Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12)[NH2:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([NH:33][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)Nc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of the acid 1 (465 mg, 2.59 mmol) and BOPCl (666 mg, 2.59 mmol) was mixed in DCM (5 mL) at 0° C. and stirred at the same temperature for 15 min. The reaction mixture was then treated with a solution of 410 (500 mg, 1.29 mmol) and iPr2NEt (1.3 mL, 1 g, 7.79 mmol) in DCM (5 mL) at 0° C. and allowed to stir at room temperature for overnight. The mixture was diluted in DCM (30 mL), washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, to provide 411 (382 mg, 54% yield). 1H NMR 6 (400 MHz, CD3OD): 8.33 (d, 5.7 Hz), 7.79 (dd, 1H, J=2.4 Hz, J=12.3 Hz), 7.54 (m, 5H), 7.2-7.4 (m, 4H), 7.09 (t, 1H, J=7.2 Hz), 6.50 (d, 1H, J=5.5 Hz), 3.51 (s, 2H), 7.75 (s, 1H). MS (m/z): (M+1) 547.9 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:17][CH:18]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: COCOc1ccc(I)cc1
Product: COCOc1ccc(-n2c(C)cc3cc(Cl)ccc32)cc1
Yield: 19 %

Procedure:
5-Chloro-2-methylindole (4.14 g, 25 mmol) and 4-methoxymethyloxy iodobenzene (6.20 g, 25 mmol) were reacted according to the procedure used in Example 1a above to afford a colorless liquid (19%): 1H NMR (DMSO-d6): δ 2.25 (3H, s), 3.44 (2H, s), 5.28 (2H, s), 6.40 (1H, s), 6.96 (1H, d, J=8.8 Hz), 7.02 (1H, dd, J=2.0 Hz, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.55 (1H, d, J=2.0 Hz); MS m/z (M+H)+ 302/304 (1 Cl). Anal. for C17H16ClN02: Calc'd: C, 67.66; H, 5.34; N, 4.64. Found: C, 67.49; H, 5.17; N, 4.51.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21][CH3:22])[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:35])C=CC=CC=1>C1COCC1>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:22])=[O:35])[C:7]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: CSc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: C1CCOC1
Product: CS(=O)c1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A mixture of the 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (508) (34.5 mg, 0.092 mmol), prepared according to example 25, and 2-phenylsulfonyl-3-phenyloxaziridine (Davis reagent) (26.5 mg, 0.102 mmol) in THF (10 mL) was stirred at 20° C. for 2.5 h, then adsorbed directly onto silica gel and chromatographed. Elution with 0–3% MeOH/CH2Cl2 then 3–4% MeOH/CH2Cl2 gave (after crystallisation from THF/CH2Cl2/pentane) the 9-Hydroxy-4-[2-(methylsulfinyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (510) (I; Ar=2-(methylsulfinyl)phenyl) in a 86% yield as a yellow solid; mp 321–323° C. 1H NMR [(CD3)2SO] δ 11.86, 11.85 (2br s, 1H), 11.09 (br s, 1H), 9.30 (br s, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.04, 7.97 (2d, J=7.6 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 7.65, 7.62 (2t, J=7.4 Hz, 1H), 7.62, 7.54 (2s, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 2.43, 2.31 (2s, 3H). Found: C, 64.60; H, 3.88; N, 6.87. C21H14N2O4S requires C, 64.61; H, 3.61; N, 7.18.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[Br:12]Br.O>C(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=O)c(Br)c1O

Procedure:
Isovanillin (76.1 g, 0.5 m) was suspended in 750 ml of chloroform. Bromine (27.3 ml, 0.5 m) in 200 ml of chloroform was added at 0° slowly. Water was added to give the desired 2-bromo-3-hydroxy-4-methoxybenzaldehyde, m.p. 197°-203°.
