Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:14])(=[O:13])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:1][CH:9]([CH2:10][CH2:11][CH3:12])[CH2:8][C:7]([OH:14])=[O:13]
Reactant: CCC/C=C/C(=O)O
Reactant: Sc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(CC(=O)O)Sc1cccs1

Procedure:
A solution of 2-mercaptothiophene (51.1 g, 0.44 mol), trans-2-hexenoic acid (1) (49.1 g, 0.43 mol), triethylamine (29.3 g, 0.29 mol) in tetrahydrofuran (490 ml) was stirred and refluxed under nitrogen for 21 hours. The mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (500 ml) and 3N hydrochloric acid (200 ml), the aqueous layer was separated and extracted with ethyl acetate (200 ml), the combined ethyl acetate extracts were washed with 3N hydrochloric acid, twice with water and dried over sodium sulfate. The solvent was evaporated in vacuo to yield pale yellow oily product weighing 99 g (100%), which was >96% pure by HPLC.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:13]([CH3:15])[CH3:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.2 %

Procedure:
To a stirring solution of 8.0 g (49.6 mmol) of 4-trifluoromethylaniline in 80 mL of 1,2-dichloroethane at RT is added 4.0 mL (54.6 mmol, 1.1 equiv) of acetone, 5 drops of glacial acetic acid, and 13.7 g (64.5 mmol, 1.3 equiv) of sodium triacetoxyborohydride. The solution is stirred at RT for 72 h, cooled to 0° C., and then quenched by addition of H2O (200 mL). The organic layer is separated, washed with brine (1×200 mL), dried (MgSO4) and the solvents removed in vacuo to afford 10.1 g of crude (4-trifluoromethyl-phenyl)-isopropyl amine. A solution of 2.0 g (9.5 mmol) of this material in 50 mL of DCM is cooled to 0° C. and 1.5 mL (10.8 mmol, 1.5 equiv) of triethylamine is added, followed by dropwise addition of 0.90 mL (10.3 mmol, 1.05 equiv) of bromoacetyl bromide. The solution is stirred at RT for 4 h and then poured into Et2O (200 mL). The organics were washed with 1N HCl (2×50 mL), brine (1×50 mL), dried (MgSO4) and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using EtOAc/hexane 1/10 as eluent afforded 2.09 g of the title compound: 1HNMR (CDCl3, 300 MHz) δ7.78 (d, 2H, J=8.5), 7.40 (d, 2H, J=8.5), 5.01 (m, 1H), 3.51 (s, 2H), 1.08 (d, 6H, J=6.9).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:9]2([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cn1
Reactant: O=C1CCCC1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)nc2)CCCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
5-Bromo-2-chloropyridine (3.0 g, 15.6 mmol) was dissolved in diethyl ether (100 mL) in an oven-dried, nitrogen-flushed 250 mL round bottomed flask and cooled in a dry ice/acetone bath under nitrogen. n-BuLi (1.05 g, 16.4 mmol, 6.6 mL of a 2.5 M solution in hexanes) was added via syringe and the orange heterogenous mixture allowed to stir for 1 hour. Cyclopentanone (1.3 g, 15.6 mmol) was added via syringe and the mixture allowed to warm to −20° C. before being quenched with 1N HCl. The mixture was extracted with EtOAc and the organic extract washed with sat. NaHCO3. The NaHCO3 wash was used to neutralize the first aqueous layer and the combined aqueous layers were extracted with additional EtOAc and the combined organic layers dried (Na2SO4), filtered, concentrated and purified by flash silica gel chromatography (hexanes:EtOAc; 2:1) to give 1-(6-chloro-pyridin-3-yl)cyclopentanol (2.33 g, 76%) as an off white solid: mp 92-93° C., LC/MS (ESI) m/z 197, 1H NMR (300 MHz, CDCl3) δ 8.50 (d, 1H, J=2.4 Hz), 7.77 (dd, 1H, J=8.4, 2.4 Hz), 7.28 (d, 1H, J=8.4 Hz), 2.05-1.80 (m, 8H), 1.60 (s, 1H, OH).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22]C1C=C(B(O)O)C=CC=1>>[NH2:22][C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: O
Product: Nc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (428 mg, 1.61 mmol) and 3-aminobenzeneboronic acid monohydrate (300 mg, 1.94 mmol) were coupled to yield 2-(3-aminophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 110 mg (25%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ3.03 (m, 2H), 3.39 (m, 2H), 5.24 (s, 2H), 6.59 (br d, 1H), 6.78 (d, J=7.7 Hz, 1H), 6.84 (m, 2H), 7.18 (m, 2H), 7.52 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 8.04 (br t, 1H), 11.41 (br s, 1H). HRMS (FAB, MH+) Calcd for C17H16N3O: 278.1293. Found: 278.1297. Anal. (C17H15N3O.1.1 H2O) C, H, N.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:16]=[C:15]([O:17][CH:18]([F:20])[F:19])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[F:19][CH:18]([F:20])[O:17][C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:21])=[O:2]
Reactant: CCCN(C)C(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(OC(F)F)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 5-difluoromethoxy-N-methyl-N-propyl-isophthalamic acid methyl ester (1.6 g, 5.3 mmol) in methanol (30 mL) with 2 N NaOH (4 mL, 8.0 mmol). Stir at room temperature overnight and acidify to about pH=4 using 1 N HCl. Extract with ethyl acetate (150 mL), wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound which is used in the next step without further purification.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.[CH3:26][N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:28].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CNC>CN(C=O)C.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([N:27]([CH3:28])[CH3:26])=[O:10])=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of (S)-3-(biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid (300 mg, 0.88 mmol) in DMF (1.5 mL) and DCM (1.5 mL) was added HATU (401 mg, 1.05 mmol) and triethylamine (0.37 mL, 2.64 mmol). To the mixture at room temperature was added dimethylamine (0.46 mL, 0.91 mmol). The mixture was stirred at room temperature for 2 hours, quenched with sat NaHCO3, and extracted with EtOAc. The organic layer was washed with water (8 times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by TLC preparation plates using 5% 2M Ammonia in MeOH and DCM to give (S)-tert-butyl 3-(biphenyl-4-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (196 mg). HPLC retention time=1.66 minutes (condition B); MS (m+1)=369.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 2.65 (s, 3H) 2.83 (s, 3H) 2.96 (d, J=7.1 Hz, 2H) 4.71-4.94 (m, 1H) 5.56 (d, J=8.6 Hz, 1H) 7.22 (d, J=8.1 Hz, 2H) 7.27 (t, J=7.5 Hz, 1H) 7.37 (t, J=7.6 Hz, 2H) 7.47 (d, J=8.1 Hz, 2H) 7.52 (d, J=7.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[CH:10]1([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C@@H:5]([C:6]([OH:8])=[O:7])[NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCNC1CCCCC1
Reactant: COC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NCCCNC1CCCCC1)C(=O)O
Temperature: 0 °C

