Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:15]([OH:18])[CH2:16][OH:17].C(N(CC)CC)C>C(OCC)(=O)C>[OH:17][CH2:16][CH2:15][O:18][CH2:2][N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: OCCO
Reactant: CN(C)C(=O)N(CCl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)N(COCCO)c1ccccc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
212 g (1 mole) of 1-chloromethyl-1-phenyl-3,3-dimethylurea were dissolved in 100 ml of anhydrous ethyl acetate and 63 g (1.0 mole) of ethylen glycol and 60 g (1.0 mole) of triethylamine were added dropwise whilst cooling with ice. After stirring for 2 hours at 10° to 15°C, the triethylamine hydrochloride used was filtered off and the solvent was distilled off. 238 g of 1-β-hydroxyethoxymethyl-1-phenyl-3,3-dimethylurea were obtained as an oil, in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13](O)=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-c2ccccc2Cl)s1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccccc2Cl)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
350 mg (1.47 mmol) of the compound from Example 48A were dissolved in 5 ml of THF, the mixture was cooled to 0° C. and 0.20 ml (1.47 mmol) of triethylamine and 0.21 ml (1.61 mmol) of isobutyl chloroformate were added. The mixture was stirred at 0° C. for 1 h. The suspension was then filtered through a Seitz frit into a flask cooled to 0° C., and the residue was rinsed with about 2 ml of THF. With vigorous stirring, the filtrate obtained was then added to a solution, cooled to 0° C., of 166 mg (4.40 mmol) of sodium borohydride in 2 ml of water. After 1 h, 5 ml of saturated sodium bicarbonate solution were added and the mixture was warmed to RT. The mixture was extracted with 15 ml of ethyl acetate. The organic phase was washed successively with in each case 5 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution. After drying over sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 252 mg (63% of theory) of the title compound in a purity of 83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](OCC)=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH:10]([CH2:14][OH:15])[CH2:11][C:12]2=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(=O)N(c2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Product: O=C1CC(CO)CN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (0.25 g, 1.0 mmol) in ethanol (10 ml) was added lithium chloride (0.085 g, 2.0 mmol) and sodium borohydride (0.080 g, 2.0 mmol). The reaction was stirred 24 hours at room temperature. The solvent was removed and 30 ml water was added to the residue. The aqueous solution was acidified with conc. HCl until the pH was ˜2-3. The acidic solution was extracted was acidified with conc. HCl until the pH was ˜2-3. The acidic solution was extracted sodium sulfate and evaporated. The residue was purified using preparative TLC (15:1 DCM:MeOH) to yield 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (H HNMR). This was repeated twice.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C>[CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([CH3:11])[O:12][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Reaction time: 0.17 h
Yield: 41 %

Procedure:
(2R,3R)-3-Benzyloxybutan-2-ol in diethyl ether were admixed with sodium hydride in portions at 0° C. with stirring. After 10 minutes, the ice bath was removed and the mixture was stirred for a further 3 minutes at room temperature. The suspension formed was added, at 0° C., to a solution of 2,4-dichloro-5-iodopyrimidine. The mixture was stirred for 4 hours at 40° C. and then admixed with dilute sodium chloride solution. The mixture was extracted with acetic ester (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 41%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:11]1[CH:32]=[CH:31][C:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[N:24][CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[OH:10][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:11]1[CH:32]=[CH:31][C:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[N:24][CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccc1)c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 88.4 %

Procedure:
Sodium borohydride (9 mg, 0.24 mmol) was added in one portion to a suspension of 2-(4-benzoylanilino)-4-(imidazo-[1,2-a]-pyridin-3-yl)-pyrimidine (27 mg, 0.069 mmol) in methanol (2 mL). The mixture was stirred at room temperature for 63 hours. HCl (5 mL, 1 M) was added and the mixture was stirred for another 15 min. After evaporation of the solvent in vacuo, the residue was suspended in water and extracted with chloroform. The phases were separated and the organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude material was purified on a silica gel column using chloroform/EtOH, 95:5, as the eluent to give 24 mg (88% yield) of the product as a pale yellow solid: mp 213-216° C.; MS (TSP) m/z 394 (M+1), 1H NMR (400 MHz, DMSO-d6) δ 9.87 (d, J=5.9 Hz, 1 H), 9.43 (s, 1 H), 8.43 (s, 1 H), 8.23 (d, J=5.48 Hz, 1 H), 7.58 (d, J=9.0 Hz, 1 H), 7.46 (d, J=8.4 Hz, 2 H), 7.29 (m, 1 H), 7.23 (m, 2 H), 7.20 (d, J=5.5 Hz, 1 H), 7.14 (m, 4 H), 7.04 (m, 1 H), 6.88 (m, 1 H), 5.51 (s, 1 H).
