Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=2[S:34]([CH3:37])(=[O:36])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: CS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-bromo-2-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C20H17FN2O3S, 384.09; m/z found, 385.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27-8.24 (m, 1H), 7.99-7.93 (m, 1H), 7.71-7.65 (m, 1H), 7.63-7.57 (m, 1H), 7.47 (m, 1H), 7.41-7.38 (m, 1H), 7.33-7.27 (m, 3H), 4.32-4.24 (m, 2H), 3.67-3.59 (m, 2H), 2.76 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH:29]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na]>ClC(Cl)C.O>[CH2:16]([O:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=1[CH2:29][NH:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(OCCOCc2ccccc2)c(C=O)c1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc(OCCOCc2ccccc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Yield: 78 %

Procedure:
To stirred solution of 4.6 g (23 mmol) 1b, 6.3 g (23 mmol) 2a and one drop of glacial acid in 35 ml dichloroethane (pH=5) were added 7.4 g (35 mmol) sodium tris-acetoxy hydro borane. The reaction mixture was stirred over night and diluted with 3 ml water. The pH value was adjusted with aqueous sodium hydroxyd solution to pH=8-9. The mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and brine and were dried with magnesium sulfate. The desired crude product 2b was obtained in 78% yield (8.5 g, 17.9 mmol) as yellow oil. The crude product 2b was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[C:10]1([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:12][CH2:11]1.[H][H]>CO.[Pd+2]>[NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[C:10]1([NH2:13])[CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: O=C(NC1(c2nc3cnccc3[nH]2)CC1)OCc1ccccc1
Agent: [Pd+2]
Solvent: CO
Product: NC1(c2nc3cnccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.5 %

Procedure:
To a small RBF was added benzyl 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate (939 mg, 3.05 mmol) in methanol (13 ml). The flask was sealed with a septa and the solution was degassed and flushed with nitrogen several times. To the solution was then added 10% Palladium(II) on carbon (97 mg, 91 μmol), and a balloon of hydrogen was added to the top of the flask. The mixture was stirred overnight at room temperature. The mixture was pushed through a plug of celite in a Whatman Autovial (equipped with a 0.45 uM nylon membrane and a glass microfiber prefilter). Volatiles were removed giving 640 mgs (100% yield) of 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropanamine as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.67-1.72 (m, 2 H), 1.73-1.80 (m, 2 H), 7.92 (m, 1 H), 8.40 (d, J=7.0 Hz, 1 H), 9.05 (s, 1 H). LCMS rt=0.293 min., m/z 175.1 (M+H), 90.7% purity.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][NH2:40]>>[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][NH:40][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([C:11]2[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])[N:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: Cn1ccnc1CN
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4nccn4C)cc3)oc2C)cc1
Yield: 69.9 %

