Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CCO
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.07 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL), the solution was treated with ethanol (0.075 mol, 4.1 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer was acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 27.6 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-glucopyranosyl)urea and 6 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 1.1 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-glucopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)[CH3:4])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:59][C:58]([CH2:82][C:83]#[N:84])([N:60]3[CH:64]=[C:63]([C:65]4[C:66]5[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=5[N:68]=[CH:69][N:70]=4)[CH:62]=[N:61]3)[CH2:57]2)[CH2:52][CH2:51]1>O1CCCC1>[CH2:1]([N:3]([CH2:5][C:6]1[N:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:9]=[C:8]([C:16]([N:50]2[CH2:51][CH2:52][CH:53]([N:56]3[CH2:57][C:58]([CH2:82][C:83]#[N:84])([N:60]4[CH:64]=[C:63]([C:65]5[C:66]6[CH:73]=[CH:72][NH:71][C:67]=6[N:68]=[CH:69][N:70]=5)[CH:62]=[N:61]4)[CH2:59]3)[CH2:54][CH2:55]2)=[O:18])[CH:7]=1)[CH3:4])[CH3:2]
Reactant: CCN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
After prestirring a mixture of 6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (40.1 mg, 0.152 mmol, from Step A), triethylamine (56.6 μL, 0.406 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (54.0 mg, 0.142 mmol) in tetrahydrofuran (1.1 mL) for 30 minutes, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (50.0 mg, 0.101 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was successively washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The product was deprotected by stirring first in a 1:1 mixture of DCM:TFA for 1 hour, followed by evaporation and stirring with ethylenediamine (0.2 mL) in methanol (1 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product. Yield: 0.025 g (41%); LC-MS: 608.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.61 (d, 1H), 7.06 (d, 1H), 4.11-4.02 (m, 1H), 3.78-3.71 (m, 4H), 3.63-3.48 (m, 5H), 3.32-3.21 (m, 1H), 3.17-3.07 (m, 1H), 2.62-2.53 (m, 1H), 2.48 (q, 2H), 2.21 (s, 3H), 1.84-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.37-1.18 (m, 2H), 1.03 (t, 3H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][C:6]([CH3:14])(C)[CH2:5][C:4]=2[N:3]=1.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH:6]([C:14]3[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=3)[CH2:5][C:4]=2[N:3]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CO
Reactant: CC1(C)CC(=O)c2ccc(Cl)nc2C1
Product: CC(C)COc1ccc2c(n1)CC(c1ccccc1)CC2=O
Yield: 35 %

Procedure:
In analogy to the procedure described in Example 8, 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with iso-butyl alcohol to give the title compound in 35% yield.
Reaction SMILES: C1C=CN=CC=1.[FH:7].[Cl:8][C:9]1[CH2:10][C:11]2[C:16](=[O:17])[O:15][C:13](=[O:14])[C:12]=2[CH2:18][CH:19]=1.[Br:20]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:20][CH:19]1[CH2:18][C:12]2[C:13]([O:15][C:16](=[O:17])[C:11]=2[CH2:10][C:9]1([Cl:8])[F:7])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: F
Reactant: O=C1OC(=O)C2=C1CC=C(Cl)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1OC(=O)C2=C1CC(Br)C(F)(Cl)C2
Reaction time: 3.25 h

Procedure:
Pyridinium poly(hydrogen fluoride) was added to a solid mixture of 4-chloro-3,6-dihydrophthalic anhydride (0.22 g) and N-bromosuccinimide (0.21 g) at room temperature. The reaction mixture was stirred for 3.25 hours and then carefully poured into a two phase system containing saturated sodium carbonate and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was analyzed by NMR and GC-MS and contained 5-bromo -4-fluoro-3,4,5,6-tetrahydrophthalic anhydride as the major product along with some 4-fluorophthalic anhydride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC#N>[C:1]([C:5]1[CH:10]=[C:9]([Br:19])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 2-tert-butylphenol (250 g, 1.67 mol) in CH3CN (1500 mL) was added NBS (300 g, 1.67 mol) at room temperature. After addition, the mixture was stirred at room temperature overnight and then the solvent was removed. Petroleum ether (1000 mL) was added, and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give the crude 2-tert-butyl-4-bromophenol (380 g), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:10][CH2:11][CH2:12][C:13]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:15])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CCCS(=O)c1ccc(O)cc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CCCS(=O)c3ccc(O)cc3)[C@H]2SC1

