Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH3:9][N:10]1[CH2:30][CH2:29][C:14]2=[C:15]([N:22]3[CH2:25][CH:24]([C:26](O)=[O:27])[CH2:23]3)[N:16]3[C:20]([N:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[N:17]3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2([N:22]3[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]3)[C:14]3[CH2:29][CH2:30][N:10]([CH3:9])[CH2:11][CH2:12][C:13]=3[N:21]=[C:20]3[N:16]2[N:17]=[CH:18][CH2:19]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C2(N3CC(C=O)C3)C3=C(CCN(C)CC3)N=C3CC=NN32)CC1
Reaction time: 2 h

Procedure:
To 11.4 mg (0.10 mmol) N-ethylpiperazine was added a solution of 43 mg (0.10 mmol) 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid and 0.026 mL (0.15 mmol) DIPEA in 0.5 mL DMF at room temperature. 35.3 mg (0.11 mmol) TBTU was dissolved in 0.5 mL DMF and the solution was added to the reaction mixture. Stirring was continued for 2 h and the reaction mixture was allowed to stand for overnight. The mixture was filtered over basic alumina followed by two washing cycles with 1.5 mL DMF. The solvent was removed and the residue was purified by column chromatography to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[C:10]([C:16](OC)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1.N12CCCN=C1CCCCC2>O>[NH2:8][C:9]1[C:10]([C:16]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][N:14]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: Nc1cccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To 3-aminopyridine (10 g, 106 mmol) at 70° C. were added methyl 3-amino-6-bromo-2-pyrazinecarboxylate (1.0 g, 4.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (645 μL, 4.3 mmol). The reaction solution was stirred for 4 h, diluted with water (75 mL) and extracted with methylene chloride. The combined organic layers were washed with a saturated ammonium chloride solution, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified on a silica gel column using methylene chloride/ethanol, (9:1), as the eluent to give 750 mg (59% yield) of the title compound as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 9.50 (br s, 1H) 8.82 (d, J=3 Hz, 1H), 8.43 (dd, J=5 and 1 Hz, 1H), 8.31 (s, 1H), 8.23 (ddd, J=8, 3 and 2 Hz, 1H), 7.34 (dd, J=8, 5 Hz, 1H); MS (TSP) m/z 294 (M++1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O.C(=O)C1C=CC=CC=1>C(O)C>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: CCOC(=O)[C@H](N)c1ccccc1
Reaction time: 24 h

Procedure:
Solutions of ethyl DL-phenylglycinate (5.0 g., 27.95 mmole), (+)-tartaric acid (4.417 g., 29.45 mmole, 1.05 equiv.), and benzaldehyde (2.85 ml., 27.95 mmole, 1.0 equiv.) in ethanol (total volume 47 ml.) were mixed at 58°. The solution was cooled to 20° to 26° and stirred for 24 hours to give a white solid which was washed with ethanol (2 × 10 ml.), and dried at 29°/2 mm. for 6 hours to give ethyl D-phenylglycinate (+)-hemitartrate as a mono-ethanol solvate (7.95 g., 76%), [α]D20 -47° (c 2.5, H2O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]2[N:16]=[CH:17][N:18]=[C:8]2[NH:7][C:6]=1[CH3:19])=[O:4].[Br:20]Br.O>C(O)(=O)C>[Br:20][CH2:19][C:6]1[NH:7][C:8]2[N:9]([N:16]=[CH:17][N:18]=2)[CH:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: BrBr
Reactant: COC(=O)C1=C(C)Nc2ncnn2C1c1cccs1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1=C(CBr)Nc2ncnn2C1c1cccs1
Yield: 50.6 %

