Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:12](Cl)[N:11]=1)=[O:8])=[O:5].N[C:29]1C=NC(C2C=CC(Br)=CC=2)=C(Cl)N=1.ClC1C=CC=CC=1C(N=C=O)=O>>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[C:12]([CH3:29])[N:11]=1)=[O:8])=[O:5]
Reactant: Nc1cnc(-c2ccc(Br)cc2)c(Cl)n1
Reactant: O=C(NC(=O)c1ccccc1Cl)Nc1cnc(-c2ccc(Br)cc2)c(Cl)n1
Agent: O=C=NC(=O)c1ccccc1Cl
Product: Cc1nc(NC(=O)NC(=O)c2ccccc2Cl)cnc1-c1ccc(Br)cc1

Procedure:
1-(2-Chlorobenzoyl)-3-[5-(4-bromophenyl)-6-chloro-2-pyrazinyl]urea, weighing 1.4 g., and having a melting point of about 240°-242° C., from 0.9 g. of 2-amino-5-(4-bromophenyl)-6-chloropyrazine and 0.65 g. of 2-chlorobenzoylisocyanate.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][OH:24])[CH3:5].[CH3:25]I.O>O1CCCC1>[CH3:3][N:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:5]
Reactant: CI
Reactant: CCCCOc1ccc(OCCCN(C)C)c(CCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(OCCCN(C)C)c(CCCOC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (51 mg) was added portionwise over a period of 5 minutes to a stirred solution of N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine (330 mg) in tetrahydrofuran (8 ml) at a temperature of 0° C. and under an atmosphere of argon. The reaction mixture was allowed to warm to 25° C. and stirred for a further 0.5 hour. The reaction mixture was cooled to 0° C. and methyl iodide (0.4 ml) added. The reaction mixture was allowed to warm to 25° C. and the reaction mixture was stirred for a further 15 hours. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (4×15 ml). The ethyl acetate extracts were combined, washed with water (10 ml), dried (MgSO4) and evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 75:25:0.2 mixture of ethyl acetate, hexane, and triethylamine as eluent to give N,N-dimethyl-3-[4-butoxy-2-(3-methoxypropyl)phenoxy]propylamine as a yellow oil (70 mg), NMR ([CD3 ]2SO): 0.92(3H,t), 1.42(2H,m), 1.70(4H,m), 2.1(2H,m), 2.5(6H,s), 2.9(2H,m) and 3.2(3H,s), 3.31(2H,t), 3.9(4H,m), 6.7(2H,s), and 6.82(1H,d); m/z 324 (M+H). The N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine used as starting material was prepared as follows.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[N:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:2].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C.[Na:42].[OH-].[Na+]>C(Cl)Cl.C(O)C>[Na:42].[C:28]([NH:23][S:20]([C:17]1[CH:18]=[N:19][C:14]([N:6]2[C:7]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:3]([C:1]#[N:2])[C:4]([C:24]([F:26])([F:27])[F:25])=[N:5]2)=[CH:15][CH:16]=1)(=[O:21])=[O:22])(=[O:30])[CH3:29]
Reactant: CC(C)(C)CNc1c(C#N)c(C(F)(F)F)nn1-c1ccc(S(N)(=O)=O)cn1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2NCC(C)(C)C)nc1
Yield: 80 %

Procedure:
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid amide (166.3 mg, 0.413 mMol), was dissolved in methylene chloride (10 ml) and stirred under nitrogen. Acetic anhydride (126.5 mg, 1.239 mMol), triethylamine (49.3 mg, 0.49 mMol) and N,N-dimethylaminopyridine (25.2 mg, 0.5 mMol) were added into the methylene chloride solution, and stirred for 18 hours. The reaction mixture was washed with water and brine, dried with magnesium sulfate, filtered, and evaporated. The residue was chromatographed on silica, eluting with 0.75% methanol/methylene chloride, to give a free acid in 80% yield. The free acid was converted to the sodium salt by reacting the free acid with one equivalent of sodium hydroxide in ethanol, evaporation, and drying under high vacuum. The desired product was isolated by chromatography on silica gel column. MS: 443.5 ES, r.t.: 3.0 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cccc(F)c1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cccc(F)c2)cc1

