Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:10]=[C:11]=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C:11]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1oc(C(C)(C)C)cc1N=C=O
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1oc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 1 h

Procedure:
The 2-carbomethoxy-5-tert-butyl-3-furyl isocyanate prepared in Step 3 was dissolved in anh. toluene (40 mL), p-toluidine (2.05 g, 6.02 mmol, 1.0 equiv) was added, and the resulting solution was stirred at room temp. for 1 h. The toluene mixture was concentrated under reduced pressure, then diluted with CHCl3 (150 mL). The organic solution was washed with a 1N HCl solution (2×100 mL) and a saturated NaCl solution (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (100 g SiO2, gradient from hexane to 10% EtOAc/hexane) to give N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(4-methylphenyl)urea as a yellow solid (0.71 g, 35): mp 78-9° C.; TLC (20% EtOAc/hexane) Rf0.46; 1H NMR δ1.28 (s, 9H), 2.33 (s, 3H), 3.80 (s, 3H), 7.03 (s, 1H), 7.10 (br s, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H) 8.60 (brs, 1H); 13C NMR δ20.8, 28.5 (3C), 33.2, 51.3, 100.3, 121.7 (br s, 2C), 126.2, 129.8 (br s, 2C), 134.3 (br s), 135.0, 137.5 (br s), 152.6, 160.8, 168.5; FAB-LRMS m/z (rel abundance) 331 (M+H, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([CH3:39])[CH:16]([N:21]([CH3:38])[C:22]([C:24]1[S:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)=[O:23])[C:17]([O:19][CH3:20])=[O:18]>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([C:26]3[S:25][C:24]([C:22]([N:21]([CH:16]([CH:15]([CH3:39])[CH3:14])[C:17]([O:19][CH3:20])=[O:18])[CH3:38])=[O:23])=[N:28][CH:27]=3)=[CH:30][CH:31]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COC(=O)C(C(C)C)N(C)C(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1
Yield: 56 %

Procedure:
The title compound was synthesized analogous to Example 27, using 4-tert-butylbenzoyl chloride and intermediate 4. Yield: 56%; 1H NMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.37 (s, 1H), 8.04 (m, 4H), 7.78 (d, 2H), 7.57 (d, 2H), 6.27-4.76 (d, 1H), 3.69 (s, 3H), 3.47-2.95 (s, 3H), 2.35 (m, 1H), 1.33 (s, 9H), 1.11 (bs, 3H), 0.90 (bs, 3H); MS (ESI): m/z 508.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:21].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in 2 mL NMP and to this was added KOH (560 mg, 10 mmol) followed by 2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1 mmol) The reaction was kept overnight at RT. Water was added and the compound extracted with EtOAc. The organic layer was washed with water, concentrated and purified by column chromatography using silica gel (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by reverse phase chromatography. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (d, 2H), 7.50 (s, 1H), 7.30 (d, 1H), 7.10 (m, 1H), 5.80 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.05 (s, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.BrC1C=CC([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[CH:21][C:20]=2[O:28][CH3:29])=NC=1>>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH2:25][CH2:26][CH3:27])[CH:23]=[CH:24][C:19]=1[O:18][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CCCc1ccc(Oc2ccc(Br)cn2)c(OC)c1
Product: CCCc1ccc(Oc2ccc([N+](=O)[O-])nc2)c(OC)c1
Yield: 103.3 %

Procedure:
According to the procedure of example 20(a), except substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for 5-bromo-2-nitropyridine (406 mg, 2 mmol), the title compound (220 mg; 38%) was prepared as a white solid, after chromatography on silica gel (gradient cyclohexane/dichloromethane), along with 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (238 mg; 37%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[S:32][C:33]([Cl:38])=[C:34]([CH2:36]Br)[CH:35]=2)[O:11][C@@H:10]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:48][C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[S:32][C:33]([Cl:38])=[C:34]([CH2:36][C:52]3[CH:53]=[CH:54][C:49]([CH3:48])=[CH:50][CH:51]=3)[CH:35]=2)[O:11][C@@H:10]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1sc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)sc2Cl)cc1
Temperature: 120 °C
Yield: 70.7 %

