Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:23]4[C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][CH2:24]4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:23]4[C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][CH2:24]4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N4CNc5ncccc54)cc23)CC1
Solvent: ClCCl
Product: c1cnc2c(c1)N(c1ccc3[nH]cc(C4CCNCC4)c3c1)CN2
Yield: 100 %

Procedure:
1-[3-(N-t-Butoxycarbonylpiperid-4-yl)indol-5-yl]-3H-imidazo[4,5-b]pyridine was used, and methylene chloride was used as the solvent. Filtration afforded the title compound (100%) as a yellow solid: mp 260°-268° C. with effervescence; 13C NMR (CD3OD) δ 149.7, 145.6, 144.0, 138.5, 127.7, 126.0, 125.8, 125.5, 124.6, 123.9, 120.6, 119.7, 117.4, 113.7, 45.7, 32.6, 30.7; FAB LRMS (m/z, relative intensity) 318 (M+, 22), 277 (12), 261 (4), 235 (5), 185 (100).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:3]=1[CH:4]=O.[NH2:16][C:17](N)=[O:18]>O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[C:3]2[C:2]=1[N:1]=[C:17]([OH:18])[N:16]=[CH:4]2
Reactant: NC(N)=O
Reactant: COc1ccc(C(F)(F)F)c(C=O)c1N
Solvent: O
Product: COc1ccc(C(F)(F)F)c2cnc(O)nc12
Temperature: 175 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 2-amino-3-methoxy-6-(trifluoromethyl)benzaldehyde (1 eq) (obtained from step 7) and urea (15 equiv.) was heated to 175° C. with vigorous stirring for 2 h. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol as yellow solid in 70% yield. ES/MS m/z 245.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:24])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN(C)S(=O)(=O)c1ccc(Br)s1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 71) (210 mg) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (32 mg). After stirring for 45 minutes, methyl iodide (100 μL) was added. Water was added, the solution was extracted with ethyl acetate. After washing the organic layer with saturated sodium chloride water, and then was dried with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (110 mg) was obtained as a colorless oily matter.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>[Pd].O>[CH2:11]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A mixture of 74.5 g (0.5 mol) of L-glutamic acid, 54 g (0.5 mol) of benzaldehyde, 41 g (1.0 mol) of sodium hydroxide, and 1 liter of water was stirred at room temperature for 3 hours. A 5 g portion of 10% palladium on carbon catalyst was added and the mixture hydrogenated for 83 minutes at 51 psig. The catalyst was filtered and the pH of the filtrate was adjusted to 4.2 with 1 N HCl. The solids were filtered, washed with water and dried to give 55.1 g of N-benzyl-L-glutamic acid mp 151°-153° dec., [α]D23 +16° (c4, 1 N HCl). (c 4.1, 1 N HCl). Concentration of the filtrate gave a second crop of 24.9 g, mp 157°-158° dec., [α]D23 +16° (c 4, 1 N HCl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].[NH2:10][CH2:11][CH2:12][OH:13].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:10][CH2:11][CH2:12][OH:13])=[CH:4][C:3]=1[CH3:9]
Reactant: NCCO
Reactant: Cc1cc(I)ccc1Br
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(NCCO)ccc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A mixture of 2-bromo-5-iodotoluene (1.60 g, 5.40 mmol), 2-aminoethanol (0.49 mL, 8.14 mmol), CuI (53.3 mg, 0.28 mmol), L-proline (63.4 mg, 0.55 mmol) and K2CO3 (1.49 g, 10.8 mmol) in DMSO (3.24 mL) was stirred at 60° C. for 12 hours. The reaction mixture was cooled and then diluted with AcOEt, and the organic layer was sequentially washed with H2O and saturated brine. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/AcOEt=1/1) to give 2-(4-bromo-3-methyl-phenylamino)-ethanol as a brown solid (1.00 g, 81%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(B(O)O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:23]2[C:24]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:20]=[CH:21][CH:22]=2)[CH:11]=1)([O-:14])=[O:13]
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1cccc2ccccc12

