Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C@@H:4]([C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)[C@@H:5]([CH3:17])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57](O)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][C:41]([CH3:66])([C:43]([NH:45][C@H:46]([C:50]([N:52]([C@@H:54]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:55]([O:60][CH3:61])[CH2:56][C:57]([N:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C@H:4]([O:3][CH3:2])[C@@H:5]([CH3:17])[C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:58])[CH3:53])=[O:51])[CH:47]([CH3:49])[CH3:48])=[O:44])[CH3:42])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 18 h
Yield: 19.5 %

Procedure:
To a solution of #24 (104 mg, 0.256 mmol, 1 eq.) in dichloromethane (10 mL, 0.094 M) were added #32 (156 mg, 0.256 mmol, 0.9 eq.), diisopropylethylamine (135 μL, 0.768 mmol, 3 eq.) and HATU (120 mg, 0.307 mmol, 1.2 eq.). After stirring for 18 hours, the mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (10 mL), washed with 1 M aqueous hydrochloric acid solution (2×5 mL) and with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure onto silica and purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #55 (44 mg, 19%) as a white solid. LC-MS: m/z 884.5 [M+2H+], retention time=1.04 minutes.
Reaction SMILES: [OH:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([N+:10]([O-])=O)=[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.[H][H]>CO.[OH-].[Na+].[Pd]>[NH2:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([OH:1])=[N:3][C:4]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: Cn1c(O)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(O)nc(-c2ccncc2)c(N)c1=O
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-3-methyl-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (22.6 mmol) in 200 mL methanol and 75 mL 1N sodium hydroxide was added 50 mg Pd/C and stirred overnight under a balloon filled with hydrogen. The solvents were removed under vacuum. The solids were suspended in water and acidified to pH 5 with SN HCl. The solid was collected by filtration. M+1=219.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Cl:33])=[CH:14][CH:13]=2)[C:9]=1[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CO)cc2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CCl)cc2)c1C
Reaction time: 12 h

Procedure:
[1-(4-Hydroxymethyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 16.1.1, 4.8 g, 16.7 mmol) was dissolved in 60 ml dichloromethane. Triethylamine (3.5 ml, 25 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (1.29 ml, 16.7 mmol). After 12 h at room temperature, the mixture was washed with water, aqueous KHSO4 solution, water, aqueous NaHCO3 solution and with water. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2)[CH3:2].N[C:24]1[CH:25]=C2C(=C[CH:32]=1)NC(CCC(C)C)=C2>>[CH3:32][CH:24]([CH3:25])[CH2:2][CH2:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)CCc1cc2cc(N)ccc2[nH]1
Reactant: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1
Product: Cc1ccc(S(=O)(=O)Nc2ccc3[nH]c(CCC(C)C)cc3c2)cc1

Procedure:
Refer to 45a) using 5-amino-2-(3-methyl-n-butyl)indole.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:43]=[CH:42][CH:41]=[CH:40][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[CH:26]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[CH2:29][CH2:28][CH:27]([N:25]2[CH:26]=[C:22]([NH:21][C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:8]4[CH:40]=[CH:41][CH:42]=[CH:43][C:7]=4[C:4]4([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]4)[C:16]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:14]=3)[CH:23]=[N:24]2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNCC4)c3)ncc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A77 (0.213 g, 0.355 mmol) in DCM (10 mL) was treated with TFA (1.09 mL, 14.2 mmol) and stirred for 16 hours at room temperature. The volatiles were evaporated in vacuo before aq. HCl (2 M, 25 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×25 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (Biotage Isolera, 12 g C18 cartridge, 0-100% MeOH in H2O) to give a yellow oil. This oil was taken up in a minimum amount of DCM and the desired product was precipitated by the addition of petroleum spirits. The solid was isolated by filtration to give the title compound 66 as a yellow solid (0.114 g, 64%). LCMS-D: rt 3.07 min; m/z 500 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:13]1[CH2:22][OH:23].Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:13]2[O:12][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COc2ccccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A solution of toluene-4-sulphonyl chloride (60.25 g) in pyridine (75 ml) was added dropwise at 20° C. to a stirred solution of 1-(1,4-benzodioxan-2-yl)methanol (50 g) in pyridine (100 ml) and the mixture was stirred at ambient temperature for 18 hours then poured onto an excess of ice and hydrochloric acid (5M). The resulting solid was collected by filtration, washed well with water and dried in vacuo to give 1,4-benzodioxan-2-ylmethyl toluene-4-sulphonate as an off-white solid (82.3 g), m.p. 75°-78° C.
Reaction SMILES: [CH:1](Br)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(C)=[O:20].C([O-])(O)=O.[Na+]>>[CH:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CS(C)=O
Reactant: CCCCCCCCCCCCCCC=CBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC/C=C\CCCCCCCCCC=O
Temperature: 60 °C
Yield: 38 %