Reaction SMILES: Br[C:2]([CH3:20])([CH2:18][Br:19])[C:3](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[Br:19][CH:18]=[C:2]([CH3:20])[C:3](=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)(CBr)C(=Nc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=CBr)C(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 1.83 g (4.59 mmol) of phenyl 2,3-dibromo-2-methyl-N-phenylpropanimidate in 10 ml of THF was added 770 mg (5.05 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred at room temperature for 2 hours. To the mixture was added 1N HCl and extracted with tert-butyl methyl ether. The combined organic layer was washed sequentially with a saturated aqueous NaHCO3 solution and a saturated NaCl solution, dried over anhydrous MgSO4, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 1.26 g of phenyl 3-bromo-2-methyl-N-phenyl-2-propenimidate.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:26])[C:13]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:5])C.[OH-].[K+].Cl>CCO.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:13]([CH3:14])([CH3:15])[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:8]=2)=[O:26])=[O:25])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1sc(NC(=O)C(C)(C)NC(=O)c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
To a solution of Ethyl-2-(2-(4-fluorobenzamido)-2-methylpropanamido)-4-(4-fluorophenyl)thiazole-5-carboxylate (4.3 g, 9 mmol) in EtOH (25 mL) was added KOH (1 eq) in water (25 mL). The reaction was stirred at 65 C for 15 hours followed by stirring at room temperature over 3 days. It was then acidified with 1 N HCl and the resulting precipitates were collected by filtration and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) ppm 1.53 (s, 6H) 7.20 (t, J=8.97 Hz, 2H) 7.32 (t, J=8.84 Hz, 2H) 7.70 (dd, J=8.72, 5.68 Hz, 2H) 8.03 (dd, J=8.72, 5.56 Hz, 2H) 8.64 (s, 1H) 12.43 (s, 1H) 12.94 (br. s., 1H). MS m/z 446 (M+H), 444 (M−1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24](=[O:25])[N:15]3[CH2:16][NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]3=[N:13]2)=[CH:8][CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:24](=[O:25])[N:15]3[CH2:16][NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]3=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-n2nc3n(c2=O)CNc2ccccc2-3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=c1n(-c2ccc(CO)cc2)nc2n1CNc1ccccc1-2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-[4-(Ethoxycarbonyl)phenyl]-5,6-dihydro-1,2,4-triazolo-[4,3-c]-quinazolin-3-one (Compound 18) (1 g, 3.0 mmol) was mixed with THF at 0° C. DIBAL (1.5M in Toluene, 4.6 ml) was added to the reaction dropwise and stirred for 10 min. at 0° C. The reaction was quenched with 10% NaOH solution and extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to afford 2-[4-(hydroxymethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 19), m.p. 152°-154° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:25][C:26](OC(C)(C)C)=[O:27])[NH:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:25][CH2:26][OH:27]
Reactant: CC(C)(C)OC(=O)CC1(NS(=O)C(C)(C)C)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of tert-butyl 2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol) in dry THF (25 mL) was cooled to −78° C. and diisobutylaluminum hydride (54.8 mL, 54.8 mmol) was added drop wise. The mixture was warmed to 0° C. and kept at this temperature for 1 h. The reaction mixture was quenched with a aqueous, saturated solution of Rochelle's salt and vigorously stirred for 15 h. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by chromatography (0-30% EtOAc/hexanes) to afford N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 89% yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[C:42](Cl)=[O:43]>ClCCl>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:42]([C:33]3[CH:34]=[CH:35][C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:32]=3)=[O:43])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.10 g) was dissolved in dichloromethane (30 ml), and potassium carbonate (0.82 g) was added. Then, a solution of 2-naphthoyl chloride (0.33 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.25 g of 4-amino-5-chloro-2-methoxy-N-(1-(4-(2-naphthoylamino)butyl)piperidin-4-ylmethyl)benzamide.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].O=[CH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:4]([CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][CH3:3]
Reactant: O=CCCCNC(=O)c1ccccc1
Reactant: CCCNC1CCc2ncsc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN(CCCCNC(=O)c1ccccc1)C1CCc2ncsc2C1
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 395 mg (2 mmol) propyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine and 478 mg (2.5 mmol) N-(4-oxo-butyl)-benzamide in 1,2-dichloroethane (20 mL) is stirred for about 30 minutes. Then 0.75 g (3 mmol) of sodium triacetoxyborohydride is added and the mixture is stirred overnight. After hydrolysation with 30 mL of 1N aqueous NaOH solution the organic phase is separated, dried over sodium sulfate and concentrated in vacuum. The crude product obtained is purified via column chromatography on silica gel eluting with dichloromethane/methanol (98:2). The methanol used is saturated with NH3-gas. Evaporation of the solvent yields 1.88 mmol (700 mg) of a colorless viscous oil. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[C:9](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>[OH-].[Na+].C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH3:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](O)CC1

