Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCI)OCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 6.92 g of N-benzyloxycarbonyl-2-iodo-ethylamine, 4.00 g of 1-benzylpiperazine, 15.66 g of potassium carbonate and 40 ml of hexamethylphosphoramide (HMPA) was stirred at room temperature for overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) to give 5.63 g of N-benzyloxycarbonyl-2-(4-benzylpiperazin-1-yl)ethylamine (yield: 70%, oily product, IR: 3230, 2910, 1710 cm-).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:8])[NH:4][N:3]=1.O1CCOCC1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.ClCCl>CC(N(C)C)=O.Cl>[Cl:40][CH2:39][CH2:38][CH2:37][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:1][C:2]3[CH:6]=[C:5]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[O:8])[NH:4][N:3]=3)=[N:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: Nc1cc(C(=O)Nc2cccc(F)c2)[nH]n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cc(C(=O)Nc4cccc(F)c4)[nH]n3)ncnc2cc1OCCCCl
Yield: 88 %

Procedure:
3-Amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (153 mg, 0.69 mmol) in dimethylacetamide (1.8 ml) and HCl in dioxane (4 M solution in dioxane, 174 μl, 0.69 mmol) was reacted with 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (200 mg, 0.69 mmol) at 90° C. for 1.5 hour. Dichloromethane (35 ml) was added to the cooled reaction mixture, and the solid recovered by filtration, washed with dichloromethane and dried to yield 3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (286 mg, 81% yield):
Reaction SMILES: O[NH:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:22]([O:26][C:27](=[O:28])[NH:29][C:30]1([C:33]([NH:2][C:3](=[O:21])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:6]=2)=[O:34])[CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: O=C(Cc1ccc(CCCCc2ccccc2)cc1)NO
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(=O)Cc2ccc(CCCCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
N-hydroxy-2-(4-(4-phenylbutyl)phenyl)acetamide 174 (1 equiv, 156 mg, 0.55 mmol) was dissolved in DMF (3 mL). 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (1.5 equiv, 166 mg, 0.83 mmol) was then added followed by the sequential addition of HOBt (1 equiv, 74 mg, 0.55 mmol) and EDC (1.5 equiv, 158 mg, 0.83 mmol). The reaction was then stirred overnight. The reaction was then partitioned between EtOAc (5 mL) and H2O (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by trituration with Et2O to afford tert-butyl-1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropylcarbamate in 166 mg (65%). LRMS: 466.5 (calc) 489.3 (MNa)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1ccc(-c2ccc3ccccc3n2)c(F)c1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
2-Chloroquinoline (1.20 g, 12.2 mmol), 2,4-difluorophenylboronic acid (2.32 g, 14.7 mmol), were added to 10 mL of ethylene glycol dimethyl ether (DME) and 12 mL of a 2 M solution of potassium carbonate. Triphenylphosphine (0.32 g, 1.2 mmol) and palladium acetate (0.069 g, 0.3 mmol) were added to the stirred reaction mixture and refluxed for 17 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and the aqueous phase was separated from the organic phase. The aqueous phase was extracted with 2×30 mL of ethyl acetate. The combined organic extracts were washed first with distilled water followed by brine. The solvent was dried over magnesium sulfate and concentrated to give 2-(2,4-difluorophenyl)quinoline (2.9 g, 98.6%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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(OCC)(=O)C>[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Brc1cccc(Br)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cccc(Br)n2)C1
Temperature: 100 °C
Yield: 38 %