Procedure:
In 300 ml of acetic acid is dissolved 29.5 g of 6-methoxycarbonyl-5-methyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine at 60° C. To the solution is added dropwise a solution of 16 g of bromine in 50 ml of acetic acid for 20 minutes with stirring. After stirring at room temperature for an hour, the reaction mixture is poured into water, extracted with chloroform, washed with water and potassium carbonate solution, dried and the solvent is evaporated under reduced pressure. The obtained pale yellow crystals are recrystallized from ethanol to give 18 g of 5-bromomethyl-6-methoxycarbonyl-7-(2-thienyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 155° C. with decomposition.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.Br[C:9]1[S:13][C:12]([NH2:14])=[N:11][CH:10]=1.[SH:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C.O>[NH2:14][C:12]1[S:13][C:9]([S:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][N:11]=1
Reactant: COC(=O)CCS
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCSc1cnc(N)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
K2CO3 (14.0 g, 100 mmol) was added to a solution of 5-bromothiazol-2-amine hydrobromide (13.0 g, 50 mmol) in 90 ml of dry DMF at 0° C. under nitrogen. After 0.5 h, methyl 3-sulfanylpropanoate (6.0 g, 50 mmol) was added dropwise to the mixture over the course of 30 min and stirred at ambient temperature for 48 h. Then the mixture was diluted with 500 ml of water and extracted with TBME. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give the title compound (7.6 g, 70% yield) 1H NMR (400 Mz, CDCl3) δ2.53 (t, 2H), 2.75 (t, 2H), 3.58 (s, 3H), 7.25 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:10]1[CH2:13][N:12](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C.C(O)(=O)C>[C:31]([O:30][C:28]([NH:27][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]1[CH2:11][NH:12][CH2:13]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CNC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 3-[bis-(tert-butoxycarbonylamino)methyl]-1-(diphenylmethyl)azetidine (Intermediate 152, 6.4 g) and 10% palladium on carbon (3 g) in ethanol (100 mL) and acetic acid (2 mL) was stirred under an atmosphere of hydrogen overnight. The solid was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give 3-[bis-(tert-butoxycarbonylamino)methyl]azetidine (4.0 g) as a colourless liquid, which was used without further characterisation.
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C=O)C>[Si:9]([O:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
In 10 ml of DMF was dissolved 1.2 g of methyl (R)-β-hydroxybutyrate, and 1.8 g of t-butyldimethylsilyl chloride and 1.0 g of imidazole were added to the solution and reaction was carried out at room temperature overnight. Water was added to the solution and the mixture was extracted with ether. The extract was subjected to distillation to obtain 2 g of methyl (R)-β-t-butyldimethylsilyloxybutyrate. The obtained compound was dissolved in anhydrous ether and the solution was added dropwise into a suspension of 0.5 g of lithium aluminum hydride in anhydrous ether. After the dropwise addition, the mixture was refluxed for 3 hours. After the reaction, 0.5 ml of water, 0.5 ml of 15% NaOH and 1.5 ml of water were added in turn to the reaction mixture, 20 ml of THF was further added, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration, and the filtrate was dried over magnesium sulfate and concentrated under a reduced pressure. The residue was subjected to distillation under reduced pressure to obtain
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH3:13].[NH2:15][NH2:16]>CO>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:15][NH2:16])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(OC)cc1OC
Solvent: CO
Product: COc1ccc(C(=O)NN)c(OC)c1
Yield: 78.1 %

Procedure:
Ex-109A: A solution of 2,4-dimethoxy-benzoic acid methyl ester (4.24 g, 21.6 mmol) and hydrazine (3.4 mL, 108.1 mmol) in methanol (50 mL) was refluxed overnight. Solvent was removed under reduced pressure. The residue was re-dissolved in ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate and brine, dried over sodium carbonate and concentrated to afford 2,4-dimethoxy-benzoic acid hydrazide (3.31 g, 78%) as a white solid: 1H NMR (CDCl3) δ 8.77 (bs, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.58 (dd, J=8.8, 2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 4.10 (bs, 2H), 3.91 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:24][C:25](=O)[NH:26][C:27]1[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:32]([C:30]1[CH:31]=[C:27]([NH:26][C:25]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:20]=[CH:19][C:14]3[C:15]([CH3:18])=[N:16][O:17][C:13]=3[CH:12]=2)=[O:24])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[N:29]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(F)(F)F)cc1
Reactant: Cc1noc2cc(Oc3ccc(F)cc3CN)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(C)noc3c2)cc1
Temperature: 75 °C
Yield: 77.5 %

