Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([CH3:33])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=O)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-methyl-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 483.1.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:34][CH2:35][C:36]([O:38]C)=[O:37].O.[OH-].[Li+]>C1COCC1.O>[C:28]1([S:25]([NH:24][C@H:11]([C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C:8]2[CH:7]=[CH:6][C:5]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[C:4]([CH:9]=2)[C:3]([OH:40])=[O:2])(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)[C@H](Cc2ccc(OCC(=O)O)c(C(=O)O)c2)NS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
5-[(2S)-2-Benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester Step H (17 mg, 0.30 mmol) is stirred in 3:2 THF/H2O (3 mL) at RT. Lithium hydroxide monohydrate (20 mg, 0.5 mmol) is added and the reaction is stirred overnight. The mixture is partitioned between EtOAc (15 mL) and 2N HCl (15 mL). The organics are washed with saturated NaCl (1×15 mL), filtered and concentrated to afford the title compound (compound 1), 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-carboxymethoxy-benzoic acid; 1H NMR (400 MHz, CDCl3) δ7.65 (d, 2H), 7.51 (m, 1H), 7.38 (m, 3H), 7.20 (d, 1H), 7.01 (d, 2H), 6.80 (d, 2H), 6.68 (d, 1H), 4.73 (s, 2H), 4.17 (m, 2H), 3.94 (m, 1H), 3.78 (s, 3H), 2.99 (dd, 1H), 2.91 (dd, 1H); MS (ES−) m/z 541 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:24]([C:26]1([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([NH:1][C:2]2[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:20][CH2:19]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:36])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)#[N:25]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCOCC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CCOCC1
Yield: 58.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoic acid (120 mg, 0.51 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol), triethylamine (130 μL, 0.97 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (150 mg, 58%) was obtained as a white powder.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[OH:10][CH2:9][C:3]1([CH3:2])[CH2:8][CH2:7][N:6]([C:12]2[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=2)[CH2:5][CH2:4]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CC1(CO)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(CO)CCN(c2ncc(B(O)O)cn2)CC1
Temperature: 25 °C

Procedure:
(4-Methylpiperidin-4-yl)methanol hydrochloride (2.09 g, 12.63 mmol), (2-chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and triethylamine (1.8 mL, 12.630 mmol) in ethanol (15 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to r.t. and concentrated in vacuo to give the title compound as an orange semi-solid. This material was used without any further purification. HPLC-MS: MH+ m/z 252.2, RT 0.34 minutes.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[CH:18]=[CH:17][C:16](=O)[C:15](=O)[C:14]=2[C:13]1=[O:24]>>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]1[C:13](=[O:24])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21]
Reactant: Oc1cccc(I)c1
Reactant: O=c1ccc2c(=O)n(CCO)c(=O)c=2c1=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(I)c1

Procedure:
Alkylation of 3-iodophenol with 2-(2-hydroxyethyl)isoindoline-1,3-dione dione following method used in Example 31 gave 2-(2-(3-iodophenoxy)ethyl)isoindoline-1,3-dione. Yield (2.8 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.87 (m, 2H), 7.71-7.73 (m, 2H), 7.22-7.26 (m, 3H), 6.94 (t, J=8.4 Hz, 1H), 6.81:6.84 (m, 1H), 4.19 (t, J=5.6 Hz, 2H), 4.09 (t, J=5.2 Hz, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][CH2:21][CH3:22]>>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH3:22])=[C:13]([Cl:12])[C:18]=1[Cl:19])=[O:6]
Reactant: CCOc1cccc(Cl)c1Cl
Reactant: COc1ccccc1C(=O)Cl
Product: CCOc1ccc(C(=O)c2ccccc2O)c(Cl)c1Cl