Procedure:
Run 3 (invention): The oxidation procedure employed for run 2 was repeated on a larger scale. Thus, 360 g (1.2 mol) of hexadecenyl bromide and 1800 mL (1980 g; 25.4 mol) of DMSO were mixed and heated to 60° C., with temperature maintained at 60° C. for about 30 minutes. Then, 240 g (2.9 mol) of NaHCO3 was added and the temperature of the reaction mixture raised to 130° C., which was maintained for 2 hours. The reaction mixture was then cooled and filtered. The lower layer (DMSO layer) was separated and extracted with about 1 L of hexane. The hexane extract and upper (aldehyde) layer were combined, washed once with about 100 mL of water, then concentrated on a rotary evaporator. GLC analysis indicated an aldehyde/alcohol ratio of 4.5:1. A distilled yield of 38% Z-11-hexadecenal was obtained.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8]>>[CH2:6]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH:7]([CH3:9])[CH3:8]
Reactant: ClCC1CO1
Reactant: CC(C)CNCC(C)C
Product: CC(C)CN(CC(C)C)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A stirred solution of epichlorohydrin (21.0 g, 0.23 mole) is treated dropwise with diisobutylamine (31.14 g, 0.24 mole) over a 1 hour period followed by continuous stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour and then extracted with 3×100 ml portions of ether. The etheral extracts are pooled with the organic layer and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to leave the crude product. The crude product is distilled at 68°/0.1 mmHg to yield 15.83 g (37.14%) pure product to oe used as an intermediate in Part B.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])(=O)C.CO.O1CCOCC1>N>[CH2:11]([O:10][C@@H:9]1[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:19])[F:20])[O:7][C@@H:6]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[C@@H:5]1[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O[C@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Yield: 66.2 %

Procedure:
A solution of compound 6 (0.52 g, 1 mmol) in NH3.MeOH/dioxane (6 mL/6 mL) was stirred at 20° C. After 18 h the reaction mixture was evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1 to 1.5:1)] provided 32 (0.314 g, 61%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[C:7]1=[O:31].FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:29]=3)=[CH:12][CH:13]=2)[N:8]([CH3:30])[C:7]1=[O:31]
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Reaction time: 18 h

Procedure:
tert-Butyl 5-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl}-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (14-1, 100 mg, 0.22 mmol) was added to a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2) as a white solid. This material was carried on without further purification.
Reaction SMILES: [O:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:8][CH2:7][CH2:6][C:5]1[O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: OCCc1cc2ccccc2o1
Reactant: BrCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: BrCCCCCOCCc1cc2ccccc2o1
Reaction time: 21 h

