Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH2:14][CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>ClCCl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21](=[O:31])[C@@H:22]([N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=[O:30])[CH3:23])[CH2:14][C:13]([OH:32])=[O:12]
Reactant: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF)n1ccccc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)NC(CC(=O)O)C(=O)CF)n1ccccc1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 ml) was added to a stirred ice cold solution of 5-Fluoro-4-oxo-3-[(S)-2-(2-oxo-2H-pyridin-1-yl)-propionylamino]-pentanoic acid tert-butyl ester (115 mg, 0.32 mmol)in anhydrous dichloromethane (2 ml). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was redissolved in dry dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as an off white solid: IR (solid) 1789, 1730, 1654 cm−1; 1H NMR (400 MHz, DMSO) δ 1.4-1.6 (3H, m), 2.5-2.9 (2H, m), 4.2-4.7 (2H, m), 5.0-5.5 (2H, m), 6.2-6.3 (1H, m), 6.3-6.5 (1H, m), 7.3-7.4 (1H, m), 7.6-7.7 (1H, m), 8.4-8.9 (1H, m); 13C NMR (100 MHz, DMSO) δ 17.15, 17.27, 17.61, 17.87, 17.94, 33.50, 33.57, 35.02, 35.23, 35.31, 52.69, 53.08, 53.31, 53.42, 53.47, 53.79, 53.91, 54.49, 54.85, 81.55, 81.92, 83.31, 83.68, 83.95, 84.07, 85.72, 85.84, 105.87, 106.07, 106.19, 119.67, 119.86, 120.26, 137.05, 137.31, 137.36, 137.40, 137.43, 140.60, 140.65, 140.74, 140.85, 162.14, 162.18, 162.28, 162.32, 171.25, 171.48, 171.62, 171.69, 172.55, 172.63, 173.63, 173.67, 174.52, 203.04, 203.18, 203.28, 203.42; MS (FAB+ve, HR) Calculated for C13H16FN2O5 (MH+) 299.1043, found 299.1045.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=S)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:38]#[C:39][NH2:40]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=[N:40][C:39]#[N:38])[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Reactant: N#CN
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Yield: 76.9 %

Procedure:
The product of Example 27D (1.2 g, 2.6 mmol), triethylamine (1.4 mL, 10 mmol), cyanamide (0.32 g, 7.7 mmol) and Hg(OAc)2 (1.6 g, 5.1 mmol) in acetonitrile (20 mL) were processed as described in Example 16E to provide the title compound (0.93 g, 2.0 mmol, 77% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 1.73-1.96 (m, 2H), 1.99 (s, 3H), 2.22-2.46 (m, 4H), 3.91 (s, 3H), 4.76 (s, 2H), 6.63 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 7.31-7.39 (m, 2H); MS (DCI/NH3) m/z 475 (M+H)+. Anal. calculated for C23H27ClN4O3S: C, 58.16; H, 5.73; N, 11.80. Found: C, 58.16; H, 5.66; N, 11.85.
Reaction SMILES: [C:1]1([C:7]2([OH:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.O>CS(C)=O>[C:1]1([C:7]2([O:20][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN2CCC(Oc3cnccn3)(c3ccccc3)CC2)cc1
Reaction time: 24 h
Yield: 18.8 %

Procedure:
A solution of 4-phenyl-1-phenylmethyl-4-piperidinol (5.35 g, 20 mM) in DMSO (50 ml) was treated with sodium hydride (960 mg of a 50% dispersion, 20 mM) followed by chloropyrazine (2.29 g, 20 mM); the reaction was stirred for 24 hours and then poured on to water (200 ml). The aqueous layer was extracted with ether (3×100 ml), the combined organic phases washed with water (100 ml) and dried. Removal of the solvents under reduced pressure followed by recrystallisation gave the title compound (1.3 g), m.p. 107°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:33]([C@H:30]3[CH2:31][CH2:32][C@H:27]([OH:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)[C@H]2CC[C@H](O)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step f), the title compound rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(trans-4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester using trans-4-hydroxycyclohexanecarboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 509.3 [M]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.[N+:31]([O-])([O-:33])=[O:32].[NH4+]>S(=O)(=O)(O)O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[C:26]([N+:31]([O-:33])=[O:32])[C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 19.3 %

