Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)([C:53]([O:55]CC)=[CH2:54])CCCCC)CCC.[F-].[K+]>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.O1CCCC1>[C:53]([C:2]1[CH:42]=[CH:41][C:5]([O:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)=[CH:4][CH:3]=1)(=[O:55])[CH3:54]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCCC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(Br)cc3)CC2)c2ncnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12

Procedure:
A mixture of 4′-({4-[trans-4-(4-bromophenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.67 g), dibutyl(1-ethoxyethenyl)pentylstannane (0.45 mL), dichlorobis(triphenylphosphine)palladium (0.038 g) and tetrahydrofuran (3 mL) was heated under reflux for 64 hr. Aqueous potassium fluoride solution was added, and the obtained mixture was extracted with ethyl acetate. The organic layer was 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 (0.39 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.Br[CH2:14][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C>CCOCC>[OH:16][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH2:8][CH2:9]1
Reactant: NC(=O)c1cc(C(O)CBr)ccc1O
Reactant: Cc1csc(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1csc(N2CCN(CC(O)c3ccc(O)c(C(N)=O)c3)CC2)n1
Reaction time: 2 h

Procedure:
18.9 g of 1-(4-methyl-2-thiazolyl)-piperazine and 26 g of 5-(2-bromo-1-hydroxyethyl)-salicylamide (obtainable by acylation of salicyamide with bromoacetyl bromide/AlCl3 to give 5-bromoacetyl-salicylamide and subsequent reaction with NaBH4) are dissolved in 400 ml of ether, 15 ml of triethylamine are added, the mixture is boiled for 2 h and subjected to the usual working-up, and 5-[1-hydroxy-2-(4-(4-methyl-2-thiazolyl)-piperazino)-ethyl]salicylamide ("A"), m.p. 182°, is obtained. Dihydrochloride m.p. 244°-245°.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.C(OCC)(=O)C.O.[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(N(CC)CC)C>[C:8]1([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](N)C(=O)O
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(Nc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
A mixture of alanine (356 mg, 4.0 mmol), iodobenzene (816 mg, 4.0 mmol), trans-dichlorobis(tri-o-tolylphosphine) palladium (II) {Pd[P(o-Tol)3]2Cl2} (160 mg, 0.2 mmol), copper (I) iodide (40 mg, 0.2 mmol), K2CO3 (552 mg, 4.0 mmol), benzyltriethylammonium chloride (160 mg, 0.8 mmol), triethylamine (1.6 mL) and water (0.8 mL) in DMF (8 mL) was stirred under nitrogen atmosphere at 100° C. for 20 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL), acidified with 6N HCl to the pH=2 to 3. The aqueous layer was extracted with ethyl acetate (50 mL×4). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a red oil. Flash chromatography using hexane/ethyl acetate/acetic acid (95/5/0.5 to 80/20/0.5) to afford 300 mg (45% yield) of the title compound as a pink solid. 1H-NMR (500 MHz, CDCl3/CD3OD=0.5 ml/3 drops) δ 1.45 (d, 3H), 4.02-4.15 (m, H), 6.57-6.70 (m, 3H), 7.11-7.25 (m, 2H); Analytical HPLC: 6.10 min. LC-MS: m/e=166 (M+H+).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:12][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1OCCO1.CS(O)(=O)=O.F[P-](F)(F)(F)(F)F.[K+]>O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[F:27][C:25]1[CH:26]=[C:9]([F:8])[C:10]2=[CH:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N+:13]=3[CH:12]=[C:11]2[CH:24]=1
Reactant: Fc1cc(F)cc(C[n+]2ccccc2C2OCCO2)c1
Agent: CS(=O)(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: Fc1cc(F)c2cc3cccc[n+]3cc2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 1-(3,5-difluorobenzyl-2-(1,3-dioxolan-2-yl)pyridinium hexafluorophosphate (9 g; 0.021 mol), polyphosphoric acid (90 g), and 9 ml of methanesulfonic acid was heated at 110° C. for 7 hours and then stirred at room temperature overnight. The reaction mixture was poured into 200 ml of water and a warm solution of 9 g of potassium hexafluorophosphate in water was added with stirring. The resulting pale yellow solid product was filtered and dried to afford 6.5 g (86%) of 8,10-difluorobenzo [b]quinolizinium hexafluorophosphate (Formula IV: R1 =R7 =H; R2 =8,10--F2 ; X- =PF6-).
Reaction SMILES: N#[C:2][Br:3].C(N(CC)C[C:8]#[C:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]([CH3:16])[C:12]1=[O:17])C>O1CCOCC1>[Br:3][CH2:2][C:8]#[C:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]([CH3:16])[C:12]1=[O:17]
Reactant: CCN(CC)CC#CCn1ccn(C)c1=O
Reactant: N#CBr
Solvent: C1COCCO1
Product: Cn1ccn(CC#CCBr)c1=O