Procedure:
456 mg. of 4-(p-hydroxyphenylsulfinyl)butyric acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 245 mg. of 7-[4-(p-hydroxyphenylsulfinyl)butyramido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH:13]([CH2:11][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH2:14]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCC1CO1
Product: c1cc(OCC2CO2)c2cc[nH]c2c1

Procedure:
The title compound was synthesized from 4-hydroxyindole and epichlorohydrin by the method of Troxler et al. (Chem. Abs. 71, 70493c).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:27][CH2:28][C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:35](O)([CH3:37])[CH3:36])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Si:10]([O:27][CH2:28][C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:35]([F:7])([CH3:37])[CH3:36])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(O)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of diethylaminosulfur trifluoride (414 μL, 3.0 mmol) in DCM (10 mL) at −78° C. was added a solution of (3S,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-hydroxy-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40e, 1.03 g, 2.5 mmol) in DCM (10 mL) dropwise. The resulting mixture was warmed up to room temperature and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-20% EtOAc in petroleum ether) to afford 820 mg of (3R,5S)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-(1-fluoro-1-methyl-ethyl)tetrahydrofuran-2-one (compound 40f) as a viscous oil. MS obsd. (ESI+) [(M+H)+]: 415.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1>>[ClH:1].[CH3:33][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:2]2[N:7]=[C:6]([N:8]([CH3:21])[C:9]3[CH:20]=[CH:19][C:12]4[N:13]([CH3:18])[C:14]([NH:16][CH3:17])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:28][C:27]=1[S:29]([NH2:32])(=[O:31])=[O:30]
Reactant: CNc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: CNc1nc2cc(N(C)c3ccnc(Nc4ccc(C)c(S(N)(=O)=O)c4)n3)ccc2n1C
Product: Cl

Procedure:
The title compound was prepared following the procedure of Example 1 with N5-(2-chloropyrimidin-4-yl)-N2,N5,1-trimethyl-1H-benzimidazole-2,5-diamine (58 mg, 0.20 mmol) and 5-amino-2-methyl-benzenesulfonamide (35 mg, 0.20 mmol) as a pink solid (78 mg, 84%). 1H NMR (300 MHz, d6-DMSO) δ 10.63 (br s, 1H), 9.22 (d, J=4.2 Hz, 1H), 8.40 (br s, 2H), 7.91 (d, J=6.9 Hz, 1H), 7.67 (m, 2H), 7.47 (d, J=1.5 Hz, 1H), 7.28-7.36 (m, 3H), 5.83 (m, 1H), 3.67 (s, 3H), 3.53 (s, 3H), 3.08 (d, J=4.5 Hz, 3H), 2.54 (s, 3H). MS (ESI) m/z=453 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:28]([NH:35][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (22.6 mg) and benzylamine (7.5 μL) were mixed in CH2Cl2 under nitrogen. Triethylamine (26 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (approx. 18 mg) and 4-dimethylaminopyridine (approx. 1 mg) were added and the mixture stirred at room temperature. After approximately 1.5 h another portion of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.5 mg) was added. One hour later the mixture was eluted directly on silica gel (95:5 CH2Cl2:MeOH) to yield 17.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.46 (br s, 1H); 8.38 (d, J=5.2 Hz, 1H); 7.94 (s, 1H); 7.81 (d, J=7.7 Hz); 7.67 (m, 1H); 7.59 (d, J=7.8 Hz, 1H); 7.44 (t, J=7.7 Hz, 1H); 6.78 (d, J=5.5 Hz, 1H); 6.44 (s, 1H); 5.77 (br s, 1H); 5.24 (br s, 1H); 4.65 (m, 2H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 449.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].Cl.[Cl:25][C:26]([Cl:32])([Cl:31])[C:27](=N)OC.O>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:27]([C:26]([Cl:32])([Cl:31])[Cl:25])=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: COC(=N)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: ClC(Cl)(Cl)c1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in acetic acid (3 mL) was added methyl 2,2,2-trichloroacetimidate hydrochloride (94.1 mg, 0.533 mmol), and this was stirred at room temperature for 4 hours. After the reaction was complete, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (196 mg, 93% yield) as gray crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][CH2:22][O:23]C(=O)C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][CH2:22][OH:23])=[O:11])=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CCO
Reaction time: 0.5 h