Reaction SMILES: [Br-].[F:2][C:3]1([F:34])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]=2[O:4]1.C([Li])CCC.[CH2:40]1[O:50][C:43]2([CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)[O:42][CH2:41]1>O1CCCC1>[F:34][C:3]1([F:2])[C:7]([F:8])([F:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=[C:46]3[CH2:47][CH2:48][C:43]4([O:50][CH2:40][CH2:41][O:42]4)[CH2:44][CH2:45]3)[C:5]=2[O:4]1
Reactant: FC1(F)Oc2c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cccc2C1(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC1(F)Oc2c(C=C3CCC4(CC3)OCCO4)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 20.1 grams (0.039 mole) of (2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7ylmethyl)triphenylphosphonium bromide, 15.4 mL (0.0) 39 mole) of n-butyllithium (2.5M in hexanes), and 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 55 mL of dry tetrahydrofuran, yielding 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=O.O.NN.[OH-].[K+].O>C(O)COCCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2oc(CC3CCCCN3)cc2c1
Temperature: 25 °C
Yield: 5.1 %

Procedure:
To a solution of (RS)-2-(2-benzofuranylcarbonyl)-1-(tert-butyloxycarbonyl)piperidine (0.30 g, 0.91 mmol) in diethylene glycol (20 g), was added hydrazine hydrate (0.16 ml, 2.79 mmol) and the resultant mixture heated at 170° C. for 30 min. then cooled to room temperature. Potassium hydroxide (0.44 g, 7.86 mmol) was added and the mixture heated at 200° C. for 18 h. The resultant was then poured into water (100 ml) and extracted with diethyl ether (3×20 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (10 mg, 36%) as a golden oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:30]([CH3:31])[CH3:29])=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Product: CN(C)c1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 42 mg (0.092 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 1 mL 2 M dimethylamine solution. Yield: 17 mg of a yellow powder. LC-MSD, m/z for C23H19BrN4O2 [M+H]+=463.0, 465.0; HPLC retention time: 0.6 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[Cl:41][C:42]1[S:43][C:44]([CH2:47]Cl)=[CH:45][CH:46]=1.FC1C=CC(CBr)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:47][C:44]4[S:43][C:42]([Cl:41])=[CH:46][CH:45]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccccc2C12COc1ccc(Br)cc12
Reactant: ClCc1ccc(Cl)s1
Agent: Fc1ccc(CBr)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure described in EXAMPLE 10, and making non-critical variations using 5-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloro-5-(chloromethyl)thiophene to replace 4-fluorobenzyl bromide, the title compound was obtained (95%) as a white solid: mp 140-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.16-7.02 (m, 2H), 6.94 (d, 1H), 6.97-6.75 (m, 4H), 5.07-4.91 (m, 3H), 4.68 (d, 1H); MS (ES+) m/z 446.7 (M+1), 448.7 (M+1).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24]CC)=O.[C:29]1([N:35]=[C:36](Cl)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:22](=[O:24])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:27])([F:28])[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: ClC(=Nc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-phenylbenzimidoyl chloride (1.8 g, 68%).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([OH:21])=O)=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3].C[N:23](C(N(C)C)=[N+]1C2C(=NC=CC=2)N=N1)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[N:1]([C:4]1[S:5][C:6]([C:19]([NH2:23])=[O:21])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(=O)O)s1
Reactant: CN(C)C(N(C)C)=[N+]1N=Nc2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)s1
Reaction time: 0.3 h
Yield: 78.9 %

Procedure:
To a solution of 1.76 g (5.60 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid and 30 mL of dimethylformamide was added 2.75 g (7.01 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium, 3-oxide, hexafluorophosphate(1-) (1:1) and 3.0 mL (17.2 mmole) of ethyldiisopropylamine. The mixture was stirred for 18 minutes, then 0.4541 g (8.49 mmole) of ammonium chloride was added. The mixture was concentrated under reduced pressure and diluted with 350 mL of ethyl acetate and 75 mL of water. The ethyl acetate layer was washed with 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 10:90-100:0) to give 1.384 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(=O)=O.[Li]CCCC.Cl[SiH:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>C1COCC1.CC(C)=O>[CH:20]([SiH:19]([CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([SiH](C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