Procedure:
Methyl 2-bromo-4-nitrobenzoate (3.86 g, 14.85 mmol) was coupled with 1-naphthylboronic acid (3.06 g, 17.79 mmol) in DMF in the presence of K2CO3 (3.0 eq) and Pd(PPh3)4 (0.03 eq) at 110° C. for 15 hrs. After flash column chromotography purification, the desired compound was obtained as a pale yellow oil (3.86 g, yield 85%). 1H NMR (CDCl3) δ 8.34 (d, J=8.5 Hz, 1H), 8.28 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.92 (m, 2H), 7.47-7.56 (m, 2H), 7.41 (d, J=3.8 Hz, 2H), 7.34 (d, J=6.8 Hz, 1H), 3.40 (s, 3H); 13C NMR (CDCl3) δ 166.4, 149.2, 142.7, 137.2, 136.8, 133.2, 131.3, 131.0, 128.6, 128.4, 126.6, 126.2, 126.0, 125.0, 124.7, 122.3, 52.3.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(O)(O)=O>CC#N.O>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([F:26])([F:25])[F:14])[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 13.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (1.1209 g, 5.261 mmol), 2-(trifluoromethyl)phenylboronic acid (1.099 g, 5.787 mmol), tetrakis(triphenyl-phosphine)palladium (0.3040 g, 0.2630 mmol), and sodium carbonate anhydrous (2.788 g, 26.30 mmol) in 53 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 13.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 20 min as eluent to give 5-chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline as a red solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1H, dd, J=8.4, 1.4 Hz), 8.02 (1H, dd, J=7.6, 1.2 Hz), 7.98 (1H, d, J=7.8 Hz), 7.73-7.92 (4H, m), 2.47 (3H, s); LC-MS (ESI) m/z 323.0 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1>CC(C)=O.C([O-])(=O)C.[NH4+]>[CH3:22][S:19]([NH:18][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([B:4]([OH:5])[OH:3])=[CH:10][CH:11]=2)[CH2:17][CH2:16]1)(=[O:20])=[O:21]
Reactant: CC1(C)OB(c2ccc(C3(NS(C)(=O)=O)CC3)cc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CS(=O)(=O)NC1(c2ccc(B(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 810 mg (2.40 mmol) of the compound obtained in Step C and 1.95 g (9.12 mmol) of NaIO4 in a mixture of 25 ml of acetone and 7 ml of 1M aqueous ammonium acetate solution is stirred for 24 hours at ambient temperature. The solid is filtered off and rinsed with copious amounts of acetone. The filtrate is concentrated by half and the residual solution is extracted with AcOEt. The organic phase is washed (saturated NaCl solution) and dried (MgSO4) to yield, after evaporation in vacuo, the title compound.
Reaction SMILES: [Si]([O:18][C:19]1[CH:63]=[CH:62][C:22]([O:23][CH2:24][C@@H:25]([OH:61])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:60]=[CH:59][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51])=[CH:45][CH:44]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:53]([NH:52][C:50]([NH:49][C:46]1[CH:45]=[CH:44][C:43]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:59]=[CH:60][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:61])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:63][CH:62]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:48][CH:47]=1)=[O:51])[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 50 %

Procedure:
N-[4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)phenyl]-N′-hexylurea (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.06 g, 0.09 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[CH:7]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)c1

Procedure:
The 4-methyl-2′-(3-nitro-phenyl)-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl was prepared from 2′-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.94) (1.25 g, 3.6 mmol) and commercially available 3-nitrophenylboronic acid (0.718 g, 4.3 mmol) according to the general procedure VI. Obtained as a light brown solid (1.03 g, 66%). MS (ISP) 436.1 [(M+H)+]; mp 91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1.C(Cl)(Cl)Cl.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([O:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])[C:7]=2[N:20]=1
Reactant: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)c(CC[N+](=O)[O-])c1n2CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and in an anhydrous medium, 340 mg (1.23 mmol) of the compound obtained in Step H are suspended in 7 ml of isopropanol and 21 ml of chloroform in the presence of 810 mg of 230-400 mesh silica; 234 mg (6.18 mmol) of sodium borohydride are added slowly. After 2 hours' stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered, concentrated and purified by flash chromatography over silica gel (eluant: ethyl acetate/petroleum ether, 6:4) to yield the title compound in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)C>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A degassed mixture of 2-amino-5-bromopyridine (3.5 g, 20.23 mmol), 6-methoxypyridin-3-ylboronic acid (3.71 g, 24.28 mmol) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (413 mg, 0.51 mmol) in 1,4-dioxane (36 mL) and a 2M aqueous potassium carbonate solution (36.4 mL) was heated at 90° C. under a nitrogen atmosphere for approximately 16 h. The reaction mixture was allowed to cool to room temperature and diluted with diethyl ether (100 mL). The organic phase was separated off, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with DCM (10 mL) and filtered, to afford the title compound (3.36 g, 83%) as a light brown solid. Method C LCMS: MH+ m/z 202, RT 0.60 minutes.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:19]1([PH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:5]=[C:4]1[CH2:3][CH:2]([CH2:1][P:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:6]1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C1CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1CC(CP(c2ccccc2)c2ccccc2)O1
Temperature: 85 °C

Procedure:
A mixture of 2.1 parts of diketene and 0.4 parts of azobisisobutyronitrile were added dropwise over 15 minutes to 18.6 parts of diphenylphosphine which was stirred and heated at 85° C. in a nitrogen atmosphere. After the addition, the reaction mixture was heated for a further 5 minutes at 85° C., then cooled to room temperature. The excess diphenylphosphine and volatile impurities were removed by distillation on a wiped wall still at a wall temperature of 85° C. and a pressure of 0.04 mb, then the residue was distilled in the wiped wall still at 120° C. and a pressure of 0.013 mb. The product, (2-oxo-4-oxetanylmethyl)-diphenylphosphine, was obtained as a colourless oil and had an absorption at 1825 cm-1 in the infra-red spectrum, characteristic of a β-lactone.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:14]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:12]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:12]=[C:11]([NH2:10])[CH:16]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCCC(=O)OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(OCCCCC(=O)OC)c1
Yield: 97.2 %

