Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:28][C:23]1[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:30][CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 86.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-nitrobenzoyl chloride (2.3 mmol) and N1-(4-methoxy-benzoyl)-1,2-benzenediamine (2.1 mmol) yielded 708 mg (86%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])[CH:5]=[C:6]([CH3:7])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: CCOC(=O)CC(=N)N
Reactant: CC(=O)C=Cc1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccccc1Cl
Yield: 62 %

Procedure:
Upon boiling a solution of 18.1 g of 2-chlorobenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 171°C (ethanol) is obtained. Yield: 62 percent of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:16][N:17]1[CH:21]([CH2:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][N:19]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[C:18]1=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:13])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][CH2:22][CH:21]2[CH2:20][N:19]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=3)[C:18](=[O:46])[N:17]2[CH3:16])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
To a solution of 3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methyl ester (31 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 15 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:4 hexanes:ethyl acetate) produced an oil (69 mg, 94%).
Reaction SMILES: CC[C@H]([C@H](CN(C)C)C)C1C=CC=C(O)C=1.[ClH:17].[CH3:18][N:19]([CH3:35])[CH2:20][C@H:21]([CH3:34])[C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(O)[CH2:23][CH3:24].S(Cl)([Cl:38])=O>>[ClH:38].[Cl:17][C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)([CH2:23][CH3:24])[C@@H:21]([CH3:34])[CH2:20][N:19]([CH3:35])[CH3:18]
Reactant: CC[C@@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Reactant: O=S(Cl)Cl
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Agent: Cl
Product: CC[C@@](Cl)(c1cccc(OC)c1)[C@@H](C)CN(C)C

Procedure:
According to the '737 patent, tapentadol is prepared by the reaction of (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with thionyl chloride to produce (−)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride, followed by subsequent removal of the ‘Cl’ substituent by treatment with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride, to produce (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride. The (−)-(2R,3R)-[3-(3-methoxy phenyl)-2-methylpentyl]-dimethylamine hydrochloride is then converted to (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol (tapentadol) by reacting with concentrated hydrobromic acid at reflux.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[CH:11][C:10]=1[CH:17]([CH3:19])[CH3:18].[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.CCO.O>[Cl:8][C:9]1[C:10]([CH:17]([CH3:19])[CH3:18])=[CH:11][C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: CC(C)c1cc(NN)nnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: CC(C)c1cc2nnc(N)n2nc1Cl
Reaction time: 8 h

Procedure:
(6-Chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.013; 400 mg) was initially charged in ethanol/water (6/1 ml) at RT while stirring. Thereafter, cyanogen bromide (353 mg, dissolved in a mixture of 1 ml of EtOH and 0.5 ml of water) was cautiously added dropwise. After stirring for 5 hours, the mixture was left to stand overnight and stirred for a further day. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 400 mg of the title compound were obtained in sufficient purity.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:28]([NH:35][CH2:36][CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>ClCCl>[CH2:28]([NH:35][CH2:36][CH2:37][NH:38][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCNCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (50.0 mL, 359 mmol) and a solution of trityl chloride (93 g, 326 mmol) in dichloromethane (251 mL) were added dropwise over 1 hour to an ice bath cooled solution of N1-benzylethane-1,2-diamine (50 g, 326 mmol) in dichloromethane (251 mL) under argon. The mixture was then allowed to warm to room temperature and stirred for 48 hours. Water was added and the product was extracted with dichloromethane. The organic layer was washed with brine and water, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.44-7.36 (m, 5H), 7.32-7.24 (m, 10H), 7.21-7.15 (m, 5H), 3.56 (s, 2H), 2.62 (t, J=6.1 Hz, 20H), 2.10 (d, J=6.6 Hz, 2H).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C=C(C)C=1)C(O)=O.CC1C=C(C(Cl)=O)C=C(C)C=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:51]=[C:52]([C:57]([N:59]=[C:60]=[S:61])=[O:58])[CH:53]=[C:54]([CH3:56])[CH:55]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:52]2[CH:51]=[C:50]([CH3:49])[CH:55]=[C:54]([CH3:56])[CH:53]=2)=[S:61])=[CH:44][CH:43]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cc(C)cc(C(=O)N=C=S)c1
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cc1cc(C)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)cc(C)c4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) was added to commercially available 3,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3,5-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 3,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,5-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (39 mg, yield 47%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC=C(Cl)Cl
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(OCC=C(Cl)Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.8 %

Procedure:
A reaction vessel was charged with 30.5 g of 4-hydroxyphenyl benzoate, 21.6 g of potassium carbonate, 20.8 g of 1,1,3-trichloropropene and 100 ml of N,N-dimethylformamide. After stirring at room temperature for 15 hours, the reaction mixture was poured into water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 44.1 g of 4-(3,3-dichloro-2-propenyloxy)phenyl benzoate (96% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:12])[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].[CH2:14]([OH:17])[CH2:15][OH:16].O.[OH-].[K+]>C1C=CC=CC=1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]1[O:17][C:3]([OH:2])([CH2:4][C:5](=[O:12])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[O:16][CH2:15]1
Reactant: COC(=O)CCC(=O)CC(=O)OC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CCC(=O)CC1(O)OCCO1
Reaction time: 2.5 h
Yield: 100.3 %

