Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1.[Li+].C[Si]([N-:28][Si](C)(C)C)(C)C.Cl>C1COCC1.O>[NH2:28][C:2]1[N:6]=[C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:22])[C:11]3[CH:15]([CH2:16][C:17]([OH:19])=[O:18])[O:14][B:13]([OH:20])[C:12]=3[CH:21]=2)[S:4][N:3]=1
Reactant: Cc1cc(Oc2nc(Cl)ns2)cc2c1C(CC(=O)O)OB2O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nc(N)ns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (100 mg, 0.27 mmol) in THF (1.5 mL) was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol). The resulting solution was stirred at room temperature for overnight. LC-MS showed still half starting material left. The mixture was added LHMDS (1M in Hexanes, 0.54 mL, 0.54 mmol) again. After 3 hours, the mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give title compound (30 mg, 40%) as a white solid. 1H NMR (CD3OD) δ7.38 (d, 1H), 7.26 (d, 1H), 5.66 (dd, 1H), 3.16 (dd, 1H), 2.39 (s, 3H), 2.34 (dd, 1H). MS found: (M+H)+: 322.
Reaction SMILES: [CH2:1]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)(Cl)=O.CN(C)[CH:21]=[O:22]>>[CH2:1]([C:9]1[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C=O
Reactant: CCCCCCCCc1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCc1ccc(C=O)s1

Procedure:
To a stirred solution of 80.1 g. of 2-octylthiophene in 70 ml. dimethylformamide is added dropwise 42.4 ml. of phosphorus oxychloride. After addition, the solution is made warmed at 100° for 1 hour, then poured into 600 ml. ice. After neutralization with sodium acetate, the resulting oil is extracted with ether. The ether is washed with water and aqueous potassium carbonate, dried, and distilled in vacuo to give the title compound as an oil.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([NH2:18])=[CH:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:19]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:20]=[O:21]>>[C:2]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([NH:18][C:20]([NH:19][C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=2)=[O:21])=[CH:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ncc(N)c(-c2ccccc2)n1
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Product: CC(C)(C)c1ncc(NC(=O)Nc2cccc(Oc3ccccc3)c2)c(-c2ccccc2)n1
Yield: 25.3 %

Procedure:
Using general method A, 2-t-butyl-4-phenylpyrimidin-5-amine hydrochloride (100 mg, 0.379 mmol, available from Example 279) and 1-(3-isocyanatophenoxy)benzene (88 mg, 0.417 mmol) were combined to yield 1-(2-t-butyl-4-phenylpyrimidin-5-yl)-3-(3-phenoxyphenyl)urea (42 mg, 25% yield). 1H NMR (DMSO-d6): δ 1.38 (s, 9H), 6.61-6.63 (m, 1H), 7.01-7.56 (m, 1H), 7.73-7.75 (m, 2H), 8.10 (s, 1H), 9.02 (s, 1H), 9.19 (s, 1H). LC-MS (EI) m/z: 439.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:29]([CH2:28][CH2:27][O:26][CH3:25])[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Reactant: COCCC(=O)Cl
Product: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(6-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C. The crude product obtained in Part D was recrystallized from acetonitrile. The crystals were washed with cold acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[C:9]([O:21][CH3:22])[CH:8]=2)[O:3]1.O.[NH2:24][NH2:25]>CO>[O:1]=[C:2]1[NH:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:24][N:25]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)[O:3]1
Reactant: NN
Reactant: COc1cc(C2CNC(=O)O2)ccc1C(=O)C(C)CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(C2CNC(=O)O2)ccc1C1=NNC(=O)CC1C

Procedure:
5.9 g (0.019 mole) of 4-(4-(2-oxo-oxazolidin-5-yl)-methoxyphenyl)-4-oxo-3-methyl-butyric acid and 1.5 ml (0.031 mole) of hydrazine hydrate are heated under reflux in 30 ml of methanol for 1 hour.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39](O)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:73]([NH2:79])[C@H:74]1[O:78][CH2:77][CH2:76][CH2:75]1>C(Cl)Cl.CCOCC>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:79][CH2:73][C@H:74]4[CH2:75][CH2:76][CH2:77][O:78]4)=[O:40])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC[C@@H]1CCCO1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(NC[C@H]1CCCO1)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Yield: 71.8 %

