Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1[C:12](=[O:13])[C:11](=C2N(C)C3C=C(O)C=CC=3S2)SC1=NC1C=C(C=CC=1NCC)C#N)C1C=CC=CC=1.[CH2:37]([N:44]1[C:48](=[O:49])[C:47](=[C:50]2[N:54]([CH3:55])[C:53]3[CH:56]=[CH:57][C:58]([OH:60])=[CH:59][C:52]=3[S:51]2)[S:46][C:45]1=[N:61][C:62]1[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=1[NH:70][CH2:71][CH3:72])[C:65]#[N:66])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:44]1[C:48](=[O:49])[C:47](=[C:50]2[N:54]([CH3:55])[C:53]3[CH:56]=[CH:57][C:58]([O:60][CH2:11][CH2:12][OH:13])=[CH:59][C:52]=3[S:51]2)[S:46][C:45]1=[N:61][C:62]1[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=1[NH:70][CH2:71][CH3:72])[C:65]#[N:66])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(O)ccc3N2C)C(=O)N1Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCO)ccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 59 by replacing the product of Example 57 with the product of Example 249. MS(ESI): 558 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18](F)[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][CH:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1C=Cc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of [8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate prepared in Example 61, step 1 (204 mg, 0.459 mmol) and sodium azide (119 mg, 1.834 mmol) in anhydrous dimethyl sulfoxide (8 mL) was heated at 70° C. under nitrogen for 19 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 120 mg (67%) of 2-azidomethyl-8-(2-chloro-phenyl)-2H-chromene as a yellow syrup that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.Cl.[N:24]1([C:29]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:24]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (50 mg, 0.16 mmol) and 4-(pyrrolidinylcarbonyl)phenylamine hydrochloride (43 mg, 0.19 mmol) in pyridine (3 mL) cooled in ice-bath, POCl3 (0.028 mL, 0.31 mmol) was added. The mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (15 mg). MS 491.4 and 493.4 (M+H, Cl pattern).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.[CH:21](OC)=[O:22]>C1COCC1>[Cl:13][C:14]1[C:19]([CH:21]=[O:22])=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of diisopropylamine (2.6 mL, 18.5 mmol) in THF (18.5 mL) was stirred at −78° C. as a 2.5 N solution of n-butyl lithium (7.4 mL, 18.5 mmol) was added. The solution was stirred at 0° C. for 30 minutes, then cooled to −78° C. for 30 minutes before the addition of 2,4-dichloropyridine (2 mL, 18.5 mmol). The solution was stirred at −78° C. for another 30 minutes before the addition of methyl formate (1.14 mL, 18.5 mmol). The solution was stirred for 30 minutes then was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide 2,4-dichloro-3-pyridinecarbaldehyde (2.18 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.54 (d, J=5 Hz, 1H), 7.75 (d, J=5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1.[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:22])[C:16](=[O:20])[NH:17]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3F)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(2,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethylpropanol employing methods similar to those described in Example 9 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.80 (1H, br s ), 10.93 (1H, br s), 10.22 (1H, br s), 8.18 (0.29H, s), 8.13 (0.71H, s), 7.45-7.38 (1H, m), 7.30 (1H, s), 7.27-7.21 (1H, m), 7.09-7.05 (1H, m), 4.59 (1H, m), 4.02 (2H, s), 3.17-3.05 (4H, m), 0.81 (6H, s); HRMS calcd for C21H21F2N3O4+H+: 418.1578. Found 418.1569.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:11]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1cccc(-c2nsc(Cl)n2)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 3-fluorobenzenecarboximidamide hydrochloride (1.75 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (2.00 g, 50.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.52 g (71.0%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([CH2:13][NH:14][C:15]([NH:24][CH3:25])=[C:16]([C:22]#[N:23])[C:17]([O:19]CC)=O)[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30][N:31]=[C:32]=[S:33].O>CN(C=O)C>[C:22]([C:16]1[C:17](=[O:19])[N:31]([CH3:30])[C:32](=[S:33])[N:24]([CH3:25])[C:15]=1[NH:14][CH2:13][CH:9]1[O:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)[CH2:8]1)#[N:23]
Reactant: CCOC(=O)C(C#N)=C(NC)NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(NCC2CN(Cc3ccc(F)cc3)CCO2)c(C#N)c(=O)n(C)c1=S
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl 3-[4-(p-fluorobenzyl)-2-morpholinylmethylamino]-3-methylamino-2-cyanoacrylate (1.00 g, 2.66 mmol) in DMF (10 ml) was added under ice-cooling sodium hydride (0.11 g, 2.66 mmol) and the mixture was stirred for one hour. To the reaction mixture was added dropwise a solution of methyl isothiocyanate (0.19 g, 2.66 mmol) in DMF (1 ml) and the mixture was stirred under ice-cooling for 8.5 hours. Then, the reaction mixture was poured into water (30 ml) and extracted with chloroform (50 ml×4). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound from the fraction from ethyl acetate. Yield=90%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[OH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N+:1]([O-:20])=[CH:2][CH:3]=[CH:4]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1cccc2cccnc12
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
8-Quinolinol (351 g, 2.42 mol) was dissolved in dichloromethane (3.5 L) and, under ice-water cooling, meta-chloroperbenzoic acid (675.3 g, 2.74 mol) was added thereto in portions, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration and was washed with dichloromethane. The filtrate and the washing were mixed and concentrated under reduced pressure. To the residue, 2% aqueous ammonia (2.1 L) was added and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with purified water, and dried under reduced pressure to obtain 8-hydroxyquinoline-N-oxide (318.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][C@@H:35]1[C:53](=[O:54])[N:37]2[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]3[S:45][C:46]([CH3:49])=[N:47][N:48]=3)[CH2:40][S:41][C@H:36]12>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([NH:34][C@@H:35]2[C:53](=[O:54])[N:37]3[C:38]([C:50]([OH:52])=[O:51])=[C:39]([CH2:42][S:43][C:44]4[S:45][C:46]([CH3:49])=[N:47][N:48]=4)[CH2:40][S:41][C@H:36]23)=[O:18])=[CH:12][CH:11]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cc4ccc(CNC(=O)OC(C)(C)C)s4)[C@H]3SC2)s1
Reaction time: 4 h

