]4)[C:10]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:11][N:12]=3)[N:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(Br)c1noc(-c2cccc(Cl)c2)n1
Reactant: Cc1nnc(-c2ccncc2)n1C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)c1noc(-c2cccc(Cl)c2)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-BuLi (210 ml, 2.5 M in hex., 0.52 mmol) was added dropwise to a solution of 4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine (80 mg, 0.4 mmol) in THF (10 ml) at −78° C. under an atm. of nitrogen. After stirring for 15 min 3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (115 mg, 0.4 mmol) in THF (2 ml) was added. The mixture was stirred for 2 h at −78° C. and then at r.t. for 1 h. The solvent was removed under reduced pressure and the desired product was obtained by prep. HPLC in 20 mg yield. 1H NMR: 0.7 (m, 2 H) 1.2 (ddd, 2 H) 1.6 (d, 3 H) 3.2 (dd, 1 H) 3.3 (ddd, 1 H) 3.6 (dd, 1 H) 3.9 (m, 1 H) 7.5 (t, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.0 (m, 1 H) 8.1 (t, 1 H) 8.7 (m, 2 H)
Reaction SMILES: Br[C:2]1([O:24][CH3:25])[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]2[N:7]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:6][CH2:5][C:4]=2[CH2:3]1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:21]1[CH:22]=[C:17]([NH:16][C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([O:24][CH3:25])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:5][CH2:6]2)=[O:23])[CH:18]=[N:19][CH:20]=1
Reactant: COC1(Br)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Reactant: Cc1ccncc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(-c3cnccc3C)c1)CC2
Yield: 66.7 %

Procedure:
1-[5-Bromo-(3-pyridylcarbamoyl]-5-methoxy-6-trifluoromethylindoline (D26) (0.3 g 0.7 mmoles) and 4-methyl-3-pyridylboronic acid (0.12 g, 0.9 mmoles) was heated under reflux in dimethoxyethane (80 ml) and water (10 ml) with sodium carbonate (0.15 g, 1.4 mmoles) and palladium tetrakis triphenylphosphine (0.1 g, 12 mole %) under an inert atmosphere for 18 hours. After cooling the mixture was partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated and washed with saturated sodium chloride solution then dried (Na4SO4). Evaporation of the solvent followed by flash chromatography on silica gel eluting with 3-7% MeOH/CH2Cl2 and recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E35) (0.2 g, 65%) m.p. 125-8° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O>ClCCl>[Cl:31][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1nc(-c2ccccc2)oc1-c1cccnc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of (2-phenyl-5-(pyridin-3-yl)oxazol-4-yl)methanol (210 mg, 832 μmol) and triethylamine (253 mg, 348 μL, 2.5 mmol) in dichloromethane (4 mL) was added at 0-5° C. methanesulfonyl chloride (191 mg, 130 μL, 1.66 mmol). The ice bath was removed after 10 min and the reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give the product as light brown solid (197 mg, 728 μmol, 87.4%) which was used without further purification for the next step.
Reaction SMILES: N([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=C=O.[NH2:43][CH2:44][C:45]1([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:47][CH2:46]1>C1COCC1>[C:51]([O:50][C:49]([NH:48][C:45]1([CH2:44][NH:43][C@:4]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:46][CH2:47]1)=[O:55])([CH3:52])([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)NC1(CN)CC1
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(NCC3(NC(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 1.053 mmol) and N,N-diisopropyethyllamine (0.734 mL, 4.21 mmol) in THF (6 mL) was added tert-butyl 1-(aminomethyl)cyclopropylcarbamate (294 mg, 1.579 mmol). The resulting mixture was stirred at rt. After 16 h, the solvent was concentrated. The crude material was dissolved in THF (1 mL) and MeOH (2 mL), filtered and purified by reverse phase preparative HPLC (method 1) to give the title compound (499.5 mg, 58% yield) as a white solid. LCMS: m/e 756.7 (M+H)+, 2.75 min (method 7). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.0 (2H, d, J=8.5 Hz), 7.2 (2H, d, J=8.5 Hz), 5.3-5.3 (1H, m), 5.1 (1H, br. s.), 4.8 (1H, s), 4.7 (1H, s), 3.9 (3H, s), 3.5-3.5 (1H, m), 3.4 (1H, d, J=14.3 Hz), 2.8 (1H, br. s.), 2.6 (1H, d, J=12.8 Hz), 2.4 (1H, dd, J=12.2, 8.2 Hz), 2.1 (1H, dd, J=17.4, 6.4 Hz), 1.9-2.1 (2H, m), 1.8 (1H, d, J=13.4 Hz), 1.7-1.8 (1H, m), 1.7 (3H, s), 1.7-1.7 (2H, m), 1.5-1.7 (3H, m), 1.5 (9H, s), 1.4-1.5 (5H, m), 1.2-1.3 (1H, m), 1.1-1.2 (2H, m), 1.1 (3H, s), 1.0 (3H, s), 1.0 (3H, s), 0.9 (6H, s), 0.8-0.9 (3H, m). 13C NMR (CHLOROFORM-d) δ ppm 14.1, 15.4, 16.1, 19.0, 19.5, 20.7, 20.8, 24.8, 27.0, 28.1, 29.1, 29.2, 29.4, 31.4, 33.2, 35.1, 36.0, 36.6, 37.2, 40.4, 41.4, 41.6, 46.0, 49.1, 49.6, 51.7, 52.5, 77.3, 80.1, 109.9, 123.7, 127.6, 128.2, 129.8, 146.0, 148.4, 149.2, 167.0.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].CCN(CC)CC.C[O:29][C:30](=O)[C:31]1[C:36]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:43]Br>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:30](=[O:29])[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[CH2:43]2)[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Temperature: 90 °C
Yield: 25.5 %