Procedure:
Add 2,6-dibromopyridine (500 mg, 2.11 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (372 mg, 2.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (193 mg, 0.21 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (526 mg, 0.84 mmol), and cesium carbonate (1.37 g, 4.21 mmol) to a dry flask under nitrogen. Add degassed anhydrous toluene (10 mL) to the flask. Heat at 100° C. for one hour. Cool to room temperature and dilute with dichloromethane, filter through a pad of Celite®, concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (3S)-[1-(6-bromopyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (260 mg, 38%). 1H NMR (400 MHz, MeOH-d4) δ 7.31 (t, 1H, J=8.0 Hz), 6.66 (d, 1H, J=8.0 Hz), 6.36 (d, 1H, J=8.0 Hz), 4.22-4.16 (m, 1H), 3.68-3.64 (m, 1H), 3.56-3.49 (m, 1H), 3.47-3.41 (m, 1H), 3.26-3.22 (m, 1H), 2.26-2.18 (m, 1H), 1.98-1.90 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Br:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22](C)[CH:21]=2)=[N:11][N:10]=1>>[Br:4][C:5]1[CH:6]=[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[C:24]([C:1]([NH2:3])=[O:2])[CH:25]=3)=[N:11][N:10]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cc(Cc2nnc(Nc3cccc(Br)c3)c3ccccc23)ccn1
Reactant: NC=O
Product: NC(=O)c1cc(Cc2nnc(Nc3cccc(Br)c3)c3ccccc23)ccn1
Yield: 10.6 %

Procedure:
The procedure used for the preparation of Example 1, but replacing N-methylformamide with formamide, was used to prepare the title compound (0.059 g, 0.13 mmol, 10.6% yield) from 1-(3-bromoanilino) 4-[(2-methyl-4-pyridyl)methyl]phthalazine (for preparation see Novartis patent WO98/35958, 11.02.98). 1H-NMR (DMSO-d6) 9.31 (s, 1H), 8.58 (d, J=7.7, 1H), 8.49 (d, J=5.3, 1H), 8.35 (s, 1H), 8.13 (d, J=7.5, 1H), 8.05 (broad s, 1H), 7.89 to 7.99 (m, 4H), 7.59 (broad s, 1H), 7.53 (dd, J=5.1, 1.5, 1H), 7.29 (t, J=8.0, 1H), 7.18 (d, J=7.8, 1H), 4.68 (s, 2H); MS ES 434/436 (M+H)+ w/1Br, calc. 433; TLC (1:4:15 v/v methanol-acetone-dichloromethane) Rf=0.59.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C@:11]4([O:30][CH3:31])[C@@H:16]([CH2:17][C:4]([C:5]=23)=[CH:3]1)[N:15]([CH3:18])[CH2:14][C@H:13]([CH2:19][O:20][C:21]([C:23]1[CH:28]=[N:27][CH:26]=[C:25]([Br:29])[CH:24]=1)=[O:22])[CH2:12]4.C[Si](C)(C)[Cl:34].C1C=CC=CC=1>CC(C)=O>[Br:29][C:25]1[CH:26]=[N:27][CH:28]=[C:23]([CH:24]=1)[C:21]([O:20][CH2:19][CH:13]1[CH2:12][C@@:11]2([O:30][CH3:31])[C@@H:16]([CH2:17][C:4]3[C:5]4[C:6](=[CH:7][CH:8]=[CH:9][C:10]2=4)[N:2]([CH3:1])[C:3]=3[Cl:34])[N:15]([CH3:18])[CH2:14]1)=[O:22]
Reactant: C[Si](C)(C)Cl
Reactant: CO[C@]12C[C@@H](COC(=O)c3cncc(Br)c3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CO[C@]12CC(COC(=O)c3cncc(Br)c3)CN(C)[C@@H]1Cc1c(Cl)n(C)c3cccc2c13