Procedure:
31.5 mg of white lyophilizate 3-{4-[3-(3-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 3-fluorophenyl isocyanate.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12](OC)=[O:13])[C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][C:3]1=2.[NH3:19]>CO>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([NH2:19])=[O:13])[C:6]2=[N:5][C:4]2[CH2:16][CH2:17][CH2:18][C:3]1=2
Reactant: N
Reactant: COC(=O)c1cccn2c(=O)c3c(nc12)CCC3
Solvent: CO
Product: NC(=O)c1cccn2c(=O)c3c(nc12)CCC3
Reaction time: 24 h

Procedure:
A solution of 2.44 g. of the product from Example 5 in 50 ml of methanol is cooled to -10° and a stream of dry ammonia gas is introduced. When the increase in weight of the absorbed ammonia is 3.4 g., the addition is stopped, the flask is sealed, and kept at 20°-25° for 24 hours. The solid that separates is filtered and recrystallized from 2-propanol to give the named compound as colorless needles.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.O1CCCC1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.1 g), p-toluenesulfonic acid monohydrate (0.1 g), methanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetone (20 mL), 1 N hydrochloric acid (20 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2 g, 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8].[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.B>CO>[C:34]1([CH2:33][NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]2[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[N:22]=2)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:20]=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:8])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Agent: B
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(N(CCCNCc2ccccc2)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Reaction time: 0.25 h

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (50 mg, 0.11 mmol) (a compound of formula (Yc6)) in methanol (2 mL) was added benzaldehyde (0.2 M in methanol, 68 μL, 0.14 mmol). After stirring for 15 minutes, borane-pyridine complex (0.2 M in methanol, 0.14 mmol) was added. After 2 hours, the solution was evaporated. The residue was partitioned into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (2:1 ethyl acetate/hexanes) to provide 2-[[3-(phenylmethylamino)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc8); as a white solid; NMR (CDCl3) 8.65 (s, 1), 7.7 (s, 1), 7.2 (br, 5), 7.1 (s, 1), 6.6 (d, 1), 6.55 (s, 1), 6.5 (d, 1), 6.1 (br, 2), 5.9 (s, 2), 3.95 (br, 2), 3.5 (br, 6), 2.7 (m, 3), 2.35 (s, 6) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:17])=[O:16])=[C:13]=[O:14].CCCCCCC>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13](=[O:14])[NH:12][S:15]([O:18][C:19]2[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=2[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22])(=[O:16])=[O:17])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1C(=O)OCCCl
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
2.02 g (0.013 mole) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 80 ml of dichloromethane, and 4.28 g (0.014 mole) of 2-chloroethyl 2-isocyanatosulfonyloxybenzoate, dissolved in 20 ml of dichloromethane, are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours and is then stirred into 600 ml of n-heptane. In this manner, 4.72 g (79% of theory) of 2-chloroethyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyloxy]-benzoate of melting point 148°-150° C. are obtained.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]([OH:20])[C:1]([CH3:3])=[CH2:2])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: C=C(C)[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
35.9 ml (16.33 mmol) of a 0.5 M isopropenylmagnesium bromide solution in THF are slowly added at −78° C. to a solution of 3.0 g (11.66 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 50 ml of THF. After addition is complete, the mixture is stirred at −78° C. for 2 h, then treated with 40 ml of water and warmed to room temperature. The mixture is treated with 10 ml of 1 N hydrochloric acid, the aqueous phase is extracted 2× with ethyl acetate, and the combined organic extracts are dried over sodium sulphate and freed from the solvent in vacuo. Purification of the crude product on silica gel (CH2Cl2) affords 1.7 g (48.7%) of 1-[5-(benzyloxy)-2-nitrophenyl]-2-methyl-2-propen-1-ol as a yellow oil.
Reaction SMILES: [CH2:1]([S:5]Cl)[CH2:2][S:3]Cl.[CH2:7]([NH:14][C:15](=[S:17])[S-:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+]>>[CH2:7]([NH:14][C:15]([S:16][S:3][CH2:2][CH2:1][S:5][S:17][C:15](=[S:16])[NH:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[S:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: S=C([S-])NCc1ccccc1
Reactant: ClSCCSCl
Agent: [Na+]
Product: S=C(NCc1ccccc1)SSCCSSC(=S)NCc1ccccc1