Procedure:
13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-N-[[(2S)-tetrahydro-2-furanyl]methyl-7H-indolo[2,1-a[2]benzazepine-10-carboxamide. A solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol), N,N-diisopropylethylamine (60 μL, 0.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), 1-hydroxybenzotriazole (14 mg, 0.1 mmol), and (S)-(+)-tetrahydrofurfurylamine (10 mg, 0.1 mmol) in CH2Cl2 (1.5 mL) was stirred at r.t. overnight, diluted with CH2Cl2 (5 mL), and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to afford a yellow oil. Et2O (5 mL) was added to dissolve the oil, and concentration afforded the title compound as an off-white solid (32 mg, 72% yield). LC/MS (ESI) retention time: 1.73 min, m/z 637 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.27-1.43 (m, 3 H) 1.47-1.57 (m, 1 H) 1.58-1.70 (m, 2 H) 1.70-1.81 (m, 2 H) 1.86-1.97 (m, 3 H) 1.98-2.12 (m, 4 H) 2.25-2.35 (m, 1 H) 2.42 (s, 3 H) 2.63-2.77 (m, 1 H) 2.78-2.89 (m, 1 H) 3.29-3.46 (m, 1 H) 3.65 (s, 4 H) 3.74-3.85 (m, 2 H) 3.85-3.98 (m, 1 H) 4.09 (ddd, J=14.16, 7.11, 3.40 Hz, 1 H) 4.39 (s, 1 H) 5.08 (s, 1 H) 6.67-6.75 (m, 1 H) 6.82 (s, 1 H) 7.34-7.39 (m, 1 H) 7.40-7.50 (m, 3 H) 7.52-7.59 (m, 1 H) 7.86 (d, J=8.56 Hz, 1 H) 7.99 (s, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=S)[NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)[CH3:2].IC.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]1[N:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8](=[O:10])[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)[CH3:18]
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Solvent: CO
Solvent: CI
Product: CCN(CC)c1nc2ccccc2c(=O)n1NC(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 13.5 %

Procedure:
Methyl 2-(3,3-diethyl-thioureido)benzoate (0.500 g, 1.88 mmol) was dissolved in methanol (10 mL), followed by addition of iodomethane (234 μL, 3.75 mmol). The reaction mixture was heated at 80° C. for 10 minutes under microwave conditions making sure the temperature did not exceed 80° C. The reaction mixture was evaporated to dryness and then redissolved in ethanol (20 mL), followed by addition of phenylacetic acid hydrazide (0.367 g, 2.44 mmol). The mixture was stirred for 48 h at reflux. After cooling the mixture was filtered and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (EtOAc/Heptane) giving the title compound (0.089 g, 14%). LC-ESI-HRMS of [M+H]+ shows 351,1818 Da. Calc. 351,182101 Da.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc(Br)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-(4-bromobenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[ClH:14]>O.S>[Cl:14][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cl
Reactant: Cc1ccnc(O)c1N
Agent: O=N[O-]
Agent: S
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(O)c1Cl

