Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:19])OC)[N:8]=1.[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24]>CO>[C:23]([NH:26][NH:27][C:16](=[NH:19])[CH2:15][CH2:14][CH2:13][CH2:12][N:9]1[CH:10]=[N:11][C:7]([NH:6][C:5]([NH2:20])=[N:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[N:8]1)(=[O:25])[CH3:24]
Reactant: CC(=O)NN
Reactant: COC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: CC(=O)NNC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A solution of methyl 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valerimidate (0.5 g.) in MeOH (5 ml.) and acethydrazide (0.17 g.) was allowed to stand at room temperature for 3 hours. The solution was evaporated to give a sticky solid which was triturated with ether/EtOH to give N-acetylamino-5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramidine as a white solid (0.71 g.), m.p. 157°-159°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17]O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:42]C(=O)C2=CC=CC=C12.N(C(OCC)=O)=NC(OCC)=O.O.NN>O1CCCC1.C(O)C>[NH2:42][CH2:17][C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CN)cc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In tetrahydrofuran (100 ml), 5-tert-butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (WO94/21599) (2.10 g) was dissolved. After the addition of triphenylphosphine (2.66 g) and phthalimide (1.15 g), diethyl azodicarboxylate (1.28 ml) was added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby a colorless solid was obtained. The resulting solid was dissolved in ethanol (40 ml), followed by the addition of hydrazine hydrate (0.39 ml). The resulting mixture was heated under reflux for 5 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=25:1), whereby the title compound (448 mg, 21%) was obtained.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.[NH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C1CCC(N=C=NC2CCCCC2)CC1>ClC(Cl)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
2.03 g of TEA was added to a mixture of 5.84 g of Boc-Phe-OH and 7.03 g of TosOH.β-Ala-OBzl in 80 ml of dichloroethane. 4.54 g of DCC was added to the solution at 0 ° C. After stirring for 3 hrs at 0 ° C. and overnight at room temperature, precipitated DCUrea was filtered off and the solvent was distilled in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 10% citric acid aqueous solution, water, 5% sodium hydrogencarbonate aqueous solution and brine. After dehydration over sodium sulfate anhydride, the solvent was evaporated to give 8.36 g of Boc-Phe-β-Ala-OBzl; yield 98%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:12]1[CH:17]=[C:16]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:28]([O:37][CH3:38])([C:33]([F:36])([F:35])[F:34])[C:29]([F:32])([F:31])[F:30])[CH:13]=1)([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].C(Cl)(=[O:42])C=C>>[C:18]([OH:27])(=[O:42])[CH:16]=[CH2:17].[CH3:38][O:37][C:28]([C:14]1[CH:15]=[C:16]([C:18]([OH:27])([C:23]([F:24])([F:25])[F:26])[C:19]([F:20])([F:21])[F:22])[CH:17]=[C:12]([C:3]([O:2][CH3:1])([C:4]([F:5])([F:6])[F:7])[C:8]([F:9])([F:10])[F:11])[CH:13]=1)([C:29]([F:32])([F:31])[F:30])[C:33]([F:36])([F:35])[F:34]
Reactant: C=CC(=O)Cl
Agent: COC(c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(OC)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Product: C=CC(=O)O
Reaction time: 2 h

Procedure:
A solution of 14.00 g (0.232 mole) 1,3-bis-(2-methoxyhexafluoro-5-(2-hydroxyhexafluoro-2-propyl)-benzene (II) in 40 ml of Freon 113 was stirred magnetically in a 200 ml 3-deck flask equipped with a dropping funnel, thermometer, dry ice-acetone condenser and drying tube (CaCl2). 24.6 g of triethylamine dissolved in 15 ml of Freon 113 was added dropwise during 20 minutes with slight exotherm. An external cooling bath (ice water) was applied. Then a second dropping funnel charged with 2.20 g (0.024 mole) of acryloyl chloride (III) dissolved in 15 ml of Freon 113 was quickly substituted in place of the empty funnel. The latter charge was added during 30 minutes at 10°-20° C. After stirring an additional 2 hours, the resulting white slurry was vacuum filtered (60 ml C filter -3 g of Celite cake). Flash evaporation of the filtrate left 15.5 g of honey-like residue that readily crystallized (mp 58°-62° C.) and analyzed 80 mole % diether acrylate (IV), 17% unreacted diether o1 (II), and 3% acrylic anhydride. Trituration of this mixture in 100 ml of a 2% sodium hydroxide solution followed by neutralization led to 13.1 g of white crystals (mp 61°-62° C.) analyzing 90.6% (IV) and 9.4% (II), with no acrylic anhydride. The 13.1 g of crude ester was submitted again to the customary esterification procedure using 1.21 g of triethylamine and 1.07 g of acryloyl chloride. This led to 12.9 g of crystals analyzing 94.3 mole % (IV) and 5.7% acrylic anhydride. Workup in 2% sodium hydroxide solution led to 12.6 g of white crystals (mp 65°-66° C.) of 100% purity (IV) by GLC. Recrystallization from petroleum ether at -70° F. (-57° C.) gave 11.7 g analytical (IV) as extremely water repellent white crystals; 76.7% yield; mp 66° C. By analysis as calculated for C20H12F18O4 : C, 36.49; H, 1.84; F, 51.95; as found: C, 36.58; H, 1.79; F, 51.96.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:20]3[CH:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:15][C@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: c1ccc(CN2CC[C@@H]3CNC[C@@H]32)cc1
Product: Clc1ccc(N2C[C@H]3CCN(Cc4ccccc4)[C@H]3C2)cn1
Yield: 65.3 %