Procedure:
Cyanogen bromide (6.0 g, 0.057 mol) was added to a stirred solution of 1-[4-(diethylamino)-2-butynyl]-1,3-dihydro-3-methyl-2H-imidazol-2-one in dioxane (130 mL). After evaporation of the dioxane, the residual oil was chromatographed on silica gel using chloroform:1% methanol as the eluant to give 10.8 g of 1-(4-bromo-2-butynyl)-1,3-dihydro-3-methyl-2H-imidazol-2-one as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(OCC(C)C)=O.[CH3:38][N:39]1CCOC[CH2:40]1.CN>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([N:39]([CH3:40])[CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)N(C)C)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at −10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stirred for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The solid was chromatographed on silica (95:5 methylene chloride:isopropyl alcohol) to give the desired product as a white powder (0.31 g, 30%). 1H NMR (400 MHz, CD3OD) δ 7.64 (m, 1H), 7.50 (dd, J=2.4 and 7.2 Hz, 1H), 7.45 (t, J=9.6 Hz, 1H), 7.04 (t, J=9.2 Hz, 2H), 6.65 (s, 1H), 5.36 (s, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.51 (1F), −115.88 (1F), −121.90 (1F) ppm. ES-HRMS m/z 495.0508 (M+H calcd for C22H19BrF3N2O3 requires 495.0526).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][OH:14]
Reactant: O=Cc1nccs1
Reactant: NCCNCCO
Solvent: CCO
Product: OCCNCCNCc1nccs1
Reaction time: 4 h
Yield: 59.8 %

Procedure:
3 Å molecular sieves (22.5 g) and a solution of 2-thiazole-carboxaldehyde (14.5 g, 128 mmol) in ethanol (90 ml) were sequentially added to a solution of 2-(2-aminoethylamino)ethanol (13.35 g, 128 mmol) in anhydrous ethanol. The reaction mixture was stirred for 4 hours, filtered through a pad of Celite while washing with ethanol (100 ml) and placed in a high-pressure flask. After adding acetic acid (3 ml) and Pd (10% on C, 2 g), the solution was introduced into Parr apparatus and, after several hydrogenation cycles, was stirred for 2 days under a hydrogen atmosphere at 40 psi. The reaction mixture was filtered through a pad of Celite, evaporated under vacuum and purified by flash chromatography (silica, 80/20/10 CH2Cl2/MeOH/NH3 eluent) to, give 2-[2-[(2-thiazolylmethyl)amino]ethylamino]ethanol (15.4 g, 60% yield) as a brown oil.
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:18][CH2:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: Clc1ccccc1CBr
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)CC
Product: CCCc1c(C(=O)CC)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Yield: 115.2 %

Procedure:
Methyl 1-(2-chlorobenzyl)-3-propionyl-2-propylindole-6-carboxylate (436 mg) was prepared from methyl 3-propionyl-2-propylindole-6-carboxylate (260 mg) and 2-chlorobenzyl bromide (215 mg) in a similar manner to that of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:14]2[CH2:15][O:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.1 g piperidine-4-carboxylic acid ethyl ester, 6.4 ml epichlorohydrin and 0.1 g tetrabutyl-ammonium bromide in 15 ml toluene and 15 ml concentrated sodium hydroxide solution was stirred for 4 h at room temperature and subsequently admixed with 50 ml water. The organic phase was separated, the aqueous phase was shaken three times with 20 ml methylene chloride each time, the combined organic phases were dried over sodium sulfate and the solvent was removed in a vacuum. 2.1 g (rac)-1-oxiran-2-ylmethyl-piperidine-4-carboxylic acid ethyl ester was obtained. EI-MS: m/z 213 M+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH-].[Na+].[CH3:10][O:11][CH:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13]>N>[CH3:10][O:11][CH:12]([N:14]([CH3:5])[C:15](=[O:17])[CH3:16])[CH3:13]
Reactant: COC(C)NC(C)=O
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Product: COC(C)N(C)C(C)=O
Reaction time: 3 h
Yield: 457.4 %