Procedure:
The starting material is prepared as follows: A solution of 4.08 g of 2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetic acid in 200ml of methylene chloride containing 1.65 ml of 4-methyl-morpholine is cooled to -20° under exclusion of moisture and treated dropwise with 1.95 ml of chloroformic acid isobutyl ester. After 30 minutes a solution of 5.16 g of 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 7.20 ml N,O-bis-(trimethylsilyl)-acetic acid amide in 150 ml of methylene chloride is added, whereupon the reaction mixture is stirred during one hour at -20° and during four hours while the temperature is allowed to slowly rise to room temperature and is then evaporated under reduced pressure. The residue is dissolved in water with the addition of sodium hydrogen carbonate until the pH reaches 8. The solution is washed with ethyl acetate, the separated aqueous layer is acidified to pH 2 with aqueous phosphoric acid of 20% strength and is extracted with ethyl acetate. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. One thus obtains the 7β-[2-(5-tert.-butyloxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid; thin layer chromatogram (silicagel): Rf = 0,40 (system: n-butanol/acetic acid/water45:45:10), ultraviolet absorption spectrum (ethanol): λmax 244 mμ (ε = 16900); infrared absorption spectrum (in mineral oil): characteristic bonds at 2,93 μ, 5,60 μ, 5,90 μ, and 6.55 μ.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[OH:7][CH:1]([CH3:6])[CH2:2][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:3][CH:4]([CH3:5])[CH2:8][OH:11]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)COc1ccccc1CC(C)CO
Temperature: 25 °C

Procedure:
To the phenol T81-6(S) (1.4 g, 8.42 mmol, 1.0 eq) in DMF (16 mL) was added potassium carbonate (1.6 g, 8.42 mmol, 1 eq), and (R)-methylcarbonate (T81-A, 0.73 mL, 8.42 mmol, 1.0 eq). The resulting mixture was stirred at 85° C. for 72 h with monitoring of the reaction by TLC [(ethyl acetate/hexanes:2/8); Rf=0.30, UV, CMA]. The mixture was cooled to room temperature and brine was added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were extracted with brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexanes, 2/8, Rf=0.30) to give T81-7(1R,8S) (1.45 g, 76%). Use of (S)-methylcarbonate in this reaction led to T81(1S,8S) containing a (1S)-stereocenter through the same transformations as described below for the corresponding (1R)-isomer.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[O:30]([CH3:32])[Na]>CO>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:30][CH3:32])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CO[Na]
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 98 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) was reacted with 30% NaOCH3 in CH3OH to give the title compound (39 mg, 98%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16]O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16][N:26]4[C:25](=[O:27])[C:24]5=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]5[C:22]4=[O:32])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarhoxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2, eluted with DCM, 11, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([NH:38]C(OC(C)(C)C)=O)[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.CO.[ClH:48]>O1CCOCC1>[ClH:48].[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]([NH2:38])[CH2:15][C@H:16]([OH:37])[C@@H:17]([NH:25][C:26](=[O:36])[C@H:27]([CH:33]([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cnccn2)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cnccn2)cc1)C(C)C