Procedure:
A solution of the product of Example 320C (47 mg, 0.11 mmol) in concentrated sulfuric acid (2 mL) at 0° C. was treated with ammonium nitrate (10 mg, 0.13 mmol). After stirring at ambient temperature for 25 minutes, the solution was poured into ice water and the precipitate was filtered, dried, and purified by flash chromatography, eluting with 2% methanol in dichloromethane to yield the title compound (10 mg, 19%). MS (ESI−) m/z 470 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=6.99 Hz, 2 H) 7.44 (m, 2 H) 7.77 (d, J=9.56 Hz, 1 H) 7.88 (t, J=7.91 Hz, 1 H) 8.08 (d, J=8.46 Hz, 1 H) 8.16 (dd, J=8.09, 1.10 Hz, 1 H) 11.83 (s, 1 H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[C:30]([Si:34]([CH3:44])([CH3:43])[O:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([Si:34]([CH3:44])([CH3:43])[O:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:38][CH2:37]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19](=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)C1=O)([CH3:3])[CH3:2].C(OC1C=CC=CC=1O)(C)C.C([O-])([O-])=O.[K+].[K+].BrCCC[N:47]1[C:55](=[O:56])C2[C:49](=[CH:50][CH:51]=[CH:52]C=2)[C:48]1=O>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:19][C:18]1[CH:17]=[C:16]([C:55]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:56])[CH:15]=[CH:14][CH:13]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccccc1OCCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CC(C)Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1OCCCNCc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
2-[3-(2-Isopropoxy-phenoxy)-propyl]-isoindole-1,3-dione. To a solution of 2-isopropoxy-phenol (0.50 g, 3.3 mmol) in DMF (5 mL) was added K2CO3 (2.3 g, 17 mmol), and the resulting suspension was stirred at 25° C. for 15 min. A solution of 2-(3-bromo-propyl)-isoindole-1,3-dione (0.97 g, 3.6 mmol) in DMF (2 mL) was added, and the reaction mixture was heated to 80° C. for 18 h. The mixture was filtered, and the filtrate was diluted with 1:1 Et2O/EtOAc (100 mL), washed with H2O (2×20 mL) then brine (20 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (5-20% EtOAc/hexanes) to provide the desired product (0.956 g, 87%). 1H NMR (400 MHz, CDCl3): 7.87-7.82 (m, 2H), 7.73-7.69 (m, 2H), 6.93-6.86 (m, 4H), 4.46 (hept, J=6.1 Hz, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.92 (t, J=7.1 Hz, 2H), 2.20 (quint, J=6.4 Hz, 2H), 1.33 (d, J=6.1 Hz, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][S:22]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCNS(=O)(=O)c1cccc2ccccc12
Reaction time: 12 h
Yield: 54.9 %

Procedure:
Then, 5.43 g of 6-aminocaproic acid methyl ester hydrochloride, 6.78 g of 1-naphthalenesulfonyl chloride and 3.03 g of triethylamine were dissolved in 50 mL of dichloromethane and stirred for 12 hours. The reaction mixture was washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 5.50 g of 6(1-naphthalenesulfonyl)aminocaproic acid methyl ester. The resulting 6-(1-naphthalenesulfonyl)aminocaproic acid methyl ester (3.35 g) was dissolved in methanol, and the solution was added with 20 mL of 1 N sodium hydroxide, and stirred for 3 hours. Then, the methanol was evaporated under reduced pressure, and the residue was made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.02 g of 6-(1-naphthalenesulfonyl)aminocaproic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:23]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:10]=1.Cl.CO>CCOC(C)=O>[NH2:23][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:10]=2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Yield: 53 %

