Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CCN1

Procedure:
175 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-3-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 35 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.20 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 175 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 28.0 mg of the title compound as a powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:76][CH2:75][N:74]([CH:77]2[CH2:82][CH2:81][CH:80]([NH2:83])[CH2:79][CH2:78]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:72][CH2:73][N:74]([C@H:77]2[CH2:82][CH2:81][C@H:80]([NH:83][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:14][CH2:13]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:79][CH2:78]2)[CH2:75][CH2:76]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for min before the addition of 4-(4-benzylpiperazin-1-yl)cyclohexanamine (Intermediate 18) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide N-((trans)-4-(4-benzylpiperazin-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide (white solid, 13 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH:17]=[O:19])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C=O)c2c1oc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
4-methoxy-dibenzofuran (3.07 g, 15.5 mmoles) is dissolved in DCM (50 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and dichloromethyl-methyl ether (1.68 mL, 18.6 mmoles) and subsequently TiCl4 (1N solution in DCM, 18.6 mL, 18.6 mmoles) are added dropwise. The solution is stirred at 0° C. and the reaction is completed after 1 hour. The reaction mixture is poured into cold water and extracted with DCM. The combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give 3.54 g of crude compound. The reaction is repeated on additional 2.04 g of starting material to yield additional 2.51 g of crude compound. The two crude mixtures are combined and purified together by flash chromatography on SiO2 (eluent: gradient AcOEt/hexane from 10/90 to 20/80) to give 3.8 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(Br)c1
Yield: 94 %

Procedure:
A solution of 3-bromo-4-methylbenzoic acid (20 g, 93.00 mmol, 1.00 equiv) and sulfuric acid (20 mL) in methanol (100 mL) was stiffed overnight at 80° C. The mixture was then concentrated under reduced pressure and the residue was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 3×200 mL of water, 1×200 mL of sodium bicarbonate (aq), followed by 1×200 mL of brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried to yield 20 g (94%) of the title compound as a dark red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([C:10]#N)=[CH:9][C:5]=2[CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[S:7][C:8]([CH:10]=[O:27])=[CH:9][C:5]=2[CH:4]=1
Reactant: CO
Reactant: COc1cc2cc(C#N)sc2cc1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2cc(C=O)sc2cc1OC
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile (2.0 g) was suspended in dry toluene (40 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to -5° C. and treated dropwise with a solution of diisobutylaluminium hydride in toluene (1.5M, 13 ml). After 30 minutes the solution was treated with methanol (5 ml) then poured into hydrochloric acid (1M, 200 ml) and stirred for 15 minutes. The resultant solution was extracted into dichloromethane (4×100 ml) then the organic extracts were combined, washed with brine, dried over magnesium sulphate and evaporated to dryness. The orange residue (1.6 g) was crystallised from dichloromethane:ether to give 5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde as a white solid, m.p. 155°-156° C.
Reaction SMILES: C12BC(CCC1)CCC2.[F:10][C:11]([F:33])([F:32])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH:30]=[CH2:31])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15].[OH-:34].[Na+].OO>C1COCC1.O>[F:10][C:11]([F:32])([F:33])[CH2:12][NH:13][C:14]([C:16]1([CH2:29][CH2:30][CH2:31][OH:34])[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15]
Reactant: [OH-]
Reactant: C=CCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCO)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
12 ml of 9-borabicyclo[3.3.1]nonane are added dropwise to a solution of 1.5 g (4.52 mmol) of 9-allyl-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide in 40 ml of THF under nitrogen. Then the mixture is stirred for three hours at ambient temperature. 6 ml of 1M sodium hydroxide solution and 4 ml of 33% hydrogen peroxide solution are then added successively and the resulting mixture is stirred for one hour. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[N:29]=[N:28][CH:27]=[N:26]3)=[CH:20][CH:19]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].B(Cl)(Cl)Cl.O>C(Cl)Cl>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[N:29]=[N:28][CH:27]=[N:26]3)=[CH:20][CH:19]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
