Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH:16]1OCCO1)([O-])=O>CC(C)=O.C(O)(=O)C.[Zn]>[S:12]1[C:11]2[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:1][CH2:16][C:15]=2[CH:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccccc1Cc1sccc1C1OCCO1
Agent: [Zn]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)Cc1sccc1CN2
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A stirred solution of 4 gms of 2-[2-[(2-nitrophenyl)methyl]-3-thienyl]-1,3-dioxolane in acetone (50 ml) and acetic acid (90% 50 ml) is heated to 60° C. Zinc dust (10 gms) is slowly added and after the addition, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water. The organic layer is dried (Na2SO4) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate:hexane to give 2.0 g of the desired product as a pale yellow crystalline solid, m.p. 86° C. Mass Spectrum; M+ 202.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][C@@H:42]([C@@H:73]([NH:81][C:82]([O:84][CH2:85][C:86]1[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=1)=[O:83])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:43][C:44]([NH:46][C@H:47]1[CH2:51][CH2:50][N:49]([C:52]([C@@H:54]2[CH2:58][C@H:57]([SH:59])[CH2:56][N:55]2[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=2)=[O:61])=[O:53])[CH2:48]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:59][C@@H:57]3[CH2:56][N:55]([C:60]([O:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=4)=[O:61])[C@H:54]([C:52]([N:49]4[CH2:50][CH2:51][C@H:47]([NH:46][C:44](=[O:45])[CH2:43][C@@H:42]([OH:41])[C@@H:73]([NH:81][C:82]([O:84][CH2:85][C:86]5[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=5)=[O:83])[CH2:74][C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[CH2:48]4)=[O:53])[CH2:58]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)C[C@@H](O)[C@H](Cc5ccccc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 81.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (1.40 g) and (2S,4S)-2-[(3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]-pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.80 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl)-2-[(2S,4S)-2-[(3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)-pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.13 g) was obtained as an amorphous substance.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]2[NH:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[OH-].[Li+].CO>C1COCC1>[CH2:1]([CH:4]1[C:8]2[NH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCc2cc(C(=O)OC)[nH]c21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCc2cc(C(=O)O)[nH]c21
Yield: 53.9 %

Procedure:
The title compound was synthesized from methyl 6-propyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.15 g, 0.72 mmol) and lithium hydroxide monohydrate (0.3 g, 7.24 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound (75 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.94 (t, J=7.0 Hz, 3H) 1.32-1.49 (m, 3H), 1.62-1.80 (m, 1H), 1.93-2.08 (m, 1H), 2.43-2.65 (m, 3H), 3.01 (br. s, 1H) 6.57 (s, 1H). LCMS m/e 249 (M−H) and 96% pure by HPLC.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([OH:13])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.Cl.[CH3:40][NH:41][C:42]([C@@H:44]1[NH:56][CH2:55][C:47]2[NH:48][C:49]3[C:54]([C:46]=2[CH2:45]1)=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:43]>CC#N.C(OCC)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([N:56]1[C@@H:44]([C:42]([NH:41][CH3:40])=[O:43])[CH2:45][C:46]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[NH:48][C:47]=2[CH2:55]1)=[O:13]
Reactant: O=C(O)c1occc1C1OCCO1
Reactant: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)c1occc1C1OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of product (3-A) (2.19 g, 11.9 mmol) in CH3CN (200 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMMCl, 4.9 g, 17.8 mmol), and then 4-methylmorpholine (NMM, 4.8 g, 47.6 mmol) was added drop-wise while maintaining the temperature below 20° C. After stirring for 16 h at rt, product (5-A) (3 g, 13.1 mmol) was added, and the solution was stirred at rt for another 6 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated and purified by CC (DCM:MeOH=200:1 to 100:1) to give product (6-A) (2.2 g, 47%) as a brown solid. LC-MS (M+H)+=396.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:45]=[CH:46][CH:47]=1)[O:31][C:32]1[CH:44]=[CH:43][C:35]2[N:36]=[C:37]([NH:39][C:40](=[O:42])[CH3:41])[S:38][C:34]=2[CH:33]=1>O1CCCC1.C(OCC)(=O)C.O>[C:40]([NH:39][C:37]1[S:38][C:34]2[CH:33]=[C:32]([O:31][C:30]3[CH:29]=[C:28]([NH:27][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([C:11]5([C:14]#[N:15])[CH2:13][CH2:12]5)[C:2]=4[Cl:1])[CH:47]=[CH:46][CH:45]=3)[CH:44]=[CH:43][C:35]=2[N:36]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)cc2s1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (237 mg, 1.07 mmol) in tetrahydrofuran (4 mL) were added oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in N,N-dimethylacetamide (4 mL). N-[6-(3-Aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) was added and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and triturated with ethyl acetate/diisopropyl ether to give the title compound (215 mg, 80%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CN(C)C=O>[C:3]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[C:25]([CH3:26])[CH:24]=2)[CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(CBr)c1
Reactant: O=C(c1ccccc1)C1CNc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccccc3)c(=O)c3ccccc32)c1