Procedure:
To a solution of bromide 38 (850 mg, 1.16 mmol) in toluene/EtOH (18 mL/2 mL) were added 4-methylphenylboronic acid (200 mg, 1.39 mmol), tetrakis(triphenylphosphin)palladium (70 mg, 0.058 mmol) and Cs2CO3 (770 mg, 2.32 mmol) at room temperature. The mixture was stirred at 120° C. The mixture was cooled to room temperature and filtered off thorough silica gel to remove insoluble materials. The filtrate was ure was extracted with EtOAc/H2O (100 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 39 (611 mg, 71%).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[S:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=O)C.O.[NH2:17]N>CC(O)=O>[N+:13]([C:10]1[S:9][C:8]([C:6]2[N:5]=[CH:4][NH:2][N:17]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc([N+](=O)[O-])s1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2nc[nH]n2)s1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
N-[(1E)-(Dimethylamino)methylene]-5-nitrothiophene-2-carboxamide (7.00 g, 30.8 mmol) was combined with AcOH (70 mL) and hydrazine hydrate (65% wt, 2.76 mL, 37.0 mmol) and stirred at 90° C. for 1.5 h. The yellow solution was cooled to room temperature and concentrated. The resulting slurry was diluted with CH2Cl2 and saturated NaHCO3 and stirred. The yellow precipitate was isolated by filtration and dried to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:16][CH:18]3[CH2:19][O:20]3)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(c2ccc(O)cc2)CC1
Reactant: ClCC1CO1
Product: CC1(C)CCC(c2ccc(OCC3CO3)cc2)CC1

Procedure:
The title compound was prepared from 4-(4,4-dimethylcyclohexyl)-phenol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:1]1([C@@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NC1CC[C@@H](c2n[nH]c3cnc4[nH]ccc4c23)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@@H]2CC[C@@H](c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Yield: 4 %

Procedure:
(3R)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (0.12 g, 0.48 mmol, Preparation #29), 6-chloronicotinonitrile (0.069 g, 0.48 mmol), and DIEA (0.13 mL, 0.75 mmol) were heated in EtOH (3.0 mL) at about 80° C. for about 10 h. The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC (Table 2, Method h) to give 6-((1R,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.007, 4%): LC/MS (Table 2, Method a) Rt=1.86 min; m/z: 344 (M+H)+ and 6-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.009 g, 5%): LC/MS (Table 2, Method a) Rt=1.89 min; m/z: 344 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[OH:26][C@H:27]1[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[C:36]([O:40][C:41]([NH:43][CH:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C@@H:44]([C@H:48]([CH3:56])[CH2:49][CH:50]([CH3:55])[CH2:51][CH2:52][CH:53]=[CH2:54])[C:45]([N:30]1[CH2:31][C@H:27]([OH:26])[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 31.7 g, 83 mmol) was added to a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate HCl (16.68 g, 92 mmol), (3R)-2-((tertbutoxycarbonyl)amino)-3,5-dimethylnon-8-enoic acid (25 g, 83 mmol) and NEt3 (34.9 mL, 250 mmol) in DCM (250 mL) and stirred at RT for 16 h. The reaction was washed with 1N HCl (3×) and then brine. The organics were dried with magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified via silica gel chromatography using 20-60% Acetone in hexanes to give the desired product (2S,4R)-methyl 1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (10.8 g, 30% yield), MS: MS m/z 427.2 (M++1) and the undesired product (2S,4R)-methyl 1-((2R,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (12 g, 34% yield). MS: MS m/z 427.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)N[C:32](=[O:37])/C/2=C\C1NC=CC=1OC)#C.IC1C=CC(O)=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:37][CH3:32])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1[nH]ccc1OC)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Oc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(C#Cc3ccc(O)cc3)cc21

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (75 mg, 0.28 mmol) (from Example 93) was coupled with 4-iodophenol (75 mg, 0.34 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-5-(4-hydroxyphenyl) ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)-methylene]-2H-indol-2-one as a yellow powder. (Yield 62 mg, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>>[CH3:20][O:21][C:22]1[C:27]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 20 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (2-methoxypyridin-3-yl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC.
Reaction SMILES: [Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]1[NH:12][CH:13]([CH3:15])[CH3:14].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:44]1[O:56][C@@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@@H:45]1[O:46][C:47](=[O:49])[CH3:48])(=O)C>ClCCCl>[Cl:1][N:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C@H:44]2[O:56][C@@H:55]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[C@H:50]([O:51][C:52](=[O:54])[CH3:53])[C@@H:45]2[O:46][C:47](=[O:49])[CH3:48])[CH:3]1[NH:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)NC1Nc2cccc(Cl)c2N1Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](N2c3cccc(Cl)c3N(Cl)C2NC(C)C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 56.4 %

Procedure:
3,4-Dichloro-2-(isopropylamino)-1H-benzimidazole (2.01 g, 7.31 mmol), N,O-bis(trimethylsilyl)acetamide (2.0 mL, 1.65 g, 8.09 mmol), trimethylsilyl trifluoromethanesulfonate (0.9 mL, 1.06 g, 4.50 mmol), 1,2,3,5-tetra-O-acetyl-beta-L-ribofuranose (3.03 g, 9.52 mmol) and 1,2-dichloroethane (35 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 95:5 dichloromethane/acetonitrile to afford 2.08 g (56%) of a yellow foam. MS (EI): m/z 502.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.[C:33]([C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([C:35]1[S:39][C:38]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=2)=[CH:37][CH:36]=1)#[N:34]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccc(C#N)s4)c3C2=O)c(OC)c1
Temperature: 160 °C