Procedure:
A mixture of 8.9 g of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenylcarbamic acid phenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 6.8 g (97% yield, mp 57°-59°) of 5-[3-amino-5-(octadecyloxy) phenoxy]pentanoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([CH2:23][CH2:24][CH2:25][NH2:26])[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[I-:27].[Na+].CN(C)[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu](I)I>[I:27][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([CH2:23][CH2:24][CH2:25][NH2:26])[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: NCCCc1nc(N2CCN(c3ccc(Br)cc3)CC2)nc2c1SCC2
Agent: I[Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: C1COCCO1
Product: NCCCc1nc(N2CCN(c3ccc(I)cc3)CC2)nc2c1SCC2
Temperature: 140 °C
Yield: 98.1 %

Procedure:
1.55 g (3.6 mmol) of {2-[4-(4-bromophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine (VII), 1.1 g (7.2 mmol) of sodium iodide, and 0.036 g (0.19 mmol) of copper iodide are taken, and under an argon atmosphere 0.060 mL (0.38 mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine and 7 mL of anhydrous/degassed dioxane are added. The reaction mixture is heated for 1.5 hours at 140° C. in the microwave, then diluted with dioxane, and suction filtered through Alox. The dioxane was concentrated by evaporation. 1.70 g of product VIII (81%) is obtained as a powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.CS([Cl:28])(=O)=O.CO>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@@H:14]([Cl:28])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOP(=O)(CO[C@@H]1C=C[C@H](Cl)C1)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (220 mg, 0.88 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to 0° C. under nitrogen. Triethylamine (192 mg, 192 mmol) was added followed by methanesulphonyl chloride (220 mg, 192 mmol) and the reaction mixture leftto stir for 0.5 hrs at 0° C. The reaction mixture was allowed to warm to room temperature and MeOH was added. The aqueous solution was diluted with CH2Cl2 (10 mL) and washed with water, saturated NaHCO3 and brine. The solution was dried (MgSO4), filtered, concentrated and then purified by flash column chromatography with 5% MeOH/95% CH2Cl2 (144 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][N:18]([C@@H](C2C=CC=CC=2)C)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC[C@@H](C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(c1ccccc1)[C@@H]1CCNC1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
To an ethanol (20 ml) solution of 3-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine [F1] (495 mg, 1.30 mmol) was added a 10% palladium-carbon catalyst (water content 53.8%, 500 mg) and catalytic hydrogenation was carried out under heating at an outer temperature of 50° C. at normal pressure for 4 hours. The reaction solution was filtered and the solvent was removed under reduced pressure to obtain a crude product of the title compound (359 mg, quantitative) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14].[N+:16]([O-])([OH:18])=[O:17].O>S(=O)(=O)(O)O>[N+:16]([C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([Cl:15])=[C:5]2[C:10]=1[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH3:14])([O-:18])=[O:17]
Reactant: COc1ccc2[nH]c(=O)cc(C)c2c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c2[nH]c(=O)cc(C)c2c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 200 ml, three-necked round bottom flask equipped with a mechanical stirrer, thermowatch, and addition funnel was placed 96% sulfuric acid (50 ml) and 6-methoxy-5-chloro-4-methyl-2-quinolone (10) (12.0 g, 53.66 mmoles). This was cooled to 0° C., then a solution of 70% nitric acid(6.04 g, 67.1 mmoles) in 96% sulfuric acid (10 ml) was added dropwise over 35 minutes. The mixture was stirred for 90 minutes at 0° C., then poured into 350 ml of water. The crude orange-brown solid was collected by suction filtration, washed with water (three×20 ml) and air dried. Crude yield is 10.82 g.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([OH:15])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCCCN(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCCCN(CC2CC2)C1=O

Procedure:
A solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-1,3-diazepan-1-yl]acetate (240 mg, 0.85 mmol) in CH2Cl2 (5 mL) and CF3CO2H (2 mL) was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a clear oil. MS: m/z=227 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1)(=[O:3])[CH3:2].NC1C=CC(C(O)=O)=CN=1.CN1CCOCC1.ClC(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)cn1
Agent: CCOC(=O)Cl
Agent: Nc1ccc(C(=O)O)cn1
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)Nc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
A solution of 219 mg (1.22 mmol) of 6-(acetylamino)nicotinic acid [preparable from 6-aminonicotinic acid according to A. Zafar et al., Tetrahedron 56, 8419-8428 (2000)] in 25.4 ml of dry THF is cooled to −10° C., and 123 mg (1.22 mmol) of 4-methylmorpholine and 132 mg (1.22 mmol) of ethyl chloroformate are added dropwise with stirring. The reaction solution is stirred at −10° C. for 30 min 2.44 ml (2.44 mmol) of a 1 M solution of lithium aluminium hydride and THF are then added dropwise. The reaction mixture is stirred for 8 h and slowly warmed to RT during this time. The reaction solution is then cooled to 0° C., 0.4 ml of water and 0.8 ml of 1 N aqueous sodium hydroxide solution are added carefully and, after warming to RT, the mixture is stirred at this temperature for 8 h. The mixture is filtered and the filtrate is concentrated on a rotary evaporator. The crude product that remains is used for the subsequent reaction without further purification.