Procedure:
356 g (3.4 mols+14% excess) of maleic acid monomethyl ester are placed into a glass flask provided with stirrer, thermometer, condenser and dropping funnel, and, with vigorous stirring and ice-water cooling, 480 ml of triethylamine are added dropwise at 5°-8° C. internal temperature within 2 hours. 372.6 g (2.4 mols) of 3-cyclohexylaminopropylamine are then quickly introduced; the exothermic reaction is subsequently allowed to subside, and the reaction mixture is heated within 30 minutes to 85° C., in the course of which the reaction product crystallises out. After the reaction has finished, the temperature is lowered to room temperature; the product is mixed with 1100 ml of acetone and is filtered off; the filter residue is again mixed with 900 ml of acetone, and the suspension is filtered; the filter residue is then washed with acetone, and the product is dried at 60° C. and 53.2 mbars. The yield is 555.4 g (87.2% of theory) of a white crystalline aspartic acid derivative, which decomposes at 163° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: Cn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2Cl)=N/O)ccc1=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-phenyl)-3-(2-chloro-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 203, step 4) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as an off-white solid, MS (ESI−): m/z=485.2 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:24]3[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cncc1-c1ccc2ccn(C)c2c1
Yield: 83.6 %

Procedure:
A solution of 6-bromo-1-methyl-1H-indole (6.2 g, 29.5 mmol) in toluene was degassed by bubbling argon through the solution for 10-20 min. Et3N (8.2 mL, 59 mmol), tetrakis(triphenylphosphine)palladium (0) (681 mg, 0.59 mmol) and 1-methyl-5-(tributylstannyl)imidazole (Gaare, K.; Repstad, T.; Benneche, T.; Undheim, K. Acta Chem. Scan. 1993, 47, 57.) (11.6 g, 31.2 mmol) in toluene (30 mL) were added and the mixture was heated to 120° C. for 18 h until Pd black appeared. The mixture was cooled, filtered through a pad of silica gel and the pad was washed well with EtOAc. The filtrate was evaporated and chromatography of the residue over silica gel using 0.5-1% methanol in EtOAc gave 1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (5.21 g, 84%) as an off white crystalline solid.
Reaction SMILES: [Li].[CH3:2][O:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[CH3:7].[N+:10]([CH:13]=[C:14]([CH3:17])[CH:15]=[CH2:16])([O-:12])=[O:11]>C1COCC1>[CH3:2][O:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[CH2:7][CH2:16][CH:15]=[C:14]([CH3:17])[CH2:13][N+:10]([O-:12])=[O:11]
Reactant: C=CC(C)=C[N+](=O)[O-]
Reactant: COC(=O)C=C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C=C(C)CCC=C(C)C[N+](=O)[O-]

Procedure:
To the lithium salt of methylsenecioate in THF at -70° was added an equimolar amount of 1-nitro-2-methyl-1,3-butadiene. Quenching in ice, followed by ether extraction yielded a crude product which was purified by Kugelrohr distillation and chromatography. The product had the appearance of a yellowish colored liquid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](F)[CH:4]=[C:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[S:12])[CH:2]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:5]1[CH:4]=[C:3]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[S:12])[CH:2]=[CH:1][CH:6]=1
Reactant: CO
Reactant: Fc1cccc(CCNC(=S)Nc2ccc(Br)cn2)c1
Product: COc1cccc(CCNC(=S)Nc2ccc(Br)cn2)c1

Procedure:
N-[2-(3-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (II-5) yield: 73%; mp 171-172° C.; UV (MeOH) λmax: 202, 208, 258, 275 and 306 nm; IR(KBr) ν 3213, 3155, 3084, 3028, 2866, 1595, 1533, 1477, 1336, 1308, 1229, 1211, 1173, 1136, 1092, 1026, 935, 870, 827, 791, 740 cm−1; 1H NMR (CDCl3)δ 811.3 3 (br s, 1H), 9.46 (br s, 1H), 8.05-8.04 (d, 1H), 7.73-7.69 (dd, 1H), 7.31-7.26 (m, 1H), 7.08-6.97 (m, 3H), 6.87-6.83 (d, 1H), 4.06-3.99 (q, 2H), 3.05-3.00 (t, 2H); 13C NMR (CDCl3) δ 179.1, 163.1, 151.7, 146.2, 141.2, 130.1, 129.9, 124.5, 115.9, 115.6, 113.7, 113.5, 113.4, 112.8, 46.7 and 34.6; 19F NMR(CDCl3) δ −37.30 & −37.33 (d); Maldi Tof found: 354.0 (M+), calculated: 354.0; Anal. (C14H13BrFN3S) C, H, N, S.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[NH2:8][C:9]1[C:10]([C:16](O)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:16]([NH:7][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:17])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1
Reactant: Cn1cc(N)cn1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(NC(=O)c2nc(Br)ccc2N)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100 mL round bottom flask containing 1-methyl-1H-pyrazol-4-amine (700 mg, 7.0 mmol), 3-amino-6-bromopicolinic acid (1.86 g, 8.5 mmol) and PyBop (4.12 g, 8.0 mmol) was added methylene chloride (30 mL) and diisopropylethylamine (3.8 mL, 21.6 mmol). The reaction mixture was stirred for 24 hr at room temperature and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, heptane/ethyl acetate 0% to 100% to afford a yellow solid. A fraction of it was purified via reverse phase HPLC to afford 317. 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.02 (br, 2H), 3.81 (s, 3H). MS (ESI) m/z: 296.0/298.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:43][C:44]([F:56])([F:55])[C:45]1[CH:54]=[C:53]2[C:48]([CH2:49][CH2:50][NH:51][CH2:52]2)=[CH:47][CH:46]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:51]3[CH2:50][CH2:49][C:48]4[C:53](=[CH:54][C:45]([C:44]([F:43])([F:56])[F:55])=[CH:46][CH:47]=4)[CH2:52]3)[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 216A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.53-7.33 (m, 2H), 7.31-7.18 (m, 3H), 7.02 (td, J=3.4, 8.7, 2H), 4.74 (d, J=23.8, 2H), 4.31 (t, J=18.2, 1H), 4.20-4.02 (m, 1H), 3.86 (t, J=6.0, 1H), 3.78-3.69 (m, 2H), 3.66-3.53 (m, 2H), 3.04-2.87 (m, 2H), 2.66-2.49 (m, 1H), 2.27-2.09 (m, 1H); MS (DCI) m/z 421.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([C:32]5[NH:36][C:35](=[O:37])[NH:34][N:33]=5)=[CH:30][CH:31]=4)=[CH:25][CH:26]=3)C(=O)OC(C)(C)C)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][C:29]([C:32]5[NH:36][C:35](=[O:37])[NH:34][N:33]=5)=[CH:30][CH:31]=4)=[CH:25][CH:26]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ccc(-c3n[nH]c(=O)[nH]3)s2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)s2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To tert-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(5-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridazin-3-yl)carbamate (86 mg, 0.16 mmol) in DCM (6 mL) was added TFA (2 mL) at rt. The reaction mixture was stirred at rt for 2 hr followed by concentration to dryness. The crude mixture was purified by reverse phase chromatography to provide the title compound as a pale yellow solid (73.6 mg, quantitative). LRMS (M+H+) m/z 424.2.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[N:9]=[C:10](O)[C:11]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)[C:11]3[N:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1nc(NCc2ccc(F)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(CNc2nc(-n3cncn3)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Yield: 92.1 %

