Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH2:9](O)[CH3:10]>S(=O)(=O)(O)O>[N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CC[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC[N+](=O)[O-]
Yield: 69 %

Procedure:
A mixture of 25 g (0.21 mole) of 3-nitropropionic acid, 300 mL of absolute ethanol and 10 drops of concentrated sulfuric acid is refluxed overnight. The reaction mixture is evaporated, and the residue partitioned between water and ether. The ether layer is washed with water, aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate. The ether is removed in vacuo and the product distilled as a clear liquid to provide 21.54 g (69%) of Ethyl 3-nitropropionate as a clear oil, b.p. 160–165° C. at 120 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:4]([Cl:35])[CH:3]=1.CCN(CC)CC>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:35][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]([NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:11]2=[CH:10][C:9]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:19]([O:20][CH3:21])=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CC(C)(C)Oc2nc(-c3ccc(Br)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)OC(C)(C)C)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of Example 314 (840 mg, 1.45 mmol), palladium(II) acetate (16.3 mg, 0.07 mmol), dppf (81 mg, 0.15 mmol), and NEt3 (405 μL, 2.90 mmol) in 20 mL of CH3OH was stirred at 100° C. under 50 psi of CO for 24 h. After cooling to rt, the reaction mixture was filtered. The filtrate was concentrated and chromatography on a Biotage 25+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.46 (s, 3H), 1.49 (s, 9H), 1.54 (s, 3H), 1.82 (m, 1H), 2.29 (dd, J=6.2, 13.3, 1H), 3.90 (s, 3H), 4.89 (br. s, 1H), 5.12 (m, 1H), 7.01 (d, J=8.5, 2H), 7.16 (d, J=8.4, 2H), 7.40 (m, 1H), 7.73-7.92 (m, 3H).
Reaction SMILES: [B:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])([OH:3])[OH:2].CN.[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:6]([C:7](=[O:8])[NH:18][CH3:17])=[CH:5][C:4]=1[B:1]([OH:3])[OH:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)c1ccc(OC)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
3-Borono-4-methoxybenzoic acid (2.5 g, 12.50 mmol) was dissolved in DMF (6 ml) and 12.50 ml methylamine (2 M solution in THF, 25 mmol) was added followed by HATU (4.75 mg, 12.5 mmol) and NMM (1.375, 12.50 mmol). The reaction mixture was stirred at RT for 20 hours and concentrated. The crude material was added to 50 ml water and extracted 3 times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated. The crude material was triturated in EtOAc and filtered. The residue was purified by chromatography (Silicagel, CH2Cl2/MeOH 95:5) to give 1.92 g (7.11 mmol, 56.9% yield) of the title compound as a colorless solid. LCMS: (M+H)=210; tR=0.50 min (LC-MS 1). TLC: Rf=0.27 (CH2Cl2/MeOH 95:5). HPLC: tR=3.76 min (HPLC 3). 1H-NMR (d6-DMSO, 600.13 MHz) δ ppm 8.29 (bs, 1H), 8.03 (s, 1H), 7.87 (d, 1H), 7.85 (s, 2H) 7.02 (d, 1H), 3.84 (s, 3H), 2.75 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].Br[C:14]1[CH:31]=[C:30]2[C:17]([CH2:18][CH2:19][C:20]3([C:23]42[N:27]=[C:26]([NH2:28])[C:25]([CH3:29])=[N:24]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C>[Cl-].[Na+].O.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.CCOC(C)=O.O>[NH2:28][C:26]1[C:25]([CH3:29])=[N:24][C:23]2([C:30]3[C:17](=[CH:16][CH:15]=[C:14]([C:5]4[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=4)[C:1]#[N:2])[CH:31]=3)[CH2:18][CH2:19][C:20]32[CH2:21][CH2:22]3)[N:27]=1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CCC21CC1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[PH+](CCCS(=O)(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=NC2(N=C1N)c1cc(-c3cc(F)cc(C#N)c3)ccc1CCC21CC1
Temperature: 100 °C
Yield: 86.4 %