Procedure:
Following the process of Example 25, 1 g of nicergoline (8-[(5-bromonicotinoyl)oxymethyl]-1,6-dimethyl-10-methoxyergoline) is reacted with 1.6 ml of trimethylchlorosilane and the obtained product is isolated by chromatography on a Kieselgel column, using a 7:3 mixture of benzene and acetone as eluant, to give the title compound in a yield of 0.65 g (0.00125 mole, 60%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:38]=[CH:37][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:38][CH:37]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccsc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccsc2)CN1C(=O)Cn1cncn1
Yield: 35 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(thien-3-ylmethyl)pyrrolidine-2-carboxamide, gave Compound 72, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thiophen-3-ylmethyl)pyrrolidine-2-carboxamide (172 mg, 35%). 1H-NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.42 (d, 2H), 7.32-7.30 (m, 1H), 7.03-6.90 (m, 8H), 5.05 (d, 1H), 4.97 (d, 1H), 4.81 (d, 1H), 3.87 (t, 1H), 3.24 (t, 1H), 3.05-2.97 (m, 1H), 2.96-2.89 (m, 1H), 2.77-2.64 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C26H24FN5O3S found 505.9 (MH+).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O)=[S:3].O.[NH2:13][NH2:14]>CO>[NH:13]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:2]([NH2:1])=[S:3])[NH2:14]
Reactant: COC(=O)CCCNC(N)=S
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CCCNC(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Methyl 4-[(aminocarbothioyl)amino]butanoate (176.24 mg; 1.00 mmol; 1.00 eq.) (prepared from methyl 3-aminobutanoate, hydrochloride salt (Fluka), following procedure D) is dissolved in MeOH (10.00 ml). Hydrazine hydrate (2.97 ml; 48.89 mmol; 48.89 eq.) is added. The reaction mixture is stirred 5 hours under refux and overnight at RT. Solvents are evaporated. The resulting oil is dissolved in MeOH and EtOH is added. A white product precipitates. It is filtrated and washed with EtOH, affording N-(4-hydrazino-4-oxobutyl)thiourea (128.5 mg; 72.91%). HPLC, Rt: 6.50 min (purity: 86.9%).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].O.[F:6][CH:7]([F:34])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:12]([C:30]([O:32][CH3:33])=[O:31])[CH:11]=1>CC(O)=O>[C:2]([N:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([F:34])[F:6])=[CH:11][C:12]=1[C:30]([O:32][CH3:33])=[O:31])[CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]1)(=[O:3])[NH2:1]
Reactant: [N-]=C=O
Reactant: COC(=O)c1cc(OCC(F)F)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(OCC(F)F)ccc1N(C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h
Yield: 95 %

Procedure:
1.95 g of potassium isocyanate in solution of 4 ml of water are added to a solution of 6.63 g of 1,1-dimethylethyl 4-{[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.3 in 40 ml of AcOH. The mixture is stirred at AT for 12 h 00. It is extracted with AcOEt and the extract is washed with a saturated K2CO3 solution and then with water. It is dried over MgSO4, filtered and evaporated under reduced pressure to give 6.95 g of the expected product.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CO[C:11](=[O:27])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:13]=1[N:22]=[CH:23]N(C)C.C(O)(=O)C>O1CCCC1.O>[OH:27][C:11]1[C:12]2[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[N:22]=[CH:23][C:7]=1[C:6]#[N:8]
Reactant: CC#N
Reactant: COC(=O)c1c(OC)ccc(OC)c1N=CN(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c2c(O)c(C#N)cnc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 12.5 ml of tetrahydrofuran at −78° C. was added 8.8 ml of 2.5M n-butyllithium in hexanes. Then 1.18 ml of acetonitrile in 25 ml of tetrahydrofuran was added dropwise. The mixture was stirred at −78° C. for 15 minutes. Then a solution of 2-(dimethylamino-methyleneamino)-3,6-dimethoxy-benzoic acid methylester in 62 ml of tetrahydrofuran was added dropwise. The mixture was stirred at −78° C. for 10 minutes, then warmed to room temperature in 15 minutes. Acetic acid (3 ml) was added, followed by 200 ml of water. The product was collected, washed with water, and dried to give 1.57 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 300-305° C.; mass spectrum (EI, m/e): M 230.0685.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:14]=2)=[CH:8][N:7]=1)(=[O:4])=[O:3]>C(O)C.[C].[Pd]>[CH3:1][S:2]([CH2:5][C:6]1[N:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:14]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(Oc2ccc(N)c(OC3CCOCC3)c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
To a solution of 2-[(methylsulfonyl)methyl]-5-[4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]pyridine (22 g) in ethanol (250 mL) was added 10% palladium carbon (2 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hr. Palladium carbon was removed, and the residue was concentrated under reduced pressure to give the title compound (20 g, yield 100%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[CH3:36][O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](Br)[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:36][O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([CH2:30][CH3:31])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:33][CH3:34])([OH:35])[CH2:1][CH3:2])=[C:7]([CH3:32])[CH:8]=3)[CH2:13][CH3:14])=[CH:20][CH:19]=2)[CH:45]=1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 140 °C
Yield: 93.1 %

