Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[C:11]([C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])(=[O:13])[CH3:12].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:19][C:15]1[N:16]=[CH:17][O:18][C:14]=1[C:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([OH:13])[CH3:12]
Reactant: c1ccsc1
Reactant: CC(=O)c1ocnc1C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(C)(O)c1cccs1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Thiophene (3.36 g) in dry tetrahydrofuran (20 ml) was stirred and cooled to -40° C. under a dry nitrogen atmosphere and n-butyllithium (2.5M solution in hexane, 16 ml) was added dropwise. The mixture was allowed to warm to -20° C. and then after 1 hour was cooled to -70° C. 5-Acetyl-4-methyloxazole (5 g) in dry tetrahydrofuran (15 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm the room temperature and was stirred for a further 2 hours. Aqueous sodium hydrogen carbonate was added and the mixture was extracted with diethylether. The material thus obtained was purified by flash chromatography to give the title compound. M.p. 84°-85° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])[NH2:23])=[C:13]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:12]=1[OH:37])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])=[C:13]([CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:12]=1[OH:37])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 0.36 ml (3.57 mmol) of methyl chlorooxalate in 5 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 1.75 g (3.57 mmol) of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline (Example 1) and 0.55 ml (3.57 mmol) of triethylamine in 15 ml of methylene chloride in the course of 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate of melting point 139°-140°.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[N:20]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:26]([N:20]1[CH2:25][CH2:24][N:23]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22][CH2:21]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCN(C(C)=O)CC3)s2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (100 mg; 0.3 mmol; 1 eq) is dissolved in anhydrous DCM (5 ml). The reaction is put under nitrogen. 1-Piperazin-1-yl-ethanone (76.1 mg; 0.59 mmol; 2 eq), diisopropylethylamine (0.3 ml; 1.78 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. The solvents are evaporated and the crude product is purified by preparative HPLC. Compound (2) is isolated as a pale yellow powder (35 mg; 27%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:22]([N:21]([CH2:2][CH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(C(CCCl)c1ccccc1)N1CCCCCC1
Reactant: CNCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(C(=O)N1CCCCCC1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of 2,3,4,5,6,7-hexahydro-1-[4-chloro-2-phenylbutanoyl]-1H-azepine (10.0 g, 35.7 mmol) in acetonitrile (100 ml) was added to a solution of N-methylbenzylamine (4.03 g, 33.3 mmol) and diisopropylethylamine (4.62 g, 35.7 mmol) in acetonitrile (40 ml) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water (100 ml). The aqueous phase was washed with ethyl acetate (3×50 ml) and the combined organic phases washed with brine (50 ml), water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The crude oil obtained was chromatographed on alumina, eluting with hexane:ethyl acetate (2:1) to afford the title compound as an oil (6.93 g, 53%).
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:8][C:7]1[C:2]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(N)c(Br)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)OC(C)(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 4-amino-5-bromopicolinate (546 mg, 2 mmol) in CH2Cl2 (5 mL) and pyridine (1 mL) at 0° C., was added ethyl chloroformate (271 mg, 2.5 mmol). The mixture was stirred at rt for 2 h, diluted with dichloromethane, washed with 5% citric acid, and sat. K2HPO4 aq. solution. The organic layer was dried over MgSO4 and the product was purified by flash column chromatography (SiO2, eluting with 20% EtOAc/CH2Cl2) to give a white solid (570 mg, 83%). LC-MS: m/z 345 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9](I)[CH:10]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([C:48]2[N:47]([CH3:46])[CH:51]=[CH:50][CH:49]=2)[CH:10]=1
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(I)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cccc1-c1cc(Br)c2c(Sc3ccc(Cl)cc3)c3n(c2c1)CCC3CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (+/−)-methyl {8-bromo-9-[(4-chlorophenyl)thio]-6-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (see Example 30, 145 mg, 0.25 mmol) in DMF (3 mL) were added tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), triphenyl arsine (31 mg, 0.1 mmol) and 1-methyl-2-(tributylstannyl)-1H-pyrrole (111 mg, 0.3 mmol). The mixture was degassed and stirred at r.t. for 2 hours. The reaction mixture was poured into 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 15% EtOAc/hexane to give methyle ester of the title compound which was hydrolyzed following the procedures described in Step 10 of Example 7.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:18])([F:17])[C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH2:16])=[NH:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+].CN(C)[CH:23]=[CH:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=O>C(O)(C)C>[F:5][C:6]([F:17])([F:18])[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:16]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=CC(=O)c1ccncc1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)(F)c1cccc(Nc2nccc(-c3ccncc3)n2)c1

