Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:28][CH2:29][C:30]#[C:31][CH2:32][OH:33].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([NH:28][CH2:29][C:30]#[C:31][CH2:32][OH:33])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC#CCO
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)NCC#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
4-[(tert.-butoxycarbonyl)amino]butanoic acid (5.20 g, 25.6 mmol, prepared in analogy to Houssin et al., (1988) Synthesis 3, 259-261) was dissolved in anhydrous tetrahydrofuran (20 mL), carbonyldimidazole (CDI) (4.56 g, 28.1 mmol) was added and the resulting clear solution was stirred at room temperature for 2 h. Then, the primary amine 11 (3.11 g 25.6 mmol) and trietylamine (7.10 mL, 50.9 mmol) were added and stirring was continued at room temperature for 2 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 40 g, chloroform/ethylacetate 1:1) to give compound 12 (3.59 g, 52%) as a light yellow oil (Rf 0.3, chloroform/ethyl acetate 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10](C(=O)[C@@H]3CCCN3S(C3C=CC5C(=CC=CC=5)C=3)(=O)=O)[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CNc3c(ccc4ccccc34)S2)cc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A mixture of (R)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (11.50 g, 0.019 mole), 86% potassium hydroxide (15.0 g, 0.227 mole) and ethanol-water (10:1, 230 ml) is refluxed under argon for one hour. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saline, dried over sodium sulfate and distilled to remove the solvent. The residue is purified by silica gel column chromatography (CHCl3) and thereafter recrystallized from ethyl acetate-hexane to give (R)-(+)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (3.74 g, 63%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:29][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:3])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and isoamylamine (39.5 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-methylbutyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (22.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7](O)([C:11]([NH2:13])=[O:12])[C:6]=2[CH:15]=1.S(Cl)([Cl:18])=O>C(OCC)C>[Cl:18][C:7]1([C:11]([NH2:13])=[O:12])[C:6]2[CH:15]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: NC(=O)C1(O)CCOc2ccc(F)cc21
Solvent: CCOCC
Product: NC(=O)C1(Cl)CCOc2ccc(F)cc21
Temperature: 28 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 6-fluoro-4-hydroxy-3,4-dihydro-2H-1-benzopyran-4-carboxamide (60 mg, 0.28 mmol) and thionylchloride (60 mg, 0.28 mmol) in 1.0 ml of diethyl ether was stirred for 5.0 hours at 28° C. The reaction mixture was evaporated in vacuo to give a pale yellowish oil which was chromatographed on silica gel, eluting with ethyl ether to give 43 mg (67.2%) of the desired refined compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F.[CH2:32]([NH2:34])[CH3:33].O>C(#N)C>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:9]([F:11])([F:10])[F:12])[C:13]([F:16])([F:15])[F:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:34][CH2:32][CH3:33]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CCN
Solvent: O
Solvent: CC#N
Product: CCNc1ccc([N+](=O)[O-])cc1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-5-nitrobenzamide (5.0 g, 11 mmol) (see Example I4) in acetonitrile (100 ml) was added a solution of N-ethylamine in water (70% by weight) (2.23 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-ethylamino-5-nitrobenzamide (4.8 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[N:6][CH:5]=1.CS(C)=O.[N-:17]=[N+:18]=[N-:19].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]=[N+:18]=[N-:19])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Add 6-chloromethyl-nicotinic acid methyl ester (9.1 g, 40.98 mmol) and dimethylsulfoxide (100 mL) into a flask and cool to 0° C. Add sodium azide (4 g, 61.47 mmol) and sodium carbonate (13 g, 122.9 mmol) to the reaction mixture. Let the mixture slowly warm to room temperature. Stir for 1 hr at room temperature. Add water (100 mL) to the mixture. Extract with diethyl ether (100 mL×3). Wash the organic layer with water and brine. Dry with sodium sulfate. Remove solvent under reduced pressure to give the product (6.8 g, 86% yield) as light yellow oil. MS (m/z): 193.3 (M+1).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH2:17].NC(N)=S>CC(C)=O>[Br:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[C:16]=1[NH:17][C:11]([NH2:12])=[S:10]
Reactant: Nc1c(Br)cccc1Br
Reactant: N#C[S-]
Agent: NC(N)=S
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1c(Br)cccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 4.6 ml. of benzoyl chloride in 10 ml. of acetone was added over a period of 5 minutes to a solution of 3.32 g. of ammonium thiocyanate in 60 ml. of dry acetone at reflux. The resulting solution was refluxed for 10 minutes and a solution of 10.0 g. of 2,6-dibromoaniline in 40 ml. of acetone was added over a period of 10 minutes. After 15 minutes at reflux, the reaction mixture was poured onto 300 ml. of water and filtered. The resulting solid was suspended in 30 ml. of 10% sodium hydroxide and boiled for 10 minutes. The clear solution was acidified, neutralized to pH 8 with ammonia and filtered, giving 12.0 g. (97%) of 1-(2,6-dibromophenyl(thiourea, m.p. 186°-189°. Recrystallization from aqueous methanol gave the analytical sample, m.p. 192°-193°.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH3:25][C:24]([CH3:26])=[CH:23][CH2:22][N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1
