Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:39]>C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([C:14]([NH:16][C@H:17]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:15])[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)(=[S:39])[NH2:2]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C#N)cc2)C(=O)O1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)NC(=O)C1CN(c2ccc(C(N)=S)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 g of tert-butyl (2R)-2-[3-(4-cyanophenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate [obtainable according to Example 8] are dissolved in a solvent mixture consisting of 30 ml of pyridine and 5 ml of triethylamine and the mixture is stirred for 1.5 h with ice cooling, with H2S gas being passed in continuously during this phase. The reaction mixture is subsequently stirred at room temperature for 24 h. Concentration by evaporation and customary workup give tert-butyl (2R)-2-[3-(4-thiocarbamoylphenyl)-2-oxo-5-oxazolidinylcarbonylamino]-3-phenylpropionate, m.p. 185°-186°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[C:6]([CH:16]=[O:17])=[CH:5]2.S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][C:3]1[C:2]([OH:1])=[C:14]([CH3:15])[CH:13]=[C:12]2[C:4]=1[CH:5]=[C:6]([C:16]1[O:17][CH:31]=[N:30][CH:29]=1)[C:7]1([O:11]2)[CH2:8][CH2:9][CH2:10]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc2c(c(C)c1O)C=C(C=O)C1(CCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc2c(c(C)c1O)C=C(c1cnco1)C1(CCC1)O2
Temperature: 80 °C
Yield: 37.6 %

Procedure:
To a solution of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutane]-3-carbaldehyde (315 mg), prepared as described herein, in 4 mL of MeOH was added tosylmethyl isocyanide (TosMIC) reagent (218 mg) and potassium carbonate (310 mg). The reaction mixture was allowed to heat at 80° C. for 20 min. The mixture was quenched with water and extracted with ethyl acetate. After concentrated in vacuo, the residue was purified by flash chromatography eluted with 30% ethyl acetate in hexane to give 118.8 mg of 5,7-dimethyl-3-(1,3-oxazol-5-yl)spiro[chromene-2,1′-cyclobutan]-6-ol as a yellow solid.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[C:9]([OH:16])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13].[NH3:17].C([O-])(=O)/C=C\C([O-])=O.[NH4+].[NH4+]>>[NH2:17][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5].[C:9]([OH:16])(=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: N
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
Still alternatively, both an immobilized biocatalyst with immobilized cells containing maleate isomerase and an immobilized catalyst with immobilized cells containing aspartase are combined and packed into a column and an aqueous solution of maleic acid and ammonia or an aqueous solution of ammonium maleate is passed through the column, to produce L-aspartic acid by a single-step process from maleic acid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=1.O.[NH2:18][NH2:19].O.[NH:21](C(=O)CCC1C=C(C=CC=1)C(OC)=O)[NH2:22]>CO>[NH:18]([C:3](=[O:2])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:21][NH2:22])=[O:11])=[CH:8][CH:7]=1)[NH2:19]
Reactant: COC(=O)c1cccc(CCC(=O)NN)c1
Reactant: COC(=O)CCc1ccc(C(=O)OC)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)CCc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a suspension of methyl 4-(3-methoxy-3-oxopropyl)benzoate (500 mg, 2.25 mmol) in MeOH (10 mL) was added hydrazine hydrate (1.09 mL). After stirring for 18 h at rt, the reaction mixture was poured into water (30 mL). The solvent was evaporated off until a final volume of 5 mL and a white solid precipitated out. Filtration and drying under vacuo at 70° C. overnight gave a white solid which was identified as methyl 3-(3-hydrazino-3-oxopropyl)benzoate (38 mg, 8%) [1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H), 4.17 (s, 2H), 3.82 (s, 3H), 2.87 (t, J=7.7 Hz, 2H), 2.33 (t, J=7.7 Hz, 2H)]. And the filtrate was evaporated off under vacuo. The white residue was washed with MeOH and dryed under vacuo at 70° C. overnight to give 4-(3-hydrazino-3-oxopropyl)benzohydrazide (278 mg, 56%) [1H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.94 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.3 Hz, 2H), 4.43 (s, 2H), 4.14 (s, 2H), 2;84 (t, J=7.8 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H)].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:12]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:12])[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(S(C)(=O)=O)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1cccc(CBr)c1