Procedure:
A solution sodium nitrite (2.38 g) in water (10 ml) was added dropwise to a stirred mixture of 3-amino-2-hydroxy-methylpyridine (4.8 g) in aqueous hydrochloric acid (48% 10 ml) and water (5 ml) at 0°-5° C. This solution of the diazonium salt was added to a hot solution of cuprous chloride (2.5 g) in conc. hydrochloric acid and following cessation of nitrogen evolution the mixture was heated on the steam bath for 0.5 hours, diluted with water and saturated with hydrogen sulphide. Filtration, concentration to low bulk and extraction with chloroform yielded 3-chloro-2-hydroxy-methyl-pyridine (3.7 g), m.p. 42°-44° (from n-pentane). This was dissolved in aqueous hydrobromic acid (48%, 50 ml), cysteamine hydrochloride (3.22 g) added and the solution obtained was heated under reflux for 6 hours. Concentration, followed by recrystallisation from aqueous ethanol afforded 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine dihydrobromide (6.0 g), m.p. 250°.
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@@H:5]2[CH2:1][C@@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The mixture was stirred for 10 min. Quinine (10.87 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×200 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.95 g, 30.3 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.31 (1H, d, J=8.5 Hz), 1.98 (1H, d, J=8.6 Hz), 2.51 (2H, d, J=1.6 Hz), 2.95 (2H, bs), 3.52 (3H, s), 6.17-6.21 (2H, m), 12.16 (1H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]CO)=[C:35]([N+:42]([O-:44])=[O:43])[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:20][Cl:24])=[C:35]([N+:42]([O-:44])=[O:43])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCCl
Reaction time: 8 h
Yield: 97 %

Procedure:
Triphenylphosphine (1.98 g, 7.55 mmol), CCl4 (2.18 mL, 22.62 mmol), and dry CH2Cl2 (13.7 mL) were added to 2-(4-benzyloxy-2-nitrophenyl)ethanol (1.03 g, 3.77 mmol) in a round bottom flask. A red solution with pink precipitate formed, but dissolved after 30 min. The solution was allowed to stir overnight under positive pressure of nitrogen. The solution was checked by TLC (20% ethyl acetate/petroleum ether) and then concentrated using a rotoevaporator. The brown oily residue was purified using silica gel column chromatography and a 10% ethyl acetate, 5% CHCl3, and 85% petroleum ether solvent system. 2-(4-Benzyloxy-2-nitrophenyl)ethyl chloride was isolated as a thick yellowish oil which solidified upon standing in the refrigerator (1.06 g, 3.64 mmol, 97% yield). Mp 38-40° C.; TLC (20% ethyl acetate/hexane) Rf=0.53; 1H-NMR (500 MHz, CDCl3) 7.51 (d, 2.5, 1H), 7.33 (m, 5H), 7.23 (d, 8.5, 1H), 7.10 (dd, 2.5, 8.5, 1H), 5.02 (s, 2H), 3.70 (t, 7.0, 2H), 3.20 (t, 7.0, 2H); 13C-NMR (125 MHz, CDCl3) 158.1, 149.5, 135.7, 143.0, 128.7, 128.4, 127.5, 125.1, 120.4, 110.7, 70.6, 44.0, 35.8; IR (neat) 3092, 3038, 2962, 2919, 2865, 1618, 1570, 1532, 1499, 1451, 1343, 1294, 1197, 1160, 1062, 1019, 906, 847, 809, 739, 696, 652; EI-MS m/z (relative intensity) 291 (M+, 10); isotope pattern of M+ and M++2 agrees with the presence of one chlorine atom. Accurate mass (EI-MS) for C15H1435ClNO3: calcd. 291.0662, obsd. 291.0667.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1(B(O)O)[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]1[C:19]3[C:28]4=[C:27]5[C:16](=[CH:17][CH:18]=3)[CH:15]=[CH:14][CH:13]=[C:26]5[CH:25]=[CH:24][C:23]4=[CH:22][CH:21]=1)[CH:11]=[CH:10]2
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 12.1 g (42.4 mmol) of 2,6-dibromonaphthalene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified, by column chromatography on silica (hexane-dichloromethane) to give product 8.3 g (48%) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[H][H]>O=[Pt]=O.CC(O)=O>[CH3:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH:8]1[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccncc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Temperature: 25 °C