Reactant: CC(C)=CCBr
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 16.2 %

Procedure:
Following the procedure of Example 3, step 4, 0.163 g (0.872 mmol) of crude trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 10 ml of anhydrous DMF was reacted with 0.133 g (0.962 mmol) of anhydrous potassium carbonate and 0.106 ml (0.917 mmol) of 4-bromo-2-methyl-2-butene. Chromatography on flash silica, eluting with 3-10% methanol/dichloromethane gave 0.036 g (16%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from ethanol/ethyl acetate, the title product hydrochloride was obtained as a white solid, m.p. 222°-225° C. NMR δ(D2O/CD3CN) 1.56 (1H, m), 1.67 (1H, m), 1.78 (3H, s), 1.86 (3H, s), 1.76-1.92 (2H, m), 2.62-2.73 (2H, m), 2.84 (1H, t, J=12.0 Hz), 2.92-2.94 ( 2H, m), 3.11 (1H, m), 3.53 (1H, m), 3.69 (1H, m), 3.75 (2H, d, J=7.9 Hz), 5.34 (1H, t), 7.22-7.26 (3H, m), 7.32-7.34 (1H, m). m/z (CI+, NH3) 256 (M+H)+, 188 (M-CH2CH=CMe2 +2H)+, 159, 130, 108, 94, 84, 70.
Reaction SMILES: [F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13](O)=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3].[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29]>>[F:1][C:2]([C:5]1[N:9]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[O:14])[N:8]=[N:7][N:6]=1)([F:4])[CH3:3]
Reactant: C[C@@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(C)(F)F)c2)nc1
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-n3nnnc3C(C)(F)F)c2)nc1

Procedure:
3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with (R)-2-amino-propan-1-ol using the procedure of step 4 of Example 5, to afford 3-[5-(1,1-Difluoro-ethyl)-tetrazol-1-yl]-N-((S)-2-hydroxy-1-methyl-ethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=403.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:9]=O)[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]=[O:20])=[CH:14][CH:13]=1>O.CO>[F:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](=[CH:9]/[CH:3]2[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4]2)/[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: O=CC1CC=CCC1
Reactant: O=CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C/C(=C\C1CC=CCC1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
5.5 g of sodium hydroxide in 30 ml of water are added to a solution of 40 g of 3-cyclohexenecarbaldehyde in 300 ml of methanol. The reaction mixture is cooled to 10° C., and 49.7 g of 4-fluorophenylacetaldehyde are rapidly added dropwise, the temperature of the solution not exceeding 30° C. After the mixture has been stirred for 2 hours at room temperature, 200 ml of water are added to the colorless reaction solution and the resulting emulsion is extracted by shaking with methyl tert-butyl ether. The organic phase is separated off, and 34 g (41%) of Z-2-(4-fluorophenyl)-3-(3-cyclohexenyl)-propenal are obtained under 0.5 mbar and at 136°-142° C. by distillation of the remaining residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.C(Cl)Cl.C(Cl)Cl.[OH2:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:8]([O:9][CH:5]([CH3:6])[CH3:4])=[O:23])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Reactant: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Intermediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (50 mol) and added TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to 0° C., isopropylchloro formate (2.7 ml, 6.62 mmol) was added and stirred the reaction mixture for 3 h at rt. Work up (DCM/H2O) followed by column purification on 60-120 mesh silica gel using EtOAc and Petether (15:85) as eluent afforded the titled compound (500 mg) as a pale-red solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)CCl.[NH2:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:15][CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: N[C@@H]1CCNC1
Solvent: CC#N
Solvent: ClCCCl
Product: O=C(NC1CCNC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A solution of 3-bromobenzoic acid (4.0 g, 20 mmol) and EDC (3.83 g, 20 mmol) in 50 mL acetonitrile was added dropwise to a solution of (3R)-(+)-3-aminopyrrolidine (1.72 g, 20 mmol) in 100 mL acetonitrile. The reaction mixture was stirred at room temperature for 2 h and the solvent was removed. The residue was dissolved in 50 mL CH2Cl2 and washed with brine (50 mL). The organic phase was dried (MgSO4) and the solvent was removed. The crude product was purified by silica gel column chromatography (Rf=0.22, CH2Cl2/MeOH, 75:15) to give 3-bromo-N-pyrrolidin-3-yl-benzamide as a colorless solid (2.0 g, 37%). To a solution of the above precursor (1.14 g, 4.24 mmol) in 30 mL CH2Cl2 were added di-tert-butyldicarbonate (925 mg, 4.24 mmol) and triethylamine (596 μl, 4.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the crude product was purified by silica gel column chromatography (Rf=0.66, CH2Cl2/MeOH, 90:10) to afford the title intermediate compound 106, as a viscous, colorless oil (1.1 g, 70%). MS (ESI+) m/z=369/371.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][C:17]([OH:19])=[O:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 6 h