Procedure:
3-Cyano-5-fluorophenylboronic acid (83 mg, 0.50 mmol) was added to 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 100 mg, 0.31 mmol) in dry 2-Me THF (2.85 mL), followed by aq. potassium carbonate (2.0 M, 0.471 mL, 0.94 mmol). Argon was bubbled through the mixture for one min. and then sodium tetrachloropalladate(II) (9.3 mg, 0.03 mmol) and 3-(di-tert-butylphosphonium)propane sulfonate (16.9 mg, 0.06 mmol) were added and the mixture was heated in a microwave reactor for 60 min at 100° C. Water, brine, 2-Me THF and EtOAc were added to the mixture and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and water. The organic phase was dried (Na2SO4), filtered and concentrated. Recrystallization from MeOH and CHCl3 and purification by preparative HPLC gave the title compound (96 mg, 85% yield).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:12](=[O:25])[C:11]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CI>O>[CH3:3][O:8][CH2:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:17])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:24])[C:12](=[O:25])[C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC1=C(c2ccccc2)C(=O)N(C(C)(C)c2ccccc2)CO1
Temperature: 25 °C
Yield: 67 %

Procedure:
Sodium hydride (60% in oil, 0.11 g) was suspended in diformaldahyde (2 ml), cooled with ice; then a dimethylformamide solution (6 ml) of 6-hydroxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 53, 0.8 g) was added slowly thereto. After stirring the mixture, methyl iodide (0.71 g) was added, and the mixture was stirred again at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography to afford the captioned compound (0.56 g, yield 67%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]([C:31]([O:33][CH2:34][Cl:35])=[O:32])[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[C:4]2[CH:3]=1
Reactant: O=C(Cl)OCCl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(s1)=Nc1ccccc1N(C(=O)OCCl)C=2N1CCN(C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16 mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and once a clear solution formed, the reaction was cooled to 5° C. To this was added chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes. The reaction was stirred at room temperature for 30 min and allowed to warm to room temperature. After 15 min at room temperature the reaction mixture was diluted with dichloromethane (100 mL), then washed with aq satd NaHCO3 (75 mL) and water (350 mL). The organic phase was dried over MgSO4 and filtered. The organic phase was then concentrated under vacuum at 45° C. to a volume of ˜150 mL. The mixture was diluted with ethyl acetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. The mixture was cooled to room temperature and the resulting solid precipitate filtered and washed with ethyl acetate. After drying under vacuum at 35° C. for 90 min chloromethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate [A] (17.1 g, 73%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH3:20])[CH2:18][CH2:17][C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:15][C:14]=3[CH:28]=2)=[CH:6][CH:5]=1)[CH3:2].[ClH:29]>C(COC)OC>[ClH:29].[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH3:20])[CH2:18][CH2:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15][C:14]=3[CH:28]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Agent: Cl
Solvent: COCCOC
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C)cc1

Procedure:
In dimethoxyethane (100 ml) was dissolved t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), and to the mixture was added 6N hydrochloric acid (25 ml). The mixture was refluxed for 3 hours, and the solvent was evaporated. Precipitated yellow powder was filtered and washed with ethyl acetate-hexane to give 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylic acid hydrochloride (3.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.[O:20]=[C:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1>C1COCC1.CCCCC>[C:10]([O:9][C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:21]1([OH:20])[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a flame-dried round bottomed flask with thermometer side-arm, equipped with a stir bar, was added tert-butyl pyridin-3-ylcarbamate (1.104 g, 0.005684 mol) in 75 mL THF under inert atmosphere. The solution was cooled to −78° C. and then 1.7 M of tert-butyllithium in pentane (7.4 mL) was added dropwise. The resulting solution was stirred for 2 h at −78° C., followed by the addition of benzyl 3-oxopyrrolidine-1-carboxylate (1.038 g, 0.004736 mol) in 75 mL THF. The reaction was allowed to warm to rt and stirred for 5 hrs. The reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic phases were treated with brine and then magnesium sulfate, filtered, and concentrated. The crude product was purified by combiflash using 50-80% ethyl acetate/hexane to recover the starting material (0.9 g) and then 100% ethyl acetate to obtain the product (0.5 g). The product was verified by LCMS and NMR data.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](CCN)=[CH:7][CH:6]=1.CC(C)=O.N1C=CC=CC=1.C(OC1C=CC(Cl)=CC=1C(Cl)=O)C>O1CCOCC1>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CCN)cc1
Agent: CCOc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1