To a solution of 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-2-ylmethylphenyl)-thiophene-2-sulfonamide (42.1 mg, 0.111 mmol, see step (c) above) in CH2Cl2 (10 mL) was added BCl3 (0.5 mL, 1M, 0.5 mmol) under N2 (g). The reaction mixture was stirred for 0.5 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over MgSO4 and the solvent was removed in vacuo. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[S:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (7.26 g, 50.0 mmol) in methylene chloride (100 mL) was added with tosyl chloride (11.4 g, 60.0 mmol) and diisopropylethylamine (7.75 g, 60.0 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-tosyl-1H-indole-3-carboxaldehyde (11.8 g, 78%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C([Mg]Cl)(C)C.[CH:12]([C:15]1[NH:19][N:18]=[C:17]([NH:20][C:21]2[C:22]3[CH2:38][CH2:37][CH2:36][C:23]=3[N:24]=[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32](OC)=[O:33])[N:26]=2)[CH:16]=1)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([C:15]1[NH:19][N:18]=[C:17]([NH:20][C:21]2[C:22]3[CH2:38][CH2:37][CH2:36][C:23]=3[N:24]=[C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:33])[N:26]=2)[CH:16]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: Nc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3nccs3)nc3c2CCC3)n[nH]1
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
To a solution of thiazol-2-amine (1.08 g, 10.8 mmol) in THF (12 mL) was added isopropyl magnesium chloride (5.4 mL, 10.8 mmol) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 20 min., followed by dropwise addition of solution of methyl (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate (1 g, 2.702 mmol) in THF (5 mL). The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by LCMS. The reaction mixture was quenched with a saturated solution of ammonium chloride (200 mL) and extracted with EtOAc (2×200 mL). The organic layer was washed with water (2×200 mL) followed by brine (200 mL) and dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product, which was recrystallized in diethyl ether (50 mL) to afford (2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-thiazol-2-yl-pyrrolidine-2-carboxamide (600 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.30 (d, 6H), 2.00-2.22 (m, 5H), 2.50-2.70 (m, 3H), 2.80-3.05 (m, 3H), 3.61-3.80 (m, 2H), 4.85 (d, 1H), 6.28 (brs, 1H), 6.93 (d, 1H), 6.99 (brs, 1H), 7.40 (d, 1H). The other enantiomer is prepared using chiral (R) starting material.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)=[O:11])[CH:2]=[C:3]([CH3:4])[CH3:5]
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
2,5-diprenyloxybenzoic acid(1.99 g) was dissolved in chloroform(38 ml) and triethylamine(1.91ml), and then diphenylphosphinic chloride(1.31 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.85 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.41 g of the aimed compound.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[S:7][C:6]([NH:8][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[O:10])=[N:5][N:4]=1.OO.[CH3:17]C(O)=O>>[CH3:17][CH2:1][CH2:2][C:3]1[S:7][C:6]([NH:8][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[O:10])=[N:5][N:4]=1
Reactant: CC(=O)O
Reactant: CCc1nnc(NC(=O)CN(C)C)s1
Agent: OO
Product: CCCc1nnc(NC(=O)CN(C)C)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of AK-2 (3.3 g, 13.1 mmol) in AcOH (10 mL) is slowly added H2O2 (1.37 mL, 13.7 mmol). The reaction mixture is stirred at rt for 3 h and is then quenched with saturated Na2SO3(aq) and neutralized with 1N NaOH(aq). The mixture is extracted with EtOAc and concentrated to yield AK-3.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.Br[CH2:24][C:25]#[N:26]>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][C:25]#[N:26])[C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1
Reactant: N#CCBr
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
LHMDS (1.0 M solution in THF, 13.1 mL, 13.1 mmol) was added dropwise at −78° C. under nitrogen to a stirred solution of methyl 2-(4-chlorophenyl)acetate (2.20 g, 11.9 mmol) in THF (40 mL). The resulting solution was stirred at −78° C. for 1 hour. A solution of 2-bromoacetonitrile (2.50 g, 20.9 mmol) in THF (16 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. The reaction was then warmed to room temperature and stirred overnight. The reaction was then quenched with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes: EtOAc, 4:1) to give methyl 2-(4-chlorophenyl)-3-cyanopropanoate (2.60 g, 98%) as a white solid. A solution of EtMgBr in THF (1.0 M, 8.0 mL, 8.0 mmol) was added dropwise at room temperature to a stirred solution of this methyl 2-(4-chlorophenyl)-3-cyanopropanoate (0.894 g, 4.00 mmol) and Ti(i-PrO)4 (1.30 mL, 4.40 mmol) in Et2O (20 mL). After the mixture was stirred at room temperature for 1 hour, water (4 mL) was added, followed by DCM (100 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 1:1) to give 6-(4-chlorophenyl)-4-azaspiro[2.4]heptan-5-one (0.330 g, 37%) as a white solid. LCMS (APCI+) [M-Boc+H]+ 222.2; Rf: 2.44 min.