Procedure:
(2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(2-acetoxyethyl)-4-acetylthiopyrrolidine (204 mg) was dissolved in 5 ml of methanol and 1 ml of 1N sodium hydroxide solution was added thereto at room temperature under nitrogen stream, followed by stirring for 30 minutes. 1H Hydrochloric acid (1.2 ml) was added to the reaction mixture. The resulting mixture was diluted with ethyl acetate, washed with brine five times, dried over anhydrous sodium sulfate and evaporated to give an oily residue, which was purified by silica gel thin layer chromatogaraphy to give (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4-mercaptopyrrolidine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=3[CH:11]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCOc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 105 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
To a solution of 7-bromo-4-chromanone (1.0 g, 4.4 mmol) in DMF (15 mL) was added [4-(trifluoromethyl)phenyl]boronic acid (1.25 g, 6.6 mmol), Pd(PPh3)4 (580 mg, 0.5 mmol) and K2CO3 (1.22 g, 8.8 mmol). The mixture was stirred at 105° C. for 4 h under nitrogen. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (PE:EtOAc=4:1) to give 830 mg (61%) of the title compound as white solid. [M+H] Calc'd for C16H11F3O2, 293. Found, 293.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[S-:13][C:14]#[N:15].[Na+].[CH3:17][O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21]>C(O)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([C:3]2[N:15]=[C:14]([NH:21][C@@H:20]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:19]([O:18][CH3:17])=[O:30])[S:13][CH:2]=2)=[CH:6][CH:7]=1)#[N:10]
Reactant: N#C[S-]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 12 h
Yield: 53 %