Procedure:
A solution of 4.00 g (21 mmol) of 3-ketohexanedioic acid dimethyl ester [B. J. Whitlock and H. W. Whitlock, J. Org. Chem., 39:3144 (1974)] in 100 mL of benzene was refluxed in the presence of 14.5 g (230 mmol) of ethylene glycol and 100 mg of p-toluene-sulfonic acid while water was azeotropically removed in a Dean-Stark trap. After 2.5 h, the mixture was cooled and washed with equal volumes of saturated sodium bicarbonate solution and water. The benzene layer was dried (MgSO4) and reduced to dryness to leave a clear oil; IR (neat) 1740 cm-1, NMR (CDCl3) δ2.30 (A2B2 multiplet, 4), 2.60 (s,2), 3.65 (s,6), and 3.95 (s,4). The oily ketal was immediately hydrolyzed under reflux for 1.5 h in a solution of 4.4 g of 86% KOH in 50 mL of 95% ethanol. After cooling, the slight precipitate formed was dissolved by adding a small amount of water. Sufficient cation exchange resin AG50W-X8 (H+) was added to neutralize the base (pH~6.5) and removal of the resin afforded a filtrate which was reduced to dryness to leave 4.3 g (99%) of 3-ketohexanedioic acid ethylene ketal as a yellowish oil which yielded a very hygroscopic solid after trituration with acetone; IR 1720 cm-1 (broad); NMR δ(D2O) 2.20 (A2B2 multiplet, 4), 2.60 (s,2), and 4.0 (s,4). This compound was not further characterized and used as such in the following step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1

Procedure:
Methyl ester 6.1 (53 mg) was stirred with 1N LiOH (2 ml) in 5 ml of MeOH/THF (4:1) over 18 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl and extracted with EtOAc (3×). The organic extracts were washed with H2O, brine, and dried (Na2SO4). The residue after concentration was triturated with hexanes/Et2O (10:1) to afford acid 6.2, 39 mg (100%). HRMS (ESI) calc'd for C25H29N2O3 405.2100, found 405.2198 (MH+); MS (ESI); 1H NMR (300 MHz, CDCl3) δ 7.48–7.34 (m, 5H), 7.27 (d, J=7.0, 2H), 7.06 (d, J=8.7, 2H), 6.01 (s, 1H), 5.13 (s, 2H), 4.06–3.98 (m, 1H), 3.02–2.97 (m, 2H), 2.85–2.81 (m, 2H), 1.91–1.83 (m, 6H), 1.26 (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:17][CH2:18][C:19]#[N:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>O1CCCC1>[OH2:9].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:17][CH2:18][C:19]2[NH:45][N:44]=[N:43][N:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:17][CH2:18][C:19]2[NH:45][N:44]=[N:43][N:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Solvent: C1CCOC1
Product: O
Product: O=S(=O)(NCCCCC(CCCc1cccnc1)CCc1nnn[nH]1)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 0.528 g 8-(p-chlorophenylsulfonamido)-4[3-(3-pyridyl)propyl]octanenitrile and 1.04 mL tributyltin azide in 5 mL tetrahydrofuran is heated at 120° C. for 64 hours. The solvent is evaporated and subjected to flash chromatography over silica gel using methylene chloride/hexane/methanol/acetic acid (45:25:5:0.8) as eluent to give an oil which is purified again by preparative thin layer chromatography using methylene chloride, methanol, hexane, acetic acid (45:5:25:0.8) as eluent to yield an oil which is triturated with ether and hexane to give 5-{7-(p-chlorophenylsulfonamido)-3-[3-(3-pyridyl)-propyl]-heptyl}-1H-tetrazole hemihydrate, m.p. 56-81°.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].CN(C1C=CC=CN=1)C.[C:23]([N:33]1[CH2:36][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH2:49])[O:45][C:44]3=[O:50])=[CH:39][C:38]=2[F:51])[CH2:34]1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[F:51][C:38]1[CH:39]=[C:40]([N:43]2[CH2:47][C@H:46]([CH2:48][NH:49][C:7](=[O:9])[CH3:8])[O:45][C:44]2=[O:50])[CH:41]=[CH:42][C:37]=1[CH:35]1[CH2:36][N:33]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:34]1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4 dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].ClC([O:28][C:29](Cl)(Cl)Cl)=O.[CH2:33]([NH2:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>O1CCOCC1>[CH2:33]([NH:39][C:29]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11])=[O:28])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N)cccc21
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCNC(=O)Nc1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 65 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
To a stirred solution of 4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.33 g, 1.00 mmol) in 1,4-dioxane (20 mL) was added trichloromethyl chloroformate (0.14 mL, 1.2 mmol). The reaction mixture was heated at 65° C. for 24 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and the resultant solution was cooled to 0° C. in an ice bath. n-Hexylamine (0.40 mL, 3.0 mmol) and triethylamine (0.70 mL, 5.0 mmol) were added. The reaction mixture was allowed to warm to ambient temperature, stirred for 24 h and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (4×150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford 1-hexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea (0.294 g, 64%) as a pale brown solid: mp 154-155° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.78-7.75 (m, 1H), 7.30-7.25 (m, 1H), 6.63-6.60 (m, 1H), 6.52 (s, 1H), 6.34 (s, 1H), 6.09 (s, 1H), 4.76 (ABq, 2H), 4.22-4.11 (m, 5H), 3.28 (s, 3H), 3.14-3.00 (m, 2H), 1.48-1.41 (m, 2H), 1.32-1.25 (m, 6H), 0.89 (t, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 176.3, 154.6, 154.2, 145.1, 142.8, 139.4, 135.9, 129.8, 119.0, 118.3, 115.8, 112.2, 103.3, 99.3, 78.2, 64.5, 63.8, 57.1, 40.5, 31.5, 29.8, 27.0, 26.4, 22.5, 14.0; MS (ES+) m/z 452.2 (M+1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Yield: 110.1 %