Procedure:
A mixture of N-(3-fluoro-4-(2-(4-fluorophenylamino)pyrimidin-4-yloxy)phenyl)acetamide (32 mg, 0.09 mmol), 6 M HCl (0.2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The mixture was cooled, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using 30-40% EtOAc in hexanes containing 1% Et3N gave the title compound (15 mg, 46%) as a white solid. 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.25 (d, 1H, J=5.5 Hz), 7.43 (br s, 2H), 6.92-6.85 (m, 3H), 6.45 (dd, 1H, J=13.5, 2.1 Hz), 6.38-6.35 (m, 2H), 5.35 (br s, 2H). MS(ESI+) m/z 315.17 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: NC(=O)c1cc(F)c(F)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)c(F)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4,5-difluorobenzamide (4.15 g, 23.9 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,5-difluorobenzamide was isolated as a white solid (1.80 g, 43% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H), 6.67 (d, J=4.03 Hz, 1 H), 7.46 (d, J=8.61 Hz, 2 H), 7.76 (d, J=4.03 Hz, 1 H), 7.92-8.01 (m, 4 H), 8.35 9s, 1 H), 8.55 (dd, J=13.55, 7.69 Hz, 1 H), 12.50 (s, 1 H).
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:20]1[N:15]([CH2:14][CH2:13][NH+:12]([CH2:24][C:25]([O-:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C([O-])C[NH+](CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1

Procedure:
DTPA (78.6 g.) was heated to about 70° C. with a mixture of acetic anhydride (75.6 ml) and anhydrous pyridine (102.2 ml) for 18 hours and 65.9 g. of diethylenetriamine pentaacetic acid dianhydride ("DTPADA") was obtained. DTPADA (64.3 g.) was then heated with an excess of 2,6-dimethylaniline (50.2 g) in anhydrous pryridine (1200 ml) and refluxed at a temperature of about 115° C. for 2 hours. The reaction mixture was then cooled and added to 1500 ml of ethyl acetate. The resulting mixture was chilled for about 16 hours to a temperature of about 4° C. The precipitate was collected, washed with ethyl acetate and dried under vacuum at 97° C. and 0.5 mm for about 16 hours. About 59.8 g of N,N"-bis (2,6-dimethylcarbaniloylmethylene) diethylenetriamine triacetic acid ("DTPA-bis 2,6-dimethylaniline") was obtained as the monohydrate. The melting point was determined to be 195°-199° C. and elemental analysis determined for C30H43N5O9 was 58.4% C, 6.76% H, and 11.22% N.
Reaction SMILES: [CH2:1]([S:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21]>CO.C(O)(=O)C>[CH2:1]([S:8]([C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])=[N:17][C:12]=2[CH:11]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1ccc(S(=O)Cc2ccccc2)cc1N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cc(S(=O)Cc3ccccc3)ccc2[nH]1

