Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][CH3:11])[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: CNc1cc(Cl)ncc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CNc1cc(Cl)ncc1C=O
Temperature: 30 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7 mmol) and MnO2 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30° C. for 6 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to give 6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.52 (br s, 1H), 8.40 (s, 1H), 6.75 (s, 1H), 2.87 (d, J=5.8 Hz, 3H); MS (ESI) m/z: 171.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[C:5]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12]
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN(C)C
Temperature: 0 °C
Yield: 22.1 %

Procedure:
A solution of Compound 107 (800 mg, 2.11 mmol), 2-dimethylamino ethyl chloride hydrochloride (1.52 g, 10.55 mmol), and potassium carbonate (2.91 g, 21.10 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 210 mg (24%) of pale yellow solids. M.P. 132° C. 1H NMR (DMSO-d6): δ 2.24 (s, 6H), 2.40 (s, 3H), 2.44 (m, 2H), 3.63 (m, 4H), 3.97 (m, 4H), 4.29 (m, 2H), 7.17 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.57 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 450 (M+1). Anal. (C24H27N5O2S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].Cl>O.C(O)C>[ClH:1].[F:18][C:19]([F:28])([F:29])[O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)(F)Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), 3-trifluoromethoxyaniline (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (23 mg, 59%). 1H NMR (CDCl3): 8.88-8.85 (m, 1H), 8.59-8.55 (m, 1H), 7.93-7.87 (m, 1H), 7.59 (s, 1H), 7.48 (t, J=8.3 Hz, 1H), 7.45 (dd, J=1.2, 7.5 Hz, 1H), 7.36 (s, 1H), 7.30-7.29 (m, 1H), 7.16-7.10 (m, 1H), 7.05 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>ClCCl>[C:18]([Si:15]([CH3:17])([CH3:16])[O:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cccs1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 3-(thiophene-2-yl)propanol (500 mg, 3.52 mmol) and imidazole (288 mg, 4.22 mmol) in 9 mL anhydrous dichloromethane was added TBS-Cl (584 mg, 3.87 mmol). The resulting mixture was stirred at room temperature for 30 minutes and poured into 50 mL water. Organics were extracted with ether (2×40 mL), dried over magnesium sulfate, filtered and concentrated. The crude oil was subjected to chromatography on silica gel with gradient elution (1-2% ethyl acetate in hexanes) to give tert-butyldimethyl(3-(thiophen-2-yl)propoxy)silane (787 mg, 87%). Used without further characterization.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH2:3].[H][H]>[Pd].C(O)C>[CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3]
Reactant: C=CCc1c(C(=O)OCC)nc2ccccc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C(=O)OCC)nc2ccccc2c1O

Procedure:
A solution of 49.0 parts of ethyl 3-allyl-4-hydroxy-quinoline-2-carboxylate in 600 parts of boiling ethanol was stirred for 5 minutes in 3 parts of 3% palladium-on-carbon catalyst, then filtered and the filtrate together with 5 parts of fresh catalyst was charged to a stainless steel autoclave and hydrogen added at room temperature to a pressure of 50 atmospheres. After stirring at 16 hours 1.38 moles of hydrogen had been absorbed. The reaction mixture was dissolved in hot ethanol, filtered to remove catalyst, and evaporated to give 39.3 parts of ethyl 3-n-propyl-4-hydroxyquinoline-2-carboxylate, pale yellow needles, m.pt. 155°-157°C which were collected and dried; a further 4.8 parts of less pure product m.pt. 140°-146°C were recovered from the ethanolic mother liquors after concentration in vacuo. After repeated recrystallisation from ethanol very pale yellow prismatic needles, m.pt. 158°-159.5°C were obtained. (Found: C 69.3; H 6.3; N 5.2%. C15H17NO3 requires C 69.5; H 6.6; N 5.4%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]=[O:32])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:33][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:30][C:29]([CH:31]([OH:32])[CH3:33])=[N:28][N:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=Cc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
To a solution of 5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (700 mg) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1M tetrahydrofuran solution) (3.27 mL) and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). The pale-yellow amorphous solid was purified by preparative HPLC to give the title compound (301 mg, yield 42%) as a colorless amorphous solid. MS: 488 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[CH3:16][O:17][C:18](=[O:21])[C:19]#[CH:20]>CO>[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH:20][C:5](=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: C#CC(=O)OC
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Solvent: CO
Product: CCOC(=O)C(C=CC(=O)OC)=C(C)Nc1ccccc1
Yield: 59.6 %