Procedure:
10.5 g of 4-(2-aminoethyl)-benzoic acid methyl ester-hydrochloride were suspended in 40 ml of dioxane and 20 ml of acetone and the suspension was combined with 8 ml of pyridine. To this suspension, a solution of 10 g of 2-ethoxy-5-chloro-benzoyl chloride in a small amount of acetone was added dropwise, while stirring, and the whole was heated for 2 hours under reflux. After cooling, the mixture was concentrated under reduced pressure, combined with ice-water, filtered with suction, stirred with dilute hydrochloric acid and with a NaHCO3 solution and the resulting product was again filtered off with suction and recrystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid methyl ester obtained was found to melt at 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[O:15][C:21]([C:20]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:28][C:19]=4[O:18][CH3:17])=[N:23][N:24]=3)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCOCC2)ccc1C(=O)NN
Reactant: Cc1onc(-c2cccc(Cl)c2)c1C(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3cccc(Cl)c3)noc2C)o1
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid (200 mg, 0.85 mmol) in dichloromethane (4 mL) was added 2-methoxy-4-morpholin-4-yl-benzoic acid hydrazide (266 mg, 0.85 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (313 mg, 1.85 mmol). After the solution was stirred for 15 min at ambient temperature triethylamine (0.59 ml, 4.21 mmol) was added over a period of 2 min and the reaction mixture was stirred for 18 h at this temperature. It was diluted with ethyl acetate (20 mL 1) and washed with aqueous sodium carbonate (half saturated). The aqueous layers were extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (235 mg, 62%) as a white solid. MS: m/e=453.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:26].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:26][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=1
Reactant: Br
Reactant: COc1cc(C(=O)C#CCNC(=O)OC(C)(C)C)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2cc(Br)cn2C(=O)OC(C)(C)C)cc(OC)c1OC
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
To a stirred solution of 3-(tert-butoxycarbonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (1.0 g, 2.78 mmol, Example 76c) in CH2Cl2 (10 ml) a solution of HBr (732 μl, 1.5 equiv., 33% in acetic acid) is added at 4° C. The reaction mixture is stirred for 45 min at 4° C., and poured onto ice, saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated and the residue chromatographed on SiO2 with ethyl acetate/hexane (1:3) to yield the title compound (1.0 g, 89.9%) as a white solid. 1H-NMR (300 MHz, DMSO-d6): 7.45 (d, J=2.0, 1H); 6.66 (s, 2H); 6.38 (d, J=2.0, 1H); 3.77 (s, 2MeO); 3.67 (s, MeO); 1.33 (s, tBu).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=O)[CH3:8])=[O:6].[NH:28]1[CH2:31][CH:30]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([N:40]3[CH2:43][CH2:42][CH2:41]3)=[O:39])[CH2:34][CH2:33]2)[CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[N:40]1([C:38]([CH:35]2[CH2:36][CH2:37][N:32]([CH:30]3[CH2:29][N:28]([CH2:12][CH2:11][C@@H:10]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:9][N:7]([CH3:8])[C:5](=[O:6])[C:4]4[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:2]([Br:1])[CH:3]=4)[CH2:31]3)[CH2:33][CH2:34]2)=[O:39])[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C(C1CCN(C2CNC2)CC1)N1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.16 g, 0.36 mmol) and 1-azetidin-3-yl-4-(azetidin-1-ylcarbonyl)piperidine (see method 2; 0.10 g, 0.47 mmol) were dissolved in methylene chloride (10 mL) together with a small amount of dry methanol (0.2 mL). To the resultant solution were added DIPEA (0.14 g, 1.08 mmol) and sodium triacetoxyborohydride (0.15 g, 0.72 mmol). The mixture was stirred under nitrogen for 4 h at RT. The mixture was diluted with methylene chloride and washed twice with saturated aqueous NaHCO3 and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1). There was obtained 0.14 g (59%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): δ 1.4-1.8 (cm, 6H), 2.1 (m, 1H) 2.2 (qn, 2H), 2.3-2.4 (cm, 2H), 2.5-3.5 (cm, 14H), 3.6 (d, 1H), 3.9 (t, 2H), 4.1 (t, 2H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 654 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:23][C@@H:24]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38]C)=[O:37])[CH2:25]3)=[CH:8][C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)=[N:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1>[C:32]([O:31][C:29]([N:27]1[CH2:28][C@@H:24]([O:23][C:7]2[C:6]3[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:9]([C:14]3[S:15][CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=3)[CH:8]=2)[CH2:25][C@H:26]1[C:36]([OH:38])=[O:37])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Temperature: 40 °C
Yield: 98.3 %

