Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:16])([F:15])[C:10](=[O:14])[CH2:11][C:12]#[N:13]>C(OCC)C>[F:8][C:9]([F:16])([F:15])[C:10]([O:14][CH3:1])=[CH:11][C:12]#[N:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CCOCC
Product: COC(=CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 2M in diethyl ether) was added dropwise to a solution of 4,4,4-trifluoro-3-oxobutanenitrile (3.79 g, 26 mmol) in anhydrous diethyl ether (25 mL) previously cooled to 0° C. The resulting mixture was allowed to slowly warm to room temperatureand stirred overnight. The solvent was removed under reduced pressure to give 4,4,4-trifluoro-3-methoxybut-2-enenitrile, which was directly used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.00 (s, 1H), 4.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27](=[N:29][OH:30])[NH2:28])[CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]=1.N1C=CC=CC=1.[C:37]([O:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=O)(=[O:39])[CH3:38]>O1CCOCC1>[C:37]([O:40][C:41]([C:46]1[O:30][N:29]=[C:27]([C:4]2[CH:5]=[C:6]([Cl:26])[C:7]([NH:8][C:9]3[C:18]4[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=4[C:16]4[C:11](=[CH:12][CH:13]=[N:14][CH:15]=4)[N:10]=3)=[C:2]([Cl:1])[CH:3]=2)[N:28]=1)([CH3:45])[CH3:42])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C(N)=NO)cc3Cl)nc3ccncc3c12
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOc1nccc2c(Nc3c(Cl)cc(-c4noc(C(C)(C)OC(C)=O)n4)cc3Cl)nc3ccncc3c12
Temperature: 110 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]-N′-hydroxybenzenecarboximidamide (50 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added pyridine (0.1 mL) and 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.016 mL, 0.11 mmol). The reaction was heated to 110° C. for 4 h in a sealed tube. After cooling to room temperature, the solvents were evaporated and the residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[N+:7](/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:9])=[O:8].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH:3]([C@@H:2]([C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][N+:7]([O-:9])=[O:8])[CH:1]=[O:6])([CH3:5])[CH3:4]
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from isovaleraldehyde and (E)-(2-nitrovinyl)benzene according to the general procedure. The enantiomeric excess was determined by HPLC with an AD-H column at 210 nm (2-propanol:hexane=1:99), 1.0 mL/min; major enantiomer tmajor=21.8 min, minor enantiomer tminor=17.9 min, the diastereomeric ratio was determined by 1H NMR. [α]D20=−6.5 (c=2.3, CHCl3).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:22][C:21]1[C:15]2[C:16](=[N:17][N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=3)[N:14]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Cc1nc(Br)cn1C
Product: Cc1nc(C#CCCn2nc3cccc(Cl)c3n2)cn1C
Reaction time: 0.25 h
Yield: 5510.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 4-bromo-1,2-dimethyl-1H-imidazole (85 mg, 0.49 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (100 mg, 0.49 mmol, Example 146(B)). Microwave conditions: 100° C. for 15 min. The crude residue was purified by C18 flash chromatography to yield 8.0 mg (27 mmol, 5%) of 4-chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4](Cl)[N:3]=1.[NH2:27][CH2:28][CH:29]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH:29]([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[CH2:28][NH:27][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[CH:31][CH:32]=1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl-carbamoyl]-methyl ester (Intermediate ZJ; 1 equivalent) and 4,4′-(2-aminoethylidene)bis-phenol (1.1 equivalents; prepared as described by Schelkun, R. M. et al. Bioorg. Med. Chem. Lett. (1999), 9(16), pp 2447-2452) are combined in dry THF and treated with DIPEA (1.2 equivalents) and stirred at 50° C. overnight. The reaction is diluted with ethyl acetate and washed consecutively with water (×2) and brine, before drying over magnesium sulfate, filtering and removal of the volatile components under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: Nc1ccccc1C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)(F)F)n1
Reaction time: 8 h
Yield: 111.3 %

Procedure:
To 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid chloride (1.6 g) in CH2Cl12 (25 mL) at 0° C. was added dropwise a solution of 2-cyclohexylaniline (1.3 g) and triethylamine (1.0 mL) in CH2Cl2 (25 mL). The contents were stirred overnight, coming to RT. The contents were washed with water, 2N HCl (2×100 mL), dried (MgSO4) and concentrated in vacuo leaving an amber foam (2.9 g). Crystallization from EtOAc/hexane gave the desired amide as white crystals (1.2 g). Most of the compounds of the present invention were made via this coupling procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[CH:17]=[CH:18][CH:19]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Product: Cl
Temperature: 25 °C