Procedure:
cis-1-Benzyloctahydropyrrolo[3,4-b]pyrrole (500 mg, 2.48 mmol), prepared as described in (U.S. Pat. No. 5,071,999), and 2-chloro-5-iodopyridine (643 mg, 2.69 mmol), prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496), were processed as described in Example 1E to provide the title compound as a tan solid (508 mg, 65% yield). MS (DCI/NH3) m/z 314, 316 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1Cl)=[O:11].[SH2:25].[Na]>CCOCCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]=1[SH:25])=[O:11]
Reactant: S
Reactant: Cc1nn(-c2ccccc2)c(Cl)c1C(=O)NCCc1ccccn1
Agent: [Na]
Solvent: CCOCCO
Product: Cc1nn(-c2ccccc2)c(S)c1C(=O)NCCc1ccccn1
Yield: 81.5 %

Procedure:
Using the procedure of Preparation 34, 29.3 g (0.087 mol) of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (2-pyridin-2-yl-ethyl)-amide was reacted with 19.3 g (0.27 mol) sodium hydrogen sulfide in cellosolve to give 24.0 g of the title compound, which was used in Example 22 without purification.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=2)(=O)=O)=CC=1.[CH2:22]([O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([Br:21])=[CH:14][N:13]=2)=[CH:35][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ncc(Br)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
5-Bromo-3-nitropyridin-2-yl 4-methylbenzenesulfonate (38.2 g, 0.102 mmol) and 4-benzyloxyaniline (24.13 g, 0.102 mmol) were suspended in 900 mL of toluene under N2, treated with triethylamine (14.27 mL, 0.102 mmol) and the mixture heated at 110° C. for 16 h. Then, the reaction mixture was diluted with CH2Cl2 (1 L), washed with 2M HCl (aq) (4×500 mL) and brine (500 mL), and the combined organic extracts dried over Na2SO4 and then concentrated in vacuo. The crude product thus isolated was crystallized twice from ethanol to yield N-[4-(benzyloxy)phenyl]-5-bromo-3-nitropyridin-2-amine. 1H NMR (400 MHz, CDCl3) δ 5.11 (s, 2H), 7.04 (d, 2H, J=9.2 Hz), 7.34-7.50 (m, 7H), 8.48 (d, 1H, J=2.4 Hz), 8.66 (d, 1H, J=2.4 Hz), 9.94 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1)#[N:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:26])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(CO)cn1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
2-Cyano-5-hydroxymethylpyridine (13.4 g) and pyridine (8.7 g) were dissolved in toluene (150 ml), and a solution of p-toluenesufonyl chloride (19.1 g) in toluene (50 ml) was added dropwise at room temperature to the solution. After the addition, the mixture was gradually heated, and stirred at 70° to 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and washed with water. The organic layer was dried. Toluene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2-cyano-5-pyridylmethyl chloride (7.7 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:32])=[CH:11][C:10]=1[C:16]1[N:17]([CH3:22])[N:18]=[CH:19][C:20]=1[Br:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccccc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2)ccc1OCc1ccccc1
Yield: 22.2 %