Procedure:
5-Fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzylamine (9v) (60 mg, 0.22 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (12v) (89 mg, 0.22 mmol) and diisopropylethylamine (0.058 mL, 0.33 mmol) were combined in DMF (2 mL) and heated at 75° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 30 to 40% EtOAc/hexanes) to provide compound (10v) (90 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.15 (s, 1H), 5.99 (s, 1H), 5.28 (t, J=7.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.31 (s, 9H); MS (ESI+) m/z 528 (M+H) detected; HPLC (5 to 95%) 3.49 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]Cl)=[O:9])[CH3:4].[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][C:8](=[O:9])[CH2:10][O:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:4]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC(C)(C)C
Temperature: 0 °C

Procedure:
A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil) in dimethyl formamide (50 ml), at 0° C., was treated dropwise with ethyl-4-chloroacetoacetate (5 ml) and then with tert-butyl alcohol (7.08 ml). This mixture was maintained at 0° C. for 2 hours, then a further 2 hours at ambient temperature and then poured onto 2N hydrochloric acid/ice and then extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then with water, then with brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to give 4-tert-butoxy-3-oxo-butyric acid ethyl ester (5.20 g) as a yellow oil. TLC (silica, 1:4, v/v ethyl acetate/petrol): RF=0.51. NMR (400 MHz, CDCl3): δ 1.21(9H, s), 1.28(3H, t), 3.55(2H, s), 4.19(2H, q).
Reaction SMILES: O.[NH2:2][NH2:3].C(OCC)C.[CH3:9][C:10](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=O>O>[CH3:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3][N:2]=[CH:11]1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: NN
Solvent: CCOCC
Solvent: O
Product: CC1C=NNC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.22 ml (1 equiv.) hydrazine hydrate was added to 100 mL diethylether. The emulsion was cooled with an ice bath. 15.0 mL 2-Methyl-3-phenyl-propenal was added dropwise, and the mixture was stirred overnight at room temperature. H2O was added, the organic layer was separated and the aqueous layer was extracted with diethylether. The combined organic layers were dried over Na2SO4, filtrated and concentrated in vacuo. Vacuum distillation yielded 5.9 g of desired product (mixture of diastereomeric pairs) as a clear fluid (76-82° C., 0.2-0.3 mbar). 1H NMR (400 MHz, CDCl3) of first diastereomeric pair; δ 0.71 (d, J=7 Hz), 3H), 3.20-3.31 (m, 1H), 4.77 (d, J=10 Hz, 1H), 6.73 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H). 1H NMR (400 MHz, CDCl3) of second diastereomeric pair: δ 1.24 (d, J=7 Hz), 3H), 2.90-3.11 (m, 1H), 4.22 (d, J=11 Hz, 1H), 6.71 (br s, 1H), 7.23-7.42 (m, 5H), 8.55-8.60 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:24]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([N:32]=[C:33]=[O:34])=[O:31])=[CH:28][CH:27]=1)#[N:25]>C(#N)C>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)=[O:31])=[CH:35][CH:36]=1)#[N:25]
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Yield: 52.6 %