Procedure:
A solution of 1.0 g of 3-methanesulphonyltoluene in 5.9 ml of tetrachloromethane was admixed with 1.05 g of N-bromosuccinimide 11.8 mg of 2,2′-azoisobutyronitrile at 25° C. and subsequently refluxed for 5 hours. After decanting the orange precipitate was washed with tetrachloromethane and the combined organic phases were concentrated under reduced pressure. The 3-bromomethylphenyl methyl sulphone thus obtained was used in the next stage without further clarification. 100 mg of (E/Z)-N′-(4-bromo-2-cyano-5-hydroxyphenyl)-N,N-dimethylformimidamide are suspended in 1.5 ml of acetone together with the bromide freshly prepared above and after admixture of 95.4 mg of potassium carbonate refluxed for 3 hours. After cooling to 25° C., the reaction mixture was admixed with 25 ml of water and washed twice with 25 ml of ethyl acetate each time. The combined organic phases were washed with 25 ml of saturated sodium chloride solution, dried over sodium sulphate and, after filtration, concentrated under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel with ethyl acetate to obtain 166 mg of (E/Z)-N′-[2-Cyano-5-(3-methanesulphonylbenzyloxy)-4-bromophenyl]-N,N-dimethylformamidine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:16]=[CH:17][CH:18]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.Cl>C(#N)C.O1CCOCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[N:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH:14]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)c3)c2n1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(N5CCNCC5)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
80 mg (0.16 mmol) of tert-butyl 4-{2-[3-(5-methyl-2-oxooxazolo[4,5-b]pyridin-3-ylmethyl)phenyl]pyrimidin-5-yl}piperazine-1-carboxylate are dissolved in 6 ml of acetonitrile, and 6 ml of 4 M HCl in dioxane are added. The reaction mixture is stirred at room temperature for 1 h and evaporated. The residue is taken up in water and ethyl acetate, and the water phase is adjusted to pH 12 using NaOH and extracted with ethyl acetate and dichloromethane. The organic phases are combined, dried over sodium sulfate and purified by column chromatography.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17]>[Zn].O>[CH3:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[OH:17]
Reactant: CSc1ccc([N+](=O)[O-])cc1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CSc1ccc(N)cc1O

Procedure:
The suspension obtained on mixing 150 ml of 96° strength ethanol, 16 ml of water, 2.3 g of ammonium chloride and 78 g of finely powdered zinc is brought to reflux. 25.1 g (0.15 mol) of 2-methylthio-5-nitrophenol are added portionwise so as to maintain the reflux without heating (exothermic reaction).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=CC(N)=CC=2)[CH:34]=[CH:33][CH:32]=[CH:31]1>>[N:30]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)=[CH:21][CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Nc1ccc(-n2cccc2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2cccc2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(1H-pyrrol-1-yl)aniline in step 1. MS: 392.4 (M+H).
Reaction SMILES: [C:1]([O:4][N:5]1[CH:9]=[C:8]([CH2:10]O)[N:7]=[C:6]1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[C:1]([O:4][N:5]1[CH:9]=[C:8]([CH2:10][Cl:17])[N:7]=[C:6]1[CH2:12][CH:13]=[CH2:14])(=[O:3])[CH3:2]
Reactant: C=CCc1nc(CO)cn1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCc1nc(CCl)cn1OC(C)=O
Product: Cl

Procedure:
React allyl-4-hydroxymethylimidazol-1-yl acetate with excess thionyl chloride in CH2Cl2 at ice bath temperatures for about 8 hours to form the title compounds.
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH2:12])=[N:5]2)[CH3:2].[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(N(CC)CC)C>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH:12][C:23]([C:13]13[CH2:22][CH:17]4[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]4)[CH2:20]1)[CH2:14]3)=[O:24])=[N:5]2)[CH3:2]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC12COCC1SC(N)=N2
Solvent: CCN(CC)CC
Product: CCOC12COCC1SC(NC(=O)C13CC4CC(CC(C4)C1)C3)=N2

Procedure:
The product of Example 72B, triethylamine, and adamantane-1-carbonyl chloride were processed according to the method of Example 1A to afford the title compound. MS (ESI+) m/z 351 (M+H)+.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH:6]([SiH:9]([CH:11]([CH3:13])[CH3:12])Cl)([CH3:8])[CH3:7]>C1COCC1>[C:1]([SiH:9]([CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7])([CH3:3])=[CH2:2]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)[SiH](C(C)C)C(C)C
Temperature: 40 °C

