Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:11])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24](I)=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([O:4][C@H:3]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]([NH2:1])[CH3:11])=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1O[C@H](c1ccccc1)[C@H](C)N

Procedure:
Prepared as described in Example 1 from (1R,2S)-2-amino-1-phenylpropan-1-ol (257 mg, 1.70 mmol), and 1-(4-fluorophenyl)-5-iodo-6-methylindazole (200 mg, 0.57 mmol). Yield 169 mg (79%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]1([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: c1ccc2c(Cn3ccnc3)cccc2c1
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)O
Reaction time: 0.17 h

Procedure:
A solution of fumaric acid (0.21 g) in hot ethanol (10 ml) was added to a solution of 1-(1-naphthylmethyl) imidazole (0.4 g) in ethanol (5 ml). After boiling for 10 minutes, the solution was evaporated under reduced pressure to afford a white solid. Recrystallisation of the solid from ethanol afforded 1-(1-naphthylmethyl) imidazole, hydrogen fumarate, m.p. 159°-161° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)c(CO)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-methoxy benzoic acid (1 eq) was dissolved in anhydrous THF (0.55M solution) and BH3SMe2 complex (2M in THF, 1 eq) was added dropwise to the solution. The mixture was stirred overnight, then HCl in MeOH was added and the mixture was warmed to 60° C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with 1N HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colourless oil was obtained (94%), which was used without further characterization in the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])(C)(C)C>C1(C)C=CC=CC=1.C1COCC1>[C:9]([C:8]([CH3:12])([CH3:11])[C:4]1[CH:3]=[C:2]([B:13]([OH:18])[OH:14])[CH:7]=[CH:6][CH:5]=1)#[N:10]
Reactant: CC(C)(C#N)c1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-2-methyl-propionitrile [0.5 g, 2.2 mmol, Intermediate (65)] in toluene (8 mL) and THF (2 mL) is added triisopropyl borate (0.61 mL, 2.68 mmol) at −78° C. tert-Butyl lithium (1.7 M in pentane, 1.55 mL, 2.68 mmol) is added dropwise during 15 min. Reaction mixture is stirred at −78° C. for additional 1 hour, warmed up to −20° C. and quenched with 2 N hydrochloric acid (10 mL). The reaction mixture is extracted with ether, combined ether layers are washed with brine, dried and concentrated to obtain 3-(cyano-dimethyl-methyl)-phenyl boronic acid (0.5 g) [Intermediate (66)] as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1)O>CCOC(C)=O.CC(O)=O.[Pd]>[CH3:19][C:4]1[CH:5]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:20][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Reaction time: 5 h
Yield: 34.8 %

Procedure:
A degassed solution of crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-(4-methoxymethoxyphenyl)methanol (12.0 g, 26.84 mmol) and Pd/C (1.2 g) in EtOAc/HOAc (19/1) was stirred under an atmosphere of hydrogen (1 atm) at r.t. After 5 h, the catalyst was filtered through a pad of Celite, rinsed with ethyl acetate and the combined filtrates concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:9) to afford 4-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-methoxymethoxybenzene (4.0 g, 41.5% for two steps): 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 4 H), 6.63 (s, 2H), 5.16 (s, 2H), 3.94 (s, 2H), 3.50 (m, 3H), 1.58 (s, 6H), 1.29 (m, 3H), 1.13 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:19); Rf=0.80.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[N+:13]([C:16]1[CH:24]=[CH:23][C:19](C(Cl)=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:5]2[O:4][C:2](=[O:3])[C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=c1oc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Temperature: 50 °C
Yield: 78.4 %

Procedure:
A 300 ml. flask equipped with a reflux condenser and a stirrer was charged with 16.3 g of isatoic anhydride and 150 ml of pyridine. They were stirred at about 50° C. to dissolve isatoic anhydride in pyridine. Then, 18.6 g of p-nitrobenzoylchloride was added in several portions over the course of about 10 minutes, and after the addition, the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 0° C. The precipitated crystals were separated by filtration, washed well with water, and dried at 120° C. for 4 hours by a hot air dryer. The resulting crystals were recrystallized from toluene to give 21 g of 2-p-nitrophenyl-3,1-benzoxazin-4-one.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1.O1CCC[CH2:21]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([O:19][CH3:21])=[O:18])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Reactant: C1CCOC1
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 1 gm of the acid of Example 22 with heating in 100 ml of tetrahydrofuran. Filter and cool the filtrate to room temperature. Add 500 mg. of diazomethane and stir at room temperature for 30 minutes. Strip to dryness and triturate the residue in methanol. Recover the title product by filtration. (m.p. 240°-257° C.).
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:10][CH:9]=[N:8][C:7]=1/[CH:11]=[C:12]1/[C:13]([NH:15][C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([NH:19]/1)=[O:18])=[O:14])([CH:4]=[CH2:5])[CH3:3].N[C@H](C(O)=O)CC1C=CC=CC=1>CCCCCC.C(O)C>[CH3:3][C:2]([C:6]1[NH:10][CH:9]=[N:8][C:7]=1/[CH:11]=[C:12]1/[C:13]([NH:15][C@H:16]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([NH:19]/1)=[O:18])=[O:14])([CH:4]=[CH2:5])[CH3:1]
Reactant: C=CC(C)(C)c1[nH]cnc1/C=C1\NC(=O)[C@H](Cc2ccccc2)NC1=O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCO
Solvent: CCCCCC
Product: C=CC(C)(C)c1[nH]cnc1/C=C1\NC(=O)[C@@H](Cc2ccccc2)NC1=O