Reaction SMILES: [Br-:1].[Mg+2].[Br-].CS([CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=O)=O>C(OCC)C>[Br:1][CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: CC1(C)OCC(CCS(C)(=O)=O)O1
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OCC(CCBr)O1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Magnesium bromide etherate (40 g, 130 mmol) and a stir bar were added to a 2000 mL round bottom flask and flushed with nitrogen. A solution of 4-(2-methanesulfonylethyl)-2,2-dimethyl-1,3-dioxolane (34) (17.5 g, 78 mmol) in anhydrous diethyl ether (900 mL) was added via canulla, and the suspension stirred overnight. The ether was first decanted into a beaker. Water (200 mL) and ether (300 mL) were added to the precipitate and stirred for 5 minutes. The precipitate was dissolved, and the ether phase was then collected and added to the ether solution from the reaction. The organic phase was then washed, concentrated to about 500 mL, washed with water, dried over anhydrous Mg2SO4, filtered, and concentrated to yield a yellow oil (16.0 g). This was purified by flash chromatography to yield 10.6 g of product (50.7 mmol, 65%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccnc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Benzyl alcohol (1.7 ml, 16.326 mmol, 1.2 eq) was added at 0° C. to a suspension of NaH (1.088 g, 27.21 mmol, 2.0 eq) in THF (50 ml) and the mixture was stirred for 30 minutes. A solution of 2,4-dichloropyridine (2.0 g, 13.605 mmol, 1.0 eq) in THF (10 ml) was added dropwise and stirring was carried out for 2 hours at RT. After monitoring by TLC, the reaction mixture was hydrolyzed with ice-water (60 ml) and extracted with ethyl acetate (2×120 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 1% ethyl acetate in hexane). Yield: 27% (800 mg, 3.653 mmol)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1.[OH-].[Na+].CC1C=CC([CH2:27][O:28]C(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CN(C)C=O>[CH2:6]1[C:10]2=[C:11]([CH:27]=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[N:9]2[CH2:8][CH2:7]1
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Reactant: c1cnc2c(c1)cc1n2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1c2n(c3ncccc13)CCC2
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
Phosphorus oxychloride (3.85 ml) was added dropwise to N,N-dimethylformamide (25 ml) cooled in an ice-bath. The mixture was stirred 10 min before the addition of 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene (4.40 g) in N,N-dimethylformamide (7 ml). The mixture was stirred 45 min at 40° C., cooled to room temperature and concentrated aqueous sodium hydroxide added dropwise to pH10. The mixture was heated at 50° C. 10 min, cooled to room temperature and poured onto crushed ice. The organics were extracted with ethyl acetate (2×), the combined organic phases washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1 to 1:0) to afford 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene-8-carbaldehyde (2.4 g, 46%) as a light orange oil which solidified on standing. Mp. 137-141; MS (EI): 187 (M+H)+, 143, 100; 1H NMR (δ, CDCl3) 10.01 (s, 1H), 8.45 (dd, 1H, J=1,8 Hz), 8.32 (dd, 1H, J=1,5 Hz), 7.23 (dd, 1H, J=5,8 Hz), 4.31 (t, 2H, J=6 Hz), 3.38 (t, 2H, J=8 Hz), 2.76 (dt, 2H, J=6,8 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[K+]>O.C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
12.66 g of ethyl α-methoxyimino-α-[2-(chloroacetamido)-thiazol-4-yl]acetate is added to a solution of 11.74 g of potassium hydroxide in a mixture of 25 ml of water and 500 ml of ethanol. After stirring for 20 minutes at room temperature, the reaction solution is subjected to the distillation of ethanol under reduced pressure. The residue is added to water, and the resultant solution is made acidic with addition of N-hydrochloric acid, followed by separating the insoluble materials by filtration. The procedure yields 10.54 g of α-methoxyimino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid. Melting point: 182°-183° C.
Reaction SMILES: Cl[C:2](OCC)=O.[OH-].[Na+].[CH3:9][NH:10][CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]>O.C(Cl)(Cl)Cl>[CH3:9][N:10]([CH3:2])[CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]
Reactant: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.7 g) and sodium hydroxide (0.3 g) dissolved in water (10 ml) are added to 2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol (1.3 g) in chloroform (25 ml). The mixture is stirred vigorously for 2 hours at about 10° C. The chloroform layer is separated, washed with water and dried. The solvent is removed in vacuo and the residual crude 2-(N-ethoxycarbonyl-N-methylamino)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is dissolved in tetrahydrofuran (75 ml) and added to lithium aluminium hydride (2.0 g) in tetrahydrofuran (25 ml). The mixture is refluxed for 3 hours, and the excess of hydride is destroyed with a slight excess of saturated aqueous sodium sulphate solution. The inorganic salt precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried over sodium sulphate and the solvent is removed under reduced pressure. The crude title compound is dissolved in acetonitrile and treated with a slight excess of oxalic acid dissolved in acetonitrile. The slowly depositing hydrogen oxalate is collected by filtration and recrystallization from acetonitrile; m.p. 133°-134° C.