Procedure:
Bis-dithiocarbamates from primary amines are similarly prepared. For example, addition of 1,2-ethanedisulfenyl chloride solution to an aqueous solution of sodium benzyldithiocarbamate gives nearly a quantitative yield of 1,2-bis(N-benzylthiocarbamoyldithio)ethane, m.p. 105°-110°C, decom., NMR 7.3 singlet, 4.9 mult., 3.4 singlet and 3.15 singlet.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][NH:21][C:22]([O:24]CC)=O)=[O:19])=[CH:13][CH:12]=1)[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].Cl.O1CCOCC1>CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18](=[O:19])[NH:20][NH:21][C:22]2=[O:24])=[CH:15][CH:16]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(NC(=O)NNC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: C#CCOCCOCCOc1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To ethyl 2-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenylcarbamoyl)-hydrazinecarboxylate (1.31 g, 3.59 mmol) in methanol (17.93 mL) was added K2CO3 (1.239 g, 8.96 mmol). The mixture was stirred at 55° C. for 30 minutes. After cooling to room temperature, 4N HCl in dioxane (3.59 mL, 14.34 mmol) was added. The precipitate was filtered, and the filtrate was concentrated in vacuo. The residue was then purified by silica gel chromatography (40-100% ethyl acetate/heptane) giving 4-(4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenyl)-1,2,4-triazolidine-3,5-dione (I-7d: 318 mg, 28%) as a white oily solid. LC-MS (M+1) 320.0, t=0.73 minute. 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=2.15 Hz, 1 H) 3.68-3.83 (m, 4 H) 3.83-3.97 (m, 2 H) 4.11-4.32 (m, 4 H) 7.04 (d, J=8.84 Hz, 2 H) 7.36 (d, J=8.84 Hz, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>>[CH3:14][O:15][CH2:16][C:17]([N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1)=[O:18]
Reactant: COCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Product: COCC(=O)N1CCCc2ccc([N+](=O)[O-])cc21

Procedure:
Using the procedure outlined in Description 4, the title compound was prepared from 7-nitro-1,2,3,4-tetrahydroquinoline (D1) (178 mg, 1 mmol) and methoxyacetyl chloride (101 ul, 1.1 mmol) as a yellow gum (212 mg). 1H NMR (250 MHz, CDCl3) δ (ppm): 8.54 (br, 1H), 7.96 (dd, 1H), 7.30 (d, 1H), 4.25 (s, 2H), 3.81 (m, 2H), 3.48 (s, 3H), 2.88 (t, 2H), 2.04 (qn, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][OH:11])[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(O)(=O)C(C)O>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][O:11][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[C@H:8]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]1=[O:22]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CO)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2COS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Under stirring at 0° C., 1.73 g of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine is added to a solution of 1.12 g of p-toluenesulfonyl chloride in 6 ml of pyridine. The reaction mixture is stirred for 2 hours and then allowed to stand overnight in a refrigerator. To the reaction mixture is added 0.68 ml of lactic acid and the mixture is stirred for one hour. The reaction mixture is diluted with 45 ml of ethyl acetate and 15 ml of tetrahydrofuran, and then washed with dilute hydrochloric acid, and aqueous sodium chloride solution, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution in this order. The organic solution is dried over magnesium sulfate and the solvent is distilled off in vacuo. To the residue is added a mixed solvent of ether and ethyl acetate (5:1) and the resulting crystals are collected by filtration to give 2.21 g (91%) of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymethyl)-2-oxoazetidine, m.p. 109°-110° C.
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[N:14]=[C:13]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@H:7]([O:12]2)[CH2:6]3)[CH:3]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:6][CH2:7][C:8]([O:11][CH2:10][CH:8]1[O:9][CH:5]2[N:4]3[C:13]([O:12][CH:7]1[CH2:6]2)=[N:14][C:15](=[O:16])[C:2]([CH3:1])=[CH:3]3)=[O:9]
Reactant: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO
Reactant: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCC1OC2CC1Oc1nc(=O)c(C)cn12
Reaction time: 8 h

