Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([OH:25])=[O:24].O.Cl>[Cu]Br.O.COCCOCCOC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][C:23]([OH:25])=[O:24])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccccc1Cl
Agent: [Cu]Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCOC
Product: O=C(O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 176.4 %

Procedure:
A mixture of 552.0 g (4.0 mol) of potassium carbonate and 1500 mL of diglyme was kept at 0-20° C. while adding 283.1 g (2.2 mol) of 4-chlorophenol thereto and mixing, and then 5.74 g (0.04 mol) of copper(I) bromide was added. The obtained mixture was heated to 100° C., and 90.3 g (0.53 mol) of 2-chlorophenylacetic acid was added. This mixture was stirred at the same temperature for 1 hour, and then 159.4 g (0.93 mol) of 2-chlorophenylacetic acid was further added. After stirring the obtained mixture at 120-130° C. for approximately 8 hours, completion of the reaction was confirmed by high-performance liquid chromatography. The reacted mixture was cooled to near room temperature, and then approximately 700 mL of water and approximately 650 mL of 35 wt % hydrochloric acid water were added in that order. The pH of the aqueous layer was below 1. After further adding about 500 mL of water to the obtained mixture, it was extracted once with 400 mL and once with 200 mL of toluene, in that order. The obtained organic layers were combined and washed 3 times with 500 mL of water and once with 500 mL of brine, in that order. The obtained organic layer was subjected to dehydration treatment with anhydrous magnesium sulfate, and 100 mL of heptane was added dropwise to approximately 400 g of the residue obtained by partially concentrating the treated organic layer. The internal temperature of the mixture after the dropwise addition was about 70° C., and crystals precipitated in the mixture. Upon completion of the dropwise addition, the mixture was cooled to 20-25° C. and the crystals were separated off by filtration. The obtained crystals were washed with 100 mL of a heptane/toluene=1/1 mixed solvent and dried under reduced pressure to obtain 245.6 g of 2-(2-(4-chlorophenoxy)phenyl)acetic acid as a white solid. The yield was 68.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([C:18]3[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=3)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:35]([F:38])([F:37])[F:36])=[N:9]1.C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:17][C:16]([C:18]3[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=3)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([OH:25])=[O:24])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:35]([F:38])([F:36])[F:37])=[N:9]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)c1
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)(Oc1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)s2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To a solution of tert-butyl 2-(3-(5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl)phenoxy)-2-methylpropanoate (47 mg, 84 μmol) in dichloromethane (0.5 mL) was added formic acid (1.0 mL). The resulting pale orange solution was allowed to stir at ambient temperature. After 5 hours at ambient temperature, LC/MS analysis of the reaction showed ˜5% of the starting ester remaining. After 7 hours stirring at ambient temperature the reaction mixture was concentrated under reduced pressure to afford crude product. This material was purified by flash column chromatography eluting with a gradient from CH2Cl2 to 10% MeOH/CH2Cl2 to afford 2-(3-(5-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-yl)phenoxy)-2-methylpropanoic acid (21.7 mg, 51% yield) as an off white foam. MS(ES): 509 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](OB(C2C=CC=CC=2)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: COc1ccc(OB(O)c2ccccc2)cn1
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, off-white solid (68 mg, 80%), MS (ISP) m/z=342.5 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 6-methoxy-pyridin-3-ylphenylboronic acid (49.7 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[CH:14][C:3]=12.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+]>CO>[C:15]1([N:21]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH:14]=[CH:13][NH:12][C:4]=4[NH:5][CH:6]=3)=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cnc2[nH]ccc2c1Cl
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Temperature: 90 °C