Procedure:
22.3 g (0.1 mol) of 4-(bromoacetyl)benzonitrile and 8.66 g (0.107 mol) of dry sodium thiocyanate in ethanol (200 ml) were stirred for 3 h at 50° C. Then 19.51 g (0.1 mol) of (S)-tyrosine methyl ester in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 h. After removing ethanol by distillation, water and ethyl acetate were added. Aqueous phase was extracted twice with ethyl acetate, combined organic phases were dried over sodium sulfate and the solvent was evaporated. The product was purified by chromatography (SiO2, ethyl acetate/hexane). The yield was 53%. MS (ES) 379 (M+, 100%)
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1)#[N:2].[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])(=[O:16])=[O:15]>N1C=CC=CC=1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:14]([CH3:13])(=[O:16])=[O:15])(=[O:25])=[O:24])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C#N)c2c1
Yield: 11.5 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 0.55 g of 3-cyano-5-amino-1H-indazole, 10 ml of pyridine and 0.88 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.15 g of N-(3-cyano-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide is thus obtained in the form of a yellow powder melting at 272° C. (analysis C15H12N4O4S2.0.85H2O, % calculated C, 47.87; H, 3.21; N, 14.88; S, 17.04%, found C, 47.88; H, 3.01; N, 14.75; S, 17.45).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)=[O:4].BrBr.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(Cl)Cl.C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:5]([C:3]2([OH:4])[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[NH:15][CH:2]2[CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: CCC(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(N)CO
Agent: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: CC1NC(C)(C)COC1(O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of 3,5-dichloropropiophenone (8m, 3.81 g, 0.0188 mol) in CH2Cl2 (28 mL) was added bromine (0.986 mL, 19.1 mmol) dropwise. The bromine was immediately consumed upon addition of each drop until the end of addition when it had a consistent brownish color, indicative of excess bromine. The reaction was immediately quenched with saturated aqueous NaHCO3, extracted three times with CH2Cl2. The organic layer was separated, combined and concentrated under reduced pressure, without drying to afford a yellow oil. The oil was dissolved in anhydrous diethyl ether (50 mL) and 2-amino-2-methyl-1-propanol (6.7 g, 0.075 mol) was added. The reaction mixture was stirred overnight and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted three times with CH2Cl2, and the organic layers concentrated to afford another yellow oil. Purification by column chromatography on silica gel afforded 2.51 g (46%) of the title compound. The hemi-fumarate salt was prepared by dissolving the free base in methanol and adding 1.0 g of fumaric acid to form the title compound: mp 188-190° C.; 1H NMR (DMSO-d6) δ 7.58-7.57 (m, 1H), 7.47 (m, 2H), 6.67 (s, 0.5H), 4.09 (d, 1H, J=11.9 Hz), 3.53 (d, 1H, J=12.0 Hz), 3.41-3.37 (m, 1H), 1.53 (s, 3H), 1.28 (s, 3H), 1.02 (d, 3H, 6.6 Hz); 13C NMR (DMSO-d6) δ 134.9, 133.6, 127.7, 125.2, 94.7, 67.2, 52.5, 50.1, 25.0, 21.6, 14.6; Anal. (C15H19Cl2NO4.0.25H2O) calcd: C, 51.08; H, 5.57; N, 3.97. found: C, 51.13; H, 5.64; N, 3.90.
Reaction SMILES: C1C2(CC(=O)NC(=O)C2)CCC1.[H][H].[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[C:29][CH2:30][N:31]2[C:40](=[O:41])[CH2:39][C:34]3([CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:33][C:32]2=[O:42])[CH2:23][CH2:22]1>O1CCCC1.[Pd]>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[C:40](=[O:41])[CH2:39][C:34]3([CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:33][C:32]2=[O:42])[CH2:23][CH2:22]1
Reactant: [H][H]
Reactant: O=C1CC2(CCCC2)CC(=O)N1CC#CCN1CCN(c2ncccn2)CC1
Agent: [Pd]
Agent: O=C1CC2(CCCC2)CC(=O)N1
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0 h
Yield: 98.7 %

Procedure:
A solution of 100 g (0.26 mole) of 8-[4-[4-pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione in 50 ml of tetrahydrofurane is added to a suspension of 1 g of a palladium/carbon catalyst (palladium content about 5% by weight) and 50 ml of tetrahydrofurane under vigorous stirring under the introduction of hydrogen under a pressure of 2 bar at such a rate that the hydrogen uptake of the unsaturated 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione added is substantially identical with the calculated hydrogen consumption. This means practically that when the addition of the starting material is stopped, the decrease of the hydrogen pressure in the apparatus ceases within 5-10 seconds. The addition of the starting material takes 1-4 hours, depending on the intensity of stirring. The reaction temperature is adjusted to 15°-30° C. during the complete period of addition. At the end of hydrogenation the catalyst is filtered off. The catalyst can be directly used in the next hydrogenating operations without any further treatment. The filtrate is evaporated, the residue is suspended in isopropanol and filtered. Thus in the form of white crystals 99.7 g of 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7,9-dione are obtained, yield 98.7%. Melting point: 105°-106° C. (according to prior art 90°-98° C.). Content (on the base): 99.8-100.1%. According to HPLC analysis the product contains only 0.1% of contaminations.