Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[C:8]([CH3:15])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:16]([C:18]1[CH:33]=[C:32]([C:34](=[NH:37])[NH:35]O)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:17]>>[CH2:16]([C:18]1[CH:33]=[C:32]([C:34]2[N:37]=[C:12]([C:10]3[CH:9]=[C:8]([CH3:15])[CH:7]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[N:11]=3)[O:14][N:35]=2)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27])[CH3:17]
Reactant: CCC(CC)c1cc(C)cc(C(=O)O)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3cc(C)cc(C(CC)CC)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 21.8 %

Procedure:
The title compound (35 mg) is prepared by coupling and cyclizing 6-(1-ethyl-propyl)-4-methyl-pyridine-2-carboxylic acid (67 mg, 323 μmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (137 mg, 420 μmol) as described in Example 1; LC-MS*: tR=1.01 min, [M+H]+=497.23; 1H NMR (CDCl3): δ0.85 (t, J=7.5 Hz, 6H), 1.31 (t, J=7.3 Hz, 3H), 1.79 (quint, J=7.0 Hz, 4H), 2.38 (s, 3H), 2.49 (s, 3H), 2.70-2.80 (m, 3H), 3.48-3.56 (m, 2H), 3.75-3.93 (m, 3H), 4.18-4.24 (m, 3H), 7.11 (t, J=5.5 Hz, 1H), 7.16 (s, 1H), 7.90 (s, 1H), 7.91 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](I)[CH3:26].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][CH3:26])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using ethyl iodide (0.27 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C15H18ClN3, 275.12; found, m/z 276.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.11 (q, J=7.3 Hz, 2H), 3.38-3.36 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.94-2.92 (m, 2H), 1.30 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](F)[CH:6]=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].O.[NH2:13][NH2:14]>>[NH:13]1[C:6]2[C:7](=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:8]=[N:14]1
Reactant: NN
Reactant: N#Cc1cc(F)cc(C=O)c1
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Cyano-3-fluorobenzaldehyde (4 g, 26.8 mmol) was dissolved in hydrazine hydrate and stirred at room temperature for 18 hours. The solution was poured onto ice and the resultant solid was separated by filtration and then dried under vacuum at 60° C. to afford the title compound (1.27 g) as a pink solid. Further material was isolated from the aqueous layer. MS (ES): C8H5N3 requires 143; found 144 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[CH2:17][C:16]3([CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:15][N:14]2[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:45]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:45][C:11]([CH:13]3[CH2:17][C:16]4([CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:15][N:14]3[C:23](=[O:33])[C@@H:24]([NH:28][C:29](=[O:32])[O:30][CH3:31])[CH:25]([CH3:27])[CH3:26])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
In a 10 ml seal tube, methyl (2S)-1-(3-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-8-oxa-2-azaspiro[4.5]decan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (200 mg, 371 μmol) was combined with dioxane (6 ml) to give a colorless solution. Ammonium acetate (286 mg, 3.71 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc (10 ml). The mixture was filtered and concentrated in vacuo to afford methyl (2S)-1-(3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-8-oxa-2-azaspiro[4.5]decan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a yellow solid (170 mg, 88.1%). ESI-LRMS m/e calcd for C24H31BrN4O4 [M+] 519. found 520 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:9].O.[OH-].[Li+]>O1CCCC1.O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)NCCOCCO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round bottom flask, was placed a solution of methyl 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoate (10 g, 37.45 mmol, 1.00 equiv) in tetrahydrofuran (40 mL), and a solution of lithium hydroxide hydrate (23.4 g, 558.33 mmol, 15.00 equiv) in water (30 mL). The resulting solution was stirred for overnight at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 3-4 with hydrochloric acid (2 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (50:1). This resulted in 5 g (53%) of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid as a yellowish solid. 1H-NMR (300 MHz DMSO-d6, ppm): δ 13.25 (s, 1H), 8.71 (m, 1H), 8.48 (d, J=8.5 Hz 1H), 8.06 (m, 2H), 7.62 (m, 1H), 4.59 (s, 1H), 3.41˜3.60 (m, 8H). MS (ES, m/z): 254 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CC(C)([O-])C.[K+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([CH3:40])[CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:24])=[CH:33][C:34]=1[CH3:40])#[N:37]
Reactant: Cc1cc(F)ccc1C#N
