Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 8-aminooctanoic acid, methyl ester hydrochloride in the presence of diisopropylethylamine as more fully described in Example 11 of European Patent Application 136,883 to give (±)-8-[[2-[(acetylthio)methyl]-1-oxo-3phenylpropyl]amino]octanoic acid, methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>[Pd]>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Product: FC(F)(F)Oc1ccc(-c2nccc(Cl)n2)cc1

Procedure:
The title compound was prepared by palladium-catalyzed arylation of 2,4-dichloropyrimidine and 4-trifluoromethoxyphenyl boronic acid: mp 70-73° C.; 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J=5.6 Hz, 1H), 8.16 (d, J=9.1 Hz, 2H), 7.65 (d, J=5.3 Hz, 1H), 7.36 (dd, J=9.2, 0.9 Hz, 2H); EIMS m/z 274 (M+).
Reaction SMILES: [NH2:1][C:2]1C=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1.Cl.[N:28]1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>C(OCCO)C>[NH2:1][C:2]1[N:28]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccncc1
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: Nc1nccc(Nc2ccc(NC(=O)OCc3ccccc3)cc2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
2-Amino-4-chloropyridine (257 mg) was dissolved in 2-ethoxyethanol (10 ml), and then benzyl N-(4-aminophenyl)carbamate (533 mg) and pyridine hydrochloride (462 mg) were added thereto, followed by stirring at 120° C. overnight. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which ethyl acetate-hexane was then added to precipitate crystals. The solid was filtered, and dried under aeration to provide the titled compound (321.5 mg, 48%) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)=[CH:6][C:5]([C:26]#[N:27])=[CH:4][C:3]=1[NH:28]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:9]2)[C:2]=1[Cl:1])[C:26]#[N:27]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg, 0.221 mmol) was taken up in DCM (3 mL) and TFA (0.341 mL, 4.43 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was azeotroped 2× with DCM and 2× with MeOH, and then dried under vacuum. The solid was dissolved in EtOAc, and then washed with 2M K3PO4 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-5% MeOH/DCM). (+/−) 3-amino-4-chloro-5-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (36 mg) was obtained as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][NH:11]2)=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:14])[CH:9]=[CH:10][N:11]2[CH2:23][CH3:24])=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2]
Reactant: CCOc1cc2[nH]ccc(=O)c2cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)c(=O)ccn2CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-Ethoxy-6-methoxy-4(1H)-quinolone (compound 62, 0.68 g) was dissolved in dimethylformamide (14 ml). Potassium carbonate (640 mg) and ethyl iodide (0.3 ml) were added to the solution, and the mixture was stirred at room temperature for 4 hours. The precipitate was removed by filtration, and the filtrate was purified by silica gel column chromatography (Wako Gel C-200, 50 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 7-ethoxy-1-ethyl-6-methoxy-4(1H)-quinolone (compound 58, 0.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH2:15])[C:3]=12.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22](O)=[O:23].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[O:23])[C:3]=12
Reactant: O=C(O)c1cnccn1
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cnccn1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.200 g, 0.849 mmol, Example 11, Step G) and pyrazine-2-carboxylic acid (0.221 g, 1.78 mmol) were placed in DCM (5 mL) at room temperature. BOP-Cl (0.454 g, 1.78 mmol) was then added, followed by the addition of triethylamine (0.592 mL, 4.24 mmol). The reaction was stirred for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the reaction was filtered. The resulting solid was slurried with 10:1 DCM:MeOH and filtered to give solid N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.23 g, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[OH:14][CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1>>[ClH:1].[ClH:1].[NH2:8][C:7]1[C:2]([N:17]2[CH2:18][CH2:19][CH:15]([OH:14])[CH2:16]2)=[N:3][CH:4]=[C:5]([NH2:11])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: OC1CCNC1
Product: Cl
Product: Nc1cnc(N2CCC(O)C2)c(N)c1