Procedure:
Reaction of oxalyl chloride (75 λL, 0.86 mmol) and benzoic acid 4 (212 mg, 0.57 mmol) with subsequent coupling to (1-methyl-1H-imidazol-2-yl)methylamine (70 mg, 0.63 mmol) gave benzamide 14 (185 mg, 70%) as a white powder: mp (EtOAc) 190-192° C.; 1H NMR δ 9.05 (t, J=5.5 Hz, 1H, CONH), 8.00 (dd, J=8.6, 1.8 Hz, 2H, H-2, H-6), 7.87 (dd, J=8.6, 1.8 Hz, 2H, H-3, H-5), 7.67 (d, J=8.3 Hz, 2H, H-2′, H-6′), 7.42 (d, J=8.3 Hz, 2H, H-3′, H-5′), 7.08 (d, J=1.1 Hz, 1H, H-5″), 6.80 (d, J=1.1 Hz, 1H, H-4″), 4.62 (s, 2H, CH2SO2), 4.54 (d, J=5.5 Hz, 2H, CH2N), 3.66 (s, 3H, NCH3), 2.40 (s, 3H, CH3), 2.13 (s, 3H, CH3); 13C NMR δ 165.2, 158.0, 149.9, 144.5 (2), 135.6, 135.3, 129.6 (2), 128.8, 128.3 (2), 128.2 (2), 126.4, 126.0, 125.3 (2), 121.8, 53.0, 35.5, 32.4, 21.0, 9.6; MS m/z 462.5 (MH+, 100%). Anal. calcd for C24H24N4O4S: C, 62.05; H, 5.21; N, 12.06. Found: C, 61.76; H, 5.09; N, 11.76%.
Reaction SMILES: [Na].[C:2]1([SH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19](Cl)=[N:18][C:17]([OH:21])=[N:16]1>CO>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([S:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:18][C:17]([OH:21])=[N:16]1
Reactant: Oc1nc(Cl)n(-c2ccccn2)n1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CO
Product: Oc1nc(Sc2ccccc2)n(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 2.3 g (0.10 m) of sodium metal dissolved in 125 ml of methanol was added a solution of 5.51 g (0.05 m) of thiophenol in 25 ml of methanol. To this mixture was added 9.8 g (0.05 m) of 1-(2-pyridinyl)-5-chloro-1H-1,2,4-triazol-3-ol and the mixture stirred for three hours at room temperature. The methanol was removed by evaporation under vacuum and the residue which remained was taken up in water and the water insoluble solids were removed by filtration. The aqueous layer was acidified with concentrated hydrochloric acid. The white solid which precipitated was recovered by filtration and dried under vacuum to yield 9.5 g (~70 percent of theoretical) of the desired 1-(2-pyridinyl)-5-(phenylthio)-1H-1,2,4-triazol-3-ol product. The product melted at 235°-237° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 55.87, 3.79 and 19.90 percent, respectively, as compared with the theoretical contents of 55.91, 3.93 and 20.06 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14]Br)[CH:5]=[CH:4][C:3]1=2.CCOC(C)=O.[C:23](#[N:25])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:23]#[N:25])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: CC#N
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(CC#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) bromomethane (21) (100 mg, 0.44 mmol) in acetonitrile (2 mL) was added tetraethylammonium cyanide (83 mg, 0.53 mmol). The resulting golden yellow solution was stirred at rt overnight. The solvent was removed in vacuo and to give a residue that was subjected to chromatograpy (10% EtOAc/90% hexane) to give 59 mg (78%) of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) acetonitrile (22). 1H NMR (400 MHz, CDCl3) δ7.31 (d, J=8.2 Hz, 1H, aromatic), 7.23 (d, J=1.8 Hz, 1H, aromatic), 7.08 (dd, J=8.0 and 1.8 Hz, 1H, aromatic), 3.69 (s, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), (s, 6H, 2CH3).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.O=C1N(CC(O)=O)N=C(C2C=CC=CN=2)C2C=CC=CC=2N1CC(=O)C1C=CC=CC=1C.[C:72]([O:76][C:77](=[O:87])[N:78](C1C=CC=C(N)C=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:72]([O:76][C:77](=[O:87])[N:78]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: Cc1ccccc1C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [2-oxo-1-(2-oxo-2-o-tolyl-ethyl)-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 7, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.64 (1H, d), 8.08 (1H, d), 8.03 (1H, s), 7.79 (1H, dt), 7.59 (2H, m), 7.39-7.26 (5H, m), 7.19 (2H, m), 7.01 (1H, t), 6.90 (1H, s), 6.47 (1H, dd), 6.30 (1H, dd), 4.98 (2H, s), 4.45 (2H, br m), 3.30 (1H, br s), 2.76 (3H, s), 2.47 (3H, s). Found: C, 69.63; H, 5.45; N, 15.59%; C31H28N6O3 requires: C, 69.91; H, 5.30; N, 15.78%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([S:41](Cl)(=[O:43])=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:41]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)(=[O:43])=[O:42])=[C:3]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH:4]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2ccccc12)c1ccccc1

Procedure:
N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 40 mg of a purple solid. MS (posES-FIA) m/z=Found: 523.2; Calcd 523.14; 1H NMR δ 8.83-8.59 (m, 1H), 8.10 (d, 1H), 8.02-7.97 (m, 1H), 7.90 (d, 1H), 7.74-7.38 (m, 8H), 6.69-6.65 (m, 1H), 6.39-6.34 (m, 2H), 3.35-3.14 (m, 8H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.IC>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][CH3:1])=[CH:12][N:13]=1
Reactant: CC(C)(C)[O-]
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.6 g (23.0 mmol) of potassium tert-butoxide are dissolved in 50 ml of THF. 3.0 g (20.9 mmol) of (6-chloropyridin-3-yl)methanol are added, and the mixture is stirred at RT for 15 min. 4.4 g (31.3 mmol) of iodomethane are then added slowly, and the mixture is stirred for about 30 min until the slightly exothermic reaction has subsided. The solvent is removed, and the residue is taken up in dichloromethane and washed twice with water. The organic phase is dried over magnesium sulfate and concentrated, and the residue is purified by column chromatography on silica gel (Biotage chromatography, mobile phase: cyclohexane/ethyl acetate 85:15).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:15].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>O>[O:15]=[C:2]1[C:3](=[N:23][NH:22][C:21]2[CH:20]=[CH:19][C:18]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:17][CH:16]=2)[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=2)[NH:1]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)cc1