Procedure:
Compound 4t was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.4 mmol) of sodium hydride (60%), 75 mg (0.31 mmol) of 3-benzoyl-2,3-dihydro-1H-quinolin-4-one 3e, 3 mL of anhydrous dimethylformamide, 75.6 mg (0.40 mmol) of 3-methylbenzylbromide. The crude product 4t was purified by flash chromatography to yield 45 mg of colorless solid: LC-MSD, m/z for C24H19NO2, [M+H]+=354.4, [M+2H]+=355.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.146 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (s, 3H), 5.38 (s, 2H), 7.00 (d, 2H), 7.33 (d, 1H), 7.22-7.26 (m, 1H), 7.36-7.45 (m, 4H), 7.50-7.60 (m, 2H), 7.82-7.86 (m, 2H), 8.31 (s, 1H), 8.44-8.48 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30]Cl)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Product: O=C(O)Cc1coc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to step 1 of Example 80 using (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester and 1-(4-trifluoromethyl-benzyloxy)-2-chloromethyl-benzene. MS m/z 471 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+].N#N>O.C(OCC)(=O)C.CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[CH:16]=[CH:17][C:18]([C:31]2[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=2)=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Fc1cnc(Cl)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ncc(F)cn2)cc1
Temperature: 70 °C
Yield: 56.7 %

Procedure:
A mixed DMF/H2O (5 mL/5 mL) solution of (S,S)-5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (800 mg, 2 mmol), 2-chloro-5-fluoro-pyrimidine (340 mg, 2.6 mmol), K2CO3 (552 mg, 4 mmol) and Cl2Pd(dppf)CH2Cl2 (160 mg) was evacuated and recharged with N2 several times. The reaction was heated at 70° C. over 18 hrs. After cooling down to rt, 40 mL ethyl acetate and 10 mL water was added. The mixture was filtered through a pad of Celite and washed with additional ethyl acetate. The separated organic layer was dried (MgSO4) and concentrated. The crude was purified on silica gel column eluting with 50% ethyl acetate/hexanes to yield the title compound (420 mg) as a light yellow solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]12([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:18])=[O:31])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(C2CCCCC2)c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(C2CCCCC2)c2ccccc2c1=O