Procedure:
To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115-117° C.; 1H NMR (CDCl3) δ 0.83-0.92 (m, 2H, c-CH2), 1.09-1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66-1.70 (m, 1H, c-CH), 2.98 (s, 3H, SO2CH3), 3.64 (dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69-5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151.9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N, 5.51. Found: C, 56.72; H, 5.15; N, 5.38.
Reaction SMILES: C(O[CH:5]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1)[CH:6]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:30]([C:20]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:17](/[CH:5]=[C:6](\[CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ncc(C(OC(C)=O)C(Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 75.5 %

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-[(2-thienyl)methyl]propanoate (4.36 g, 8.92 mmol) in dry toluene (80 mL) was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.2 mL, 21.4 mmol), and the resulting solution was heated at 80° C. under argon for 3 hours. The solvent was evaporated, the residue triturated with ether and activated charcoal was added. After filtration, the filtrate was concentrated to 6.29 g of an oil that was chromatographed over silica gel with 65:35 hexane/ethyl acetate to give 2.89 g (76%) of methyl (E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate whose NMR and TLC (50% ethyl acetate in hexane on silica gel) were identical to the product prepared by Method A.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[NH:35][C:36]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:42])/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C=O
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
To a slurry of 60% of sodium hydride (224 mg, 5.6 mmol) in THF (10 mL) at 0° C. was added 1A (1.72 g, 4.8 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of tert-butyl 3-formylpyridin-4-ylcarbamate (889 mg, 4 mmol) in THF (10 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (40 mL). The aqueous layer was extracted with EtOAc (50 mL×3). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (20-100%) in hexane to give the title compound as an white foam (1 g, 58%). LC/MS (method A): retention time=2.65 min, (M+H)+=428.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[OH:10][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1ccccc1O
Product: CCC(=O)c1ccc(O)c(C(C)C)c1
Yield: 32.1 %

