Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:30]=[N:29][C:28]([NH2:31])=[N:27]2)[CH:20]=1>>[CH3:16][O:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:30]=[N:29][C:28]([NH:31][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([C:7]#[N:8])[CH:9]=3)=[N:27]2)[CH:20]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: COC(=O)c1cccc(Cn2cnc(N)n2)c1
Product: COC(=O)c1cccc(Cn2cnc(Nc3ccc(-n4cnc(C)c4)c(C#N)c3)n2)c1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 3-(3-amino-[1,2,4]triazol-1-ylmethyl)-benzoic acid methyl ester. The title compound was obtained as a colorless solid (Yield=40%). MS ISP (m/e): 414.3 (100) [(M+H)+].
Reaction SMILES: B.CSC.[CH2:5]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=O)[C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C[O:31][CH2:30][CH2:29]1>>[C:30]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH:14]1[CH2:22][N:24]([CH3:26])[CH3:25])(=[O:31])[CH3:29]
Reactant: C1CCOC1
Reactant: CN(C)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Agent: B
Solvent: CSC
Product: CC(=O)N1c2ccccc2N(Cc2ccccc2)CC1CN(C)C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Borane-dimethylsulfide complex (10M-THF solution; 5 ml) was added to a THF (20 ml) solution of 4-benzyl-N,N-dimethyl-3-oxo-3,4-dihydro-2-quinoxalinecarboxamide (1.5 g). The reaction mixture was stirred at room temperature for one hour, further at 50° C. for 18 hours, then concentrated. The residue was dissolved in methanol (30 ml) and the mixture was stirred at 50° C. for 20 hours together with 6N hydrochloric acid (10 ml). The reaction mixture was concentrated, and the residue was dissolved in pyridine (10 ml). Acetic anhydride (0.5 ml) was added to the reaction mixture, which was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/3) to obtain the entitled compound (0.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])[CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1cccc(C)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(C)c1
Yield: 86 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.10 mmol) prepared in example 4b was reacted with 1-(3-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 10a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(3-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.5 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][NH:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:9]([N:23]([O:22][CH3:21])[CH3:24])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Yield: 81 %

Procedure:
2-Allyloxycarbonylamino-succinic acid 4-tert-butyl ester, 100, (43.4 g, 0.159 mol) is dissolved in CH2Cl2(900 mL). To this solution O,N-dimethyl-hydroxylamine hydrochloride (18.6 g, 0.191 mol), 4-Methyl-morpholine (21.0 mL, 19.3 g, 0.191 mol), and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.6 g, 0.191 mol) are added. After the consumption of the starting material, the solution is washed with 1.0 N HCl (2×400 mL) and brine (1×250 mL). The organic layer is concentrated in vacuo and the residue purified over silica (hexanes/ethyl acetate 65:35) to afford 40.8 g (81% yield) of the desired product as a clear oil. 1H-NMR, (300 MHz, CDCl3): δ 1.43 (s, 9H), 2.50–2.74 (m, 2H), 3.22 (s, 3H), 3.79 (s, 3H), 4.55–4.57 (d, J=4.8, 2H), 4.97–5.04 (m, 1H), 5.17–5.32 (m, 2H), 5.67–5.70 (d, J=9.0, 1H), 5.83–5.94 (m, 1H); 13C-NMR (75.5 MHz, CDCl3): δ 28.20, 32.58, 38.48, 61.83, 65.93, 81.53, 117.85, 132.88, 155.84, 169.46, 171.83; MS (ESI): m/e=317.11 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH2:18]C(C1OCCO1)C.Cl.[CH2:27]([OH:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH2:18][C:27](=[O:29])[CH3:28]
Reactant: CCO
Reactant: CC(Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)C1OCCO1
Agent: Cl
Product: CC(=O)Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12

Procedure:
A mixture of 14g of 5-chloro-3-[2(1,3-dioxolan-2-yl)propyl]-1-(4-fluorophenyl)indole, 112 ml of 96% ethyl alcohol, and 12 ml of 6N hydrochloric acid are heated to reflux for 30 minutes. The reaction mixture is concentrated then dissolved in water and extracted with ether. The organic phase is washed in water, dried, concentrated and then distilled.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:38]([CH:35]2[CH2:37][CH2:36]2)(=[O:40])=[O:39])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)C2CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 46.5 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and cyclopropylsulfonyl chloride (39.7 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (57 mg, 47% of theory).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=O)[CH2:3]1.[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([N:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[C@@H:6]2[CH3:7])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: C[C@@H]1NC(=O)C[C@@H]1O
Reactant: N#Cc1ccc(F)cc1Cl
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)c(Cl)c1

Procedure:
Using (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one and 2-chloro-4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 2 (reaction time 1 hr).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: ClCCN1CCCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN2CCCC2)c1=O
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.6 %