Procedure:
The product of Example 74A and 2-(adamantan-1-yl)acetyl chloride were processed using a method similar to that described in Example 1C, and purified by preparative HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm); a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A)] to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1H), 8.34 (d, J=7.9 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.97-8.01 (m, 1H), 7.89 (t, J=7.5 Hz, 1H), 3.21-3.40 (m, 1H), 1.39-1.98 (m, 26H), 1.13-1.27 (m, 1H); MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[CH:6]=[C:7]([NH2:9])[CH:8]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:9][C:7]1[CH:6]=[C:5]([NH:10][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=1
Reactant: O=C(O)CCCCl
Reactant: Nc1cc(N)cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1cc(NC(=O)CCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Mix 5-(trifluoromethyl)benzene-1,3-diamine (300 mg, 1.70 mmol), 4-chlorobutanoic acid (230 mg, 1.87 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 650 mg, 3.40 mmol), 1-hydroxybenzotriazole (HOBt, 230 mg, 1.70 mmol) and diisopropylethylamine (450 mg, 3.40 mmol) in dichloromethane (10 mL), stir overnight at room temperature. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=1:10) to yield the product (250 mg, 52%). MS: (M+1): 281.2.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].[H-].[Na+].[CH3:20]I>CN(C=O)C>[CH3:20][O:1][CH2:2][C@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)[C@@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC=C(C(=O)OC)[C@@H]1COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 1-allyl 3-methyl (2R)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (234 mg, 0.97 mmol) in DMF (4.7 ml) was added at 0° C. sodium hydride (60% suspension in oil, 39 mg, 0.98 mmol) and the mixture was stirred for 30 minutes. Then thereto was added at 0° C. methyl iodide (0.95 ml, 9.7 mmol) and the mixture was stirred at room temperature for 1 hour. After cooled to 0° C., the reaction mixture was poured into ice water and extracted three times with ethyl acetate. The organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified with silica gel chromatography to give 1-allyl 3-methyl (2R)-2-(methoxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (55 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[S:7][C:6]=2[C:16]=1[Cl:17].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH:9]=[C:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C1CCCC1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A mixture of 2.5 g of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene and 10 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 15 minutes and allowed to stand overnight. The mixture is poured into a chilled solution of dilute sodium hydroxide and the organic material is extracted into ether. Washing with water, followed by drying over anhydrous magnesium sulfate and evaporation in vacuo, gives 2.0 g of wax-like crystals. Recrystallization from ether-hexane gives 1.8 g of 6,7-dichloro-2-cyclopentyl-5-methoxybenzo-[b]thiophene as fine needles, mp 59.5°-60°.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([NH:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCc2ccccn2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with 2-(Aminomethyl)pyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O3 [(M+H)+] 756.319, observed 756.3194.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19].Cl.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][CH2:31][C@H:30]2[NH2:36])=[O:26]>C(Cl)Cl.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:36][C@H:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([C:25]([O:24][CH3:23])=[O:26])[CH:28]=2)[CH2:32][CH2:31]1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1cccc(Cl)c1Cl)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
N-Ethyl-diisopropylamine (2.5 eq.) and 2,3-dichlorobenzene-1-sulfonyl chloride (1.2 eq.) were added to an ice-cold solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.88 mmol, 1 eq.) in methylene chloride at 0° C. under an inert atmosphere. The mixture was then stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (silica, cyclohexane/ethyl acetate, 2:1) to yield the desired compound (C-06). Yield: 97%
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=1[CH3:30])=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:1]1([CH2:4][O:5][NH:6][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[CH3:30])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Reactant: NOCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)NOCC3CC3)c(C)n(C)c(=O)c2C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
O-cyclopropylmethyl-hydroxylamine (0.046 g, 0.527 mmol) was added to a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (30:1 methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MS ESI (+) m/z 374 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 6.91 (d, 1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). 19F (376 MHz, CD3OD) −132.1 (s, 1F).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O>N1CCCC1>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:8]3[CH2:9][CH2:10][CH2:6][CH2:7]3)[CH2:7]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC3)C2)cc1
Yield: 53 %

Procedure:
5 g (0.0174 mol) of 1-(4-nitrophenyl)pyrrolid-3-yl methanesulphonate (2) were heated at 85° C. for 2 hours in 30 ml of pyrrolidine (mol). This mixture was poured into ice-cold water until crystallization takes place. After filtration and drying, the yellow powder obtained was chromatographed, eluting with dichloromethane/methanol (98/2), and 2.6 g of derivative (5) were recovered (53% yield).
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH3:7].C.[CH3:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:20][C:21]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([O:31]C)=O)(=[O:26])=[O:25])=[O:22])[N:11]=1>CCCCCC.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][N:6]([CH3:7])[C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:23][C:21]([NH:20][C:12]1[N:11]=[C:10]([CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:22])(=[O:25])=[O:26])=[O:31]
Reactant: CNC
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Agent: C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)N(C)C)nc2ccccc12
Reaction time: 2 h

Procedure:
To 21.2 ml of 25% trimethylaluminum in hexane (2.36 M) in 100 ml dry methylene chloride is added 2.2 g dimethylamine. The mixture is stirred at ambient temperature until evolution of methane gas ceases and then 20.0 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate and 200 ml of dry toluene is added. The resulting mixture is heated to distill off the methylene chloride and hexane, after which heating is continued at the reflux temperature of toluene. After 2 hours, the toluene is removed in vacuo, and 200 ml of methylene chloride and 100 ml of 10% hydrochloric acid are added. The phases are separated, and the methylene chloride phase is washed once with water, dried over magnesium sulfate, and filtered, and the methylene chloride distilled to yield the desired compound.