Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]([CH2:19][CH3:20])[S:17][C:16](=[O:21])[NH:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])F.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30]O[CH2:28][CH2:27]1>>[N:26]1([CH2:25][CH2:24][CH2:23][N:15]2[N:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][F:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]([CH2:19][CH3:20])[S:17][C:16]2=[O:21])[CH2:31][CH2:30][CH2:28][CH2:27]1
Reactant: ClCCCN1CCOCC1
Reactant: CCC1SC(=O)NN=C1c1ccc(OC(F)F)c(OC)c1
Product: CCC1SC(=O)N(CCCN2CCCC2)N=C1c1ccc(OCF)c(OC)c1

Procedure:
of 5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-3-morpholinopropane:
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:8]([CH2:18][NH:19][C:20]2[C:21](=[O:39])[N:22]([CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[C:23]([CH3:27])=[C:24](Cl)[N:25]=2)[CH2:7]1>[Pd].CO>[CH3:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:8]([CH2:18][NH:19][C:20]2[C:21](=[O:39])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[C:23]([CH3:27])=[CH:24][N:25]=2)[CH2:7]1
Reactant: Cc1c(Cl)nc(NC[C@H]2C[C@H](C)CCN2C(=O)C(F)(F)F)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(NC[C@H]2C[C@H](C)CCN2C(=O)C(F)(F)F)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
10% Palladium on charcoal (200 mg), followed by ammonium formate (1.1 g, 17.4 mmol) were added to a solution of benzyl 2-[3-({[(2R,4R)-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 90) (900 mg, 1.74 mmol) in methanol (20 ml) and the reaction was stirred at room temperature overnight. Additional 10% palladium on charcoal (50 mg) was added and the reaction stirred for a further 24 hrs. The mixture was filtered through Whatman® fibre and the filtrate concentrated under reduced pressure. The residue was suspended in a methanol:dichloromethane (10:90) solution, the resulting precipitate filtered off, and the filtrate evaporated under reduced pressure to provide the title compound as a white solid, (600 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH:22]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])[C:23]([O:25]C(C)(C)C)=[O:24])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C@H:20]([CH2:21][CH:22]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[C:23]([OH:25])=[O:24])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CC(C(=O)OC(C)(C)C)C(=O)N2CCOCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CC(C(=O)O)C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 9.5 g (17.97 mmol) of the compound obtained in Step B in 40 mL of dioxane there are added, dropwise, 20 mL of a 4M solution of HCl in dioxane. The batch is stirred at ambient temperature for 48 hours and then the solution is concentrated to dryness. After drying, the expected product is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:13]([CH:18]([CH2:21]O)[CH2:19][OH:20])[CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([C@@H:18]1[CH2:19][O:20][C@@H:7]([C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][CH2:21]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(CO)CO
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CO[C@H](c2ccc(C(F)(F)F)cc2)OC1

Procedure:
An equimolar mixture of p-trifluoromethylbenzaldehyde and 2-pentylpropane-1,3-diol in toluene is boiled on a water separator with catalysis by p-toluenesulfonic acid. When the water separation is complete and after conventional work-up, p-(trans-5-n-pentyl-1,3-dioxan-2-yl)-trifluorotoluene, m.p. 44.3°, Δε=+12.9, is obtained.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1csc(N2CCCCC2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(N2CCCCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 2.4 g of 2-piperidinothiazol-4-ylmethanol, 5.8 g of sulfur trioxide pyridine complex, 3.7 g of triethylamine and 30 ml of dimethyl sulfoxide, giving the title compound as pale orange prisms.
Reaction SMILES: C(NC(C)C)(C)C.[O:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:9]1.[CH3:25][CH:26]([CH3:39])[C:27](=[O:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(O)(=O)C>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:38][C:27]([CH:26]([CH3:39])[CH3:25])([CH:14]([CH:11]1[CH2:10][CH2:9][O:8][CH2:13][CH2:12]1)[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: O=C(CC1CCOCC1)OCc1ccccc1
Reactant: CC(C)C(=O)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)C(O)(C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a solution of diisopropylamine (122 mg, 1.21 mmol) in anhydrous tetrahydrofuran (2 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (703 μL, 1.11 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min and then at −78° C. for 5 min. A solution of benzyl 2-(tetrahydropyran-4-yl)acetate (250 mg, 1.07 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise over 6 min at the same temperature, and the reaction mixture was further stirred for 15 min. The cold enolate solution thus prepared was added dropwise via a cannula to a solution of benzyl a solution of benzyl 3-methyl-2-ketobutyrate (191 mg, 0.928 mmol) in anhydrous tetrahydrofuran (1 mL) solution having been cooled to −78° C. After stirring at −78° C. for 1 h, the reaction mixture was adjusted to pH 4 with acetic acid and raised to room temperature. The reaction solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and water to separate the phases for extraction. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give dibenzyl 2-hydroxy-2-isopropyl-3-(tetrahydro-2H-pyran-4-yl)succinate as oil in amounts of 115 mg (low polar diastereomer, yield: 29%) and 158 mg (high polar diastereomer, yield: 39%), respectively.
Reaction SMILES: C(O)C.C(O)(=O)C(O)=O.[C:10]([O:14][C:15](=[O:32])[CH2:16][N:17]([C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)([CH3:13])([CH3:12])[CH3:11].C([O-])(=O)C.[Na+].C([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][C:54](=O)[C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:48][CH:47]=1)C1C=CC=CC=1>[Ni].C(O)(=O)C>[C:10]([O:14][C:15](=[O:32])[CH2:16][N:17]([C:27](=[O:31])[C@H:28]([CH3:30])[NH:29][CH:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=1)[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CCOC(=O)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccc(O)cc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1