Procedure:
25 g (0.2 mole) of dimethyl sulfate are added to 500 ml of 50% strength sodium hydroxide solution at 5°-10° C., and 158 g (1.25 moles) of dimethyl sulfate and 117 g (1.0 mole) of N-α-methoxyethyl-acetamide are simultaneously added dropwise in the course of 3 hours, while stirring. After a further 3 hours, 50 ml of concentrated ammonia are added, and after 30 minutes, the phases are separated in a separating funnel and the aqueous layer is extracted with diethyl ether. After stripping off the solvent, distillation of the residue in vacuo gives 120 g (92% of theory) of N-α-methoxyethyl-N-methyl-acetamide of boiling point18 76°-81° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[CH3:39])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([O:29][CH:26]([CH3:27])[CH3:28])=[C:31]([CH3:39])[CH:32]=3)=[O:35])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CN(Cc3ccccc3)CC3(CCNCC3)O2)cc1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
To a solution of 8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecane (100 mg, 0.28 mmol) and 4-isopropoxy-3-methyl-benzoic acid (54 mg, 0.28 mmol) in DMF (1 mL) was added DIEA (98 μL, 0.56 mmol) followed by the addition of HATU (128 mg, 0.34 mmol). The reaction mixture was stirred for 10 minutes, then quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 50% EtOAc/hexanes as eluent to obtain [8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (44 mg, 29%). ESI-MS m/z calc. 532.2. Found 533.3 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)cn1
Reaction time: 24 h

Procedure:
To a stirred suspension of 14.8 g of 2,5-dichloropyridine in 50 ml of methanol was added 30 ml of a 25% solution of sodium methoxide in methanol and the mixture was heated to reflux under nitrogen. After 24 hours, another 30 ml of the sodium methoxide solution was added and reflux was continued for a total of 68 hours. The sodium chloride which precipitated was removed by filtration and the filtrate was concentrated at atmospheric pressure to about 1/4 the original volume and partitioned between ether and water. The aqueous layer was extracted with ether and the combined ether layers were washed with saturated sodium chloride solution, dried over potassium carbonate and concentrated at atmospheric pressure to a pale brown oil. This residue was distilled to give 5-chloro-2-methoxypyridine as a colorless liquid boiling at about 82°-84° C. at 20 torr.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13](=O)[CH2:14]Br)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[N:20]=[C:17]([CH3:18])[S:19][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(=O)oc3cc(Br)ccc23)cs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-4-(bromoacetyl)-2H-chromen-2-one (1.45 g, 4.19 mmol) in N,N-dimethylformamide (12.5 mL), thioacetamide (346 mg, 4.6 mmol) was added. The reaction was then stirred overnight at 100° C. After cooling, the reaction mixture was dissolved with a 4:1 mixture of CH2Cl2/hexanes. The mixture obtained was washed (3×) with water and the organic layer was concentrated under reduced pressure. The solid obtained was swished in a 4:1 mixture of hexanes/EtOAc. The solid obtained was collected by filtration and used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.32 (d, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7.54 (d, 1H), 6.73 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:51]([O:55][C:56]([N:58]1[CH2:62][CH:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH:60]2[N:72]([C:75](=[O:82])[CH:76]([NH2:81])[C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:73][CH2:74][CH:59]12)=[O:57])([CH3:54])([CH3:53])[CH3:52].[OH-].[Na+]>CN1C(=O)CCC1.O>[C:51]([O:55][C:56]([N:58]1[CH2:62][CH:61]([O:63][CH2:64][C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH:60]2[N:72]([C:75](=[O:82])[CH:76]([NH:81][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:73][CH2:74][CH:59]12)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)C(N)C(C)(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)OC(C)(C)C)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A stirred solution of Cbz-N(Me)Ala-OH (7.85 g, 7.70 mmol), HATU (2.95 g, 7.70 mmol), and DIPEA (1.60 mL, 9.10 mmol) in NMP (20 mL) was cooled to 0° C. and amine 47 (7.02 mmol) in NMP (20 mL) was added. The solution was allowed to warm to ambient temperature. After 13 h, the reaction mixture was cooled to 0° C. and 1N NaOH (10 mL) was added. The reaction mixture was diluted with water and extracted with Et2O. The combined organic extracts were washed successively with water, 1N HCl, 10% H3PO4, water, NaHCO3, water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 4.5 g (96%, 2 steps) of 48 as a white foam which was used without further purification. Mass spectrum, m/z [691.2] (M+Na)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:5])=[O:4].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:21])=[O:10])(=[O:4])=[O:5]
Reactant: CO
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1