Procedure:
Methyl 4-aminophenoxyacetate, hydrochloride salt (1.09 g), was dissolved, with warming, in acetonitrile (50 ml) containing diisopropylethylamine (0.86 ml). To this solution at ambient temperature was added gradually with stirring a solution of 4-cyanobenzoyl isocyanate (1 g, preparation described in Weikert, R. J. et al (1991), J. Med. Chem. 34, 1630) in acetonitrile (5 ml). The precipitated solid was crystallised from boiling acetonitrile to give methyl 4-[3-(4-cyanobenzoyl)ureido]phenoxyacetate (930 mg) as an off-white solid: m.p. 214°-217° C.; NMR Spectrum (DMSO-d6) 3.70 (3H, s), 4.77 (2H, s), 6.94 (2H, d), 7.48 (2H, d), 8.02 (2H, d), 8.12 (2H, d), 10.49 (1H, s), 11.19 (1H, s); Mass Spectrum m/Z 354 (M+H)+.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][S:23]([C:20]1[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
2-Indanylamine hydrochloride (9.68 g, 57.1 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (12.84 g, 51.9 mmol) prepared in Preparative Example 12 and sodium acetate (18.73 g) in ethanol (100 ml). The obtained mixture was stirred at room temperature for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(2 indanyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a white crystal (16.92 g, 95%). Ethanol (80 ml) and 1N aqueous sodium hydroxide (80 ml) were added to the white crystal. The obtained mixture was heated under reflux overnight, acidified with 1N aqueous hydrochloric acid, adjusted to pH 8 with sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (6.79 g, 46%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[OH-].[Na+].[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>>[ClH:17].[ClH:1].[OH:20][CH:18]1[CH2:19][N:6]2[C:5](=[N:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=32)[CH2:4][NH:3][CH2:16]1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: ClCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OC1CNCc2nc3ccccc3n2C1
Reaction time: 3 h
Yield: 76 %

Procedure:
22 g. (0.1 moles) of 2-aminomethyl-benzimidazole dihydrochloride are suspended in 250 ml. of alcohol, and an alcohol solution of 12 g. (0.3 moles) of sodium hydroxide is added slowly to the cooled suspnesion. Thereafter 9.2 g. (0.1 moles) of epichlorohydrine are added to the mixture, and the reaction mixture is boiled for 3 hours under reflux. The mixture is cooled, the sodium chloride is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. The oily residue is dissolved in a mixture of acetone and alcohol, and the pH of the solution is adjusted to 3 with hydrochloric acid. The separated white, crystalline substance is filtered off, washed with a small amount of the above solvent, and dried. This way 20.9 g. (76%) of 2,3,4,5-tetrahydro-4-hydroxy-1H-(1,4)-diazepino[1,2-a]benzimidazole dihydrochloride are obtained; m.p.: 248°-250°C (heating rate: 4°C/min.).
Reaction SMILES: [CH3:1]N(C)C=O.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH3:1][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CN(C)C=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Five hundred milliliters of a dimethylformamide solution of 103.2 g (0.6 mole) of 2-hydroxy-1-naphthaldehyde and 107.6 g (0.78 mole) of anhydrous potassium carbonate was stirred at 50° C. To the solution was added dropwise 145 g (0.78 mole) of methyl p-toluenesulfonate. After the addition, the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to 1.5 liters of water, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from a mixture of n-hexane and ethyl acetate (5/1) to give 93.8 g (0.504 mole) of 2-methoxy-1-naphthaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(C)C1N(CC(=O)NC2CCN(C)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 31.2 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methyl-piperidin-4-ylamine (0.134 mg, 0.95 mmol), N-methylmorpholine (99 mg, 0.95 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 75 mg, 31.2%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][NH:17][CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].CN(C)C=O.Br[CH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:34]4[CH2:33][CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCC(Br)CC1
Reactant: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with cyclobutyl (35)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.67 g, 4.71 mmol), N,N-dimethylformamide (10 mL), 4-bromo-1λ6-thiane-1,1-dione (1.0 g, 4.7 mmol), and cesium carbonate (3.08 g, 9.45 mmol). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether). The material was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 Sum, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% acetonitrile up to 100% in 10 min); Detector, UV 220&254 nm. This afforded cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.01 g, 44%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.09 (d, J=6.60 Hz, 3H), 1.62-1.74 (m, 1H), 1.75-1.92 (m, 1H), 2.03-2.35 (m, 9H), 2.36-2.45 (m, 2H), 3.06-3.18 (m, 2H), 3.38-3.56 (m, 2H), 3.67 (t, J=13.20 Hz, 1H), 4.07-4.18 (m, 1H), 4.75-4.83 (m, 1H), 4.97-5.07 (m, 2H), 7.37 (s, 2H), 7.88 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]