Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].N1CCCCC1>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:21]2[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]2=[O:20])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1csc(Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 440 mg of 2-anilinothiazole-4-carbaldehyde, 412 mg of rhodanine-3-acetic acid, 0.5 ml of piperidine and 10 ml of ethanol. The resulting product was a yellowish-brown powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14].C(=O)([O-])O.[Na+].S(Cl)([Cl:32])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:32][C:9]1([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[N:11]([CH3:22])[C:10]1=[O:23]
Reactant: CON1CCC2(CC1)C(O)=C(c1cc(C)ccc1C)C(=O)N2C
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1cc(C)ccc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.1) (35 mg, 0.111 mmol) and sodium hydrogen carbonate (23 mg, 0.274 mmol) in chloroform (5 ml) at −5° C. was added sulfuryl chloride (0.009 ml, 15.0 mg, 0.111 mmol) in chloroform (0.25 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight, poured on saturated aqueous sodium carbonate, the layers separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 2:1). Yield: 26 mg of 3-chloro-3-(2,5-dimethyl-phenyl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.5) as a pale yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1.[CH:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:20]([CH:17]2[CH2:19][CH2:18]2)[S:22][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(F)c1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(C)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide.
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=O)[CH2:5]1)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
To a solution of trans 3-azidocyclobutanecarboxylic acid (0.58 g, 4.1 mmol) in dichloromethane (10 ml) was added oxalyl chloride (0.45 ml) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (~2 h) and the solvent was evaporated in vacuo leaving a slightly yellow oil; 0.63 g, 95%, ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C--O of acyl chloride); 1Hmr (CDCl3) δ: 4.12 (1H, m, H-1), 3.6 (1H, m, H-3) and 3.1-2.1 ppm (4H, H-2, H-4).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.C(N(CC)CC)C>C(OC(=O)C)(=O)C>[CH2:21]([O:20][C:14]([CH:15]1[C:8](=[O:10])[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:11]1=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C(=O)O)c(C(=O)O)cn1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1C(=O)c2cnc(C)cc2C1=O
Reaction time: 8 h

Procedure:
6-Methyl-pyridine-3,4-dicarboxylic acid (440 mg) (see Emil J. Moriconi and Francis A. Spano, J. Am. Chem. Soc., Vol. 86, Pp. 38-46, 1964) was suspended in acetic anhydride (10 ml) and the mixture was refluxed for 10 minutes. Ethyl acetoacetate (0.325 ml) and triethylamine (0.745 ml) were dropwise added to the mixture at room temperature and the mixture was stirred overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography developed by dichloromethane and by dichloromethane-methanol (15:1). The desired compound was obtained as a dark red oil which contained 1 equivalent of triethylamine. ESI−MS: m/z 234 (MH+); 1H-NMR (CDCl3): δ1.26-1.38 (15H, m), 2.63 (3H, s), 3.28 (6H, q, J=3.3 Hz), 4.22 (2H, q, J=4.2 Hz), 7.29 (1H, s), 8.58 (1H, s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>ClCCl>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:24](=[O:27])[CH:25]=[CH2:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 101.2 %

Procedure:
To a solution of 390 mg (1.6 mmol) D-Proline benzyl ester hydrochloride and 0.47 ml (3.4 mmol) triethylamine in 20 ml dichloromethane at 0° C. was added dropwise 0.2 ml (2.4 mmol) acryloyl chloride and stirring continued for 24 h at room temperature. The reaction mixture was then washed sequentially with water, 1M hydrochloric acid and once more with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford 420 mg (100%) of the title compound (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22].Cl>C(Cl)(Cl)Cl>[Cl:26][CH2:25][CH2:24][O:23][C:21]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)OCCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OCCCl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (5.00 g) obtained in Reference Example 2(1) is dissolved in chloroform (60 ml), and thereto is added triethylamine (11 ml) under ice-cooling, followed by dropwise addition of a solution of 2-chloroethyl chloroformate (3.3 ml) in chloroform (10 ml). After stirring at room temperature for 2.5 hours, to the reaction solution is added 5% hydrochloric acid and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and then evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in chloroform/diisopropyl ether. The precipitates are collected by filtration and dried to give methyl trans-4-{[(2-chloroethoxy)carbonyl]amino}cyclohexanecarboxylate (5.11 g). APCI-MS M/Z:264/266[M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)C(=O)O

