Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:20])=[N:8][CH:9]=[C:10](/[CH:11]=[CH:12]/[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:5]=2[S:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])/[CH:12]=[CH:11]/[C:10]1[C:5]2[S:4][CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)[C:6]=2[C:7]([NH2:20])=[N:8][CH:9]=1)[CH3:16]
Reactant: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12)OCC
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of Example 176A (250 mg, 0.70 mmol), 4-phenoxyphenylboronic acid (180 mg, 0.84 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), and sodium carbonate (150 mg, 1.4 mmol) in 1,2-dimethoxyethane (8 mL) and water (4 mL) was heated to reflux for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (170 mg, 55%). 1H NMR (DMSO-d6, 400 MHz) δ 8.00 (s, 1H), 7.56 (s, 1H), 7.47 (m, 4H), 7.20 (t, 1H), 7.13 (m, 4H), 6.81 (d, 1H), 6.17 (dd, 1H), 5.67 (br s, 2H), 5.13 (d, 1H), 3.57 (m, 4H), 1.18 (t, 6H); MS m/e 447.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[N+:49]([C:52]1[CH:60]=[CH:59][C:55]([C:56](Cl)=[O:57])=[CH:54][CH:53]=1)([O-:51])=[O:50]>C(OC(=O)C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:56](=[O:57])[C:55]3[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:60][CH:59]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.5 g.) and pyridine (0.5 ml.) in ethylacetate (100 ml.) was added 4-nitrobenzoyl chloride (0.42 g) and the resulting solution was stirred at room temperature for one hour. Further portions (0.042 g 0.015 g and 0.20 g.) of the acid chloride were added, and the reaction stirred for a total of 4 hours at room temperature. Then the solution was washed with 2 N-hydrochloric acid and brine, dried, concentrated to ca. 5 ml. and added dropwise with stirring to petroleum spirit (b.p. 40°-60°). This gave a solid which was filtered and dried, yielding the title ester (1.1 g; 58%), λmax. (EtOH) 263 nm (ε 29,000), νmax. (CHBr3) 3400 (NH), 1780 (β-lactam), 1395 and 1525 (NO2), 1687 and 1515 cm.- 1 (CONH), τ (CDCl3) values include 1.70 and 2.71 (two doublets, J 8 Hz; ##STR33## 2.1-2.85 (multiplet; aromatic protons), 8.03 (singlet; OCOCH3)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)NCC(C)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and isobutyryl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:34]([N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][N:20]2[C:11]([C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:10])=[CH:12][CH:13]=[C:14]2[CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (300 mg, 0.942 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen was added N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) followed by benzoyl chloride (0.165 mL, 1.41 mmol) and the reaction mixture stirred at room temperature for 21 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (5 mL) and then the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was crystallized from diethyl ether/hexane to give the title compound (0.319 g, 80%) as a white crystalline solid, m.p. 197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[CH3:18][NH:19][NH:20][C:21](=[O:25])[CH:22]([F:24])[F:23]>C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[C:21]([NH:20][N:19]([CH3:18])[C:6]([NH:5][CH2:4][C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7])=[O:25]
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Reactant: CNNC(=O)C(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)N(C)NC(=O)C(F)F
Temperature: 60 °C

Procedure:
1.00 g of crude 2-methyl-5-phenylbenzyl isocyanate is added to 5 ml of toluene, and to the resulted suspension is added 556 mg of N′-methyl-difluoroacetohydrazide, and the mixture is stirred at 60° C. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography, to obtain 1-difluoroacetyl-2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[CH3:30][OH:31]>[Pd]>[CH3:30][O:31][C:8]1([CH2:13][C:14]2[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:7][C:6]2[C:10](=[CH:11][CH:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:5]=2)[C:9]1=[O:12]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ncccc1C(F)(F)F)C2=O
Reactant: CO
Agent: [Pd]
Product: COC1(Cc2ncccc2C(F)(F)F)Cc2cc(N3CCOCC3)ccc2C1=O
Reaction time: 6 h

Procedure:
Compound 67 (80 mg, 0.197 mmol) was dissolved in methanol 15 mL, Pd/C 50 mg added, and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude. The crude was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 26% ethyl acetate in hexane as half white coloured solid compound 68. 1HNMR (400 MHz, CDCl3) δ ppm 8.64 (d, 1H), 7.91 (d, 1H), 7.22 (d, 2H), 6.83 (s, 1H), 3.89 (m, 7H), 3.65 (dd, 1H), 3.44 (m, 1H), 3.16 (m, 6H), 2.72 (dd, 1H); MS (ESI) m/z 407.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:28][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCC3)n2n1)c1cccnc1
Yield: 104.5 %

