Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].C([O-])(O)=O.[Na+].CCOC(C)=O>CC#N>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf20 (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].O[C:27]1[CH:28]=[N:29][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:31][CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:27]1[CH:32]=[N:31][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:29][CH:28]=1
Reactant: CN(C)CCO
Reactant: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCN(C)C)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are added successively to a suspension of 67 mg (0.2 mmol) of 3-[3-(5-hydroxypyrimidin-2-yl)benzyl]-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one in 3 ml of DMF. 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mixture is shaken at room temperature for 18 hours. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for 18 h. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g), 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are subsequently added, and the mixture is shaken at room temperature for 18 h. The reaction mixture is filtered, the filtrate is evaporated in vacuo, and the residue is purified by column chromatography on silica gel, giving “A109”. The crude product is purified by preparative HPLC: ESI: 406; HPLC: Rt=2.31 min (method B);
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:42])([CH2:40][OH:41])[C:37](O)=[O:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[C:36]([CH3:42])([CH3:35])[CH2:40][OH:41])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC(C)(CO)C(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)(C)CO)CC2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.2 %

Procedure:
A solution of N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (250 mg, 0.666 mmol) in dimethylformamide (5 ml) and triethylamine (278 μl, 2.0 mmol) was treated with 2,2-dimethyl-3-hydroxy propanoic acid (86 mg, 0.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.73 mmol) and 1-hydroxybenzotriazole (114 mg, 0.73 mmol). The reaction mixture was stirred under nitrogen at room temperature for 36 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml) and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with water (2×10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. Trituration of the residue with diethylether (5 ml) gave the title compound (270 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27]>[OH-].[K+].C(O)C>[C:10]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=1)([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:27][CH2:26][C:25]([O:29][CH2:30][CH3:31])=[O:28])#[N:11]
Reactant: N#CC(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reactant: C=CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C#N)(c1cccc(C(F)(F)F)c1)N1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 5.0 g. of α-[3-(trifluoromethyl)phenyl]-4-morpholineacetonitrile in 200 ml. of tetrahydrofuran stirred at room temperature is added 30 drops of 30% potassium hydroxide in ethanol. To the mixture is added 10 ml. of ethyl acrylate. After one hour an additional 30 drops of 30% potassium hydroxide in ethanol and 10 ml. of ethyl acrylate is added. The mixture is stirred for 2 hours and the solvent removed under vacuum. Toluene is added several times and the solvent removed. The residue is stirred with ether, filtered and the solvent evaporated to give ethyl γ-cyano-γ-[3-(trifluoromethyl)phenyl]-4-morpholinebutanoate (5.6 g.) as an oil. The oil is heated with 70% glacial acetic acid for 2 hours and the solvent removed. The residue is dissolved in dichloromethane and washed with water. The organic layer is dried (Na2SO4) and the solvent removed to give an oil. A mixture of the oil and 300 ml. of 6 N hydrochloric acid is refluxed for 5 hours, cooled and extracted with dichloromethane. The organic layer is extracted with sodium bicarbonate. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The extract is dried (Na 2 SO4) and the solvent removed. The residue is crystallized from hexane to give 3-[3-trifluoromethylbenzoyl]propionic acid as crystals, mp. 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(CBr)c1

Procedure:
A mixture of 18.9 g (100 mmol) of 2-bromo-5-fluorotoluene, 17.8 g (100 mmol) of N-bromosuccinimide, 400 mg of benzoyl peroxide, and 200 ml of CCl4 were refluxed for 2 h. The resulting mixture was filtered through a glass frit (G2), and the precipitate was additionally washed with 3×50 ml of CCl4. The combined filtrate was evaporated to dryness. Fractional distillation of the residue (bp 92-96° C./ 4 mm Hg) gave the title product as colorless oil. Yield 19.0 g (71%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:28][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCC1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cnc2c(NC3CCC3)nc(F)nc21
Yield: 67.9 %