Procedure:
To 100 ml of ethanol, there are added 3 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate, 0.75 g of sodium acetate, 1.5 g of acetic acid, 5 g of molecular sieve 3A and 5 g of ethyl 4-(4-benzyloxyphenyl)-2-oxobutyrate, and catalytic reduction is carried out using Raney nickel as catalyst. When the hydrogen absorption has ceased, the catalyst is removed, and catalytic reduction is further carried out using palladium-carbon as catalyst. The catalysts is filtered off and the solvent is distilled off under reduced pressure to give N-[1-ethoxycarbonyl-3-(p-hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester as oil. This oil is converted by the reaction procedure as used in Example 4 to N-[1-ethoxycarbonyl-3-(4-hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine hydrobromide, which is further converted to the hydrochloride by the procedure of Example 6. There is thus obtained 0.65 g of N-[1-ethoxycarbonyl-3-(4-hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride as colorless crystals melting at 126°-130° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[I-:24].[Na+].CN[C@H]1[C@H](NC)CCCC1>[Cu]I.C(O)CCC>[I:24][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([NH:15][CH:16]([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC(Nc1nc2cc[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCO
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(I)ccc12)C(C)(C)C
Temperature: 130 °C
Reaction time: 22 h

Procedure:
9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (120 mg, 0.31 mmol), copper(I) iodide (5.9 mg, 0.031 mmol), and sodium iodide (93 mg, 0.62 mmol) were combined in a vial. Butan-1-ol (1.0 ml) and trans-(1R,2R)—N,N-bismethyl-1,2-cyclohexanediamine (9.9 μl, 0.062 mmol) were added, and the resulting suspension was purged with argon (subsurface bubbling) for 5 min. The reaction mixture was heated to 130° C., and stirred for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (40 mL) and brine (40 mL). The organic layer was washed with additional brine (1×40 ml). The first aqueous layer was back-extracted with ethyl acetate (1×40 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (solid SiO2 loading) using an EtOAc/Hexanes gradient to afford 9-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (ESI) calc'd for (C18H20IN3O) [M+H]+, 422.1; found 422.0.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)=O)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:30])=O>CC#N>[Cl:30][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:22]4[CH:27]=[N:26][CH:25]=[CH:24][N:23]=4)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cnccn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nc2ccc3nnc(-c4cnccn4)n3c2nc1-c1ccccc1
Temperature: 100 °C