A solution of p-bromoanisole (28.6 mL, 228 mmol, 1 equiv.) in THF (550 mL) was chilled to −78° C. (CO2(s), acetone). n-BuLi (91.2 mL, 228 mmol, 2.5M in hexanes, 1 equiv.) was added via cannula over a 5 min period. After 5 min a white precipitate begins to form. The mixture was stirred for 30 min at −78° C., after which chlorodiisopropylsilane (34.6 g, 228 mmol, 1 equiv.) was slowly added via syringe. After 1 h the ice bath was removed and the solution was allowed to come to 23° C. with stirring overnight. The reaction was quenched with NH4Cl(sat'd) (50 mL) and extracted with ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a light yellow oil. Filtration through SiO2 (gradient: 3-5% EtOAc/hexanes) yielded 47.7 g (94%) of a colorless oil. This material could also be purified by distillation bp=76-85° C. @ 275 mTorr (40 g, 63%). TLC Rf=0.61 (9:1 Hexanes/EtOAc). IR (film) 2393, 1853, 1710, 1691, 1658, 1584, 1482, 1346 cm−1. 1H NMR (500 MHz, CDCl3) δ7.48 (d, 2H, J=8.10, C3-H, C7-H), 6.95 (d, 2H, J=8.10, C4-H, C6-H), 3.97 (s, 1H, Si—H), 3.85 (s, 3H, C1-H), 1.39 (q, 2H, J=3.0, C8-H, C11-H), 1.10 (d, 6H, J=6.5, C9-H, C10-H), 1.03 (d, 6H, J=7.5, C12-H, C13-H). 13C NMR (125 MHz, CDCl3) δ137.13, 113.73, 113.62, 55.18, 18.95, 18.72, 11.08. Anal. Calcd for C13H22OSi: C, 70.21; H, 9.97; Si, 12.63. Found: C, 70.43; H, 9.83; Si, 12.39.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+].CCOCC>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(C#N)ccc2C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCc2cc(C(=N)NO)ccc2C1
Temperature: 55 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
1,1-Dimethylethyl 7-cyano-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 4) (350 mg, 1.285 mmol), hydroxylamine hydrochloride (223 mg, 3.21 mmol) and sodium bicarbonate (540 mg, 6.43 mmol) were suspended in ethanol (15 ml) and stirred at 55° C. for 5 hours. The reaction mixture was left standing overnight. LC/MS showed a single major product. Inorganics were removed by filtration, washing well with 10% MeOH/DCM to dissolve any precipitated product. Solvent evaporation yielded a white solid. Trituration with ether gave the title compound (320 mg). MS (ES) C16H23N3O3 requires 305; found 306.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[C:12]([I:29])=[C:13]([C:22]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].CC(N(C)C)=O>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:22](=[O:23])[C:13]1[C:14]([I:21])=[C:15]([C:19]([I:20])=[C:11]([NH:10][C:7](=[O:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=1[I:29])[C:16]([OH:18])=[O:17]
Reactant: COCCOCC(=O)Cl
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCOCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a maximum of 10° C. (ice cooling), 16.5 ml. of methoxyethoxyacetyl chloride is added dropwise within 30 minutes with agitation to 30.8 g. (50 mmol) of 5-amino-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid in 60 ml. of dimethylacetamide. The mixture is stirred for 1 hour at 0° C. and then for 16 hours at room temperature. Thereafter, another 2 ml. of the acid chloride is added thereto, and the mixture is stirred at room temperature for 4 hours. Then, 10 ml. of water is added and the mixture is concentrated under vacuum. The residue is dissolved in 350 ml. of water and neutralized with 32% sodium hydroxide solution. The mixture is combined with another 5 ml. of 32% sodium hydroxide solution and then stirred for some time after adding 5 g. of active carbon. After the carbon has been removed, the mixture is acidified with concentrated hydrochloric acid, allowed to stand for a period of time and vacuum-filtered. The resulting precipitate is dried under vacuum. Yield: 21.3 g. (58%), m.p. 275° C., with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23].