Procedure:
A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 36.2 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.8 mg, 0.0146 mmol) and potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (40 to 50% ethyl acetate/hexane) to give the title compound (46.5 mg, 88%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:3](=[O:5])[CH3:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: CI
Reactant: CC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc2ccn(C)c2c1
Reaction time: 1 h

Procedure:
To a slurry of 0.26 g (6.55 mmole) of NaH (60% oil dispersion) in 10 mL of dried N,N-dimethylformamide, a solution of 6-acetylindole (1.04 g, 6.55 mmole) in 5 mL of dried N,N-dimethylformamide was added at 0°-4° C. After 15 min. stirring at the same temperature, 1.45 g (10.1 mmole) of methyl iodide was added. The new mixture was stirred at the same temperature for 1 hour, poured into ice and water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 1-(1-methyl-1H-indol-6-yl)-ethanone after chromatographic purification on a silica gel column.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:27])[NH:25][CH3:26])=[CH:20][CH:19]=2)[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[F:49].O>CN(C=O)C>[Si:3]([O:10][C@H:11]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[O:27])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[CH3:26])=[CH:22][CH:23]=2)[N:13]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: Fc1ccccc1CBr
Reactant: CNC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1F)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
NaH (6.1 mg of a 60 wt % dispersion in mineral oil, 0.153 mmol, 1 equivalent) was added to a stirred, room temperature mixture tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-[4-(methylcarbamoyl)benzyl]pyrrolidine-1-carboxylate (80 mg, 0.148 mmol) in DMF (0.74 mL), and the mixture was stirred for 10 minutes. 1-(Bromomethyl)-2-fluorobenzene (0.0281 mg, 0.148 mmol, 1 equivalent) was added and the mixture was stirred overnight. Water was then added and the mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography using silica gel (0-50% hexanes/ethyl acetate). The product was collected and concentrated in vacuo to afford the title compound (95 mg, 99%). LC-MS=669.2 (M+Na)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1.[N:30]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:5][O:6][C:7](=[O:29])[C@H:8]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][N:30]=[N:17][C:12]=2[CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1ccc2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester mono acetate (2.68 g, 6.65 mmol) in acetic acid (30 mL) and water (40 mL), at room temperature was added a solution of sodium nitrite (0.46 g, 6.65 mmol) in water (8 mL), dropwise over several minutes. The resulting mixture was stirred at room temperature for 20 min, then cooled to 0° C., concentrated ammonium hydroxide was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice in the presence of solid sodium chloride, and the organic layers were dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (6:4) as eluent to afford the title compound as a tan solid (94% yield). 1H-NMR (CD3OD, 500 MHz) δ 7.75 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.31–7.25 (m, 5H), 7.18 (d, J=8.5 Hz, 1H), 5.39 (d, J=8.0 Hz, 1H), 5.10 (d, J=12.0 Hz, 1H), 5.05 (d, J=12.0 Hz, 1H), 4.74 (dd, j=13.5, 6.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J=14.0, 5.5 Hz, 1H), 3.22 (dd, J=13.5, 6.0 Hz, 1H). 13CNMR (CD3OD, 125 MHz) δ 172.1, 156.0, 136.1, 128.6, 128.3, 128.1, 67.2, 55.2, 52.7, 38.5. Mass spec. 355.18 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>CN1CCN(C)C1=O.O1CCCC1>[C:26]([NH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CCCC(=O)Cl
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
Triethylamine (1.47 g) was added to 15 ml of a suspension containing 1.57 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 1,3-dimethyl-2-imidazolidinone, and the mixture was stirred at room temperature for 10 minutes. Then, 0.83 g of butyryl chloride dissolved in 8 ml of tetrahydrofuran was added dropwise to the mixture, and the resulting mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from ethyl acetate-methanol to obtain 1.47 g of 2-(butyrylamino)methyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.