Procedure:
To a microwave vial was added N′-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)pyrazine-2-carbohydrazide (8-4, 0.412 g, 1.147 mmol), MeCN (5.0 mL), and finally phosphorus oxychloride (0.687 mL, 7.37 mmol). The reaction mixture was then heated to 100° C. in a hot oil bath (capped) overnight. The reaction mixture was then permitted to cool to room temperature, diluted with MeCN & concentrated in vacuo. The resulting residue was then suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-5 as a brown solid. HRMS (M+H)+: observed=360.0773, calculated=360.0759.
Reaction SMILES: C1(CBr)CC1.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:28]2[CH2:29][CH2:30][N:26]([C:18]3[S:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:15])[N:17]=3)[C:27]2=[O:31])=[CH:9][CH:8]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(Cl)cc3)C2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 4-chlorobenzyl chloride to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 84% yield: mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.31 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.51 (s, 2H), 4.27 (q, J=7.8 Hz, 2H), 4.09-4.04 (m, 2H), 3.44-3.41 (m, 2H), 2.59 (s, 3H), 1.25 (t, J=7.8 Hz, 3H); MS (ES+) m/z 380.2 (M+1), 382.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[CH:11][C:10]=2[CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:6]=[CH:7][CH:8]=1.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[Br:27][C:11]1[C:10]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:17]2[C:12]=1[C:13]([NH2:18])=[N:14][CH:15]=[N:16]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COc1cccc(-c2c(CCCN3CCCC3)cc3c(N)ncnn23)c1
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(CCCN3CCCC3)c(Br)c3c(N)ncnn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161 %

Procedure:
To a solution of the compound (98 mg, 0.28 mmol) prepared in Example 14 in DMF (4 mL) at −40° C. was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (40 mg, 0.14 mmol) portion wise over a period of 1 minute. The reaction was stirred for 30 minutes and was allowed to warm to room temperature, and stirred overnight. DMF was removed, and the crude solid was extracted with sodium hydroxide (1N) and DCM. The organic layer was dried, concentrated to obtain the title compound (97 mg) having the following physical data.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13][CH:12]=1>CO>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:13][CH:12]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccnc2ccccc12
Solvent: CO
Product: O=C(O)c1ccccc1N=Cc1ccnc2ccccc12
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A solution of anthranilic acid (5.46 g) in methanol was added to a melt of quinoline-4-carbaldehyde (6.26 g) and the mixture was heated on a water bath for 6 hours. The mixture was cooled to room temperature and the solid material was isolated by filtration and washed with methanol, affording 2-[(quinolin-4-ylmethylene)-amino]-benzoic acid (10.33 g). This intermediate (10.3 g) was dissolved in THF and ethanol, and sodium borohydride (1.41 g) was added portion-wise. The reaction mixture was stirred at room temperature for 3 hours. More sodium borohydride (1.41 g) and a small amount of methanol were added and stirring continued at room temperature for 4 hours. The mixture was evaporated under reduced pressure and transferred to a separatory funnel with EtOAc and water. Layers were separated and the aqueous layer was neutralised by addition of 4M hydrochloric acid. The resulting precipitated material was isolated by filtration, washed with water and dried in vacuo, affording the title compound (7.1 g). 13C-NMR (DMSO-d6) δ 170.4, 150.3, 150.3, 147.6, 144.8, 133.4, 131.7, 129.6, 129.2, 126.5, 126.1, 123.5, 118.5, 114.6, 112.9, 111.2, 42.7.
Reaction SMILES: [CH3:1][C:2]([C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19])([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].CC(C(NC1C2CC3CC(CC1C3)C2)=O)(CC1C2C(=CC=CC=2)NC=1)C(O)=O.[K+].[Br-]>>[CH3:1][C:2]([C:18]([NH:20][CH2:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:19])([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1c[nH]c2ccccc12)C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: [Br-]
Agent: [K+]
Product: CC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)NCC12CC3CC(CC(C3)C1)C2

Procedure:
Compound 10 was prepared from Compound 9 according to the procedure for Compound 6. The product was obtained as a white solid. 1.95 9 (71%) IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 746 cm-1.
Reaction SMILES: [F:1][C@H]1CCN(C(OC(C)(C)C)=O)C1.[C:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([CH2:26]O)[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].COCCN(S(F)(F)F)CCOC>ClCCl>[F:1][CH2:26][C@@H:23]1[CH2:24][CH2:25][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1