Procedure:
0.5 M isopropenylmagnesium bromide in THF (Aldrich, 320 mL, 160 mmol, 1.1 eq. to silane) was added dropwise at 0° C. to diisopropylchlorosilane (22 g, 145 mmol) in anhydrous THF (40 mL). The reaction mixture was heated to 40° C. for 8 hours, then cooled and quenched with water (50 mL) and dilute sulfuric acid (50 mL). The crude product was extracted into pentane, washed with water and brine, dried over MgSO4, filtered and concentrated. Careful removal of solvent (product is volatile) yielded 22 g of crude isopropenyldiisopropylsilane as a pale yellow liquid that was not subjected to further purification.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][C:22]([C:24]4[CH:46]=[CH:45][C:27]([CH2:28][N:29]5[CH:34]6[CH2:35][CH2:36][CH:30]5[CH2:31][CH:32](OC(N5C=CN=C5)=S)[CH2:33]6)=[CH:26][CH:25]=4)=[CH:23][C:6]=3[C:5]=2[CH:4]=1)#[N:2].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:34]12[N:29]([CH2:28][C:27]3[CH:45]=[CH:46][C:24]([C:22]4[CH:21]=[N:20][C:7]5[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:9]6[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=6[C:6]=5[CH:23]=4)=[CH:25][CH:26]=3)[CH:30]([CH2:36][CH2:35]1)[CH2:31][CH2:32][CH2:33]2
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(OC(=S)n4ccnc4)C5)cc3)cnc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCCC4CC5)cc3)cnc21
Temperature: 110 °C
Yield: 83.9 %

Procedure:
To a solution of imidazole-1-carbothioic acid O-(8-{4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzyl}-8-aza-bicyclo[3.2.1]oct-3-yl) ester (182 mg, 0.28 mmol) and AIBN (60 mg, 0.36 mmol) in toluene (10 mL) under an argon atmosphere was added tributyltin hydride (0.58 mL, 1.85 mmol). On complete addition, the reaction was heated at 110° C. for 15 minutes then allowed to cool to ambient temperature. The mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM) to afford the title compound as a white solid (123 mg, 84%). 1H NMR (CDCl3, 300 MHz): 9.26 (d, J=1.0 Hz, 1H), 9.03 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.51 (d, J=1.0 Hz, 1H), 7.72-7.60 (m, 4H), 6.12 (s, 2H), 3.74-3.65 (m, 4H), 3.37-3.22 (m, 2H), 2.16-1.40 (m, 10H), 1.06-0.97 (m, 2H), 0.00 (s, 9H). LCMS (Method B): RT=2.96 min, M+H+=524.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])=O)(C)(C)C.[H-].[Na+].CI.Cl.O1CCOC[CH2:36]1>CN(C=O)C.ClCCl>[CH3:36][N:14]([CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:23]([N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:24])[NH:8][CH2:12]1)[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccccc2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)C(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of (2S, 4R)-4-(benzoylamino-methyl)-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 0.43 mmol) in anhydrous DMF (8 mL) was added sodium hydride (13 mg, 0.56 mmol) under nitrogen. The mixture stirred for 15 minutes followed by the addition of methyl iodide (0.04 mL, 0.64 mmol). The mixture was allowed to stir for 2 hours at room temperature, concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (10 mL) and H2O (5 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a yellow oil. To a solution of the oil in dichloromethane (10 mL) was added a solution of 4N HCl in dioxane (2 mL, 8 mmol) and the mixture was allowed to stir for 12 hours at room temperature. The mixture was concentrated under reduced pressure and the residue purified by RP-HPLC(CH3CN/H2O/TFA). MS (ESI) m/e 334 (M+H)+, 332 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 2.70 (m, 1 H) 3.02 (s, 3 H) 3.10 (m, 1 H) 3.17 (t, 1 H) 3.55 (m, 2 H) 3.66 (m, 1 H) 3.78 (m, 2 H) 3.87 (m, 1 H) 4.53 (m, 1 H) 4.67 (m, 2 H) 7.44 (dd, 2 H) 7.48 (m, 3 H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][O:12]1>N1C=CC=CC=1>[C:1]1([S:7]([N:17]2[CH2:18][CH:14]3[CH2:13][O:12][CH2:11][CH:15]3[CH2:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1NCC2COCC12
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CC2COCC2C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (0.05 mole, 8.83 grams) dissolved in 15 ml pyridine was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (X), (0.05 mole, 5.66 grams) in 10 ml of pyridine at 5°C. The reaction mixture was stirred for 2 hours at 5°C. and then for 16 hours while warming to room temperature.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16]>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][CH2:15][CH3:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CCN
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Ethylamino-3-nitro-benzoic acid methyl ester (4.0 g) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (5.0 g) in ethylamine (2.0 M in THF, 50 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[C:11](#[N:14])[CH2:12]O>>[NH2:14][CH2:11][CH2:12][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: N#CCO
Product: CC1(C)CCCC(C)(C)N1CCN