[C:26](O)(=O)C>C1(C)C=CC=CC=1>[C:8]1([C:5]2[CH:6]=[CH:7][C:2]3[N:1]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:26])=[O:23])[NH:14][C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1NC(=O)CCCCCCC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCc1nc2ccc(-c3ccccc3)cc2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 8-(4-aminobiphenyl-3-ylamino)-8-oxooctanoate (120 mg, 0.34 mmol) in toluene was added a drop of acetic acid. The reaction was heated to 110° C. overnight and concentrated. The residue was purified by biotage column chromatography to give methyl 7-(6-phenyl-1H-benzo[d]imidazol-2-yl)heptanoate (99 mg)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2OC)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine (167 mg, 0.57 mmol) was dissolved in methanol (20 mL) and placed under a nitrogen atmosphere. A catalytic amount of 20% palladium hydroxide on carbon was added and a hydrogen balloon was connected to the reaction flask. The flask was flushed five times with hydrogen and stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction mixture was filtered and washed with methanol. The filtrate was evaporated under reduced pressure. Acetonitrile (10 mL) was added to the residue, swirled for 10 min, and decanted away from white film. The acetonitrile layer was evaporated under reduced pressure yielding 4-(1-isopropylpiperidin-4-yloxy)aniline as a brown oil (131 mg, 87%). LC/MS (m/z): 265.2 (MH+), Rt 0.33 minutes.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][O:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)COCCl
Product: CCOP(=O)(COCC(=O)OC)OCC
Temperature: 150 °C
Yield: 100.7 %

Procedure:
26 g (186 mmol) of methyl chloromethoxyacetate and 32 mL (186 mmol) of triethyl phosphite are placed in a round-bottomed flask and heated at 150° C. for 3 hours. The reaction progress is monitored by NMR. The reaction medium is concentrated under vacuum. 45 g (100%) of methyl (diethoxyphosphoryl)methoxyacetate are obtained directly in the form of a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:38](=[O:40])[CH3:39])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(O)cc1)O2)NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[(S)-2-(4-hydroxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-propionic acid methyl ester (240 mg) in DCM (10 mL) was added pyridine at 0° C. To this mixture was added acetic anhydride. The mixture was stirred for 2-3 h. After completion of the reaction, the mixture was diluted with DCM (50 mL) and was washed with water, 1N HCl and brine solution. The organic layer was dried and concentrated to get the desired product as a white solid (208 mg). LCMS (m/z): 473
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]([C:24]([Br:27])=[CH:25][N:26]=1)[C:20]([O:22][CH3:23])=[O:21].O>CO>[CH3:23][O:22][C:20]([C:19]1[C:24]([Br:27])=[CH:25][N:26]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:16]=[C:17]2[CH:18]=1)=[O:21]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(N)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Bromoacetophenone (17.29 g, 87 mmol) and NaHCO3 (8.03 g, 96 mmol) were added to a solution of methyl 2-amino-5-bromoisonicotinate (20.07 g, 87 mmol) in methanol (240 ml), and the mixture was heated to reflux (5 h). After cooling to r.t., water (75 ml) was added, and the brown suspension was stirred (15 min) and filtered. The precipitate was washed with a small amount of methanol. The title compound (10.11 g, 35%) was dried under vacuum and was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
0.49 g of N,N'-carbonyldiimidazole is added to a solution of 0.52 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 0.93 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.84 cm3 of triethylamine in 10 cm3 of dichloromethane, is added. The reaction mixture is stirred for 2 hours at +5° C. and then washed with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 35 cm), eluting with ethyl acetate and collecting fractions of 30 cm3. Fractions 8 to 27 are pooled, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised-from a mixture of 4 cm3 of acetonitrile and 20 cm3 of ethyl ether. The crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4S,7aR)-2-[(2-dimethylaminophenyl)-acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 160° C., [α]D20 =-162° (c=0.5, methanol).