Procedure:
A suspension of 1 equivalent of compound 15 and 10 equivalents of phenyl hydrazine was heated to 90° C. for 16 hours. Water was added to the reaction mixture at room temperature and decanted to remove the excess phenyl hydrazine. The crude reaction mixture was dissolved in MeOH and 0.1 N NaOH (2:1, 0.033 M) and stirred for 3.5 hours before concentrating to dryness. Purification by column chromatography afforded the title compound 16 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.43-6.72 (m, 1H) 7.04-7.28 (m, 1H) 7.37-7.56 (m, 4H) 7.84-8.13 (m, 2H) 8.33-8.55 (m, 1H) 11.99 (s, 1H).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:93][C:94](O)=[O:95])[CH2:92][CH2:91][O:90][CH2:89][CH2:88]1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][N:87]1[CH2:92][CH2:91][O:90][CH2:89][CH2:88]1)[CH2:19][CH2:18]2
Reactant: O=C(O)CN1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except morpholin-4-yl-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 657.6 (M+H)+, 2.20 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.91 (d, J=7.9 Hz, 2H), 7.48 (br. s., 1H), 7.19 (d, J=8.2 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 4.77 (br. s., 1H), 4.12-3.79 (m, 6H), 3.57-3.40 (m, 2H), 3.22-3.11 (m, 1H), 2.74 (br. s., 1H), 2.65 (d, J=12.8 Hz, 1H), 2.42-2.29 (m, 1H), 2.12 (dd, J=6.1, 17.1 Hz, 1H), 2.03-1.85 (m, 2H), 1.79 (d, J=12.8 Hz, 1H), 1.72 (br. s., 1H), 1.71 (s, 3H), 1.69 (br. s., 1H), 1.60-1.30 (m, 12H), 1.24 (d, J=5.8 Hz, 1H), 1.14 (br. s., 1H), 1.10 (br. s., 4H), 1.02 (br. s., 3H), 1.00 (br. s., 3H), 0.93 (br. s., 3H), 0.92 (br. s., 3H).
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18].N([O-])=O.[Na+].S([O-])([O-])(=O)=O.[Mg+2].[O:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1.O.O.O.C([O-])(=O)C.[Na+]>O.Cl>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]2[OH:18]
Reactant: c1ccoc1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCOC(=O)c1nnc2ccc(-c3ccco3)cc2c1O
Temperature: 0 °C

Procedure:
A suspension of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate hydrochloride (1.164 g.) in water (10 ml.) and concentrated hydrochloric acid (1.0 ml.) was stirred at 0° C. in an ice-salt bath, and a solution of sodium nitrite (0.5 g.) in water (3 ml.) was added during 5 minutes, maintaining the temperature at 0°-5° C. The mixture was stirred for 10 minutes at 0° C., and then magnesium sulphate (0.020 g.), furan (20 ml.) and sodium acetate trihydrate (4 g.) were added. The reaction mixture was stirred vigorously, allowed to warm to room temperature and stirred vigorously for 48 hours. The mixture was extracted with ethyl acetate (4 × 100 ml.). The combined extracts were washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The oily brown residue was dissolved in ethyl acetate and applied to a silica column (30 g., Kieselgel 60). Elution with ethyl acetate yielded ethyl 6-furyl-4-hydroxycinnolin-3-yl carboxylate, m.p. 198°-200° C.
Reaction SMILES: [P:1]([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=4)=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl>O1CCOCC1>[P:1]([OH:3])([OH:8])([O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[S:36][C:37]([CH2:40][C:41]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[C:46]([F:51])[CH:45]=4)=[O:42])=[CH:38][N:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:52][CH3:53])=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4ccc(F)c(F)c4)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4ccc(F)c(F)c4)s3)ncnc2cc1OCCCN1CCC[C@H]1COP(=O)(O)O
Yield: 90.1 %