Procedure:
307.1 mg (1 mmol) of the compound of example 35 was dissolved in 10 ml of pyridine and at 0° C., 0.19 g (1.5 mmol) of ethanesulfonyl chloride, and a catalytic amount of DMAP are added. The mixture was stirred at room temperature.
Reaction SMILES: [CH3:1][C:2]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[O:20])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][S:4][CH2:3]1.[C:22](=[O:25])([O-])N.N[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NC(N)=O>>[CH3:1][C:2]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([NH:21][C:27]3[CH:32]=[CH:31][C:30]([O:25][C:22]4[CH:8]=[CH:7][CH:6]=[CH:2][CH:1]=4)=[CH:29][CH:28]=3)=[O:20])[N:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=2)[CH2:5][S:4][CH2:3]1
Reactant: Cc1ccc(-n2nc(C3(C)CSC3)cc2NC(N)=O)cc1
Reactant: Nc1ccccc1
Reactant: NC(=O)[O-]
Agent: NC(N)=O
Product: Cc1ccc(-n2nc(C3(C)CSC3)cc2NC(=O)Nc2ccc(Oc3ccccc3)cc2)cc1

Procedure:
Preparation of 1-(2-Fluoro-4-phenoxy-phenyl)-3-([5-(3-methyl-thietan-3-yl)-2-p-tolyl-2H-pyrazol-3-yl]-urea (Analog 253). Using Procedure 2, carbamate 29 and aniline 30 are used to synthesize urea Analog 253. LC-MS retention time=3.995 min (M+H=490.4).
Reaction SMILES: C([O:5][C:6](=[O:23])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:22][C:19]1[S:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:23])=[O:5])=[CH:10]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A mixture of 4.5 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 85.0 ml dichloromethane and 13.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 3.8 g light pink solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
4-Bromoaniline (56.0 g., 0.33 Mol.), 2,5-hexanedione (37.6 g., 0.33 Mol), and acetic acid (5 mL) were placed into Toluene (500 mL) and heated under reflux for 8 hours employing a dean stark trap to remove the water from the reaction. The reaction was cooled to room temperature and concentrated under reduced vacuum. The resulting oil was taken into ethyl acetate, washed one time each with 2N hydrochloric acid, 2N NaOH, and H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield a brown solid. The material was purified by silica gel flash chromatography eluting with hexanes. Concentration of the appropriate fractions yielded 55.0 gm. of a light yellow solid. (68%) The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+ 249 m.p. 71°-73° C.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C:31]1([C:37](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.O1CCCC1>CN(C)C=O>[CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[N:26][N:25]([C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:24]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn[nH]3)cc2)ccc1[N+](=O)[O-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of t-butyl N-methyl-N-[2-nitro-5-(4-tetrazol-5-ylphenoxy)phenyl]carbamate (3.22 g), triphenylmethyl chloride (2.18 g), triethylamine (0.79 g), anyhdrous tetrahydrofuran (30 ml) and anhydrous N,N-dimethylformamide was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=5/1 as the eluant to give the title compound (3.15 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20](Cl)=[O:21])=[C:16]([CH3:26])[CH:15]=3)[O:11][C:9]=2[N:10]=1.Cl.C([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)(C)(C)C.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[C:37]([OH:43])=[O:36])=[O:21])=[C:16]([CH3:26])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
A solution of 175 mg of {4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetyl chloride in 2 ml of dichloromethane was added slowly to a suspension of 102 mg of proline tert-butyl ester hydrochloride and 170 μl of triethylamine in 5 ml of dichloromethane. After stirring for 2 h, the solvent was removed in vacuo. 1.6 ml of trifluoroacetic acid were added and the mixture was stirred for 2 h at room temperature. Then 10 ml water were added and the aqueous layer was extracted three times with 15 ml of a dichloromethane/isopropanol mixture (3:1). After drying with sodium sulfate and filtration, the solvents were removed in vacuo and the title compound was isolated via preparative HPLC. Yield: 56 mg of a white solid.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]([C:18](=[O:36])[C@H:19]([CH3:35])[NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.C(OCC)(=O)C.[ClH:44].C(OCC)C>C(O)(=O)C.C(OCC)(=O)C>[ClH:44].[ClH:44].[C:32]([C@@H:21]([NH:20][C@H:19]([C:18]([N:8]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)[CH2:7][C:6]([OH:37])=[O:5])=[O:36])[CH3:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([OH:34])=[O:33]
Reactant: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
In a mixture of 2 ml of acetic acid and 2 ml of ethyl acetate is dissolved 0.28 g of N-[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 5 ml of 5N hydrogen chloride-ethyl acetate solution is added to the solution, followed by standing at room temperature for 1 hour. 100 ml of ethyl ether is added to the reaction solution, and the precipitate which separates out is collected by filtration to give 0.22 g of N-[N-[(S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanyl]-N-(indan-2yl)glycine.dihydrochloride as a colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][N:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[CH:11][CH:10]=[CH:9][N:8]=1.P(Cl)(Cl)([Cl:34])=O>>[ClH:34].[CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][N:6]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[N:13][C:12]2[CH:11]=[CH:10][CH:9]=[N:8][C:7]1=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)CCCN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1[N+](=O)[O-]
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2[N+](=O)[O-])=Nc2cccnc21
Product: Cl

