Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=S)=[CH:5][CH:4]=1.[F:14][C:15]([F:38])([F:37])[C:16]1[NH:20][C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:29]=[C:30]([NH2:36])[C:31]([NH:34][CH3:35])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[N:18][CH:17]=1.NC(N)=S>C(#N)C.O=P(Cl)(Cl)Cl>[CH3:35][N:34]1[C:31]2[CH:32]=[CH:33][C:28]([O:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([C:19]4[NH:20][C:16]([C:15]([F:37])([F:14])[F:38])=[CH:17][N:18]=4)[CH:26]=3)=[CH:29][C:30]=2[N:36]=[C:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: CNc1ccc(Oc2ccnc(-c3ncc(C(F)(F)F)[nH]3)c2)cc1N
Agent: NC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cn1c(Nc2ccc(C(F)(F)F)cc2)nc2cc(Oc3ccnc(-c4ncc(C(F)(F)F)[nH]4)c3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Trifluoromethylphenyl isothiocyanate (200 mg, 1 mmol) was added to a mixture of 4-(2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yloxy)-N1-methylbenzene-1,2-diamine (350 mg, 1 mmol) in 3 mL of acetonitrile. After stirring for 20 min at ambient temperature, HPLC analysis showed complete conversion. A mixture of thiourea (553 mg, 1 mmol) in POCl3 (3 mL) was stirred at ambient temperature. After 4 h, the mixture was heated to approximately 50° C. After heating for 2 h and monitored by HPLC, the title compound was provided.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:17]=[N:1][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1c(F)cc(F)cc1C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1c(F)cc(F)cc1C=Nc1cccc2nc(C)ccc12
Yield: 87.2 %

Procedure:
To 2.0 g (12.6 mmol) 5-amino-2-methylquinolin and 2.2 g (12.6 mmol) 3,5-difluoro-2-methoxybenzaldehyde in 38 ml toluene are added 0.1 ml acetic acid and 5 g molecular sieve. The mixture is heated over 5 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene. 3.43 g of [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine are obtained as a yellow solid. 1.93 ml (22.3 mmol) 1,1,1-trifluoroepoxypropane in 40 ml THF and 10 ml hexane are cooled to −100° C. and 14 ml of a 1.6 M n-butyl lithium solution in hexane are added over 2 hours while the temperature does not exceed −96° C. 10 Minutes after complete addition 3.44 g (11.2 mmol) [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine in 50 ml THF are added over 1.5 hours while the temperature temperature does not exceed −95° C. After one hour at −100° C. the reaction mixture is warmed to 0° C. over two hours. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (isopropanol in hexane 5% to 20%) yields 1.68 g of the desired epoxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].[OH-].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccn2)nc1
Yield: 91 %

Procedure:
50 mmol of 2-chloropyridine are refluxed together with 50 mmol of 2-pyridylboronic acid glycol ester, 25 mmol of lithium chloride, 50 mmol of potassium hydroxide, 1 mmol of tetrabutylammonium chloride and 0.05 mmol of trans-di-μ-acetato-bis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium (0.2 mol %) in (0.2 mol %) in 150 ml of tetrahydrofuran for 5 hours. Customary aqueous work-up and crystallization of the crude product from ethanol gives 2,2′-bipyridyl as colorless crystals (m.p. 70° C.) in a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C:17]1([CH2:23][CH2:24][NH:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:26][NH:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNCCc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NNCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-phenethylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-phenylethylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1.[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Oc2ccc(F)c(F)c2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(Oc2ccc(F)c(F)c2)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To a solution of diethyl 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)malonate (25 g, 34.9 mmol) in ethanol (250 mL) was added potassium hydroxide (19.58 g, 349 mmol). The reaction mixture was stirred at 80° C. for 1 hr. and then the reaction mixture was concentrated under the reduced pressure. To the residue was added 10% HCl to adjust the solution to approximately pH 7. Then, the solution was extracted with EtOAc (300 mL), and the organic layer was separated, and dried over Na2SO4, and then concentrated under reduced pressure to give 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)acetic acid (10 g, 98%).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21]N=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:25](N)C1C=CC=CC=1>>[CH2:18]([NH:17][C:11]1[N:10]=[C:9]([NH:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:25]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccccc1
Agent: Cl
Product: Cc1nc(NCc2ccccc2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using benzylamine instead of (pyridin-2-ylmethyl)amine to afford the crude product. The solvent was removed by distillation, and the crude product was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.). The titled compound was obtained as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03-1.15 (m, 1H), 1.22-1.31 (m, 4H), 1.60 (d, J=12.63 Hz, 1H), 1.68 (s, 4H), 1.86 (s, 3H), 2.21 (s, 3H), 3.86-3.90 (m, 1H), 4.52 (d, J=5.64 Hz, 2H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 4H), 7.4 (bs, 1H), 8.02 (bs, 1H); MS (ESI) m/z 311.5 (M+1)+.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COCO[C@@H]1C[C@H](CO)N(CCc2ccc(OC)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
To a solution of 4.50 g (20.2 mmol) of (2R, 4R)-(+)-2-(hydroxymethyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl) pyrrolidine and 2.40 ml of triethylamine (23.8 mmol) in dichloromethane (35 ml) was added 2.62 ml (22.9 mmol) of methanesulfonylchloride and the mixture was stirred at room temperature for 4.5 hours. The mixture was diluted with dichloromethane and the solution was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate : n-hexane=1:2 ) to give 4.82 g (87.2%) of (3S, 5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[ClH:26].CO>>[ClH:26].[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(F)c23)CC1
Agent: Cl
Solvent: CO
Product: Fc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 72 (30.2 mg) and 10% hydrogen chloride/methanol solution (3 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (18.1 mg) as light yellow powdery solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:17]=[C:16]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:15]=2)=[CH:9][C:8]=1[Cl:35])C.[OH-].[Na+].Cl>C(O)C>[Cl:35][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][CH2:23][CH3:24])[CH:17]=[C:16]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(Cl)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(Cl)c2)c1
Reaction time: 1 h