Procedure:
48.6 g of Z-Asp(OtBu)-Phe-OCH3 in 700 ml of methanol are decarbobenzoxylated in a duck-shaped flask at room temperature after adding 33.5 ml of 3 N hydrogen chloride in dioxane and 5 g of 10 % strength palladium catalyst on charcoal. After the hydrogen uptake has ended the mixture is filtered and the filtrate evaporated. 38.7 g of a white foam are obtained. In a thin layer chromatogram on silica gel in chloroformmethanol (9:1) Rf = 0.60; in chloroform-acetone (1:1) Rf = 0.58; Rf102E =0.42. The product is employed for the subsequent condensation without additonal purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CS(C)=O.F[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CO>[N:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: Fc1ccccn1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(c4ccccn4)CC3)CC2)c(F)c1
Temperature: 120 °C

Procedure:
30 mg of 63a (0.08 mmol), diisopropylethylamine (75 μL, 0.43 mmol), DMSO (0.3 mL) and 2-fluoropyridine (11.7 mg, 0.12 mmol) were combined and heated to 120° C. overnight. The mixture was diluted with methanol and purified on preparative HPLC to give 63-1: LC-MS 447.4 (MH+).
Reaction SMILES: Cl[C:2]1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)C(=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[C:37]([O:41][C:42](=[O:52])[NH:43][C:44]1[C:45]([Cl:51])=[N:46][CH:47]=[CH:48][C:49]=1[I:50])([CH3:40])([CH3:39])[CH3:38].CI>CCCCCCC.CCOC(C)=O>[C:37]([O:41][C:42](=[O:52])[N:43]([C:44]1[C:45]([Cl:51])=[N:46][CH:47]=[CH:48][C:49]=1[I:50])[CH3:2])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1c(I)ccnc1Cl
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCCCCCC
Product: CN(C(=O)OC(C)(C)C)c1c(I)ccnc1Cl

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from (2-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (CAS RN 855784-39-3) and methyl iodide and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (88%). MS (ESI): m/z=368.99 [M+H]+.
Reaction SMILES: [OH-].[Na+].C(O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33](=[O:51])[N:34]([CH2:38][CH2:39][N:40]4[CH2:45][CH2:44][CH:43]([C:46]([O:48]CC)=[O:47])[CH2:42][CH2:41]4)[CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1.Cl>O.O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[C:33](=[O:51])[N:34]([CH2:38][CH2:39][N:40]4[CH2:41][CH2:42][CH:43]([C:46]([OH:48])=[O:47])[CH2:44][CH2:45]4)[CH:35]=[CH:36][CH:37]=3)=[CH:30][CH:31]=2)=[O:25])=[O:15])=[N:11][CH:12]=1
Reactant: CCOC(=O)C1CCN(CCn2cccc(-c3ccc(C(=O)Nc4c(O)cccc4C(=O)Nc4ccc(Cl)cn4)cc3)c2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCC(C(=O)O)CC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88.6 %

Procedure:
An aqueous 1 M sodium hydroxide solution (3.0 ml) was added to an ethanol (5 ml)-tetrahydrofuran (5 ml) solution of ethyl 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridin-1(2H)-yl]ethyl}piperidine-4-carboxylate (392 mg), followed by stirring at room temperature for 19 hours. 1 M hydrochloric acid (3.0 ml) and water (50 ml) were added to the reaction mixture, followed by extraction with chloroform-isopropanol. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1-{2-[3-(4-{[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}-6-hydroxyphenyl)amino]carbonyl}phenyl)-2-oxopyridin-1(2H)-yl]ethyl}piperidine-4-carboxylic acid (332 mg) as a pale yellow solid.