Procedure:
4-(2-Hydroxybenzoyl)-2,3-dichlorophenetole was prepared by reaction of 2-methoxybenzoyl chloride and 2,3-dichlorophenetole; m.p. of crude product 112°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13](O)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[C:6]([CH2:13][OH:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Nitrophthalic acid (40 g, 189.5 mmol) in tetrahydrofuran (500 mL) was added dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490 mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C. After the addition, the reaction was allowed to warm slowly to ambient temperature and stirred for 18 h. Methanol (100 mL) was added carefully and the precipitated solid dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0° C., and 10 N sodium hydroxide was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3×600 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=207 (M−OH+CH3CN).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:13]1[CH2:15][CH2:14]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:13]1[CH2:14][CH2:15]1)(=[O:10])=[O:11]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (10 ml/mmol) solution of tert-butyl 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetate (1 eq.) was added trifluoroacetic acid (13 eq.) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 h. The solvent was evaporated off and the residue dried under vacuum to remove traces of trifluoroacetic acid. The crude product was used in the next step without further purification. Yield: quantitative
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([CH2:12][OH:13])=[CH:4][N:3]=1>C1COCC1.O=[Mn]=O>[NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(CO)c2scc(Br)c12
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Nc1ncc(C=O)c2scc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A solution of Example 277E (1 g, 3.86 mmol) in THF (100 mL) was treated with MnO2 (2.66 g, 42.1 mmol), stirred overnight at room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with THF and dichloromethane and the combined filtrates were concentrated to provide 0.88 g (89% yield) of the desired product. MS (ESI(+)) m/e 256.8, 258.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:33]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:34]6[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1ccc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccn(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added diisopropylethylamine (0.16 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally by preparative HPLC. Yield: 0.06 g (40%) 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.16 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.82-2.83 (d, 3H, J=4.64 Hz), 3.37 (s, 3H), 5.9-6.0 (d, 1H, J=2.12 Hz), 7.39-7.48 (m, 5H), 7.58 (d, 1H, J=1.68 Hz), 7.75-7.77 (d, 1H, J=9.7 Hz), 7.81-7.83 (t, 2H, J=2.87 Hz), 7.98-8.46 (m, 2H), 8.47-8.48 (d, 1H, J=4.52 Hz), 9.14 (s, 1H). LCMS: (ES+) m/z=523.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)=[CH:11]/[CH2:12][OH:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O[C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)=[CH:11]/[CH2:12][O:13][C:22]3[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(C2CC2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 0 °C

Procedure:
The above allyl alcohol (0.98 g, 2.60 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.545 g, 2.78 mmol; compound VÚFB-21004) and triphenylphosphine (0.782 g, 2.98 mmol) were dissolved in a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (0.587 mL, 2.98 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and then was stirred over night. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 8:1) affording methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]-acetate as solid mass.
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH2:15][Cl:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCON=C(C(=O)CCl)C(=O)OCC

Procedure:
Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), acetic acid (58.5 ml.) and sulfuryl chloride (20.9 were treated in a similar manner to that of Example F-(2) to give ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
2-Amino-4,6-dichloropyrimidine (15 g, 91 mmol) was treated with 1-methylpiperazine (10.1 g, 100 mmol), treated with Et3N (90 mL, 0.64 mol), treated with EtOH (185 mL), heated to 80° C. over night, cooled, concentrated and partitioned between CH2Cl2 (100 mL) and 1 M NaOH (125 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and crystallized from EtOAc to provide 14.9 g (71%) of the title compound. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.45 (m, 4H), 3.60 (m, 4H), 4.82 (s, 2H), 5.96 (s, 1H); MS (DCl—NH3) m/z 228 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1)=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:39][CH2:38][CH:35]3[CH2:36][CH2:37][NH:33][CH2:34]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCNC1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (2.2 mmol) was coupled with 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5 mmol) using EDC (3 mmol) in DMF (20 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.9 (s, 1H) 8.5-8.75 (m, 2H) 8.3 (m, 1H) 8.0 (d, 1H) 7.65 (m, 1H) 7.3 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 3.6 (m, 2H) 3.4 (m, 2H) 3.2-3.4 (m, 2H) 2.48 (m, 3H) 2.0 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8](Cl)=[N:9][CH:10]=1>>[Br:4][C:5]1[C:6]([O:12][CH3:13])=[N:7][C:8]([N:2]([CH3:3])[CH3:1])=[N:9][CH:10]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CNC
Product: COc1nc(N(C)C)ncc1Br
Temperature: 45 °C
Yield: 98.2 %