Procedure:
15.1 g (0.0567 mmol) of 3-trifluoromethyl-phenyl-guanidine nitrate and 2.84 g (70.9 mmol) of sodium hydroxide are added to a suspension of 10 g (56.7 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 300 ml of isopropanol The reaction mixture is boiled under reflux for 24 hours. After cooling, the product is isolated by filtration, washed with water and dried at 60° under HV. N-(3-trifluoromethyl-phenyl)-4-pyridyl-2-pyrimidineamine is obtained; m.p. 197°-198°, Rf =0.58 (ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CCNCCO
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 185.2) and 2-ethylamino-ethanol to afford a white crystalline solid. (Reaction Time was 10 h). HPLC (Condition 4) tR=6.33 min, UPLC-MS (Condition 3) tR=1.25 min, m/z=466.2 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-])=O.C(N(CC)CC)C>CN(C=O)C>[NH2:14][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1

Procedure:
1-Boc-piperazine and 4-nitrobenzenesulfonyl chloride were allowed to undergo the reaction in DMF in the presence of triethylamine, and then the nitro group was reduced in the sama manner as the catalytic hydrogenation shown in Reference Example 3 to obtain tert-butyl 4-[(4-aminophenyl)sulfonyl-]piperazine-1-carboxylate. FN: 340.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:12][CH:13]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 7 g of 5-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine in 60 ml of ethanol plus 10 ml of water is added 1 g of sodium borohydride. After the mixture is stirred at room temperature for an hour, the solvent is distilled off. To the residue is added water and the mixture is extracted with chloroform. After the chloroform is distilled off, the residue is recrystallized from a mixture of toluene and ethanol to give 6.5 g of α-(4-chlorophenyl)-2-(1-imidazolyl)-5-pyridinemethanol as white crystals, melting at 147°-149° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:37]([NH:39][C@H:40]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:61]([NH:63][C@H:64]([C:98]([N:100]1[CH2:111][CH2:110][CH2:109][C@H:101]1[C:102]([NH:104][CH2:105][C:106]([NH2:108])=[O:107])=[O:103])=[O:99])[CH2:65][CH2:66][CH2:67][N:68](C(OC12CC3CC(CC(C3)C1)C2)=O)[C:69](=[NH:84])[NH:70]C(OC12CC3CC(CC(C3)C1)C2)=O)=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:38])[CH2:35][OH:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].C(OCC)C>FC(F)(F)C(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:37]([NH:39][C@H:40]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:61]([NH:63][C@H:64]([C:98]([N:100]1[CH2:111][CH2:110][CH2:109][C@H:101]1[C:102]([NH:104][CH2:105][C:106]([NH2:108])=[O:107])=[O:103])=[O:99])[CH2:65][CH2:66][CH2:67][NH:68][C:69](=[NH:70])[NH2:84])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])=[O:50])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=1)=[O:38])[CH2:35][OH:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCN(C(=N)NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 0.25 h

Procedure:
A solution of L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-Nδ,Nω-bisadamantyloxycarbonyl-L-arginyl-L-prolylglycinamide (XXI) (1.54 g) in trifluoroacetic acid (TFA) (5 ml) is allowed to stand at room temperature for 15 minutes. Absolute ethyl ether (25 ml) is then added to the reaction mixture and the precipitate is collected by filtration and washed thoroughly with absolute ethyl ether. The precipitate is dried in vacuo to give L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-L-arginyl-L-prolylglycinamide XXII.
Reaction SMILES: [CH2:1]1[C@@H:6]([C:7]#[N:8])[N:5]([C:9]([C@@H:11]([NH2:23])[C:12]23[CH2:21][C:19]4([OH:22])[CH2:20][CH:14]([CH2:15][CH:16]([CH2:18]4)[CH2:17]2)[CH2:13]3)=[O:10])[C@@H:4]2[C@H:2]1[CH2:3]2.[CH3:24][C:25]([CH3:27])=O>>[CH3:24][C:25](=[N:23][C@@H:11]([C:12]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:20][C:19]([OH:22])([CH2:18]3)[CH2:21]1)[CH2:13]2)[C:9]([N:5]1[C@H:6]([C:7]#[N:8])[CH2:1][C@H:2]2[C@@H:4]1[CH2:3]2)=[O:10])[CH3:27]
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(C)=O
Product: CC(C)=N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Saxagliptine form H-1 (100 mg) was suspended in acetone (1 ml). The suspension was stirred for 24 hours at room temperature, after which it was filtered and dried on air, yielding 54 mg of crystalline product
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:28])[CH:25]([F:27])Br)[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[F:27])[CH3:22]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)C(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)Oc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (50 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromofluoroacetate (0.2 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (500 mL) and washed with H2O (5×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 6 (0.14 g, 32%) as an yellow oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](Cl)[CH3:18])=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: CC(Cl)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C