Procedure:
To 3.34 g (14.5 mMol) of 4-(benzyl)sulfinyl-1,2-diaminobenzene in 35 ml methanol and 0.84 ml acetic acid is added 3.11 g (16 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea, and the resulting solution heated to reflux for 3 hours. The solvent is removed in vacuo, the solid digested with water and filtered and washed with ether. The resulting solid is recrystallized from ethanol to yield the title compound.
Reaction SMILES: [O-]CC.[Na+].[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][N:25]=[N+:26]=[N-:27])[CH3:21].O1CCCC1>C(O)C>[CH2:16]([O:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7](/[CH:5]=[C:24](/[N:25]=[N+:26]=[N-:27])\[C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:8][CH:9]=1)=[O:19])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Nc1ccc(C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1ccc(/C=C(/N=[N+]=[N-])C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
To a solution of 689 mg (10.13 mmol) sodium ethoxide in 5 mL absolute ethanol at 0° C. was added a solution of 500 mg (2.44 mmol) of allyl 4-formylphenylcarbamate and 1.25 g (9.75 mmol) ethylazidoacetate dissolved in 5 mL absolute ethanol and 1 mL tetrahydrofuran dropwise over 5 minutes. The mixture was stirred at 0° C. for 1.5 h, then partitioned between ethyl acetate and 1 N HCl until neutral. The organic phase was dried over magnesium sulfate, concentrated and purified by column chromatography, eluting with 25% ethyl acetate/hexane to provide 385 mg of ethyl (2E)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-azidoprop-2-enoate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OO.NC(N)=[O:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:12])[F:13])=[N+:9]([O-:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1cc[n+]([O-])c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (2.00 g, 9.56 mmol, Oakwood) and urea hydrogen peroxide addition compound (5.00 g, 53.2 mmol, Aldrich) in methylene chloride (50 mL) at 0° C. was added trifluoroacetic anhydride (7.51 mL, 53.2 mmol). The bath was removed and the reaction was allowed to warm to room temperature and stir overnight. The precipitate was filtered off. The filtrate was diluted with a small amount of water and ethyl acetate, the layers were separated and the aqueous was extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The solvent was removed in vacuo to afford a yellow solid which was used without further purification. LC-MS: 225.9 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.20 (d, 1H), 8.04 (dd, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[NH2:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>O>[NH2:19][C:20]1[CH:25]=[C:24]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A solution of 7.5 g. of 2-benzyloxyethanol in 30 ml. of dimethylformamide is treated with 1.2 g. of sodium hydride. When the mixture is homogeneous, 3.5 g. of 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated at 110°-120° for 4 hours. The mixture is cooled, diluted with water and extracted with benzene. The crude product is treated with charcoal and isolated by precipitation with cyclohexane to afford 2-amino-1-nitro-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:24])=[CH:21][CH:20]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2[nH]ccc2c1)c1ccc(F)cc1
Yield: 83.5 %

Procedure:
To a solution of 3.96 gm (30.0 mMol) 5-amino-1H-indole in 150 mL tetrahydrofuran were added 5.6 mL triethylamine followed by a solution of 5.2 gm (33.0 mMol) 4-fluorobenzoyl chloride in 30 mL tetrahydrofuran. After 18 hours the reaction mixture was poured into water, made basic with sodium hydroxide solution, and extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give a purple solid. This residue was recrystallized from ethyl acetate/hexane to give 6.37 gm (84%) 5-(4-fluoro-benzoyl)amino-1H-indole as brown crystals in two crops.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=O)(C)(C)C.[ClH:21].O1CCOCC1>COC1CCCC1>[ClH:21].[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: COC1CCCC1
Solvent: C1COCCO1
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Reaction time: 3 h
Yield: 31 %

Procedure:
To a mixture of #11 (4.09 g, 14.2 mmol, 1 eq.) in cyclopentyl methyl ether (10 mL, 0.14 M) was added a 4 N solution of hydrogen chloride in dioxane (37 mL, 100 mmol, 7 eq.). After three hours, the reaction mixture was concentrated in vacuo and azeotroped three times with heptane to give #103 (1000 mg, 31%) as a gum, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.92-10.06 (br s, 1H), 8.66-8.80 (br s, 1H), 3.89 (dd, J=5.2, 4.9 Hz, 1H), 3.43-3.53 (m, 1H), 3.39 (s, 3H), 3.06-3.17 (m, 2H), 2.66 (qd, J=7.1, 4.6 Hz, 1H), 1.71-2.03 (m, 4H), 1.11 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.C1(C)C(S(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])(=O)=O)=CC=CC=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1ccccc1CCOCCOS(=O)(=O)c1ccccc1C
Product: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
Analogously to Method I, 0.610 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 2-[2-(2-methoxyphenyl)ethoxy]ethyl toluene-sulphonate (Example 45b) are reacted. The title compound is obtained as a slightly yellowish oil. Rt=5.10.