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (114 mg, 0.245 mmol), 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol), tris(dibenzylideneacetone)di-palladium(0) (13.47 mg, 0.015 mmol), and 2-(dicyclohexylphosphino)biphenyl (5.16 mg, 0.015 mmol) in dioxane (2 mL) and DMF (0.5 mL) was heated to 160° C. under microwave irradiation for 45 min. UPLC showed 50% conversion. The reaction mixture was subsequently heated at 160° C. under microwave irradiation for 45 min. Additional 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol) was added and the reaction mixture was heated at 160° C. under microwave irradiation for 60 min. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40-80% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C27H28FN5O4S, 538; found, 538.
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].I[CH2:22][CH2:23][CH2:24][CH2:25]I>CN(C)C1C=CN=CC=1.O>[N:6]1([C:7]2[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=2)[C:17]([O:19][CH3:20])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ICCCCI
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
Anhydrous DMF (3 ml) was added to a flask charged with dimethyl 5-aminoisophthalate (0.250 g, 1.2 mmol, 1 eq) and 4-dimethylaminopyridine (0.308 g, 2.52 mmol, 2.1 eq) under Ar. 1,4-diiodobutane (0.16 ml, 0.37 g, 1.20 mmol, 1 eq) was added with stirring and the solution was heated to 90° C. After heating overnight the reaction was not complete. More diiodide (0.25 ml, 1.9 mmol, 1.6 eq) was added and the reaction was heated to 100° C. After heating overnight the reaction was cooled to room temperature and poured in water. The mixture was extracted with EtOAc (×2). The combined organic extracts were washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. The residue was stirred in CH2Cl2 and filtered through cotton to remove any insoluble material. The solvent was removed in vacuo. Purification via flash chromatography yielded the crude product. The crude was triturated with hexanes and the solid was collected via filtration. 0.167 g (0.63 mmol, 53% yield) of the product was collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:23][C:10]2[S:11][C:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Product: O=C(Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1ccc(F)cc1
Yield: 69.6 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and p-fluorobenzoyl chloride were used as starting materials, allowed to react at 35-40° C. for 24 hours, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (4:1) to obtain a product as a pale yellow solid in a yield of 69.6%, mp: 120-122 └. 1H-NMR (CDCl3, 400 MHz) δ: 4.33 (2H, s, CH2), 7.12 (2H, t, 3JFH=3JHH=8.44 Hz, ArH), 7.18 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.38 (2H, d, J=8.68 Hz, ArH), 7.49 (2H, dd, 3JHH=8.72, 4JFH=5.32 Hz, ArH), 7.99 (2H, dd, 3JHH=8.96, 4JFH=5.32 Hz, ArH); 8.20 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 451.0 (M+, 32), 123.0 (100); HREI-MS Calcd. for C23H15F2N3O3S: 451.0802. found: 451.0818. Anal. Calcd. for C23H15F2N3O3S: C, 61.19; H, 3.35; N, 9.31. found: C, 61.16; H, 3.08; N, 9.35.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:20])[NH:13][NH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32]([O:40][C@@H:41]3[O:58][C@H:57]([CH2:59][O:60][C:61](=[O:63])[CH3:62])[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]3[O:43][C:44](=[O:46])[CH3:45])=[N:33][NH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32]([O:40][C@@H:41]3[O:58][C@H:57]([CH2:59][O:60][C:61](=[O:63])[CH3:62])[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]3[O:43][C:44](=[O:46])[CH3:45])=[N:33][NH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])=[CH:26][CH:25]=1)([CH3:23])[CH3:22].[C@@H:41]1([O:20][C:12]2[C:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[C:15]([C:16]([F:17])([F:19])[F:18])[NH:14][N:13]=2)[O:58][C@H:57]([CH2:59][OH:60])[C@@H:52]([OH:53])[C@H:47]([OH:48])[C@H:42]1[OH:43]
Reactant: CC(C)c1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(C(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Example 26 using 1,2-dihydro-4-[(4-isopropylphenyl)-methyl]-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoro-methyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Example 35 using 4-[(4-isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]2(=[O:21])=[O:20])C=CC=CC=1.S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[N:11]([CH2:18][CH3:19])[S:10]1(=[O:21])=[O:20]
Reactant: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (3.97 g) and sulfuryl chloride (1.47 ml) in 80 ml of methylene chloride was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane. The solvent was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) to afford 2.4 g (77%) of 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =ethyl; X'=Cl) as an oil.