Procedure:
Compound 124 (22.24 g) was dissolved in THF (66 mL) at room temperature. Water (66 mL) was added, followed by lithium hydroxide (5 eq.) in one portion. The reaction mixture was heated at 40° C. for 3 hrs, cooled, acidified with 5M HCl, and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum to give compound 125 (21.33 g) as an off-white powder in 92% yield (7.5 w % of THF) and 99% purity.
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@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].Cl.[C:21](=[NH:26])(OCC)[CH3:22].[OH-].[Na+]>O>[C:21]([N:17]1[CH2:18][CH2:19][C@@H:15]([C:7]2[CH2:6][C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:16]1)(=[NH:26])[CH3:22]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@@H]3CCNC3)C[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=N)N1CC[C@@H](C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(3S)-pyrrolidin-3-yl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.0 g) in water (30 ml) was added ethyl acetimidate hydrochloride (2.8 g) at 0° C while adjusting pH to 8.5 with 30% sodium hydroxide solution. After stirring for 30 minutes at the same temperature, the solution was adjusted to pH 6.5 with lN-hydrochloric.acid, washed with ethyl acetate, and then concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" eluting with aqueous isopropyl alcohol (3%). The farctions containing the desired compound were collected and lyophilized to give (5R,6S)-3-[(3S)-1-acetimidoylpyrrolidin-3-yl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (550 mg).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (52.6 mg, 0.63 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.25 mmol) (Starting Material 4 supra) using (Ph3P)2PdCl2 (17.5 mg) and CuI (4.8 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 12 mg, 14%).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[CH:11]1(CO)[CH2:13][CH2:12]1>>[CH3:1][C:2]([CH2:8][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH:11]1[CH2:13][CH2:12]1)=[O:5]
Reactant: OCC1CC1
Reactant: CCCC(C)=CC(=O)OC
Product: CCCC(C)=CC(=O)OCC1CC1

Procedure:
Prepared from methyl 3-methylhex-2-enoate and cyclopropanemethanol according to the ester preparation method B described above. The Z and E isomer were separated by distillation under vacuum using a 35 cm Fischer Spaltrohr® column.
Reaction SMILES: CS[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:33][NH:34][CH3:35].ClCCl>CO>[CH3:33][N:34]([CH3:35])[C:3]([N:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[N:16]1)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7]
Reactant: CNC
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: ClCCl
Solvent: CO
Product: CN(C)C(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
Part B: To a stirred mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (4.20 gram, 8.30 mmol) in methanol (75 ml) was added dimethylamine (10 ml) and dichloromethane (75 ml) and the resulting solution was stirred at room temperature for 6 hours. Evaporation in vacuo and subsequent flash chromatographic purification (diethyl ether/petroleum ether=1/1 (v/v), followed by diethyl ether) gave a solid which was further purified by recrystallisation from diisopropyl ether to yield N1,N1-dimethyl-N2-((4-chloro-phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2.63 gram, 63% yield). Melting point: 182° C.