Procedure:
6-chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclobutylamine (0.2 g, 2.8 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (237 mg, 68%) δH (CDCl3, 500 MHz) 1.56 (6H, d, J 7.5, CH[CH3]2), 1.76-1.74 (2 H, m, CH2 of Cyclobutyl), 1.98-1.94 (2 H, m, CH2 of cyclobutyl), 2.45 (2 H, s, br, CH2 of cyclobutyl)) 4.72-4.7 (2 H, m, CH of cyclobutyl and CHMe2), 6.35 (1 H, s, br, NH), 7.75 (1 H, s, ArH); δC (CDCl3, 500 MHz) 160.08 (C), 158.43 (C), 155.34 (C), 155.18 (C), 150.09 (C), 137.44 (CH), 47.26 (CH), 31.56 (2×CH2), 22.38 (2×CH3), 15.09 (CH2); m/z 250.2 (M+H)
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-])=O)=[CH:17][C:16]([CH3:22])=[CH:15][C:13]=2[N:14]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CN(C=O)C>[C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([NH2:19])=[CH:17][C:16]([CH3:22])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cc(C)c(Nc2nc3cc(C)cc([N+](=O)[O-])c3s2)c(C)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Nc2nc3cc(C)cc(N)c3s2)c(C)c1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A mixture of N-mesityl-5-methyl-7-nitro-1,3-benzothiazol-2-amine (45 mg, 0.137 mmol) and tin(II) chloride dihydrate (124 mg, 0.550 mmol) in DMF (2 ml) was heated at 80° C. for 1 h. The mixture was poured into ice and the pH was made slightly basic (pH 7-8) by addition of 1N NaOH solution. The aqueous solution was extracted with AcOEt. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 10 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[C:3]=1[CH:16]=[O:17].OO.[O-:20]Cl=O.[Na+]>C(#N)C.[O-]S([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[C:3]=1[C:16]([OH:20])=[O:17]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C)cc(-c2cccc(C)c2C=O)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(C)cc(-c2cccc(C)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 106.8 %

Procedure:
The aldehyde 51 (2.75 g, 11.5 mmol) was dissolved in acetonitrile (18 ml, technical grade). NaH2PO4 (0.453 g, dissolved in 5.5 ml H2O) and H2O2 (1.93 ml of a 30% solution) was added. The reaction mixture was cooled to 0° C. (with ice/water) and NaClO2 (2.2 g, dissolved in 19 ml water) was added within 60 min via a syringe. The solution was allowed to warm to ambient temperature and was stirred for additional 3.5 h. Then Na2SO3 (100 mg) was added, stirred for 5 min. After treatment with HCl (50 ml of a 10% solution) the reaction mixture was extracted with ether (3×75 ml). The combined organic phase was extracted with NaOH (4×75 ml, 1 N). The combined NaOH layers were acidified with HCl to pH 1 and extracted again with Et2O. The combined organic layers were dried over MgSO4 and the volatiles removed in vacuo to afford 52 (2.95 g, quant.) as a colorless oil. The product was used without any further purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([OH:43])[CH:41]=[CH2:42].C(N(C(C)C)CC)(C)C>ClCCl>[OH:43][CH2:40][C@@H:41]1[C@H:16]2[C:15](=[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:27])[N:13]3[C@H:12]([S:17]2)[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:38]3=[O:39])[CH2:42]1
Reactant: C=CCO
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)C2=C3C[C@H](CO)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a mixture of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (20 mg, 0.0341 mmol), allyl alcohol (11.6 μl, 0.171 mmol) and dichloromethane (0.5 ml) was added diisopropylethyl-amine (6 μl, 0.034 mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compound (12 mg, 71%), (Found: M+, 4.94.1528. C26H26N2O6S requires M, 494.1512); νmax (CH2Cl2) 1787, 1722, 1687 cm-1 ; δH (CDCl3) 2.89 (1H, m), 2.96 (1H, dt, J 16.8 , 3.0), 3.22 (1H, ddd, J 16.2, 8.9, 1.2), 3.62 (2H, ABq, J 15.7), 3.65 (2H, d, J 7.2), 3.79 (3H, s), 4.44 (1H, m), 4.92 (1H, d, J 5.0), 5.17 (2H, ABq, J 12.0), 5.76 (1H, dd, J 8.9, 5.0), 6.32 (1H, d, J 8.9), 6.86 (2H, d, J 8.6), 7.28 (7H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:9][CH3:10])[C:7]#[N:8])=[CH:2]1.[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH3:12][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: CCC(C#N)c1ccsc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC(C)(C#N)c1ccsc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A cooled solution of 2-(thiophen-3-yl)butanenitrile (708 mg, 4.682 mmol) in THF (15 mL) under nitrogen was treated with LHMDS in THF (4.375 g, 4.916 mL of 1 M, 4.916 mmol) dropwise. After 1 hour the reaction was treated with iodomethane (731.0 mg, 320.6 μL, 5.150 mmol) and then allowed to warm to RT. After 2.5 hours the reaction was quenched with MeOH and then concentrated in vacuo. The mixture was diluted with EtOAc/water and the two layers separated. The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (5:1 Petroleum ether/EtOAc) to give the product as a colourless oil (693 mg, 90% Yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: N#Cc1ccc(OCC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (4.0 g, 17.39 mmol) in dichloromethane (60 mL) was added 2-(4-cyanophenoxy)acetyl chloride (3.74 g, 19.13 mmol, Intermediate 2: step a) to form a thick suspension. An additional 30 mL of dichloromethane was added. The reaction was then cooled to 0° C. and triethylamine (5.32 mL, 38.25 mmol) was added dropwise. The cold bath was removed and the reaction was stirred at room temperature for 2 hours, then filtered to give the title compound as a white solid. The filtrate was washed with water, followed by saturated aqueous NH4Cl solution. The organic layer was dried (MgSO4), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 20% EtOAc-heptane) to afford more of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.52 g, 3.1 mmol), azetidin-3-ol hydrochloride (0.5 g, 4.6 mmol) and 4 Å molecular sieves (0.7 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 40:60) to give 3-Hydroxy-[1,3]biazetidinyl-1′-carboxylic acid tert-butyl ester as yellow oil (0.69 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 4.45-4.35 (m, 1 H); 3.96 (dd, J=9.3, 6.7 Hz, 2 H); 3.74 (dd, J=9.3, 4.5 Hz, 2 H); 3.66 (td, J=8.8, 6.7 Hz, 2 H); 3.40-3.37 (m, 1 H); 3.20 (td, J=8.8, 4.5 Hz, 2 H); 1.43 (s, 9 H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2occ(C#N)c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 25 °C
Yield: 48 %