Procedure:
Anhydrothymidine (0.520 g, 2.319 mmol, as a dry white powder) was dissolved in anhydrous pyridine (10 ml) under an atmosphere of dry nitrogen, and to this stirred solution at room temperature was added GLA acid chloride (0.900 g, 3.02 mmol). Stirring was continued overnight after which period, TLC indicated complete loss of the starting material. The pyridine was
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][C:14]([CH:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)=[CH:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH:11]2[CH2:16][CH2:15][C:14]([CH:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[CH:13][CH2:12]2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(C2CC=C(C3CCC(=O)CC3)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1CCC(C2CC=C(C3CCC(O)CC3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
In 50 ml of ethanol was dissolved 4.0 g (13 mmol) of the 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)cyclohexanone described above, and the solution was cooled down to 0° C. Sodium borohydride in an amount of 0.25 g (6.6 mmol) was gradually added thereto such that the liquid temperature did not exceed 15° C., and the mixture was stirred for 1 hour. Water in an amount of 50 ml was added to the reaction solution, the product thus formed was extracted with ether, the extract was washed with 1N hydrochloric acid and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=3/1), the solvent was distilled off. The residue was recrystallized from ethanol to give 1.6 g (5.0 mmol) of 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)cyclohexanol. Yield of this compound based on 4-(4-(4-n-butylcyclohexyl)-1-cyclohexenyl)-cyclohexanone was 38%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](Br)[CH:3]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N+:8]([C:6]1[CH:7]=[C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=[C:4]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)([O-:10])=[O:9]
Reactant: C#Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 1,3-dibromo-5-nitrobenzene (0.56 g, 2.00 mmol), bis(triphenylphosphine)palladium(II) chloride (0.10 g, 0.14 mmol) and copper(I) iodide (0.027 g, 0.14 mmol) in Et3N was degassed (three times). Phenylacetylene (0.50 g, 4.88 mmol) was added and mixture was stirred overnight. The reaction mixture was filtered through a celite pad and the pad was rinsed with CH2Cl2. The filtrate was washed with brine and the organic layer was dried with (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (Dichloromethane;Hexane=1:10) to afford ((5-nitro-1,3-phenylene)bis(ethyne-2,1-diyl))dibenzene (0.33 g, 51% yield): 1H-NMR (400 MHz, CDCl3) δ 8.30 (d, J=1.3 Hz, 2H), 7.96 (t, J=1.3 Hz, 1H), 7.56 (m, 4H), 7.40 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[N:29][C:28]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:28]1[N:29]=[CH:30][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=1
Reactant: CC(C)(C)OC(=O)NCc1ncn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cnc(CN)n1)c1csc(N)n1)C(=O)O
Yield: 65.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((3-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (223 mg, 0.283 mmol), DCM (2.89 mL) and TFA (1.31 ml, 16.98 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (99 mg, 65%) as a white powder. LCMS: Rt=0.31 min, m/z=532.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.45 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.39 (br s, 3H), 7.32 (s, 2H), 6.74 (s, 1H), 5.23 (dd, J=8.5, 5.7 Hz, 1H), 4.76-4.65 (m, 1H), 4.62-4.55 (m, 1H), 4.32-4.27 (m, 1H), 4.16-4.08 (m, 2H), 1.36 (s, 3H) 1.43 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][C:22](=[O:36])[NH:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([CH2:34][OH:35])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:21][C:22]([NH:23][CH:24]2[C:33]3[C:28](=[CH:29][C:30]([CH2:34][OH:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:36])[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CC(=O)NC1CCCc2cc(CO)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC1CC(OCc2ccccc2)CN1)NC1CCCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Benzyloxy-2-[(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg. 97 mmol) was dissolved in 25 mL CH2Cl2 and treated with 10 mL TFA and stirred at RT for 15 min, then concentrated to afford the title compound as a colorless glass. (MS,395, M+H).