Reactant: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCO)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(C)c3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-methylpentanamide (0.34 g, 1.05 mmol) in DMF (8.0 mL) was added potassium-t-butoxide (0.258 g, 2.31 mmol) under argon atmosphere. The mixture was stirred at room temperature for 15 min, and 4-fluoro-2-methylbenzonitrile (0.212 g, 1.57 mmol) was added thereto. The reaction solution was stirred at room temperature for 14 hr, and ethyl acetate (80 mL) was added thereto. The organic layer was washed with cold water (2×20 mL) and saturated brine (2×20 mL), and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 30% ethyl acetate/hexane) to give the title compound (0.16 g, 35%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12]([N:50]1[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]1=[O:51])[CH3:13])=[N:7]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol (0.2875 g, 0.9497 mmol) in tetrahydrofuran (9.497 mL, 0.9497 mmol) were added triphenyl-phosphine (0.7473 g, 2.849 mmol), phthalimide (0.4192 g, 2.849 mmol), and diisopropyl azodicarboxylate (0.5518 mL, 2.849 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 20 min and 50% isocratic of EtOAc for 5 min as eluent to give 2-(1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (1 H, dd, J=8.4, 1.4 Hz), 8.09 (1 H, dd, J=7.6, 1.4 Hz), 7.91 (1 H, dd, J=8.4, 7.6 Hz), 7.73-7.80 (2 H, m), 7.60-7.68 (2 H, m), 7.31-7.38 (1 H, m), 7.14-7.24 (2 H, m), 7.00-7.09 (1 H, m), 6.04-6.13 (1 H, m), 1.77 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 432.1 [M+H]+.
Reaction SMILES: O[CH2:2][N:3]([CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]1)[C:4](=[O:8])[O:5][CH2:6][CH3:7].B(F)(F)F.CCOCC>ClCCl>[CH:10]12[CH2:15][CH:14]([CH:13]=[CH:12][CH2:11]1)[CH2:2][N:3]([C:4]([O:5][CH2:6][CH3:7])=[O:8])[CH2:9]2
Reactant: CCOC(=O)N(CO)CC1CC=CCC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)N1CC2C=CCC(C2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
To a stirred solution of ethyl N-(hydroxymethyl)cyclohex-3-en-1-ylmethylcarbamate (213 mg, 1.00 mmol) in 15 mL of dichloromethane, cooled in an ice bath, was added drop-wise boron trifluoride etherate (0.19 mL, 1.5 mmol). The initially cloudy reaction mixture slowly cleared. After it had become homogenous, it was warmed to ambient temperature and stirred for 1.5 h. The reaction was quenched by sequential addition of 5 mL of water and 5 mL of 10% KOH solution. The mixture was extracted with dichloromethane (2×20 mL), and the combined extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was column chromatographed on silica gel with 2:1 hexane/ethyl acetate to give the product as a colorless oil (145 mg, 74%).
Reaction SMILES: [I:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C@:19]12([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[C:28](Cl)=[O:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C@:19]12([CH3:31])[C:25]([CH3:26])([CH3:27])[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[C:28]([O:15][CH:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([I:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:29]
Reactant: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of racemic (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (395 mg, 1.1 mmol) and DMAP (263 mg, 2.16 mmol) in anhydrous CH2Cl2 (5.0 mL), (1S)-camphanic chloride (Corrie et al., 1992, which is incorporated by reference) (350 mg, 1.62 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (490 mg, 80%, 1:1 mixture of diastereomers).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)=[C:9]([CH:11]=1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:12][CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)=[C:9]([NH:10][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=2)=[O:26])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)(C)c1ccc(OC2CCOC2)c(N)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)ccc2OC2CCOC2)cc1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 5-tert-butyl-2-(3-tetrahydrofuranyloxy)aniline (0.078 g, 0.33 mmol) in toluene (2.0 mL) was added p-tolyl isocyanate (0.048 g, 0.36 mmol) and the resulting mixture was allowed to stir at room temp. for 8 h to produce a precipitate. The reaction mixture was filtered and the residue was sequentially washed with toluene and hexanes to give the desired urea as a white solid (0.091 g, 75%): mp 229-231° C.; 1H-NMR (DMSO-d6) δ 1.30 (s, 9H), 1.99-2.03 (m, 1H), 2.19-2.23 (m, 4H), 3.69-3.76 (m, 1H), 3.86-3.93 (m, 3H), 4.98-5.01 (m, 1H), 6.81-6.90 (m, 2H), 7.06 (d, J=8.09 Hz, 2H, 7.32 (d, J=8.09 Hz, 2H), 7.84 (s, 1H), 8.22 (d, J=2.21 Hz, 1H), 9.26 (s, 1H). B1b. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:37])[C:34]([NH2:36])=[O:35])#[CH:26].F[B-](F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.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>[NH2:36][C:34](=[O:35])[CH:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]#[C:26][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1)[CH3:37]
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: CC(C)(C)OC(=O)n1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F