Procedure:
A solution of 2-(4-fluorobenzylamino)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol (2 g), 1,2,4-triazole (1.52 g), DIEA (3.55 g) and POCl3 (3.4 g) in acetonitrile (20 mL) was stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture, which was then washed twice with brine. The organic layer was dried and concentrated to provide 2.1 g of N-(4-fluorobenzyl)-6-(4-fluorophenyl)-4-(1H-1,2,4-triazol-1-yl)pyrido[3,2-d]pyrimidin-2-amine which was characterized by its mass spectrum as follows: MS (m/z) 416 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C@@H:26]1([NH2:32])[CH2:30][CH2:29][CH2:28][C@H:27]1[NH2:31]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C@@H:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[NH2:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@@H]1CCC[C@H]1N
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CCC[C@H]3N)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and trans-cyclopentane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (d, J=7.83 Hz, 1 H), 7.93-7.81 (m, 2 H), 7.67 (t, J=7.45 Hz, 1 H), 7.61 (d, J=8.59 Hz, 1 H), 7.51 (t, J=7.71 Hz, 1 H), 7.47 (d, J=7.58 Hz, 1 H), 6.04 (s, 1 H), 5.25 (s, 2 H), 4.66 (brs, 1 H), 4.40 (brs, 1 H), 4.27 (d, J=7.07 Hz, 1 H), 3.84 (q, J=7.66 Hz, 1 H), 3.75-3.65 (m, 2 H), 2.45 (s, 3 H), 2.40-2.24 (m, 2 H), 2.08-1.79 (m, 3 H), 1.58 (dd, J=13.01, 7.71 Hz, 1 H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][S:12][C:13]1[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:11][S:12][C:13]1[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:21][CH:20]=2)=[N:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CSc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Reaction time: 8 h
Yield: 80 %

Procedure:
The phenyl chloroformate (0.84 ml, 6.68 mmole, 2.5 eq) was added to a mixture of 4-(5-(methylthio)-4morpholinopyrimidin-2-yl)benzeneamine (0.84 g, 2.18 mmole, 1 eq), NaHCO3(aq) (1M, 6.3 ml, 6.3 mmole 2.2 eq) and ACN (13 ml) at 0□. The reaction mixture was stirred for 8 hrs and then dried. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 2:1) to give a yellow solid (80%).
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=C1N(Cc2cccnc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 227° C. and MS: m/e=461.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-chloromethyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[O:10][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)c(Cl)c2)cc1
Temperature: 130 °C
Yield: 13.3 %

Procedure:
Dissolve 2-chloro-4-hydroxy-benzaldehyde (1.09 g, 7.01 mmol) in DMF (10 mL), add K2CO3 (1.06 g, 7.7 mmol) and 4-fluorobenzonitrile (932 mg, 7.7 mmol), heat the mixture at 130° C. overnight. Add water and extract the aqueous layer with EtOAc. Combine organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: EtOAc/hexane 15/85) to give the title compound (240 mg, 14%), 1H-NMR (CDCl3, 300 MHz): 10.40 (s, 1H), 7.98 (d, 1H, J=8.6 Hz), 7.74-7.71 (m, 2H), 7.17-7.00 (m, 4H).