Procedure:
In the manner described in Example 54, 4-methyl-2-oxopentanoic acid and L-phenylalanyl-L-arginine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-methylbutyl)-L-phenylalanyl-L-arginine. The product is eluted from the ion exchange resin with 10% ammonia. The nmr spectrum in D2O gave a singlet at 7.2 (5H), a broad triplet centered at 3.0 (6H), a broad multiplet at 1.3 (6H), and a broad doublet at 0.9 (6H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20]Cl)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:15]([CH2:20][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: COC(=O)c1cccnc1CCl
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1Cn1cccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (5.8 g, 0.12 mol), was in dry N,N-dimethyl formamide (25 mL) was added slowly under nitrogen a solution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was then cooled to 5° C. and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A was added slowly, the temperature being maintained at or below 20° C. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. The mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (250 mL). This solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo leaving a dark crystalline solid (23.4 g), which was purified by chromatography on silica gel eluting with a gradient of ethyl acetate/petroleum ether to provide the title compound as a tan crystalline solid (13.75 g), m.p. 91–93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][CH:4]=1.ClC1C=C[N:14]=[C:13](C#N)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: COc1cc[n+]([O-])cc1
Product: COc1ccnc(C#N)c1

Procedure:
The title compound was prepared from 4-methoxypiridine-N-oxide by using the procedure described for the preparation of 4-chloro-2-pyridinecarbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:10]([NH:12][CH:13]([CH3:14])[CH3:15])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](N[C@@H](C(=O)NC(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of methyl N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucinate (1.32 g) in methanol (15 ml) was added a solution of lithium hydroxide (294 mg) in water (15 ml). The reaction was rapidly stirred for 1.5 hours and then evaporated in vacuo. The residue was dissolved in water and neutralised using 2N hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo. The filtrate was applied to 4 Oasis cartridges (6 g), which were eluted with water (×2) and methanol (×2). The required fractions were combined and concentrated in vacuo to afford N-[(1R)-1-(2,4-difluorophenyl)-2-(isopropylamino)-2-oxoethyl]-L-leucine (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2O.P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:20][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc([N+](=O)[O-])cc2c(O)c(C#N)cnc12
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc([N+](=O)[O-])cc2c(Cl)c(C#N)cnc12
Yield: 48.6 %

Procedure:
A mixture of 4 g (16 mmol) of 8-Methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorous pentachloride, and 15 ml of phosphorous oxychloride was refluxed for 2.5 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.05 g of tan solid: mass spectrum (electrospray, m/e) M+H 263.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Br[C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:25])[CH3:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 42.5 °C

Procedure:
Ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (32.25 g) of Formula (I) is dissolved in N,N-dimethylformamide (258 ml) at room temperature. Tert.-butyl 2-bromoisobutyrate (38.47 g) and anhydrous potassium carbonate (47.61 g) are added and the resulting suspension is heated to 40-45° C. for 20-25 hrs. The reaction mass is cooled to 30-32° C. and it is added slowly to water. The resulting slurry is stirred at 25-30° C. for about one and a half hours. The product is filtered, washed with water and dried under reduced pressure. Yield: 50 g (93.37%), water content <1.0% w/w; Chromatographic purity (HPLC) >98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)ccc1Sc1ccccc1
Yield: 88.2 %