Procedure:
A degassed mixture of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate A61 (0.373 g, 1.03 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.452 g, 2.40 mmol), PdCl2(PPh3)2 (0.015 g, 0.02 mmol), t-Bu3PH.BF4 (0.011 g, 0.038 mmol) and CuI (0.007 g, 0.04 mmol) in 1,4-dioxane (6.0 mL) and DIPEA (0.90 mL, 5.2 mmol) was heated in the microwave at 100° C. for 30 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A62 (0.309 g, 58%). LCMS-D: rt 3.533 min; m/z 502.2 499.2 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26](OCC2C=CC=CC=2)=[O:27])=[CH:24][CH:23]=1)[C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:39][C:40](=[NH:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>>[F:19][C:17]([F:18])([F:20])[C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([N:8]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([C:26]3[O:27][N:52]=[C:40]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[N:39]=3)=[CH:24][CH:23]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCCCCCCCCCC(=N)NO
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)N(Cc1ccc(C(=O)OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Product: CCCCCCCCCCCc1noc(-c2ccc(CN(C(=O)OC(C)(C)C)[C@@H](C)c3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 85 %

Procedure:
The same procedure as employed in the preparation of Example 258 (step a and b) but using benzyl 4-[((tert-butoxycarbonyl){(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}amino)methyl]benzoate and N-hydroxydodecanimidamide gave the title compound as a colorless oil (85%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.34-7.17 (m, 4H), 4.47 (br s, 1H), 4.35 (br s, 1H), 2.75 (t, J=7.5 Hz, 2H), 1.83-1.69 (m, 2H), 1.60-1.14 (m, 29H), 0.90 (t, J=7.0 Hz, 311). HPLC (Condition A), Rt: 8.02 min (HPLC purity: 95.7%).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5].[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([NH:20][C:21]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCC(=O)NC(=O)c1ccccc1S
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Sc1ccccc1C(=O)NC(=O)CCN
Yield: 89 %

Procedure:
To a well stirred mixture of N-(2-mercaptobenzoyl)-β-alaninamide (0.45 g, 2.0 mmol) in 8 ml DMF was added tert-butyl isocyanate (3.0 mmol). The reaction mixture was stirred for 8-10 h at room temp. After completion of the reaction, all of the DMF was removed in vacuo and the residue was treated with ethyl ether. The white precipitate that formed was washed with water, dried in vacuo/CaCl2 and crystallized from acetonitrile. Yield: 89%. 1H NMR (DMSO-d6): 1.30(s, 9H, 3CH3), 2.38(t, 2H, CH2), 3.40(q, 2H, CH2), 6.86(brs, 1H, NH2), 7.30-7.60(m, 5H, Ar—H, NH2), 8.06(s, 1H, NH), 8.26(t, 1H, NH).
Reaction SMILES: O[C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6].C(N(S(F)(F)[F:39])CC)C>C(Cl)Cl.O>[F:39][C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)O)CC3)nc(-c3ccccc3O)nc2c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 40.3 %

Procedure:
To 4-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (330 mg, 0.76 mmol) at −78° C. in 3 mL of CH2Cl2 was added (diethylamino)sulfur trifluoride (185 mg, 1.15 mmol). The reaction mixture was stirred −78° C. for 2.5 h. The reaction mixture was diluted with 10 mL of water and 10 mL of CH2Cl2. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 11-100% EtOAc-hexanes to give 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (133 mg, 40% yield). LC/MS: m/z 435.4.3 (M+H)+ at 2.92 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]([C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.B.C1COCC1.C1COCC1>CO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][CH2:12][N:11]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24]
Reactant: C[C@H]1COCCN1C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (2.55 g, 6.17 mmol, step 1), BH3.THF (1.0 M in THF, 19.0 mL, 19.0 mmol, Sigma-Aldrich, St. Louis, Mo.) and THF (100 mL). The mixture was stirred at 50° C. for 15 h. The mixture was allowed to cool to room temperature and then additional BH3.THF complex (1.0 M in THF, 5.0 mL, 5.0 mmol) was added. The reaction mixture was heated at 50° C. for 1 h. The mixture was allowed to cool to room temperature and then MeOH was added slowly until bubbling ceased. The reaction mixture was concentrated to give di-tert-butyl (2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1,4-piperazinedicarboxylate (2.5 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCBr
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(4′-hydroxyphenyl)benzoate (2.02 g), n-butylbromide (3 ml) and sodium carbonate (3.6 g) in N,N-dimethylformamide was stirred for 17 hours at 80° C. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After dried over magnesium sulfate, the solution was evaporated in vacuo. The residue was triturated with n-hexane to afford methyl 4-(4′-butyloxyphenyl)benzoate (2.45 g).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH:45]2[CH2:47][CH2:46]2)=[C:32]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Reactant: CC1(C)OB(c2cc(Cl)ccc2C2CC2)OC1(C)C
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C2CC2)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 67 mg (0.24 mmol) of 2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 66 mg (62% of theory)