Procedure:
The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid amide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 7.04 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.26 (s, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.70 (dd, J=8.2, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.98 (d, J=1.6 Hz, 1H), 11.43 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 395 (M)−+. Anal. Calcd for C14H13N5O5S2.0.5 H2O: C, 41.58; H, 3.49; N, 17.32; S, 15.86. Found: C, 41.67; H, 3.46; N, 17.26; S, 15.78.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23](Br)[N:22]=2)=[O:20])=[CH:14][CH:13]=1>CN(C=O)C.CCCCCC.[Cu](Cl)Cl>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: Cc1cccc(O)c1
Reactant: COc1cc(Br)nc(C(=O)Nc2ccc(C)cc2)c1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(C)c2)nc(C(=O)Nc2ccc(C)cc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.45 g (0.0019×2.2 mol) of 3-methyl phenol was dissolved in about 10 ml of DMF. The obtained solution was further mixed with 0.15 g (ca. 60% in mineral oil; 0.0019×2.0 mol) of NaH and then with 0.60 g (0.0019 mol) of N-(4-methylphenyl)-6-bromo-4-methoxy-2-pyridine carboxamide. After adding 0.19 g (0.0019×1.0 mol) of copper chloride (I), the solution was stirred at about 100° C. for about 4 hours, and then allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[CH2:28][C@H:26]([OH:27])[CH2:25][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:17])=[O:15])[CH2:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)[C@H](Cc1cccnc1)NC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resultant Boc-Hyp-Pal-N(Me)Bzl-is dissolved in 40 ml of CH2Cl2 and mixed with 20 ml of TFA whilst cooling with ice. The mixture is stirred for 15 minutes at ambient temperature, concentrated on the rotary evaporator, the residue is taken up in ethyl acetate and extracted twice with saturated NaHCO3 solution. The aqueous phase is extracted successively with ethyl acetate and CH2Cl2. All the organic phases are united, dried with MgSO4, concentrated and the residue is chromatographed over silica gel by means of acetonitrile/water/MeOH (4:1:1). 0.39 g of H-Hyp-Pal-N(Me)Bzl is obtained as a highly viscous, colourless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 88 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-methoxy-phenylboronic acid (2.3 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (425 mg, 0.6 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 10:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.3 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50 (d, 1H, J=4.8 Hz), 7.90 (d, 1H, J=4.8 Hz), 7.67 (d, 2H, J=7.5 Hz), 7.42 (t, 1H, J=7.5 Hz), 7.27-7.18 (m, 3H), 6.82 ((t, 2H, J=9.0 Hz), 6.65 (s, 1H), 6.55-6.46 (m, 2H), 6.18-6.15 (d, 1H, J=10.2 Hz), 3.67 (s, 3H), 2.69-2.66 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[CH2:4][CH:3]1[CH2:5][OH:6].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27]>ClCCl>[OH:6][CH2:5][CH:3]1[CH2:4][C:2]1([NH:1][C:26](=[O:27])[O:28][CH3:29])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Step b) To a solution of ((1RS,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)methanol (2.85 g, 13.7 mmol, Eq: 1.00) in dichloromethane (27.4 ml) was added at 5° C. diisopropylethylamine (2.65 g, 3.59 ml, 20.5 mmol, Eq: 1.5) and methyl chloroformate (1.42 g, 1.17 ml, 15.1 mmol, Eq: 1.1) dropwise via syringe. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was extracted with sat NaHCO3 solution and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated to give a brown oil which was purified by silica gel flash chromatography with 0-100% EtOAc in heptane to give the title methyl (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropylcarbamate (3.52 g, 13.2 mmol, 96.6% yield) as a light brown oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reaction time: 72 h
Yield: 1243.2 %

Procedure:
A solution of 15.1 g (47.1 mmol) of (E)-6-(1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid (mycophenolic acid) and 0.7 g (3.7 mmol) of p-toluenesulfonic acid in 400 ml of methanol was allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase was further washed with brine and then dried over sodium sulfate. Concentration of the organic phase under reduced pressure gave 15.4 g (46.0 mmol, 98%) of methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 104°-105° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-])=O.[CH3:15][NH:16][CH3:17]>C(O)C>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][N:16]([CH3:17])[CH3:15])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-nitro-phenoxymethyl)-oxirane (0.2 g, 1 mmol) in 2 mL of ethanol was added a solution of dimethylamine (2 M in methanol, 2.5 mL). The solution was stirred at 80° C. for 2 hours in a capped vial. The solvent was removed in vacuo. Hydrogenation of the residue using the procedure described in Example 1(f) gave the title compound as a brown solid. 1H NMR (300 MHz, CD3OD) δ (ppm): 6.76 (m, 2H), 6.71 (m, 2H), 4.20 (m, 1H), 3.88 (d, 2H), 3.04 (m, 2H), 2.71 (s, 6H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH3:36])[C:14]([N:16]([CH2:26][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[S:30][CH:31]=1)[C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[O:15]>>[S:30]1[CH:31]=[C:27]([CH2:26][N:16]([C@@H:17]([CH3:25])[CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH3:36])[C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 67 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.