Procedure:
In a manner similar to that of Example 1(a), by reacting 10 g (73 mmol) of 2-isopropylphenol with 6.3 ml (73 mmol) of propionyl chloride, 4.5 g (32%) of the expected product are obtained in the form of white crystals with a melting point of 105° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH:7]([S:13](Cl)(=[O:15])=[O:14])([S:9](Cl)(=[O:11])=[O:10])[CH3:8].C(N(CC)CC)C.[Cl-].[Cl-].[Ca+2]>C(COC)OC>[CH:7]1([S:13](=[O:15])(=[O:14])[O:6][CH2:1][CH2:2][CH2:3][CH2:4][O:5][S:9]1(=[O:11])=[O:10])[CH3:8]
Reactant: OCCCCO
Reactant: CC(S(=O)(=O)Cl)S(=O)(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1S(=O)(=O)OCCCCOS1(=O)=O
Yield: 9.2 %

Procedure:
1,4-Butanediol, obtained from Aldrich Chemical Co. (3.6 g, 0.04 mole) was dissolved in 75 ml of glyme in a 1 liter round bottom flask. A solution of 1,1-ethanedisulfonyl chloride (9.1 g, 0.04 mole) dissolved in 25 ml of glyme wa added to the flask through a dropping funnel. The reaction mixture was kept below -20° C. with a dowanol-dry ice bath. Triethylamine (8.08 g, 0.08 mole) dissolved in 100 ml of glyme was added to the mixture through a 125 ml dropping funnel over a period of 1 hour. Care was taken to maintain anhydrous conditions by covering the dropping funnels with drying tubes containing CaCl2. The reaction mixture was brought to 25° C. in a cold water bath. The glyme was removed by roto-evaporation, at a temperature below 37° C. The oily yellow residue that remained after removal of the glyme was washed once with 100 ml of 5% sodium bicarbonate and once with 50 ml of cold distilled water, the resulting emulsion being centrifuged immediately to separate the product, and aqueous material decanted. The remaining precipitate was dried under vacuum. The white, powdery solid which remained weighed 0.90 g, representing a 9.2% yield. Product identification was confirmed by characteristic IR and proton NMR spectral features. The product decomposed between 115 and 138° C. The product was soluble to less than about 0.01 gram in 1 ml of either methylene chloride or acetonitrile.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]([NH2:11])[CH3:10].[CH3:12][C:13]1[N:14]=[C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[C:22]2=[O:38])[S:16][C:17]=1[C:18](O)=[O:19]>>[CH2:9]([NH:11][C:18]([C:17]1[S:16][C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[C:22]2=[O:38])=[N:14][C:13]=1[CH3:12])=[O:19])[CH3:10]
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: CCN
Solvent: NCc1ccccc1
Product: CCNC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Yield: 25 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with ethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 25% yield: mp 218-219° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.60 (s, 1H), 4.47 (s, 2H), 4.10-4.04 (m, 2H), 3.51-3.35 (m, 4H), 2.57 (s, 3H), 1.18 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.0, 155.4, 152.3, 148.9, 134.4, 129.7, 121.4, 120.4, 117.8, 47.3, 42.0, 41.8, 35.1, 34.8, 17.0, 14.8: MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25](Cl)=[C:20]3[CH:19]=[CH:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>C(O)C>[C:8]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]([NH:1][CH:2]4[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]4)=[C:20]3[CH:19]=[CH:18]2)(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC1CCC(O)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 3-Amino-cyclopentanol (about 2.5 g) in ethanol (50 mL) were added 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (7 g, 20.4 mmol) and diisopropylethylamine (DIPEA) (7.2 g, 60 mmol), then the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was purified by column chromatography (Hexanes/ethyl acetate=3:1) to give 7.4 g (76%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol. 1H NMR (400 MHz, CDCl3) δ: 9.56 (s, 1H), 9.54 (s, 1H), 8.19-8.16 (m, 2H), 7.62-7.56 (m, 4H), 6.82-6.81 (m, 1H), 4.56-4.50 (m, 2H), 2.25-1.96 (m, 6H).