Procedure:
A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 8.5 parts of p-(1-chloroethyl)phenyl 2-thienyl ketone and stirring at 60° C is continued for 4h.30. The reaction mixture is poured onto water and the product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile as a residue.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(4-chlorophenyl)piperazine (60 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24].[NH2-].[Na+]>C1C=CC=CC=1>[OH:9][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][C:23]#[N:25]
Reactant: CC#N
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(O)(c1ccc(Cl)cc1)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
4'-Chloro-4-biphenylyl 4-chlorophenyl ketone (16.4 g.) and acetonitrile (2.25 g.) were reacted in benzene in the presence of sodamide (2.5 g.) by the method of Lettre and Wick (Annalen, 1957, 603, 194) to give 3-hydroxy-3-(4'-chloro-4-biphenylyl)-3-p-chlorophenylpropionitrile, m.p. 123°C after recrystallisation from benzene; λ max (ethanol) = 260 nm.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.[CH:18](=O)[CH2:19][CH3:20].C([BH3-])#N.[Na+].C(Cl)(Cl)Cl>CO>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:13]([CH3:14])[CH3:15])[CH2:18][CH2:19][CH3:20])[CH2:7][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C[C@@H](NC(C)C)CO2
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(R)-8-Bromo-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (3.8 g, 11.3 mmol) was dissolved in anhydrous methanol (80 mL) and to this was propanal (8.1 mL, 0.113 mol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (1.3 g, 20.3 mmol) was added, the pH was adjusted to 5, and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were twice with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4) filtered, and taken into a 1M solution of Na2CO3 and then extracted the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 7% ethyl acetate/hexane) gave 3.75 g (97% yield) of the title compound as a clear oil [α]21D =-82.5° (C=0.1 CHCl3). GC-MS (70 eV) M=343 (29%). The hydrochloride salt was made by dissolving the base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from ethanol/diethyl ether to give a white solid. Mp: 177°-9° C.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH:19]([C:25]2[CH:30]=[C:29]([O:31][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:28]=[C:27]([CH2:32][CH3:33])[CH:26]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(O)cc(CC)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(Oc2ccccc2)c1
Reaction time: 60 h
Yield: 81.4 %

Procedure:
Copper(II) acetate (223 mg, 1.20 mmol), phenylboronic acid (164 mg, 1.32 mmol) and molecular sieve 4A were added to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-hydroxy-phenyl)-acetate (390 mg, 1.20 mmol) obtained in Example 200.1 in CH2Cl2 (12 ml). Pyridine (476 mg, 6.01 mmol) was added dropwise and the mixture was stirred for 60 h. under an atmosphere of air. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, CH2Cl2). There were obtained 391 mg (81%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-phenoxy-phenyl)-acetate as beige crystals; MS: 401 ([M+H]+).
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:21])=[O:19])[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH3:21])=[O:19])/[C:10](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)C2=O
Reactant: NNC(N)=O
Agent: Cl
Product: COC(=O)c1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)/C2=N\NC(N)=O
Yield: 28.1 %

Procedure:
By using methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/ethanol=20/1) and then recrystallized from chloroform-hexane to obtain (Z)-1-(2-diisopropylaminoethyl)-7-methoxycarbonylisatin 3-semicarbazone having a melting point of 192°-195° C. (yield: 28.1%).