Procedure:
{2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-1-ynyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 70 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.81 min.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[CH:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[C:1]([N:5]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC=O
Reactant: CC(C)(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCCCC=NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To t-butyl amine (5.25 mL, 50.0 mmol) and MgSO4 (2 g) in CH2Cl2 (10 mL) at room temperature was added slowly hexanal (6.0 mL, 50 mmol) under N2 at room temperature. The reaction became exothermic halfway through the addition so an ice bath was briefly used to control the reaction rate and avoid boiling off the solvent or amine. After the addition was complete, the reaction was stirred at room temperature for 2 h, filtered through celite under a stream of N2 and washed with 20 mL dry CH2Cl2. The solvent was evaporated to give a pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ 0.87-0.91 (m, 3H), 1.17 (s, 9H), 1.25-1.35 (m, 4H), 1.45-1.55 (m, 2H), 2.23 (m, 2H), 7.59 (t, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.O>CN1CCCC1=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=4)=[N:25][CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2cnc(NCc3ccc(Cl)cc3)nc2)c2cc(Cl)cnc21
Yield: 73.3 %

Procedure:
To 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme 191) in N-methylpyrrolidinone (1.80 mL) was added p-chlorobenzylamine (61, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on 300 watts, 150° C. for 15 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (613, 0.05 g, 74%). MS (ESI) [M+H+]+=524.3.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])(=O)C([O-])=O>>[OH:1][CH:2]([CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2
Reactant: c1cc2c(s1)CCC/C2=N\OCC1CO1
Reactant: C1CCNC1
Agent: O=C([O-])C(=O)[O-]
Product: OC(CO/N=C1\CCCc2sccc21)CN1CCCC1
Yield: 77.5 %

Procedure:
This compound is prepared by the procedure described in Example 1 by condensing E-4-(2,3-epoxypropoxy)imino-4,5,6,7-tetrahydrobenzo[b]thiophene with pyrrolidine. Oxalate: white crystals; m.p. 136° C. (recrystallised from isopropyl alcohol); yield: 77.5% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:39])[C:18]([CH3:38])([CH3:37])[CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:43](CC)CC)C.S>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:40])[CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:39])[C:18]([CH3:37])([CH3:38])[CH:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:20][C:21](=[O:30])[C:22]2[CH:23]=[CH:24][C:25]([C:28](=[NH:43])[NH2:29])=[CH:26][CH:27]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: S
Solvent: c1ccncc1
Product: CC(C)(C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1)C(NC(=O)c1ccc(C(=N)N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
N-4-Cyanobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (150 mg, 0.279 mmol) was dissolved in pyridine (10 ml). To the resulting solution was added triethylamine (1 ml) and the mixture was saturated with hydrogen sulfide gas. The reaction vessel was sealed and the reaction mixture was stirred at room temperature overnight. The pyridine was distilled off and the volatile products were removed by two cycles of toluene azeotropy. The residue was dissolved n acetone (15 ml) and methyl iodide (1 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was distilled off and the residue was dissolved in methanol (10 ml). To the obtained solution was added ammonium acetate (100 mg) and the mixture was refluxed for 2 hours. After the solvent was distilled off, the residue was dissolved in chloroform, washed with a saturated aqueous solution of NaCl and dried over an hydrous sodium sulfate. The solvent was distilled off and the residue was applied to a silica gel column (1.5×14 cm) and eluted with a mixed solution (chloroform:methanol=5:1). The desired fractions were collected and the solvents were distilled off to yield an oil of N-4-amidinobenzoyl-β-phenyl-α,α-dimethyl-β-alanyl-4-piperidineacetic acid benzyl ester (72 mg, 46.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:15]C(OC(C)(C)C)=O)[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([C:11]1([NH2:15])[CH2:12][CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)OCc2ccccc2)CCC1
Reaction time: 4 h