Procedure:
The title compound was prepared from (trans)-(4-hydroxy-cyclohexyl)-amine by reaction with di-tert.-butyl dicarbonate in aqueous sodium hydroxide under standard conditions and subsequent reduction with lithium aluminum hydride in THF under standard conditions.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
(190) A solution of 2-(oxazol-5-yl)pyridine (112 mg, 0.77 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.85 mmol, 0.34 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.58 mmol, 3.1 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.77 mmol, 146 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with heptanoic acid (2 equiv, 1.55 mmol, 202 mg, 0.22 mL) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 7.8 mmol, 0.99 g, 0.68 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of heptanoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one (190) (97 mg, 0.38 mmol, 49% yield) as a light brown powder mp 52° C.; 1H NMR (CDCl3, 250 MHz) d 8.63 (br d, J=4.8 Hz, 1H), 7.85-7.74 (m, 3H), 7.31-7.25 (m, 1H), 3.08 (t, J=7.7 Hz, 2H), 1.78-1.69 (m, 2H), 1.44-1.22 (m, 6H), 0.68 (t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.5, 157.3, 153.2, 150.0, 146.3, 137.0, 126.8, 124.1, 120.3, 39.1, 31.4, 28.8, 23.9, 22.4, 14.0; IR (KBr) umax 2933, 2847, 1698, 1604, 1430, 1387 cm−1; MALDI-FTMS (DHB) m/z 259.1436 (C15H18N2O2+H+ requires 259.1441).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.[Pd].O>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCCC(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
A solution of N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide (136 mg, 0.39 mmol) in MeOH (15 mL) was passed through the H-Cube® (70 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford the crude amine as a purple gum (121 mg). To a solution of this amine in DCM (10 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (149 mg, 0.42 mmol), HATU (0.43 g, 1.14 mmol) and DIPEA (1 mL, 5.72 mmol). The mixture was stirred at room temperature for 18 hr. Water (30 ml) was added and stirring continued for 15 min. The layers were separated and the aqueous extracted with DCM. The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a colorless solid (170 mg, 68%). 1H-NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.42-7.33 (m, 1H), 7.12-7.02 (m, 2H), 6.35 (d, J=8 Hz, 1H), 4.25-4.13 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.45-3.25 (m, 2H), 3.23-3.10 (m, 2H), 2.25-1.65 (m, 6H), 1.56 (s, 9H), 1.45 (t, J=7 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Br:10])=[CH:8][CH:9]=1)[CH:5]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>ClCCl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][NH:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:7]([Br:10])=[CH:8][CH:9]=1
Reactant: O=Cc1c(Br)ccc(Br)c1F
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Product: COc1ccc(CNCc2c(Br)ccc(Br)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-dibromo-2-fluorobenzaldehyde (9.12 g) was dissolved in dichloromethane (45 ml), and 1-(4-methoxyphenyl)methanamine (4.6 ml) was added thereto, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, toluene was further added thereto, followed by twice-repeated evaporation under reduced pressure and azotripic drying. The residue was dissolved in THF (25 ml), sodium borohydride (2.0 g) was added thereto, methanol (15 ml) was carefully added dropwise thereto, followed by stirring at room temperature overnight. Water was added thereto, the solvent was concentrated under reduced pressure, a 1M aqueous sodium hydroxide solution was added thereto to adjust pH to 8 or higher, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain, as a light yellow oily product, 1-(3,6-dibromo-2-fluorophenyl)-N-(4-methoxybenzyl)methanamine (8.03 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Na].Br[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][NH:20][C:19]2=[CH:23][N+:24]([O-:26])=[O:25])=[CH:13][N:12]=1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Br)nc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C1NCCN1Cc1ccc(OCC(F)(F)F)nc1
Temperature: 80 °C

Procedure:
2,2,2-Trifluoroethanol (3.6 g) was dissolved in toluene (20 ml), and sodium hydride (0.7 g) was added to prepare a sodium salt of 2,2,2-trifluoroethanol. Then, 3 g of 1-(2-bromo-5-pyridylmethyl)-2-(nitromethylene)imidazolidine (the known compound described in Japanese patent application No. 132,943/1984) was added, and the mixture was heated at 80° C. for 8 hours. Toluene was distilled off under reduced pressure, and the residue was poured into 20 ml of ice water and then neutralized. The aqueous solution was extracted with dichloromethane, and the extract was purified by silica gel column chromatography to give 1-[2-(2,2,2-trifluoroethoxy)-5-pyridylmethyl]-2-(nitromethylene)-imidazolidine. mp. 132°-135° C.