Procedure:
A mixture of 2-benzo(b)furanethanol (2.00 g), 1,5-dibromopentane (6 ml), 50% sodium hydroxide (7 ml) and TAB (0.2 g) was vigorously stirred at 24° for 21 h, then partitioned between water (50 ml) and ether (60 ml). The organic phase was washed with brine (50 ml), dried and evaporated in vacuo. The oily residue was purified by FCC eluting with hexane-diethyl ether (97:3) to give the title compound as a colourless oil (2.70 g), t.l.c. (hexane-diethyl ether 4:1) Rf 0.54.
Reaction SMILES: [N+:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=2[O:19][CH3:20])[CH2:7][CH2:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].Cl>C1COCC1.CO>[N+:1]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:8]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])([O-:3])=[O:2]
Reactant: COc1ccc(C2CCC=C2[N+](=O)[O-])c(OC)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCCC2[N+](=O)[O-])c(OC)c1OC
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A stirred solution of 1.78 g (6.4 mmol) of 1-nitro-5-(2,3,4-trimethoxyphenyl)-cyclopentene in 40 mL of THF and 40 mL of methanol was cooled in an ice bath and a 0.35 g (9.2 mmol) portion of solid NaBH4 was added. The mixture was stirred for 1 h and 0.38 g (10.0 mmol) of solid NaBH4 was added. The mixture was stirred for 1 h and 0.37 g (9.8 mmol) of solid NaBH4 was added. After stirring for 1 h, 100 mL of 5% aqueous HCl was added and the bulk of the THF and methanol were removed in vacuo. The residue was extracted with two 100 mL portions of ether. The combined ether extracts were washed with 30 mL of brine, dried over MgSO4 and the solvent removed in vacuo to leave 1.37 g of an oil. The crude product was purified by flash chromatography on a column of 30 g of silica gel eluted successively with 100 mL portions of 0, 10, 20, 30, 40, 50 and 60% ether in hexanes to afford 0.68 g of a 1:1 mixture of cis- and trans-1-nitro-2-(2,3,4-trimethoxyphenyl)cyclopentane (Example 45).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11]1([O:23][CH3:24])[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1.[CH:25](=[O:27])[CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:27][CH:25]([C:13]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15][C:11]([O:23][CH3:24])([O:10][CH3:9])[CH2:12]1)[CH3:26]
Reactant: CC=O
Reactant: COC1(OC)CCC(C(=O)OC(C)(C)C)C1
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(OC)CCC(C(=O)OC(C)(C)C)(C(C)O)C1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a cooled (−78° C.) solution of LDA (2M in THF/heptane, 39 mL, 78 mmol) in THF (40 mL) was added dropwise over 15 min tert-butyl 3,3-dimethoxycyclopentanecarboxylate (15.0 g, 65.0 mmol) in 100 mL of THF. The resulting mixture was stirred at −78° C. for 40 min, then was treated dropwise with acetaldehyde (7.27 mL, 130 mmol). After stirring for an additional 45 min, the reaction mixture was poured into 500 mL of 10% citric acid solution. The mixture was extracted twice with ether and the combined ethereal layers were washed with brine. The ethereal layer was then dried over anhydrous MgSO4, filtered, and concentrated. TLC analysis indicated that the reaction had not gone to completion and a considerable amount of starting material was still present. Purification/separation by flash chromatography (silica, 30% ethyl acetateihexane) gave the tert-butyl 1-(1-hydroxyethyl)-3,3-dimethoxycyclopentanecarboxylate as an approximately 1:1 ratio of threo and erythro diastereomer pairs and recovered tert-butyl 3,3-dimethoxycyclopentanecarboxylate.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:30](=[NH:35])(OCC)[CH3:31]>O>[C:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])(=[NH:35])[CH3:31]
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=N)N1CCC[C@H]1/C=C(\C)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.44 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and ethyl acetimidate hydrochloride (5.4 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with a mixture of ethyl acetate and tetrahydrofuran (9:1 V/V, 150 ml), and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (80 ml) eluting successively with water (200 ml) and 5% aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(E)-2-{(2 S)-1-acetimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (241 mg).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[C:22]([CH3:38])([CH3:37])[CH2:21][CH2:20]1)=[O:18].N1C=CC=CC=1>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][C:22]3([CH3:37])[CH3:38])[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: CCN(CC)CCOC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCC(C)(C)c3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)C(C)(C)CCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("B") and 9.8 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; Rf (THF) 0.65.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C@@H:4]1[CH2:7][C@H:6]([C:8]([O:10][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:9])[C:5]1([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A stirred solution of (1S,3R)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid (6.0 g, 35.29 mmol) in DMF (20 ml) at 0° C., Cs2CO3 (13.8 g, 42.34 mmol) followed by BnBr (5.06 ml, 42.34 mmol) were added slowly portion wise. The reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 ml) and washed with water (50 ml), brine (50 ml) and dried with Na2SO4. The solvent was evaporated and purified by silica gel column (60-120, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 5.6 g; Yield: 61.5%; 1H NMR (300 MHZ, CDCl3): δ 7.42-7.31 (m, 5H), 5.13 (s, 2H), 2.93-2.81 (m, 2H), 2.68 (q, 1H, J=10.5 Hz,), 2.05 (s, 3H), 1.97-1.88 (m, 1H), 1.43 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 261 (20%), [M+Na]+ 283 (87%); IR (KBr, cm−1): 2889, 1732, 1708, 1498, 1456, 1329, 1279, 1183, 1027, 954, 752, 698.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:20])[N:6]3[N:21]=[CH:22][N:23]=[C:5]3[C:4]=2[CH:3]=1.CN1C([Sn](CCCC)(CCCC)CCCC)=[CH:28][C:27](C(F)(F)F)=N1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[S:10][C:2]([CH:27]=[CH2:28])=[CH:3][C:4]=3[C:5]3=[N:23][CH:22]=[N:21][N:6]3[C:7]2=[O:20])=[CH:13][CH:14]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)sc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Solvent: Cc1ccccc1
Product: C=Cc1cc2c(s1)n(Cc1ccc(OC)cc1)c(=O)n1ncnc21
Temperature: 100 °C

Procedure:
To a mixture of 8-bromo-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (80 mg, 0.20 mmol) in toluene (2 ml) was added 1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole (135 mg, 0.31 mmol). The resulting mixture was heated to 100° C. for 16 hours and cooled to room temperature. It was filtered through a pad of celite with DCM washing. The resulting filtrate was concentrated under reduced pressure, diluted in methanol, filtered and purified directly via reverse-phase HPLC to afford the title compound.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].O/[N:12]=[C:13](\Cl)/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>CO>[CH2:9]([O:8][C:2]([C:3]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:12][O:5][C:4]=1[CH3:6])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: O/N=C(\Cl)c1cccc(Cl)c1
Agent: [Na]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)noc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a suspension of sodium (2.67 g, 116 mmol) in methanol (100 mL) was added ethyl acetoacetate (12.8 g, 11.9 mL, 110 mmol) at room temperature over 15 minutes and then a a solution of (E)- and/or (Z)-N-hydroxy-3-chloro-benzenecarboximidoyl chloride (19.0 g, 100 mmol) in methanol (100 mL) was added over 20 minutes and the resulting mixture allowed to stir for 4 h at room temperature. The mixture was then poured onto water and cooled to 5° C., filtered and evaporated. Purification by recrystallisation from ethanol afforded the title compound (10.1 g, 40%) which was obtained as a white solid. Mp: 71-73° C.