Procedure:
4-Chloro-3-nitrobenzotrifluoride (10 grams), glycine (7 grams), and potassium carbonate (10 grams) were mixed in a mixture of 40 ml. each of water and dimethyl sulfoxide. The mixture was heated to 80°-100°C. and held for 6 hours, then poured into 600 ml. of water, acidified, and chilled to 5°C. The mixture was filtered, yielding N-(2-nitro-4-trifluoromethylphenyl)-glycine. The product was dissolved in 5 percent sodium bicarbonate and reprecipitated by acidification. It was separated and recrystallized from a mixture of ethanol and water, m.p., 167°-170°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[N:13]([CH2:21][CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n[nH]c1=O
Reactant: BrCC=Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)nn(CC=Cc2ccccc2)c1=O
Yield: 59.3 %

Procedure:
Using 6-(3-chloro-4-fluorophenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one and cinnamyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 59.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:31])[NH:15][CH2:16][CH2:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([CH2:32][O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:11][C:10]([CH3:42])=[C:9]2[C:43]([O:45]CCC#N)=[O:44])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:31])[NH:15][CH2:16][CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:12]([CH2:32][O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[NH:11][C:10]([CH3:42])=[C:9]2[C:43]([OH:45])=[O:44])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.25 g (0.37 mmol) of 2-cyanoethyl 4-(3-chlorophenyl)-6-(2-cyclohexylethoxymethyl)-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylate was dissolved in 5 ml of methanol. 0.73 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 2 hours. 1 N hydrochloric acid and water were added to the reaction mixture. The precipitates thus formed were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:26]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:27]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)C1CCCCC1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.72 mmol), cyclohexanecarbonyl chloride (0.22 g, 1.5 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.20 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:47][CH2:48][CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCN2CCCC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 0.75 g, 4.07 mmol), HATU (1.70 g, 4.48 mmol) and DIPEA (2.1 mL, 12.21 mmol) were stirred together in DMF (10 mL) for 25 mins. N-(2-aminoethyl)pyrrolidine (Aldrich; 0.51 g, 4.48 mmol) in DMF (2 mL) was added and the solution stirred at ambient temp for 2 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCNC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCCN(C(=O)OCC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-3-ylamide (example A180) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:13])[S-:12].C([NH+](CC)CC)C.C([O:24][CH2:25][C:26]([CH2:28]Cl)=O)(=O)C.Cl>C(O)C>[OH:24][CH2:25][C:26]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:12])[S:13][CH:28]=1
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Reactant: CC(=O)OCC(=O)CCl
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (81.2 g) prepared in the same manner as in Reference Example 1 was added to ethanol (800 ml) and thereto 1-acetoxy-3-chloroacetone (37.7 g) was added dropwise at 5° to 7° C. with stirring over a period of 20 minutes. After stirring the mixture for 50 minutes, 10% solution of hydrogen chloride in ethanol (240 ml) was added and the mixture was refluxed for 3 hours. After the solvent was distilled off under the reduced pressure, cooled water was added to the residue and resultant was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from a mixed solvent of hexane - ethyl acetate to give the title compound (59 g) as pale yellow crystals. The compound had physical properties identical to those of 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione prepared in the above Reference Example 18.
Reaction SMILES: [CH2:1]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[N:24]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:25]=[O:26]>ClCCl>[C:30]1([CH2:29][CH2:28][CH2:27][NH:24][C:25]([N:13]2[CH2:12][C:11]3([N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CN2CCC23CNC3)cc1
Reactant: O=C=NCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of 1-benzyl-1,6-diaza-spiro[3.3]heptane (41 mg, 217 μmol) in dichloromethane (2 mL) was added diisopropyl-ethyl-amine (112 mg, 868 μmol)) followed by (3-isocyanato-propyl)-benzene (84 mg, 521 μmol) and the reaction mixture was allowed to stir at ambient temperature for 16 h. After complete consumption of starting material the reaction mixture was diluted with dichloromethane and was washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. Purification by HPLC afforded the title compound (9 mg, 12%) as an off-white solid. MS m/e: 350 (M+H)+.