Procedure:
It was also determined that phenylahistin has a chiral center at the C-10 position. Chiral HPLC analysis of the phenylalanine was conducted according to methods described in Larsen, T. O et al., Phytochemistry (1992) 31, 1613, under the following conditions: HPLC conditions: column; Crownpak CR(+) N4.0×150 mm (Daicel Chemical Industries, Ltd.), mobile phase; H2O (pH 2, adjusted with perchloric acid), flow rate; 0.8 ml/min, detector; UV 8 200 nm. Phenylalanine was obtained from the acidic hydrolysate of the amorphous white powder of phenylahistin, see Yamazaki, M. et al., Tetrahedron Lett. (1975) 27. The phenylalanine obtained from the hydrolysate of phenylahistin was identified using an amino acid analyzer and by measurement of EI-MS [(m+H)+:166.2]); chrial HPLC indicated that the phenylahistin was a mixture of enantiomers in the ratio of approximately R:S=3.1. In order to examine the biological activity of each enantiomer, chiral resolution was carried out by chiral HPLC under the following conditions: column; Chiracel OD N4.6×250 mm (Daicel Chemical Industries, Ltd), mobile phase; n-hexane/ethanol=75/25, flow rate; 1.0 ml/min, temperature; 25° C. Absolute configuration was determined by analysis of phenylalanine obtained from (+)-phenylahistin using chiral HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-amino-3-nitrobenzoic acid (7.40 g), 1-hydroxybenzotriazole (6.59 g) , dicyclohexylcarbodiimide (10.90 g) , dry N,N-dimethylformamide (74 ml), and morpholine (4.3 ml) was stirred at room temperature for 2 hours. The insolubles were filtered out, and washed with N,N-dimethylformamide. The filtrate and the washing were combined, and concentrated to obtain a yellowish brown solid (16.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][OH:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH:17]1([N:20]2[C:24](S(C)(=O)=O)=[N:23][N:22]=[C:21]2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][O:14][C:24]3[N:20]([CH:17]4[CH2:19][CH2:18]4)[C:21]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)=[N:22][N:23]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reactant: OCc1nnn(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([O-:13])=O)=[C:9]([O:17][CH2:18][O:19][CH3:20])[CH:8]=1.[Li+].[NH2:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([NH2:30])=[O:29]>N1C=CC=CC=1>[Cl:6][C:7]1[C:15]([F:16])=[CH:14][C:10]([C:11]([NH:22][C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([NH2:30])=[O:29])=[O:13])=[C:9]([O:17][CH2:18][O:19][CH3:20])[CH:8]=1
Reactant: COCOc1cc(Cl)c(F)cc1C(=O)[O-]
Reactant: NC(=O)c1sccc1N
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COCOc1cc(Cl)c(F)cc1C(=O)Nc1ccsc1C(N)=O
Reaction time: 1 h

Procedure:
n-butyllithium was added to a diethyl ether solution of 1-bromo-4-chloro-5-fluoro-2-(methoxymethoxy)benzene in a dry ice-acetone bath and stirred for one hour. The reaction solution was added to a mixture of dry ice and diethyl ether and stirred for two hours to give lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate. Phosphorus oxychloride was added to a mixture of the obtained lithium 4-chloro-5-fluoro-2-(methoxymethoxy)benzoate, 3-aminothiophene-2-carboxamide and pyridine in a MeOH ice bath and stirred for one hour to give 3-{[4-chloro-5-fluoro-2-(methoxymethoxy)benzoyl]amino}thiophene-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=O)[CH3:24])[CH:18]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:27]([O:31][NH2:32])[CH2:28][CH2:29][CH3:30]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[N:32][O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:24])[CH:18]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCON
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cccc(C(C)=O)c1
Agent: Cl
Solvent: CO
Product: CCCCON=C(C)c1cccc(OCc2ccccc2C(=NOC)C(=O)OC)c1
Yield: 71.3 %

Procedure:
5.8 g (0.017 mol) of methyl 2-(3-acetylphenoxymethyl)phenylglyoxylate O-methyloxime and 2.5 g (0.020 mol) of n-butoxyamine hydrochloride in 60 ml of methanol are stirred at room temperature for 24 hours. The mixture is then hydrolyzed with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried and concentrated. 5.0 g (71%) of the title compound are obtained as a colorless oil (compound no. 470).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:18]=1[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:30]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[C:17]([F:16])[CH:31]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)n2n1
Temperature: 145 °C
Yield: 38 %