Procedure:
A solution of dimethylamine (2.0 M solution in THF, 17.2 mL, 34.5 mmol) was added to 5-bromo-2-chloro-4-methoxypyrimidine (1.540 g, 6.89 mmol) at RT. The reaction was heated to 45° C. for 30 min, then cooled and concentrated. The residue was washed and filtered with diethyl ether to give 1.57 g of 5-bromo-4-methoxy-N,N-dimethylpyrimidin-2-amine as a light yellow solid. ES+=232.0 (M+H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8](=S)=[S:9].C(N(CC)CC)C.C(Cl)(=O)OCC>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[S:9]
Reactant: S=C=S
Reactant: NCCCCCO
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: OCCCCCN=C=S

Procedure:
The synthesis method of Example 45-(1) was applied. 5-Hydroxypentylamine (6.00 g), carbon disulfide (40 ml), triethylamine (8.3 ml), ethyl chlorocarbonate (5.4 ml), triethylamine (8.3 ml) and chloroform (20 ml) were used as reagents. After the reaction, a yellow liquid was quantitatively obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[C:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: Nc1ccc2cccnc2c1
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (26 mg, 0.8 mmol) and 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (50 mg, 0.22 mmol) as a white solid. MS(ES): MH+ 358, M-H+ 356.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][N:17]3[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cn1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2ccn3C)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.016 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.57 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.557 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 44 h to give 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-4-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=343.0 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 76%), MS (ISP) m/z=403.5 [(M+H)+], mp 126.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and methoxy-acetic acid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:19]=[N:20][C:21]=2[CH3:22])=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([N:18]2[C:17]([CH2:16][O:15][C:12]3[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=3)=[C:21]([CH3:22])[N:20]=[N:19]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of lithium hydroxide monohydrate (163 mg, 3.88 mmol) in water (7 mL) was added dropwise to a suspension of 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (694 mg, 1.94 mmol) in THF (7 mL). The reaction mixture was then stirred at room temperature for 30 min and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (635 mg, 99%) as a white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18]([O:20]CC)=[O:19].[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1oc2ccc(F)cc2c1-c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1oc2ccc(F)cc2c1-c1ccccc1Cl
Temperature: 0 °C
Yield: 93.3 %

Procedure:
A mixture of 3.69 g of compound D and 1.95 g of powdered potassium hydroxide in 30 cc of ethanol and 4 cc of water was heated under reflux for 6 hours. After cooling, ice water was added and the resulting mixture was washed with hexane. The aqueous layer was acidified with 1N HCl, and extracted with chloroform, which was then dried over magnesium sulfate. The solvent was distilled off to obtain 3.14 g of 3-(2-chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid. Yield: 93.3%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:3][CH2:4]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: BrCCCCCBr
Reactant: N[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1

Procedure:
2.0 g (6.8 mmol) of trans-1 amino-4-dibenzylaminocyclohexane (see Example 2) was dissolved in 50 mL DMF and stirred for 48 h at RT with 1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium carbonate. The mixture was cooled, combined with water, extracted twice with 100 mL of dichloromethane, dried and the solvent was eliminated in vacuo. The residue is purified over a column (about 100 mL silica gel, about 500 mL ethyl acetate 80/methanol 20+1% conc. ammonia). The desired fractions were evaporated down in vacuo and crystallised from petroleum ether. Yield: 1.2 g (49%).