Procedure:
To a solution of 2.2 g 1-tert-Butoxycarbonylamino-cyclobutanecarboxylic acid benzyl ester in 20 ml dichloromethane were added 8 ml TFA. After stirring for 4 h the mixture was concentrated and the residue codistilled with toluene. The free amine was obtained by treatment with (Polystyrylmethyl)trimethylammonium bicarbonate in MeCN. Yield: 1.7 g
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1>[OH:24][C@@H:13]1[CH:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:15][C@@:16]2([CH3:17])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH3:2])=[CH:12]1
Reactant: C1COCCN1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=C[C@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CBr
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@H](O)C(N5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
21-Bromo-3α-hydroxypregn-4-ene-11,20-dione (150 mg.) in tetrahydrofuran (5 ml.) was treated with morpholine (0.1 ml.) and the stirred mixture was refluxed under nitrogen for 2 hours, during which time a white precipitate formed. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with more methylene chloride and the combined organic extracts were washed with water, dried over sodium sulphate and evaporated to a foam (152 mg.) which was purified by preparative T.L.C. in acetone/petrol 1/1, the main band Rf 0.3-0.45 being separated to give title compound (99 mg.) as a white foam, [α]D + 174° (c 0.12)
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:74]([OH:76])=[O:75])[CH2:69][CH2:70][C:71]([OH:73])=[O:72]>O>[CH3:1][C@@H:2]1[C@@H:41]([OH:42])[C@@H:40]([CH3:43])[C@H:39]([CH3:44])[O:38][C:36](=[O:37])[CH2:35][C@H:34]([OH:45])[CH2:33][C@H:32]([OH:46])[CH2:31][CH2:30][C@@H:29]([OH:47])[C@H:28]([OH:48])[CH2:27][C@H:26]([OH:49])[CH2:25][C@@:23]2([OH:50])[O:24][C@H:19]([C@H:20]([C:52]([O:54][CH3:55])=[O:53])[C@@H:21]([OH:51])[CH2:22]2)[CH2:18][C@@H:17]([O:56][C@@H:57]2[O:62][C@H:61]([CH3:63])[C@@H:60]([OH:64])[C@H:59]([NH2:65])[C@@H:58]2[OH:66])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[CH:3]1.[NH2:67][C@H:68]([C:74]([O-:76])=[O:75])[CH2:69][CH2:70][C:71]([O-:73])=[O:72]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Agent: COC(=O)[C@H]1[C@@H]2C[C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](N)[C@@H]3O)C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@@H]1O)O2
Solvent: O
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Reaction time: 1 h

Procedure:
Amphotericin B methyl ester (9.36 g, 0.01 Mol) is added in portions to a solution of L-glutamic acid (0.81 g, 0.0055 Mol) in 500 ml of water and stirred until complete dissolution (1 hour). The clear solution is then lyopholized. The yield is 88.9%. The product is soluble in water even at concentrations of 10% at RT and when dissolved in water to form a 1% solution is found to have a pH of 6.02.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18]Cl>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: CC(=NO)c1cc(C)cc(C)n1
Reactant: COc1cccc(F)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CON=C(C)c1cc(C)cc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
On the other hand, 0.46 g (2.80 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone oxime was dissolved in 10 ml of N,N-dimethylformamide, and the resultant solution was added with 0.13 g (3.36 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. Then, the obtained solution was stirred for 30 min. at the same temperature and subsequently added with the whole amount of the crude product of 2-fluoro-6-methoxybenzyl chloride obtained as described above while cooling the solution with ice. The resultant mixture was. further stirred for 40 min. at a room temperature, and the reacted mixture was poured into ice water and then subjected to an extraction with diethyl ether. The resultant nonaqueous layer was washed with water and the dried with anhydrous magnesium sulfate. The dried nonaqueous layer was then condensed under reduced pressure to obtain a crude product. Then, said crude product was purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=7:3 v/v) to obtain the target compound in an amount of 0.55 g. Melting point: 87-89° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[N:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:16]([C:18]1[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)#[CH:17].C(N(CC)CC)C>O1CCCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[O:14][N:13]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCc1ccc(CC(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(Cc2cc(-c3ccc(N)nc3N)on2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Manufacturing Example 70-1-3 and 3-ethynyl-pyridin-2,6-diamine (56.5 mg, 0.424 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (232 μL, 1.66 mmol). This mixture was stirred for 5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (66 mg, 31%).