Procedure:
2 g (0.01 mol) of 3,5-dinitro-2-(3-hydroxypyrrolidin-1-yl)pyridine obtained according to Protocol A from 2-chloro-3,5-dinitropyridine and 3-hydroxypyrrolidine, were reduced according to Protocol B, to give 1.1 g of N-(3,5-diaminopyrid-2-yl)-3-hydroxypyrrolidine dihydrochloride.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([C:36]([O:38][C:39]4[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=4)=[O:37])[CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4)CC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a mixture of 1-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloric acid (154 mg, 0.40 mmol) and diisopropylethylamine (0.35 mL, 0.20 mmol) in CH2Cl2 (1.5 mL) at room temperature was added 4-bromophenyl chloroformate (prepared according to procedures described at Step B of Example 2 substituting 4-bromophenol for 1,1,1-trifluoro-2-propanol) in CH2Cl2 (1.0 mL). The resulting mixture was stirred at room temperature for 3 hrs, diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/Hexanes) to give the title compound (159 mg, 73%) as a light yellow solid. MS (ESI) 547, 549 (M+H).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([Cl:22])[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[Cl:22][C:11]1[CH:10]=[N:9][NH:8][C:13](=[O:14])[C:12]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(Cl)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]ncc(Cl)c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of 2-benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one (10.2 gm, 30.8 mmol) in toluene (154 mL) was added aluminum chloride (10.3 g, 77 mmol). The mixture was stirred at 50° C. for 1 h. After this time, the solution was cooled to RT, and the reaction mixture was poured into water (200 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one as an off-white solid (6.8 g, 92%). LC/MS (method A): RT=2.91 min, (M+H)+=241;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:19])[C:17]=1[OH:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[O:6].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[C:20]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Cl:1])[C:17]([O:18][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[CH:2][CH:3]=2)=[C:16]([Cl:19])[CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1O)c1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1OC(=O)c1ccccc1)c1cc(Cl)c(OC(=O)c2ccccc2)c(Cl)c1
Yield: 88.2 %

Procedure:
3,5-Dichloro-2',4-dihydroxybenzanilide (1 g.) was dissolved in dry pyridine (15 ml.) in the cold at 0°-5° C. and to it was added dropwise benzoyl chloride (1.2 ml.). With gentle stirring reaction was continued for several hours. The solution was then poured into ice-cold water and acidified with 1 N hydrochloric acid to pH 2, yielding oily material which was extracted by ethyl acetate. The ethyl acetate solution was washed with 1 N hydrochloric acid and 5% sodium bicarbonate solution in that order and dried with anhydrous sodium sulfate, followed by removal of the solvent by evaporation. The residue was subjected to recrystallization from ether and petroleum ether mixture to give white crystals (1.5 g.) of 2',4-dibenzoyloxy-3,5-dichlorobenzanilide. Yield: 88.2%. Melting point: 157°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[Cl:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:13])[CH3:12])=[C:4]([F:9])[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Br)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-bromo-3-chloro-2-fluoroaniline (15.0 g) in ethyl acetate (200 mL) was added dropwise acetic anhydride (7.57 mL) at 0° C. Then, pyridine (10.8 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with hexane to give the title compound as a colorless solid (yield: 17.1 g, 96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[C:39]([CH3:42])([OH:41])[CH3:40])=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:38]([C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[C:39]([OH:41])([CH3:42])[CH3:40])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(C)(O)C(=O)c1ccc(Cl)cc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg (0.31 mmol) of 3-(4-chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride in 2 mL of CH2Cl2, 54 μL (0.31 mmol) of diisopropylethylamine and 62 mg (0.31 mmol) of 1-(4-chlorophenyl)-2-methyl-2-hydroxy-propan-1-one were added. After 5 min, 99 mg (0.47 mmol) of sodium triacetoxyborohydride was added and stirred for 3 hr. The reaction was quenched with water and the layers were separated. The organic layer was dried and concentrated. The residue was purified on a prep TLC plate using 30% EtOAc/hexane as an eluant to isolate two products. The higher Rf band gave 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) and the lower Rf band gave 3-(1(S)-4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B). Diastereomer A, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min). Diastereomer B, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2-chloro-phenylamine (6 g, 29.06 mmol), 1,4-cyclohexanedione monoethyleneketal (6.908 g, 43.59 mmol), and sodium triacetoxy-borohydride (9.239 g, 43.59 mmol) in DCE (100 ml) and acetic acid (0.2 ml) was stirred at r.t. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and washed with dichloromethane. The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution), dried (MgSO4) and evaporated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/EtOAc 4:1 as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D33 (8.57 g, 85%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B>C1COCC1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccccc1
Temperature: 0 °C