Procedure:
Di(tert-butyl) ((2S)-1-(3-((4-((5-(2-((3,4-difluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)pyrrolidin-2-yl)methyl phosphate (537 mg, 0.69 mmol) in dioxane (10 ml) was treated with a solution of HCl (4N) in dioxane (1.2 ml) at ambient temperature for 15 hours. The solid was recovered by filtration, washed with dioxane, dried under vacuum at 50° C. to give the title compound (413 mg, 81% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][F:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1.CCOC(C)=O>CCO.[Pt]>[Cl:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][F:27])[CH2:23][CH2:24]3)[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[2-Chloro-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(2-fluoroethyl)piperazine (0.370 g, 0.923 mmol) was taken up in EtOH (50 mL) and EtOAc was added to help with solubility. The catalyst, 5% sulfided platinum on carbon (150 mg) was added. The reaction was placed on a Fischer-Porter Hydrogenator under 50 psi of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound of step F without further purification (0.300 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.62 (d, J=7.0 Hz, 2H), 4.51-4.79 (m, 3H), 4.37-4.51 (m, 1H), 3.73 (s, 3H), 2.95-3.21 (m, 2H), 2.20-2.80 (m, 13H), 1.72-1.85 (m, 2H), 1.37-1.61 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH2:67]([N:83]=[C:84]=[O:85])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82]>CN(C)C=O>[O:63]=[C:57]1[NH:58][C:59](=[O:62])[CH:60]=[CH:61][N:56]1[C@@H:51]1[O:50][C@H:49]([C@H:9]([O:8][CH:6]2[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:1][C:84]([NH:83][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])=[O:85])[O:7]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C@@H:53]([OH:54])[C@H:52]1[OH:55]
Reactant: CCCCCCCCCCCCCCCCN=C=O
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCNC(=O)NC[C@H]1OC(O[C@H](C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](OC)[C@H]1O
Yield: 4.8 %

Procedure:
The title compound is prepared by the procedure of Example 11, using 50.0 mg (52 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) and 14.0 mg (52 μmol) hexadecyl isocyanate in 2.0 ml of N,N-dimethyl formamide to give 3.0 mg of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH2:19][CH3:20])[CH2:17]C)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.C1(=O)CCC1>C(Cl)Cl>[CH:16]1([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:17][CH2:20][CH2:19]1
Reactant: CCC(CC)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=C1CCC1
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCC3)CC2)cc1

Procedure:
Following the general procedure described above for the synthesis of 1-(4-nitrophenyl)-4-(pentan-3-yl)piperazine, treatment of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 equiv.) with cyclobutanone (3.38 g, 48.3 mmol, 2 equiv.) in DCM (100 mL) at RT for 72 h provided the title compound as a yellow solid (4.96 g, 99% recovery, 87% purity as determined by LC/MS analysis @ UV 254 nm detection). In this case, upon addition of hexane (25 mL) to the crude residue, obtained from evaporation of the DCM extract, and stirring for 24 h the product precipitated from solution, is collected by filtration, washed with hexanes (2×25 ml), and was dried under vacuum. The crude product is used in the next step without further purification. LCMS-ESI (m/z): calcd for C14H19N3O2, 261; [M+H]+ found, 262.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]C(CC)C.C([N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O)(OC(C)(C)C)=O>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([S:2](/[CH:1]=[C:35]3/[NH:34][CH2:38][CH2:37][CH2:36]/3)(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[C:13]([O:20][CH3:21])[CH:14]=1)[CH3:19]
Reactant: CCc1ccc(Oc2ccc(S(C)(=O)=O)cc2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)/C=C3\CCCN3)cc2)c(OC)c1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (0.44 mmol; 136 mg), in anhydrous THF (1 mL), under argon, cooled to 0° C., was added sBuLi (1.2M in cyclohexane; 0.89 mmol; 0.74 mL). After stirring for 30 min, a solution of 1-BOC-2-Pyrrolidinone (0.44 mmol; 0.08 mL) in anhydrous THF (1 mL) was slowly added. The reaction was stirred at 0° C. for 30 min. then slowly warmed up to toom temperature overnight. The mixture was quenched with water and NH4Cl sat. (3 mL), extracted with ethyl acetate (2*3 mL), to yield a light yellow oil (164 mg), used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)C.C(C1C=C(CC(OCC)C(O)=O)C=CC=1O)C1C=CC=CC=1>>[CH2:16]([O:15][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[C:4]([OH:18])=[O:3])[CH3:17]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Product: CCOC(Cc1ccc(O)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from 2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (0.85 g, 2.28 mmol) in the same manner as described for 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid. The crude product was used in the next step without further purification (0.71 g, 85%). 1H NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 6.90-6.93 (d, 1H), 6.64-6.66 (d, 1H), 4.03-4.07 (dd, 1H), 3.57-3.65 (m, 1H), 3.41-3.46 (m, 1H), 2.88-3.05 (ddd, 2H), 2.20 (s, 3H), 1.15-1.20 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:23])=[CH:15][C:16]([O:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[C:14]([F:23])=[CH:15][C:16]=3[O:21][CH3:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(F)c(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (3.4 g, 20.3 mmol) and 5-chloro-4-fluoro-2-methoxy-benzaldehyde (3.2 g, 17 mmol) in methanol (50 mL) was added pyrrolidine (1.2 g, 17 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20](Cl)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1>ClCCl>[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1
Reactant: Cc1nc2ncnn2c(Cl)c1C1CCCC1
Reactant: CC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c(N2CCC(C)CC2)c1C1CCCC1