Procedure:
The title compound was prepared following procedure described for example 84, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 100 mg; 0.3 mmol; 1.0 eq.) and cyclobutylamine (125 μl; 0.150 mmol; 5.0 eq.) at 120° C. for 30 min. under microwave irradiations. Solvents were removed under vacuum to dryness after which the residue was triturated with water, filtered and washed with EtOAc to give the title compound as a white powder (59 mg; 53%). 1H NMR (DMSO-d6) δ 11.4 (s, 1H), 9.15 (d, J=2.2 Hz, 1H), 8.79 (dd, J=1.5, 4.5 Hz, 1H), 8.35 (dt, J=1.8, 7.9 Hz, 1H), 7.63-7.56 (m, 2H), 7.32 (bs, 1H), 6.36 (d, J=1.5 Hz, 1H), 4.32-4.24 (m, 1H), 2.43-2.34 (m, 2H), 2.25-2.18 (m, 2H), 1.79-1.70 (m, 2H). HPLC, Rt: 3.20 min. (purity 94.8%). LC/MS, M+(ESI): 377.0, M−(ESI): 375.0.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=O)[NH:34][C:35]1[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=[C:37]([C:54]([CH3:57])([CH3:56])[CH3:55])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:54]([C:37]1[CH:36]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:32])[N:39]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:44]=2)[N:38]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of Intermediate 81d (240 mg, 0.64 mmol), Intermediate 108b (325 mg, 0.64 mmol) and DIPEA (221 μL, 1.27 mmol) in dioxane (6 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to afford the title compound (377 mg, 80%). LCMS (Method 4): Rt 3.48 min, m/z 737 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]Br)[C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.[CH2:14]([NH2:16])[CH3:15].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][N:16]([CH2:14][CH3:15])[C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: CCN
Reactant: COC(=O)c1ncc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1Cc2cc(Br)cnc2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (0.39 g, 1.3 mmol), ethylamine in THF (0.88 mL, 2.0 M, 1.8 mmol) and potassium carbonate (0.26 g, 1.9 mmol) in ethanol (5 mL) in a sealed reaction vial was stirred at 40° C. for 2 h. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.24 g). LCMS (M+H)+=240.9/242.9.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:15]1[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=1>CN(C)C=O.O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([S:1][C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)([OH:11])=[O:10]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(Sc2ccc(CC(=O)O)cc2)s1
Temperature: 120 °C

Procedure:
4-Mercaptophenylacetic acid (2.3 g) was dissolved in dimethylformamide under a nitrogen atmosphere and 1.8 g of potassium hydroxide dissolved in a minimum amount of water was added. 5-bromothiophene-2-sulfonamide (3.3 g) dissolved in dimethylformamide was added and the mixture heated at 120° C. for 2 hours. After cooling to room temperature water was added to the reaction mixture, the pH was adjusted to 8.6 and the mixture was extracted with ethyl acetate. The aqueous phase was separated and acidified, causing a solid to precipitate. The solid was collected by filtration and dried under vacuum to a weight of 3.25 g.
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@H:7]1[CH2:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])C(O)C.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[CH:2]([C@H:6]1[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@H:7]1[CH2:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:1]
Reactant: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1C(O)C(C)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1C=O
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of 2-[[(4S,5R)-5-(1,2-dihydroxypropyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester (20 g, 72 mmol) in acetone (20 mL) was diluted with water (400 mL) and treated with solid sodium periodate (26.13 g, 122 mmol). The reaction was analyzed by TLC and was complete after stirring for 1 hour. The reaction mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried, and concentrated to give 12.6 g of 2-[[(4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (M), as a slightly yellow viscous oil; 1H NMR (CDCl3) δ 1.38 (s, 3H), 1.57 (s, 3H), 3.75 (m, 2H), 3.7 (s, 3H), 4.08 (m, 2H), 4.42 (m, 1H), 4.54 (m, 1H), 9.64 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:20])[C:17]([OH:19])=[O:18])=[C:11]([N+:21]([O-:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[C:16](=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[N+:21]([O-:23])=[O:22]
Reactant: CO
Reactant: O=C(O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Product: COC(=O)C(=O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 71 %