Procedure:
3.4 g (5.5 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 100 ml of 4N hydrogen chloride in dioxane (Aldrich) and 10 ml of methanol are stirred at room temperature for 2 hours. The solvents are removed; dioxane is added twice to the residue and evaporated off. The title compound is obtained in the form of a viscous oil, with the compound crystallising out on trituration with ether. M.p.: 194-198° C. TLC: Rf =0.35 (methylene chloride/methanol 10:1). HPLC20-100: tRet =9.77.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.C([Sn](CCCC)(CCCC)[C:21]([O:23][CH2:24][CH3:25])=[CH2:22])CCC.[F-].[K+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[CH2:22])[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Yield: 50.3 %

Procedure:
A degased solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (7 g, 26.82 mmol), tributyl(1-ethoxyvinyl)stannane (9.51 mL, 28.16 mmol) and bis(triphenylphosphine)-palladium chloride (0.376 g, 0.54 mmol) in dimethylformamide (200 mL) was heated under argon at 100° C. for 1.5 h. The mixture was poured into a solution of potassium fluoride (20 g) in water 250 mL, and the mixture was extracted with MTBE (300 mL). The organic phase was washed with water, dried over sodium sulfate, and filtered through a pad of silica gel. The residue was crystallised from heptane (50 mL) to yield the title compound (4.0 g). The mother liquor was concentrated in vacuum and purified by column chromatography on silica gel, using a gradient of 0-15% ethyl acetate in heptane as eluent to yield additional amount of the title compound (2.9 g), total yield being 6.45 g (81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18](OCC)(=[O:20])C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH3:17])[CH2:15][O:16][C:18]3=[O:20])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: CCCCCC
Product: CC1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Yield: 64 %

Procedure:
In the same manner as described in step 4 of Example 1, replacing (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol with 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol, prepared in the previous step, and purification by flash chromatography using a solvent gradient of 10 to 30% ethyl acetate in hexane gave the title compound (293 mg, 64%) as a white solid; mp 189-190° C.; MS (ESI) m/z 339 [M+H]+. Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.83; H, 3.25; N, 8.07. HRMS: calcd for C13H, BrN2O2S+H+, 338.97973; found (ESI, [M+H]+), 338.9784.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH2:27])[CH3:26])[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH:27][C:29]3[C:30]4[N:38]=[CH:37][CH:36]=[CH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH3:26])[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Cc1c(F)ccc2cc([C@H](C)N)c(N3CCN(c4ccccn4)CC3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(F)ccc2cc([C@H](C)Nc3ncnc4cccnc34)c(N3CCN(c4ccccn4)CC3)nc12
Yield: 58.1 %

Procedure:
Following the procedure described for Intermediate 13, Intermediate 14 (530 mg, 1.1 mmol) and TFA (3 mL) in DCM (6 mL) afforded (S)-1-{7-fluoro-8-methyl-2-[4-(pyridin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine as a white foam, which was used in the next step without any further purification. Following the procedure described for Example 5, (S)-1-{7-fluoro-8-methyl-2-[4-(pyridin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine (60 mg, 0.16 mmol), 4-chloropyrido[3,2-d]pyrimidine (33 mg, 0.19 mmol) and DIPEA (0.14 mL, 0.8 mmol) in NMP (1.2 mL) afforded the title compound (46 mg, 58%) as a beige solid. δH (DMSO-d6) 8.94-8.89 (2H, m), 8.56 (1H, s), 8.52 (1H, s), 8.20-8.16 (2H, m), 7.91 (1H, dd, J 8.5, 4.3 Hz), 7.74 (1H, dd, J 8.9, 6.3 Hz), 7.65-7.55 (1H, m), 7.32 (1H, t, J 9.1 Hz), 6.96 (1H, d, J 8.6 Hz), 6.71 (1H, dd, J 7.1, 4.9 Hz), 5.95 (1H, m), 3.87-3.69 (6H, m), 3.33-3.23 (2H, m), 2.58 (3H, s), 1.68 (3H, d, J 6.7 Hz). LCMS (ES+) 495 (M+H)+, RT 3.09 minutes (Method 4).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[ClH:20]>C(O)C.CCOCC>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][Cl:20])=[N:5][N:6]=1
Reactant: Cl
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: CCO
Solvent: CCOCC
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CCl)s1

Procedure:
1 g of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]1,3,4-thiadiazole is left to stand in a mixture of 100 ml of ethanol and 5 ml of a 3 N solution of hydrogen chloride in ether for 12 hours. The precipitate formed is filtered off, washed neutral with ether and chromatographed on silica gel, using chloroform. Evaporation to dryness of the eluates containing the product gives spectroscopically pure 2-methyl-5-[2-(2-hydroxy-3-chloro-propoxy)-styryl]-1,3,4-thiadiazole of melting point 168°-170° C.