Procedure:
To a mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (187 mg, 0.7 mmol), tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (293 mg, 1.2 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.034 mmol) and tripotassium phosphate (144 mg, 1.04 mmol) was added 3:1 acetonitrile/water (3 mL). The resulting mixture was heated at 145° C. (microwave) for 800 s. The reaction was then filtered and concentrated. The residue was dissolved in methanol, and then filtered again. The filtration was finally purified by preparative HPLC (neutral) to afford tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzylcarbamate (110 mg, 38% yield) as a white solid: 1H NMR (CHLOROFORM-d) δ: 8.02 (dd, J=11.9, 1.3 Hz, 1H), 7.78-7.89 (m, 2H), 7.74 (d, J=9.6 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.28 (s, 2H), 6.52 (d, J=9.6 Hz, 1H), 4.95 (br. s., 1H), 4.31-4.57 (m, 3H), 3.45 (td, J=7.1, 5.6 Hz, 2H), 1.68-1.80 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 414.3 [(M+H)+, calcd for C22H29FN5O2 414.2].
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[CH:11]=[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(NCCc2ccccc2)c2ccccc2n1
Product: Clc1cc(NCCc2ccccc2)c2ccccc2n1
Yield: 85.9 %

Procedure:
To 0.6 g of 2-hydroxy-N-(2-phenylethyl)-4-quinolinamine was added 15 mL of POCl3. The mixture was heated to reflux overnight, then cooled and concentrated to dryness. A mixture of ammonium hydroxide in water was added, then the product was extracted into CH2Cl2. This solution was concentrated to dryness, and the product was recrystallized from pentane/CH2Cl2, giving 0.55 g of the title product. Yield 85.9%. M.P. 132°-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:39]4[CH:40]=[CH:41][CH:42]=[C:37]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[N:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(S(=O)(=O)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzenesulfonyl-6-bromo-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]([CH2:39][CH2:40][NH2:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:41][CH2:40][CH2:39][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCCOc1ccccc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCCOc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-phenoxyethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.93 minutes.
Reaction SMILES: [F:1][C:2]1([CH2:18][OH:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in CH2Cl2 (10 mL) at RT was added MsCl (0.29 mL, 3.7 mmol) and TEA (1.04 mL, 7.5 mmol). The reaction mixture was stirred at RT for 5 min, and partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[N:6]1([CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=CC(=O)O
Reactant: C1CCNC1
Solvent: CO
Product: O=C(O)CCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 5 ml of absolute methanol were dissolved 500 mg of acrylic acid and 800 mg of pyrrolidine, and the resulting solution was subjected to reaction with stirring at room temperature for 24 hours.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:60][S:57]([CH:54]2[CH2:56][CH2:55]2)(=[O:59])=[O:58])=[O:35])[CH2:27][CH2:28]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained (0.144 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.74-8.63 (m, 1H), 7.64-7.56 (m, 1H), 6.61-6.52 (m, 1H), 3.93-3.84 (m, 2H), 3.16-3.04 (m, 1H), 2.26-2.08 (m, 2H), 2.08-1.66 (m, 6H), 1.60-1.42 (m, 4H), 1.20-1.10 (m, 2H), 0.99-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 432.0 (M+1).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[OH:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl>[C:22](=[O:23])([O:24][CH3:25])[O:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(F)cc1C1CCCC1
Temperature: 25 °C

Procedure:
2-Cyclopentyl-4-fluorophenol (1.70 g, 9.43 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (2.6 mL, 18.85 mmol), cooled to 0° C., then treated with methyl chloroformate (1.09 mL, 14.14 mmol) and allowed to warm to room temperature over 16 h. The reaction was quenched with 3 mL saturated NaHCO3, washed with 50% saturated NaHCO3 (1×50 mL) and brine (1×50 mL), then dried over Na2SO4. Filtration followed by concentration yielded 2-cyclopentyl-4-fluorophenyl methyl carbonate as an oil which was used for the next step without purification. 1H NMR (400.0 MHz, CDCl3) δ 7.09-7.01 (m, 2H), 6.92-6.87 (m, 1H), 3.92 (s, 3H), 3.13 (dd, J=8.4, 17.2 Hz, 1H), 2.08-2.01 (m, 2H), 1.86-1.66 (m, 4H), 1.59-1.50 (m, 2H). MS (ESI) m/z (M+H+): 239.5.
Reaction SMILES: [ClH:1].[CH2:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:22])[NH2:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])[CH:3]=[CH2:4].Cl.[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N1CCOCC1)C>CN(C=O)C>[ClH:1].[CH3:24][O:25][C:26](=[O:38])[C@@H:27]([NH:37][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][CH2:2][CH:3]=[CH2:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[NH:22])[NH2:21])=[CH:16][CH:15]=1)[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31]
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(S)allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionic acid hydrochloride (3.48 g, 10.6 mmol) and 2-(S)-amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride (2.7 g, 10.6 mmol) in 20 ml of DMF were added at −15° C. TOTU (3.83 g, 11.67 mmol) and N-ethylmorpholine (2.7 ml, 21.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, ethyl acetate was added to the residue and the organic layer was extracted with aqueous sodium hydrogen carbonate solution, potassium hydrogen sulfate solution, and water. The organic layer was evaporated. Yield: 2.8 g (50%). MS: m/z=491.3 (M+H)+.