Procedure:
Following the procedure of Example 51, N-[2-[[3-(dimethylamino)propyl]phenylamino]-3-pyridinyl]-2-nitrobenzamide was cyclized to the free base of title compound with phosphorus oxychloride and thereafter converted to the hydrochloride by reacting with ethereal hydrogen chloride. Recrystallization from isopropyl alcohol, the yellow solid melted at 239°240° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:12][CH:13]=1>>[CH:29]1([C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([N:19]3[CH2:20][CH2:21][N:16]([C:14]([C:11]4[N:12]=[CH:13][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:9][CH:10]=4)=[O:15])[CH2:17][CH2:18]3)=[N:23][CH:24]=2)[CH2:30][CH2:31]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cn2)CC1
Yield: 59.4 %

Procedure:
Using pyrrolidin-2-one (72 mg) and (5-bromopyridin-2-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (186 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([CH2:10][OH:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.O>[F:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])=[C:6]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(F)c(I)cc1CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a suspension of 8.86 mmol (5-fluoro-2-hydroxymethyl-4-iodo-phenyl)-methanol in 30 ml dichloromethane at 0° C. were added dropwise 22.2 mmol triethylamine and 19.5 mmol methanesulfonyl chloride. The mixture was stirred at 0° C. for 1 h, and then at room temperature for 5 h. The reaction mixture was diluted with water and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (67% yield) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=2[OH:20])[N:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[C:1]([O:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=2[O:20][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
(5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (500 mg, 1.63 mmol), 4-hydroxy-N-methylpiperidine (280 mg, 2.45 mmol) and triphenylphosphine (640 mg, 2.45 mmol) were dissolved in anhydrous dichloromethane (8 ml), under a nitrogen atmosphere at 0° C. A solution of di-tert-butyl azodicarboxylate (560 mg, 2.45 mmol) in dichloromethane (1 ml) was added dropwise over 5 minutes and the resulting yellow solution was allowed to warm to ambient temperature and stirred for 18 hours. A further 1 equivalent of all reagents was added in the same sequence as above under the same reaction conditions and was left to stir for a further 12 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel, eluting with 2-8% methanol in dichloromethane, to yield (7-methoxy-5-((1-methylpiperidin 4-yl)oxy)-4-oxoquinazolin-3(4H)-yl)methyl pivalate (370 mg, 56% yield) as a cream solid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][C:15](C)([O-])[CH3:16].[K+].IC(C)C>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:15]([CH3:16])[CH3:14])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CCOC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-bromophenylacetate (3.0 g, 12.3 mmol) and potassium tert-butoxide (1.38 g, 12.3 mmol) were combined in DMF (35 mL). 2-Iodo-propane (2.09 g, 12.3 mmol) was added and the reaction was stirred at room temperature for 1 hour. Aqueous workup provided the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:49]=[CH:48][C:24]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH:34]([C:45]([O-:47])=[O:46])[CH2:33]4)=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH:34]([C:45]([OH:47])=[O:46])[CH2:33]4)=[CH:29][CH:30]=3)=[CH:48][CH:49]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(Cc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-ylmethyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (80 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (65 mg, 100%): Rf 0.25 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=9 Hz, Ar—H), 8.16 (1H, d, J=9 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.72 (4H, m, Ar—H), 7.53 (2H, q, J=8 Hz, Ar—H), 7.45 (3H, m, Ar—H), 4.22 (1H, m, CHN), 3.78 (2H, s), 3.35 (1H, m), 3.08 (2H, m), 2.86 (1H, m), 2.58 (2H, m); ESI-LCMS e/z calcd for C30H26N2O3 462.546, found 563 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II) chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.