Procedure:
4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 μL, 0.10 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), similar manner as described in Example 1.2 to afford Compound 62 (0.011 g, 0.02 mmol, 26%) as a white solid. LCMS m/z (%)=511 (M+H79Br, 82), 513 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.12 (s, 2H), 7.66 (dd, J=2.6, 8.9 Hz, 1H), 7.54 (dd, J=4.8, 9.0 Hz, 2H), 7.50 (s, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.25-7.36 (m, 5H), 7.22 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 5.13 (AB quartet, J=12.0, 24.4 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].Cl[C:17]([O:19][CH2:20][CH2:21][Cl:22])=[O:18]>COCCOC.O>[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:17](=[O:18])[O:19][CH2:20][CH2:21][Cl:22])([O-:8])=[O:7]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCCCl
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
135 g of calcium carbonate are added to a solution of 345.3 g of 2-nitroaniline in a mixture of 1020 g of monoethylene glycol dimethyl ether and 150 g of water and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are then added in the course of 3 hours. The mixture is subsequently stirred at the reflux temperature for 1.5 hours, until the reaction is complete, and is cooled to 35° C., and the product is precipitated with water and ice. The product is filtered off, washed with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[O:31]1[C:33]([CH3:35])([CH3:34])[CH2:32]1>C(#N)C>[CH3:32][C:33]([OH:31])([CH3:35])[CH2:34][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(C)CO1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CC#N
Product: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (1 equiv) in acetonitrile (1 M) was added 1,8-diazabicycloundec-7ene (2 equiv) and 1,2-epoxy-2-methylpropane (3.2 equiv). The reaction mixture was stirred at 60° C. for 20 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with HCl (1 N), water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound which was directly used in the next step without further purification (73% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.26 (s, 1H), 8.09 (s, 1H), 4.13 (s, 2H), 2.64 (s, 1H) 1.24 (s, 6H). MS (ESI) m/z 186.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[OH:35][C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:20]2[S:19][C:18]([NH:17][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH2:9][OH:10])[N:7]=3)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=2)=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CO)N4CCOCC4)n3)s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (194 mg, 0.68 mmol) and 2-amino-5-[4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (190 mg, 0.69 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:31])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[N:19]=2)[C:8]1=[O:30].[OH-].[Na+:35]>O>[CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:31])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O-:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[N:19]=2)[C:8]1=[O:30].[Na+:35]
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A suspension of the product of Example 35I (0-99 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.213 mL, 0.212 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.104 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.59 (m, 1 H) 0.74 (m, 9 H) 0.95 (m, 5 H) 1.39 (m, 3 H) 1.72 (m, 1 H) 2.14 (m, 1 H) 7.30 (m, 3 H) 7.50 (m, 3 H) 7.65 (m, 1 H) 8.05 (m, 1 H) 15.45 (m, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([C:22](=[N:28][OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][P:17]([C:22](=[N:28][O:29][C:8](=[O:9])[CH:7]([O:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:16][CH2:14][CH3:15])[CH3:20]
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCCCCC(=NO)P(=O)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC(=NOC(=O)C(C)Oc1ccc(Cl)cc1)P(=O)(OCC)OCC
Temperature: 55 °C
Reaction time: 9 h
Yield: 79.5 %

Procedure:
8.8 g (0.04 mole) of 2-(4-chlorophenoxy)-propionyl chloride, dissolved in 20 ml of toluene, were added dropwise to a solution of 10.0 g (0.04 mole) of 1-hydroximinohexanephosphonic acid diethyl ester and 5.0 g (0.05 mole) of triethylamine in 80 ml of toluene. The mixture was subsequently stirred at 55° C. for 9 hours and cooled, the triethylamine hydrochloride which had precipitated was filtered off with suction and the organic phase was washed with water. After drying with Na2SO4, evaporating off the toluene on a rotary evaporator and removing, under a high vacuum, the solvent which still adhered, 13.8 g (77.8%) of 1-[2-(4-chlorophenoxy)-propionyloximino]-hexanephosphonic acid diethyl ester of nD22 =1.4919 were obtained.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbonitrile, L series (12.57 g) and triethylamine (5.5 cc) in pyridine (115 cc) is treated with hydrogen sulphide by bubbling in for 2 hours. After 16 hours' stirring at a temperature in the region of 25° C., the light brown solution obtained is purged with nitrogen for 2 hours, diluted with ethyl acetate (300 cc), washed with distilled water (10×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The yellow product (13.3 g) of meringue-like consistency is purified by chromatography on a column (height: 47 cm; diameter: 3.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (2 liters) and collecting 125-cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (10.6 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH2:21][CH3:22])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23]S(O)(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH2:21][CH3:22])([C:18]([NH2:19])=[O:23])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-ethylaminoazetidine-3-carbonitrile (I-(13A-9)d; 11.7 g, 40 mmol) in methylene chloride (150 ml) cooled in an ice bath was treated with H2SO4 (22 ml, 0.4 mol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated NH4OH to pH 11. The off-white solids that formed during the quench were collected by vacuum filtration. The aqueous mixture was then extracted with methylene chloride, the combined organic layers were washed with brine, dried (Na2SO4) and then concentrated, in vacuo, to afford additional solids. The combined solids were stirred for 1 hour in ethyl acetate (150 mL) and then collected by vacuum filtration to give I-(13A-9)e (9.2 g, 74%) as a solid: +ES MS (M+1) 310.2; 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J=7.1 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.5 Hz, 2H), 4.49 (s, 1H), 3.44 (d, J=8.3 Hz, 2H), 3.11 (d, J=8.3 Hz, 2H), 2.47 (q, J=7.1 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([OH:62])[CH3:61])=[CH:54]4)[CH:46]([O:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2].[CH3:69][N:70]([CH3:75])[CH2:71][C:72](O)=[O:73].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:65])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[NH:56][C:55]([CH:60]([O:62][C:72](=[O:73])[CH2:71][N:70]([CH3:75])[CH3:69])[CH3:61])=[CH:54]4)[CH:46]([O:63][CH3:64])[CH2:45]2)[CH:7]([CH3:66])[CH:6]([OH:67])[CH2:5][C:4]1=[O:68])[CH3:2]
Reactant: CN(C)CC(=O)O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)O)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5[nH]c(C(C)OC(=O)CN(C)C)cc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)- 1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (26.6 mg) in dry methylene chloride (0.3 mL) was added hydrochloride salt of N,N-dimethylglycine (5.8 mg), DMAP (3.4 mg) and EDC (8 mg), respectively at room temperature. The reaction mixture was stirred for 4 h, then diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The crude material was purified by flash chromatography (1:2/acetone:hexane) to give 23 mg of the title compound.