Procedure:
To a stirred solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.1 g) in N,N-dimethylformamide (3 mL), N-(2-chloroethyl)-pyrrolidine, hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction was stirred under nitrogen at 80° C. for 12 h. After 2 h additional batches of N-(2-chloroethyl)-pyrrolidine hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction mixture was stirred at 100° C. for 10 h and then at 90° C. for 10 h. Ethyl acetate was added and the mixture was washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column—acetonitrile/0.1% ammonia mobile phase) afforded the title compound as a solid (34 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Crude dimethyl 4-bromo-2-nitrophenylmalonate was heated at 110° C. in 40 mL of 6 N hydrochloric acid for 24 hours and cooled. The precipitate was collected by filtration, washed with water and dried to give 5.3 g (89% yield) of 4-bromo-2-nitrophenylacetic acid as an off white solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH2:38])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH:38][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCCC1CCCCN1CCCCC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CCCCN2CCCCC2)c2ccccc21
Yield: 36 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[4-(piperidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 36% of theory. Colourless crystals, m.p. 154°-155° C. (acetonitrile).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C:13]([CH2:14][O:15][S:16]([CH3:19])(=[O:17])=[O:18])([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[O:35][S:43]([CH3:42])(=[O:45])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
Nucleoside 27 (20 g, 37 mmol) was dissolved in anhyd dichloromethane (100 mL) and anhyd pyridine (100 mL) was added. The solution was cooled to 0° C. and methanesulfonyl chloride (4.4 mL, 56 mmol) was added dropwise. After 2 h the reaction was quenched with sat. aq NaHCO3 (200 mL), and the phases were separated. The aq phase was extracted with dichloromethane (2×150 mL), and the combined organic phases were washed with aq HCl (1 M, 2×200 mL), sat. aq NaHCO3 (2×250 mL) and brine (250 mL). The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude product was co-evaporated with toluene affording 28 (22 g, 96%) as a white foam. Rf=0.41 (100% EtOAc); ESI-MS m/z found 635.0 ([MNa]+, calcd 635.1). All analytical data were identical to those previously reported.(H åkansson, A. E.; Koshkin, A.; Sørensen, M. D.; Wengel, J. J. Org. Chem. 2000, 65, 5161-5166)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:10](=[O:15])[CH2:11][N:12]=[C:13]=[O:14])[CH:6]=[CH:7][CH:8]=1.[OH:27][CH:28]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:29]>O1CCCC1>[OH:27][CH:28]([C:30]1[CH:31]=[C:32]([NH:33][C:13](=[O:14])[NH:12][CH2:11][C:10]([N:9]([CH2:16][C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])[CH:34]=[CH:35][CH:36]=1)[CH3:29]
Reactant: CC(O)c1cccc(N)c1
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(C(C)O)c2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
2-[N-(3-Methoxyphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (3 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of 3-(1-hydroxyethyl)aniline (1.1 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 16 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2.5 cm in diameter) [eluent: dichloromethane/methanol (98:2 by volume)], collecting 20-cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in diisopropyl ether, (RS)-2-[2-{3-[3-(1-hydroxyethyl)phenyl]ureido}-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (1.7 g), m.p. 115° C., is thereby obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][NH:20][CH:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc[nH]c1
Yield: 74 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 74% yield.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19]([OH:21])=O)[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)[C:19](=[O:21])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1
Reactant: OCCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].Cl>CN(C=O)C.C(O)C>[CH3:19][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:3]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=[C:6]([CH3:8])[N:7]=2)=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:16])=[O:18]
Reactant: COc1cc(P(C)(C)=O)ccc1N
Reactant: Cc1nc(Cl)cc(Nc2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2)nc(C)n1

Procedure:
To a solution of 6-chloro-2-methyl-N-phenylpyrimidin-4-amine (0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mL of DMF, is added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixture can be heated in a sealed tube at 140 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH2:4][CH2:5][CH3:6].[C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:18][C:17]3([O:36][C:21]4=[CH:22][N:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH:31]=5)[CH:25]=[C:20]4[CH2:19]3)[CH2:16]2)[CH2:12][CH2:11]1)#N>>[CH3:35][S:32]([N:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:25]=[C:20]3[CH2:19][C:17]4([CH2:16][C:13]5([CH2:12][CH2:11][N:10]([C:8]6[O:1][N:2]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=6)[CH2:15][CH2:14]5)[CH2:18]4)[O:36][C:21]3=[CH:22][N:23]=2)[CH2:31][CH2:30]1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)n1

Procedure:
The title compound is prepared from N-hydroxy-butyramidine and 1″-cyano-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] following a procedure analogous to that described for Example 23. LC (method 3): tR=0.91 min; Mass spectrum (ESI+): m/z=500 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[Na].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:41]3[CH:45]=[CH:44][N:43]=[CH:42]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: c1c[nH]cn1
Agent: [Na]
Product: Cc1ccccc1-c1nc(-n2ccnc2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 72.5 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with sodium salt of imidazole (16.2 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(imidazole-1-yl)-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (61.0 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([NH:19][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
50 g (34.5 mL, 14.3 mmol) 3,4-difluoronitrobenzene and 44.6 mL (408.6 mmol) benzylamine were combined with 600 mL acetonitrile, and then 82.3 mL (471.5 mmol) N,N-diisopropylethylamine (DIPEA) was added thereto. The resultant mixture was slowly heated to reflux. The reaction substantially completed after refluxing 5 hours, as monitored by a real-time thin layer chromatography (TLC). Then, heating was stopped and the mixture was allowed to cool to room temperature, resulting in the precipitation of a colorless transparent crystal. The mixture was filtered when substantially no more crystal precipitated. The filtrate was evaporated in a rotatory evaporator to afford a yellowish solid, which was recrystallized with ethanol to obtain a yellow crystal. Then, the yellow crystal was dried and weighed 72.5 g, with a yield of 93.7%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44]CC)=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([OH:44])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](N[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In 20 ml of methanol is dissolved 0.55 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 5 ml of 1N aqueous sodium hydroxide is added dropwise to the solution over a period of 5 minutes. After stirring at room temperature for 1 hour, another 2 ml of 1N aqueous sodium hydroxide is added dropwise to the mixture over a period of 5 hours. After 2 ml of water is added dropwise over a period of 2 hours, 10 ml of water is added to the reaction solution, and the mixture is extracted with 10 ml of n-hexane. The aqueous layer is made weakly acidic with 1N hydrochloric acid, and extracted with 50 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.5 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.