Procedure:
3-(4-Benzyloxy-2-nitrophenyl)-2-oxopropanoic acid (40 g; 0.127 mole) was dissolved in methanol (300 ml). Hydrochloric acid (conc, 10 ml) was added under stirring. The reaction mixture was heated to reflux for 3.5 hours and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was washed with diluted sodium hydrogencarbonate solution and water, and dried with magnesium sulfate. Filtration through a short silica gel column and evaporation gave 29.6 g (71% yield) of 3-(4benzyloxy-2-nitrophenyl)-2-oxopropanoic acid methyl ester as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][C:4]([CH3:18])=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(OCc2c(F)cccc2Cl)c(N)n1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=S)Nc2ccc(Cl)cc2)n1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine (2.0 g, 0.0075 mol), 4-chlorophenyl isothiocyanate (1.53 g, 0.0089 mol) and toluene (10 ml) was heated under reflux for 2 hours, then cooled and diluted with ether to induce crystallisation of the product, which was triturated with ethanol. Yield 2.6 g (82%), m.p. 204°-205 ° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.C(N)CN.BrCC1C=CSN=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][N:2]=1)=[O:25]
Reactant: CN=C=O
Reactant: NCCNCc1ccsn1
Agent: BrCc1ccsn1
Solvent: NCCN
Product: CNC(=O)NCCNCc1ccsn1

Procedure:
N-(3-Isothiazolylmethyl)ethylenediamine, prepared by reacting ethylenediamine with 3-bromomethylisothiazole by the procedure of Example 40(a), is reacted with methyl isocyanate by the procedure of Example 24 to give, after concentrating and separating by column chromatography, the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of 4-nitroimidazole (7.28, g, 64.4 mmol) in 60 mL of dry DMF at 0° C. was added triethylamine (9.87 mL, 70.8 mmol), then chlorotriphenylmethane (17.95 g, 64.4. mmol). After 5 minutes, the solution was warmed to room temperature. After 30 minutes, the reaction mixture was poured over ice, filtered, and washed with ice water. The resulting product was dried in vacuo next to P205 to provide the titled product as a white powder (22.29 g, 97% yield) which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:24])N.[O-]Cl=O.[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:24])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
An alternative method for preparing this intermediate is as follows. 4-(2-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.72 mmol) is dissolved in 80 mL of dioxane and 20 mL of H2O. The mixture is cooled to 4° C. To this is added sulfamic acid (1.36 g, 14.00 mmol) in one portion. The mixture is stirred for an additional 30 min. To this is added 3 mL of a solution of NaClO2 (0.343 g, 3.80 mmol) in a dropwise manner. The reaction is quenched reaction with addition of 50 mL of H2O and 50 mL of brine. The mixture is extracted with 3×100 mL of CH2Cl2. The organic phase is washed with 2×50 mL of brine, dried (MgSO4), filtered and concentrated to give 500 mg of 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 95% yield.
Reaction SMILES: [C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH:14]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[NH2:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1ccccc1
Reaction time: 8 h

Procedure:
The cis-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer from above (0.095 g, 0.33 mmol) was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (2 mL) and the mixture stirred overnight. The reaction was worked up to afford the title compound (0.069 g) as a pale yellow solid. 1H NMR (CDCl3) 1.28-1.37 (m, 5H), 1.50-1.63 (m, 6H), 3.18 (br s, 1H), 3.42-3.45 (m, 1H), 6.63-6.70 (m, 3H), 7.16 (br t, 2H, J=7.5 Hz).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(OP([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(OCC)=O)C.[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:31](O)[CH2:32][O:33][C:28]=2[CH:27]=1.O>C1COCC1>[Cl:25][C:26]1[CH:43]=[CH:42][C:29]2[N:30]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH:31]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:32][O:33][C:28]=2[CH:27]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2OCC1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)OC(C)(C)C
Yield: 106.6 %

Procedure:
A 1 M solution of LiHMDS (23.0 mL, 23.0 mmol) in THF was a added dropwise to a solution of ethyl 2-(diethoxyphosphoryl)acetate (4.57 mL, 23.0 mmol) in THF (30 mL) at 0° C. under nitrogen and the resulting mixture was stirred for 10 min where after tert-butyl 7-chloro-3-hydroxy-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 17, 3.29 g, 11.5 mmol) dissolved in THF (30 mL) was added dropwise at 0° C. The reaction mixture was stirred under nitrogen at rt for 1 h where after water (100 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried by passage through a phase separator and concentrated giving crude the title compound (4.36 g, 106%) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[C:23](OCC=C)(=O)[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:23]=[CH:24][CH2:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: C=CCOC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 80 °C

Procedure:
In one embodiment, allylation of noroxymorphone with allyl acetate is accomplished by combining noroxymorphone with triethylamine (3 equivalents), toluene (50 mL) and tetrakis(triphenylphosphine)palladium[0] (0.1 equivalent), and heating the mixture at 80° C. for 64 hours. The mixture is cooled to a temperature of about 20° C. and filtered through a plug of CELITE and the filtrate was concentrated under reduced pressure. Naloxone is isolated from the concentrated filtrate using normal extractive procedures.