Procedure:
With stirring, a solution of 4-methylpiperidine (1.5 mmol) and triethylamine (1.5 mmol) in 10 ml of dichloromethane was added to a solution of 5-methyl-6-cyclopentyl-7-chloro[1,2,4]triazolo[1,5-a]pyrimidine (1.5 mmol, Ex. 3) in 20 ml of dichloromethane. The reaction mixture was stirred at 20-25° C. for about 16 hours and then washed with a 5% strength solution of HCl. The organic phase was separated off and dried. Following distillative removal of the solvent and chromatography on silica gel, this gave 0.26 g of the title compound of m.p. 145° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: COc1ccc(C(=O)O)c(O)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1O
Temperature: 25 °C

Procedure:
A solution of commercially available 2,3-dihydroxy-4-methoxybenzoic acid (11.6 g, 63 mmol) in anhydrous MeOH (150 mL) was cooled in an ice-bath and conc. H2SO4 (8 mL) added dropwise. The reaction mixture was refluxed for 12 h, then cooled to rt and the solvent was removed under reduced pressure. H2O (100 mL) and sat aq NaHCO3 (50 mL) were added and extracted with EtOAc (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford compound 513 as a pale yellow solid, which was used in the next step without further purification. LC-MS: RT=2.31 min.; m/z 197.3 (M−H)−. 1H NMR (CDCl3): δ 10.83 (1H, s), 7.41 (1H, d, J 9.0), 6.50 (1H, d, J 8.9), 5.45 (1H, s), 3.94 (3H, s), 3.93 (3H, s).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[N:16][O:17][CH2:18][CH2:19]Br)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]1>CC(CC(C)C)=O>[CH2:46]([O:45][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([CH2:19][CH2:18][O:17][N:16]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:38]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: BrCCON=C1c2ccccc2CCc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Yield: 58.6 %

Procedure:
To a solution of 2-(((10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)oxy)ethylbromide (1.4 g, 4.2 mmol) in methyl isobutylketone (40 ml) was added potassium carbonate (4.7 g, 34 mmol) and ethyl (R)-3-piperidinecarboxylate tartrate (2.6 g, 8.5 mmol) and the suspension was heated at reflux temperature for 3 days. The cooled reaction mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The oily residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). A 34% aqueous tartaric acid solution was added until pH 4. The phases were separated and the aqueous phase was extracted with ethyl acetate (25 ml). The combined organic phases were extracted with a 34% aqueous tartaric 1/2acid solution (2×5 ml) and the organic extracts were discarded. The acidic aqueous phases were combined, diluted three times with water and ethyl acetate (40 ml) was added. A 4 N sodium hydroxide solution was added until pH 7 and the phases were separated. The organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to give 1 g of (R)-N-(2-(((10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.39 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).