Procedure:
The starting material 1-(2-aminoethyl)-2,2,6,6-tetramethylpiperidine was prepared in a route similar to that of Example A39 from 2,2,6,6-tetramethylpiperidine and glycolonitrile.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[Li]CCCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15].[Cl-].[Li+]>O1CCCC1>[N:5]([CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([Si:14]([CH3:17])([CH3:16])[CH3:15])[Si:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: COC(CN)OC
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CN([Si](C)(C)C)[Si](C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 128.3 %

Procedure:
Under a nitrogen atmosphere, 5.25 g (0.05 moles) of aminoacetaldehyde dimethylacetal were dissolved in 50 ml of dry tetrahydrofuran and cooled to −78° C. 20 ml of 2.5M nBuLi (0.05 moles) were then added over 5 minutes with stirring. The mixture was then stirred for 15 minutes at −78 C then allowed to slowly warm to room temperature. 6.3 ml (0.05 moles) of chlorotrimethylsilane were then added over 20 minutes and the reaction allowed to stir for an additional 30 minutes. During this addition the mixture increased in temperature and a precipitate of lithium chloride was observed to form. The mixture was then cooled back down to −78 C and an additional 20 ml of 2.5M nBuLi added over 5 minutes with stirring and the mixture was held at this temperature for an additional 15 minutes before being allowed to warm back up to room temperature. An additional 6.3 ml of chlorotrimethylsilane was then added over a 20 minute period with stirring, during which time the mixture was observed to warm up and additional lithium chloride form. The Mixture was then stirred for an additional 30 minutes before being filtered. The tetrahydrofuran was then removed from the filtrate by vacuum and the final product was vacuum distilled from the remaining filtrate. This resulted in a yield of 8.0 g (64% of theoretical) of (Me3Si)2NCH2CH(OMe)2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[N:25]1[CH2:29][CH2:28][S:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.Cl>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1c(N2CCSC2)nc2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1c(N2CCSC2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.8 %

Procedure:
3,5-Difluorophenylacetic acid (0.152 g, 0.88 mmol), 3-Amino-2-thiazolidin-3-yl-3H-quinazolin-4-one (0.146 g, 0.59 mmol) and HATU (0.268 g, 0.71 mmol) were dissolved in dry DMF (2.5 mL), followed by addition of 2,6-lutidine (205 μL, 1.76 mmol). The reaction mixture was stirred at RT for 48 h and then poured into 1 M HCl (20 mL). The formed precipitate was collected by filtration and washed with water and heptane, which after drying gave the title compound (0.180 g, 76%). LC-ESI-HRMS of [M+H]+ shows 403,1047 Da. Calc. 403,104028 Da.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:18]=[CH:17][C:16]([CH3:20])([CH3:19])[C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:21][CH:22](O)[CH3:23].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([C:16]([CH3:20])([CH3:19])[CH:17]=[CH:18][C:7]=3[F:6])=[C:14]2[CH:13]=[N:12]1)=[N+:33]=[N-:34]
Reactant: CC(O)Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21)N=[N+]=[N-]
Yield: 89.5 %

Procedure:
1 ml (13 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.7 g (6.5 mmol) of (RS)-1-(7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.6 ml (26 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction S mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.85 g (13 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.66 g (90%) of (RS)-1-(2-azido-propyl)-7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Br)o1
Reactant: OB(O)Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccncc2)o1
Yield: 17.2 %

Procedure:
To a solution of methyl 5-bromo-2-furancarboxylate (820 mg), 4-pyridyl boric acid (500 mg), tetrakistriphenyl-phosphine palladium(0) (250 mg) in dimethoxyethane (15 ml) was added 2 M sodium carbonate solution (4 ml) and the solution was heated for 15 hours under reflux. The reaction solution was diluted with ethyl acetate, and the organic layer was separated, washed with water, extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution, extracted with ethyl acetate, dried and concentrated to give a colorless solid of methyl 5-(4-pyridyl)-2-furancarboxylate (126 mg). 1H-NMR (CDCl3) δ: 3.94 (3H, s), 6.96 (1H, d, J=3.8 Hz), 7.27 (1H, d, J=3.8 Hz), 7.64 (2H, d, J=6.2 Hz), 8.68 (2H, d, J=6.2 Hz). IR (KBr): 1727, 1608, 13.7, 1145 cm−1.