Procedure:
Prepare using the method of Intermediate 48 with (R)-N-Boc-pyrrolidine-3-methanol (0.50 g, 2.48 mmol), [bis(2-methoxyethyl)amino]sulfur trifluoride (0.55 mL, 2.98 mmol) and anhydrous dichloromethane (2.5 mL) to give the title compound as a colourless oil (0.34 g): MS (m/e): 226 (M+23).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.CC(C)=O.[C:41]([OH:50])(=[O:49])[CH:42]([CH:44]([C:46]([OH:48])=[O:47])[OH:45])[OH:43]>CCCCCC>[CH3:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[C:7]([NH:25][C@H:26]2[C@H:28]([C:29]3[CH:30]=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[CH2:27]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[C@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([O:21][CH2:22][CH2:23][OH:24])[CH2:15]3)[C:9]=2[N:10]=1.[C:46]([C@H:44]([C@@H:42]([C:41]([O-:50])=[O:49])[OH:43])[OH:45])([O-:48])=[O:47]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
Ticagrelor (0.5 g) and acetone (10 mL) were charged into a round bottom flask and the mixture was stirred at about 30° C. for about 15 minutes for clear solution. Then D (−)-tartaric acid (0.16 g) was added to the above reaction mixture at about 30° C. and mixture was stirred for overnight. To the clear solution, n-hexane (35 mL) was added and stirred for about 1 hour at 25-30° C. for solid separation. The solid was filtered, washed with n-hexane (5 mL) and dried to afford the title compound in about 93% yield having chiral HPLC purity of about 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Agent: Br
Product: Fc1ccc(C(=C2CCNCC2)c2cccnc2)cc1
Yield: 37 %

Procedure:
A mixture of 100 parts of ethyl 4-[(4-fluorophenyl)(3-pyridinyl)methylene]-1-piperidinecarboxylate and 375 parts of a hydrobromic acid solution 48% was stirred and refluxed for 3 hours. The reaction mixture was evaporated. The residue was washed with 2,2'-oxybispropane. The latter was decanted, the residue was stirred in water and the whole was alkalized with a sodium hydroxide solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography (2×) over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (80:20 by volume) as eluent. The main fraction was collected and the eluent was evaporated, yielding 30 parts (37%) of 3-[(4-fluorophenyl)(4-piperidinylidene)methyl]pyridine as a residue (intermediate 21).
Reaction SMILES: C(OC([O:6][C:7]1[C:8]([CH3:18])=[C:9]([CH3:17])[C:10]2[O:14][CH2:13][S:12][C:11]=2[C:15]=1[CH3:16])C)C.C(O)(=O)C(O)=O>C(Cl)Cl>[OH:6][C:7]1[C:8]([CH3:18])=[C:9]([CH3:17])[C:10]2[O:14][CH2:13][S:12][C:11]=2[C:15]=1[CH3:16]
Reactant: CCOC(C)Oc1c(C)c(C)c2c(c1C)SCO2
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)SCO2
Yield: 76.6 %

Procedure:
5.0 g of 5-(1-ethoxyethoxy)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 63) were dissolved in 20 ml of methylene chloride, and 10 g of silica gel-60 (a product of Merck and Co., Inc.) and 1 ml of a 10% w/v aqueous solution of oxalic acid were added. The mixture was then reacted for 1.5 hours at room temperature, after which the silica gel was filtered off. The methylene chloride was then distilled from the solution to yield a crude product, which was extracted with benzene. The extract was dried over anhydrous sodium sulfate, and the benzene was distilled off to yield crude crystals, which were recrystallized from an approximately 10:1 by volume mixture of benzene and petroleum ether, to yield 2.8 g of the title compound, melting at 131°-132° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH3:21])[CH:20]=1)([O-:14])=[O:13].C(N(CC)C(C)C)(C)C>CS(C)=O>[OH:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][C:19]=2[CH3:21])[CH2:10][CH2:11]1
Reactant: CCOCCN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(CCO)CC1

Procedure:
In the same manner as in Production Example 5-1, but using 4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used in Production Example 5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, the entitled compound was obtained as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50](=[O:60])[C@H:51]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[NH2:52])[CH3:48].CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:52][C@H:51]([C:50]([O:49][CH2:47][CH3:48])=[O:60])[CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:19])=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A mixture of 4-[(5-nitro-1H-indol-1-yl)methyl]benzoic acid (1.78 g, 6.0 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol), 1-hydroxybenzotriazole hydrate (0.81 g, 6.0 mmol), and L-phenylalanine ethyl ester hydrochloride (1.38 g, 6.0 mmol) was stirred in CH2Cl2 (150 mL). N-methylmorpholine (3.03 g, 30 mmol) was added and the mixture was stirred at room temperature for 15 h. The mixture was then washed with 0.05 N HCl and water. The resulting solution was dried with MgSO4 and concentrated to give ethyl N-{4-[(5-nitro-1H-indol-1-yl)methyl]benzoyl}-L-phenylalaninate as an off-white solid (2.55 g, 90%): MS (ESI) m/z 472; MS (ESI) m/z 470.