Procedure:
AcOH (380 mL) was added to 4-methylnicotinic acid hydrochloride (50.5 g, 291 mmol, Maybridge) and PtO2 (5.05 g, 22.2 mmol, Johnson Matthey) in a 600 mL stainless steel reactor. The mixture was stirred under 220 psi of hydrogen at ambient temperature for about 14 hr. The supernatant solution was filtered through a nylon membrane and rinsed with enough AcOH until only the catalyst remained. The filtrate was concd under reduced pressure to give a clear oil that solidified upon cooling to ambient temperature to give crude 4-methylpiperidine-3-carboxylic acid with AcOH as an excipient (88.94 g, 170% crude): LC/MS (Table 1, Method b) Rt=0.44 min; MS m/z: 144 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:22][OH:23].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:22][OH:23])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=NO)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
To a solution of 1.0 g of tert-butyl (S)—N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate and 239 mg of hydroxylamine hydrochloride in 5 ml of ethanol, 272 mg of pyridine was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 10 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 40:60) as the eluent to obtain 740 mg of the desired product as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:7]([C:11]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:7]([C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OCC(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CCCCc1nc(Cl)c(C(=O)OCC(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Ethoxy-2-oxoethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (1130 mg, 1.48 mmol) was dissolved in concentrated hydrochloric acid (24 mL). The solution was stirred at 100° C. for 30 minutes. The solution was washed with diethyl ether (2×) and the aqueous layer was concentrated in vacuo. The residue was used crude in the following step. LC-MS: m/z 495.0 (M+H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH3:20])[C:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:21][CH:22]([N:24]=[C:25]=[O:26])C.CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:21][CH2:22][NH:24][C:25](=[O:26])[O:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([N:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH3:20])=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: CC(C)N=C=O
Reactant: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNC(=O)Oc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Yield: 43.4 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]methylamino]-1,2-benzisoxazol-6-ol (2.2 g) and copper(I)chloride (0.1 g) in EtOAc (50 ml) was added 1-methylethylisocyanate (0.8 g). After 24 hours TLC (silica gel, 10% MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (3 l) and the filtrate was concentrated in vacuo. The white solid was flash chromatographed on silica gel eluting with 1% MeOH/DCM to yield 1.2 g of the product, m.p. 99°-100° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([C:15]([CH3:17])=O)[C:9]([O:11][CH2:12][CH2:13][Br:14])=[O:10])([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:29])=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH3:29][C:22]1[NH:21][C:15]([CH3:17])=[C:8]([C:9]([O:11][CH2:12][CH2:13][Br:14])=[O:10])[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
58.8 g of 2-bromoethyl 2-(3-nitrobenzylidene)-acetoacetate and 22.5 g of ethyl 3-aminocrotonate in 250 ml of tetrahydrofuran are heated at the boil for 3 h. The mixture is stirred for 8 h at room temperature, after which the solvent is distilled off in vacuo and the solid residue is dissolved in hot 2-propanol. The title compound crystallises out on cooling. It is filtered off under suction, washed with cold 2-propanol and dried. 65 g of product of m.p. 158°-159° C. are obtained.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:46])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:25][CH:24]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[C:42]([O:41][C:39]([CH:24]1[CH2:25][CH:26]([S:35]([CH3:38])(=[O:36])=[O:37])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:46])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)C1CC(S(C)(=O)=O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CC(S(C)(=O)=O)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 81.9 %

Procedure:
A The process is performed as in Example 2A, but starting with 3.4 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-methylsulphonyl-2-pyrrolidinecarboxylate, 0.3 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 2.4 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-methylsulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.3; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 1.53 (s, 9H: C(CH3)3); from 2.45 to 2.88 (2 mts, 1H each: CH2 at 3); 3.10 (s, 3H: SO2CH3); 3.70 and 4.02 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 3.96 (mt, 1H: H4); 4.67 (t, J=8 Hz, 1H: H2); 5.83 (d, J=3 Hz, 1H: H5); from 7.10 to 7.65 (mt, 6H: aromatic H); 7.92 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 7.98 (t, J=1.5 Hz, 1H: aromatic H (H2 ortho to the COOH))].