Procedure:
3-(N,N-Dimethylsulfamoyl)benzoic acid (200 mg, 0.872 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (5.64 mg, 0.044 mmol) in methanol (10 mL) at 70° C. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography affording the title compound (125 mg). 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.27 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.65 (t, 1H, J=8.0 Hz), 3.96 (s, 3H), 2.74 (s, 6H). ESI-MS: 244.0 [M+H]+.
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[CH:3])=[CH:32][CH:31]=1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve 276.5 g (0.634 mole) of bromomethyltriphenylphosphonium bromide in 1800 ml THF and cool to -78° C. Add 67.6 g (0.062 mole) potassium tert.-butoxide and stir at -78° C. for 2 hours. Add 89.12 g p-chlorobenzaldehyde in 200 ml THF to cold reaction mixture and stir for 30 minutes. Add 142.3 g potassium tert.-butoxide and then allow to warm to room temperature. After 18 hours, add 500 ml saturated aqueous ammonium chloride solution and 500 ml H2O and extract with 500 ml diethyl ether. Wash organic layer with 2×400 ml saturated aqueous sodium chloride solution, dry over magnesium sulfate, filter and evaporate solvent to dryness. Wash residue with 200 ml hexane and filter off precipitate. Evaporate hexane and dissolve material in 150 ml hexane methylene chloride (66:33) solution and elute through column containing 300 g silica gel (Merck 60-230 mesh) with hexane: methylene chloride (66:33) solution. Monitor column chromatography using thin-layer chromatography on silica gel (hexane: methylene chloride, 66:33). Collect desired fraction and evaporate solvent. Distill residue in vacuo and collect fraction boiling at 65° C. (8.5 mmHg) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cnccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 114.2 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(isoquinolin-5-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-5) 508 mg (0.70 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 406 mg (114%).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:40](=[O:41])[N:23]3[CH:24]([C:29]4[N:33](CCC(OC)=O)[N:32]=[N:31][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCC1=CCCN2>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:40](=[O:41])[N:23]3[CH:24]([C:29]4[NH:30][N:31]=[N:32][N:33]=4)[C:25]([CH3:27])([CH3:28])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCn1nnnc1C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: C1=C2CCCN2NCC1
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 71 %

Procedure:
To a stirred solution of 600 mg. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]tetrazol-5-yl)penam (containing ca 4.5% of methanol) in 1 ml. of chloroform, is added a solution of 375.2 mg. of diazabicyclo[4.3.0]non-5-ene in 0.5 ml. of chloroform. Stirring is continued for a further 3 hours, and then the solution is diluted with a further 2 ml. of chloroform. The latter solution is washed quickly with 5 ml. of 2N hydrochloric acid, and then a further 5 ml. of 2N hydrochloric are added. The resulting mixture is cooled to ca 0° C., and the solid which precipitates is filtered off, giving 323 mg. (71% yield) of the title compound. The NMR spectrum (DMSO-d6) of the product shows absorptions at 7.40 ppm(m, 15H), 5.30 ppm (s, 1H), 4.60 ppm (m, 2H), 1.58 ppm (s, 3H) and 0.78 ppm (s, 3H).