Procedure:
In carbon tetrachloride (300 ml) was suspended 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (10.65 g). To the suspension was added N-bromosuccinimide (8.90 g). The mixture was subjected to reflux for two hours under irradiation of infrared ray lamp (Toshiba, 100 V, 375 WR). The resultant was then cooled to room temperature, followed by removal of insolubles by filtration. The filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (150 ml), which was washed with water three times, dried and concentrated. The precipitating crystals were collected by filtration to give 6-(1-bromo-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless prisms (7.0 g). Melting point: 115°-117° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:16]1([Mg]Cl)[CH:21]=[CH:20]C=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
50.0 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were dissolved in 400 ml of analytical grade tetrahydrofuran; 216 ml of a commercially available two molar solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath, and stirring was carried out overnight at room temperature. For working up, 200 ml of ice-cold ammonium chloride solution (20 wt. %) were added with stirring, while cooling with an ice bath, and after 30 minutes the phases were separated. The aqueous phase was extracted twice using 250 ml of ether each time, and the extracts were combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 60.0 g of dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine were obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)(OCC)O[CH2:14][CH3:15].[Cl-].[NH4+]>C(O)C>[CH2:14]([O:11][C:9]([CH3:10])=[CH:8][C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:15]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a stirred solution of ethyl 2,4-dioxopentanoate (36.5 g, 231 mmol) and triethyl orthoformate (41 mL, 246 mmol) in ethanol (60 mL) was added ammonium chloride (3.7 g, 69 mmol). The suspension was stirred at RT overnight. LCMS showed that the reaction was mostly complete. (Hydrolyzes on LCMS to some degree?) The reaction was concentrated under vacuum. The remaining oil was taken up in Et2O (300 mL), filtered to remove insolubles, rinsed with Et2O, and concentrated under vacuum. The product was obtained by short path distillation under vacuum (bp 70 to 77° C. at 0.09 mmHg) to give the product ethyl 4-ethoxy-2-oxopent-3-enoate (36.5 g, 47.3 mmol, 79% yield) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:15])=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-4-nitro-1H-indazole (10 g, 41.3 mmol, available from Sinova) in acetonitrile (100 ml) and acetic acid (20.00 ml) was added Selectfluor® (22.10 g, 83 mmol). The resultant mixture was heated to 100° C. and stirred overnight. The resultant orange solution was concentrated under vacuum then partitioned between ethyl acetate and water. The layers were separated and the aqueous extracted again with ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated. The solid was then dissolved in 20 ml DCM, loaded onto a 330 g silica column and purified on a 0-100% EtOAc/Cyclohexane gradient. The relevant fractions were combined and concentrated to yield the title compound as an orange solid (6.9 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl-].[CH3:32][NH3+:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:33]([CH3:32])[C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=4[CH:17]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: C[NH3+]
Agent: [Cl-]
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2C)cc1
Yield: 68.5 %

Procedure:
8.0 g (20 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) and 6.7 g (0.1 mole) of methylammonium chloride were converted similarly to Example 10 and the product was recrystallized from methanol to give 5.5 g of the title compound of melting point 104°-105° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1.[CH3:20][N+:21]([CH3:23])=[CH2:22].[I-]>CN(C=O)C>[CH3:20][N:21]([CH2:23][C:6]1[N:5]([C:7]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][C:8]=2[C:9]#[N:10])[CH:4]=[N:3][C:2]=1[CH3:1])[CH3:22]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc(OC(F)(F)F)cc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(OC(F)(F)F)cc2C#N)c1CN(C)C
Yield: 38 %

Procedure:
As described for example 84b, 2-(4-methyl-imidazol-1-yl)-5-trifluoromethoxy benzonitrile (+regioisomer) was reacted with Eschenmoser's salt in DMF for 24 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as a colorless oil that was sufficiently pure to be used in the next step (yield: 38%). 1H-NMR (300 MHz, DMSO): δ=1.93 (s, 6H), 2.17 (s, 3H), 3.21 (s, 2H), 7.80-7.95 (m, 3H), 8.22 (s, 1H).