Procedure:
To acetophenone (19.47 mL, 166.6 mmol) in THF (100 mL) was added (S)-(−)-2-methyl-CBS-oxazaborolidine (4.62 g, 16.6 mmol), and the reaction was cooled to 0° C. Borane methyl sulfide complex (2M in THF; 50 mL, 100 mmol) was added over 15 minutes, and the reaction was stirred at room temperature. Aqueous work-up gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])=[O:29])[CH:26]=1>C(O)(C)C.C(OCC)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=4[F:38])=[O:29])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2F)c1
Solvent: CC(C)O
Solvent: CCOCC
Product: Cl
Product: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)c(F)cc23)cn1)Nc1cccc(F)c1F
Temperature: 80 °C
Yield: 87.1 %

Procedure:
A mixture of 7-(benzyloxy)-4-chloro-6-fluoroquinazoline (1.20 g, 4.16 mmol) and 2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (1.05 g, 4.16 mmol) in isopropanol (20 ml) was heated at 80° C. for 10 minutes and then allowed to cool to room temperature. The mixture was diluted with diethyl ether and then filtered to give 2-(4-{[7-(benzyloxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide hydrochloride (1.96 g, 87% yield) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: O=[N+]([O-])c1ccc(O)nc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc([N+](=O)[O-])cn1
Yield: 37 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was converted using 2-hydroxy-5-nitro-pyridine instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=80:0:20 to 50:30:20, 122 mg, 37%) which was obtained as a white solid. MS: m/e=312.2 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.C([Li])(C)(C)C.[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.O>C(OCC)C.CCCCC>[CH:2]1([C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: O=C1CCCC1
Reactant: BrC1CC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: O
Product: OC1(C2CC2)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of bromocyclopropane (2.54 ml, 31.7 mmol) in diethyl ether (50 ml) at −78° C. under nitrogen was added, dropwise, tert-butyllithium (18.2 ml of a 1.7 M solution in pentane, 31 mmol). Diethyl ether (30 ml) was then added and the mixture stirred for 1 hour at −78° C. A solution of cyclopentanone (2.74 ml, 34 mmol) in diethyl ether (40 ml) was then added dropwise. The reaction was stirred for 4 hours at −78° C. and was then allowed to warm to room temperature over 16 hours. Water (40 ml) was added, cautiously, and the aqueous layer extracted with diethyl ether (2×40 ml). The combined ether layers were dried using sodium sulphate, filtered and evaporated under reduced pressure to give an oily residue. This was chromatographed using silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 9:1, by volume) to provide the title compound (3.5 g). TLC Rf=0.4 (silica, dichloromethane:methanol, 9:1, by volume).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O.C(OCC)C>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:10]([C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 5 h
Yield: 42.3 %

Procedure:
4-Phenylbenzoyl chloride (2.00 g, 9.23 mmol) was added to a mixed solution of 4-aminocinnamic acid (1.51 g, 9.23 mmol) and sodium hydrogen carbonate (2.33 g, 27.7 mmol) in water and diethyl ether under ice-cooling, which was stirred for 5 hours. After the reaction mixture was separated, 5N hydrochloric acid was added to water layer, and the precipitated crude product was washed with water and ethyl acetate, to give the titled compound (1.34 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH:43]=[CH2:44]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1/[CH:44]=[CH:43]/[C:42]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Temperature: 120 °C

Procedure:
To a mixture of 2-bromo-4-(trifluoromethyl)aniline (5 g, 20.83 mmol), triethylamine (4.4 mL, 31.2 mmol) and P(o-tol)3 (2.5 g, 8.33 mmol) in DMF (42 mL, 0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (2.3 g, 23 mmol) and palladium acetate (940 mg, 4.167 mmol). The tube was sealed and heated to 120° C. for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time(min)=2.532, method [1], MS (ESI) 260.1 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[C:6]=1SC)=O.[CH3:22][NH:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:7]1[CH2:8][CH2:9][CH2:10][C:5]2[C:3](=[O:2])[N:23]([CH3:22])[NH:24][C:6]1=2
Reactant: COC(=O)C1=C(SC)N(c2c(C)cc(C)cc2Cl)CCC1
Reactant: CNN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (4.99 g), methylhydrazine (16.4 mL), p-toluenesulfonic acid monohydrate (2.91 g), and methanol (75 mL) were combined in a glass vessel sealed with a Telfon™ screw cap. The reaction mixture was stirred in a 130° C. oil bath for 24 h, then cooled to room temperature and concentrated on the rotary evaporator. The residue was chromatographed on silica gel using a methanol/dichloromethane gradient to give 3.21 g of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo-[3,4-b]pyridin-3-one, mp 95.9–99.9° C.