Procedure:
A solution of 4-chloro-2-nitro-1-(phenylthio)benzene (11.0 g) and Raney nickel in ethanol (3A; 9.3 mL) was reacted in a Parr Hydrogenator under hydrogen atmosphere at 5 psi and room temperature. When the theoretical amount of hydrogen uptake was reached, the reaction was filtered to remove the catalyst and evaporated in vacuo to yield 8.61 g (88%) of a light orange solid. mp: 59°-61° C.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([Cl:26])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncsc1-c1cccc(F)c1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncsc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (55 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reaction time: 12 h

Procedure:
0.01 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzisothiazol-3(2H)one 1,1-dioxide is dissolved in 30 ml of absolute pyridine and, via cooling in ice, 0.02 mol of ethyl chloroformate is added. The mixture is then allowed to reach room temperature and is stirred for 12 hours. The solvent is evaporated off, ice-water is added and the mixture is extracted by shaking several times with methylene chloride. Colourless crystals are obtained after evaporating off the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=1)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[N:22][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(NC(C)=O)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-(5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (95 mg, 75%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[C:7](O[K])(C)(C)[CH3:8].[CH3:13][C@@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].O>CC(O)(C)C>[CH3:13][C@H:14]1[N:15]([C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:17][C@:18]2([O:20][CH2:8][CH2:7]2)[CH2:19]1
Reactant: CC(C)(C)O[K]
Reactant: C[C@@H]1CC(=O)CCN1[C@H](C)c1ccccc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H]1C[C@]2(CCO2)CCN1[C@H](C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (10.1 g, 46.0 mmol) in t-BuOH (anhydrous, 10 mL) was added tBuOK (1M in t-BuOH, 36.8 mL, 36.8 mmol) and the resulting mixture was stirred at 60° C. for 1 h. Then a solution of (R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-one (2 g, 9.20 mmol) in t-BuOH (6 mL) was added slowly. The reaction mixture was heated at 60° C. for 72 h, then cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-30% EtOAc/heptanes) to provide the desired isomer (4S,6R)-6-methyl-7-((R)-1-phenylethyl)-1-oxa-7-azaspiro[3.5]nonane as a colorless oil (0.67 g, 30%). 1H NMR (400 MHz, CD2Cl2) δ ppm 7.48 (d, J=7.83 Hz, 2H), 7.34 (t, J=7.58 Hz, 2H), 7.24 (t, J=6.82 Hz, 1H), 4.39-4.51 (m, 2H), 4.25 (q, J=6.74 Hz, 1H), 2.78-3.01 (m, 1H), 2.30-2.45 (m, 3H), 2.21-2.30 (m, 1H), 2.13 (td, J=2.56, 13.07 Hz, 1H), 1.85-1.95 (m, 1H), 1.44-1.62 (m, 2H), 1.28 (d, J=6.82 Hz, 3H), 1.20 (d, J=6.32 Hz, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8].O>CN(C)C=O>[N:1]([CH2:6][C:7]([NH:9][C:10]1[C:11]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[N+:2]=[N-:3]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Yield: 94.7 %

Procedure:
In 40 ml of dimethylformamide was suspended 2.84 g of sodium azide, and 10 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine was added thereto and the mixture was reacted at room temperature for 2 hours. After addition of 32 ml of water to the mixture, precipitated crystals were filtered to give 9.7 g of 9-azidoacetylamino-1,2,3,4-tetrahydroacridine. Melting point: 190° C. (decomposed). These crystals were suspended in 500 ml of methanol, and hydrogenolysis was carried out by adding 0.5 g of palladium black at room temperature for one hour. After removal of the catalyst by filtration, the filtrate was condensed and recrystallized from methanol - isopropanol, and then filtered to give 7.4 g of the title compound. Melting point: 225° to 230° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[NH2:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:15]([C@H:16]1[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]1)[CH2:12]2
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Product: O=C1c2ccc(Br)cc2CN1[C@H]1CC[C@@H](O)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 15, Step 1 starting from methyl 4-bromo-2-(bromomethyl)benzoate and cis-4-aminocyclohexanol hydrochloride. LCMS (M+H)+=310.0/312.0.