Procedure:
A mixture of 3-phenylamino-but-2-enoic acid ethyl ester (7 g, 34.1 mmol) and propynoic acid methyl ester (4.6 mL, 51.2 mmol) in MeOH (114 mL) was refluxed for 48 h. The solvent was evaporated, and the crude oil was purified by silica gel chromatography (0-20% EtOAc/hexanes) to give 5.88 g of the title compound as an orange oil. MS: (+) m/z 290.27 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:21][NH2:22])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Br)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(Br)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{9} (6.23 g, 18.3 mmol, 1 equiv.), anhydrous hydrazine (2.3 mL, 73.1 mmol, 4 equiv.), ethanol (25.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{9} (4.64 g, 78%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.39 (d, 2H, J=8.5 Hz) 7.15 (d, 2H, J=8.5 Hz), 3.83 (br s, 2H), 3.41 (s, 2H) 3.04 (s, 2H), 2.49 (br s, 4H), 2.41 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 136.9, 131.2, 130.5, 120.8, 61.9, 60.4, 53.5, 52.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](Cl)=[O:27])=[N:24][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:26]([C:23]2[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=2)=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cnc(Cl)cn2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) and triethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-5° C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO3 (20 ml), brine (20 ml), dried (anhyd. Na2SO4) and concentrated to get 0.42 g of crude 5-chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide, which was directly used in the next reaction.
Reaction SMILES: Cl[C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:17][OH:18].[OH-].[K+]>CS(C)=O>[CH3:17][O:18][C:2]1[C:3]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: CO
Reactant: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(N)c([N+](=O)[O-])cc1-n1cccc1

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-pyrrol-1-yl-phenylamine (Example F3) (5.94 g, 25 mmol), methanol (25 mL) and KOH (1.98 g, 30 mmol) in DMSO (25 mL) according to the general procedure E. Obtained as an orange solid (5.88 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]Br>O>[Br:12][C:5]1[N:4]=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ncccc1O
Reactant: BrBr
Solvent: O
Product: COC(=O)c1nc(Br)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A stirred solution of methyl 3-hydroxy-2-pyridinecarboxylate (1.69 g, 11.0 mmol) in water (75 mL) at ambient temperature was treated dropwise with bromine (2.39 g, 15.0 mmol). The reaction mixture was stirred at ambient temperature for 3 h, during which time a fine white precipitate formed. The mixture was extracted with CH2Cl2 (100 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to give 2.11 g (82%) of methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 10.69 (s, 1H), 7.55 (d, 1H, J=8.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 4.04 (s, 3H); LRMS (APCI), m/z 232/234 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C@H:3]([NH:24][C:25](=[O:36])[C@@H:26]([NH:28]C(=O)OC(C)(C)C)[CH3:27])[C:4](=[O:23])[N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:26]([CH3:27])[C:25]([NH:24][C@@H:3]([CH:2]([CH3:37])[CH3:1])[C:4]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][C@H:6]1[C:14]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:22])=[O:23])=[O:36]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
In a 100 mL round-bottomed flask, tert-butyl (S)-1-((S)-3-methyl-1-oxo-1-((S)-2-(phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)butan-2-ylamino)-1-oxopropan-2-ylcarbamate (75 mg, 147 μmol, Eq: 1.00) was combined with DCM (6 mL) to give a colorless solution. TFA (1.9 mL, 24.9 mmol, Eq: 169) was added. The reaction was stirred for 30 min and then concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (55 mg) which was used without further purification.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[N:19]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[N:22][CH:21]=[N:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:32][CH:31]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-n4cncn4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.71 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCc1ccc2ccccc2c1Cl
Reactant: O=Cc1cccs1
Product: Clc1c(CCCNCc2cccs2)ccc2ccccc12
Yield: 70 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and thiophen-2-carbaldehyde in 70% yield as a slightly red oil.
Reaction SMILES: [CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH3:16])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:19]Br.O>C(O)(=O)C>[CH:1]([N:4]([C:12](=[O:18])[CH:13]([CH3:17])[C:14]([CH2:16][Br:19])=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)C(=O)N(c1ccc(Cl)cc1)C(C)C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)CBr)C(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a reactio flask which contained 71.6 g (0.267 mole) of N-isopropyl-4'-chloro-2-methylacetoacetanilide dissolved in 360 ml of glacial acetic acid, there was added dropwise a solution of 42.7 g (0.267 mole) of bromine in 30 ml of acetic acid. The solution was stirred overnight at ambient temperature. On the following morning, the reaction solution was added to two liters of cold water and the organic material was extracted into toluene. The latter was washed with water and dried over sodium sulfate. After removal of the solvent, there was obtained 86.6 g (97%) of residual oil. N.M.R. (CDCl3)∂0.9-1.4 (CH3, 9 protons), 3.3-3.6 (CH), 3.9-4.0 (CH2Br), 4.8-5.2 (CH, isopropyl), 7.1-7.6 (aromatic).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([O:15][C:16](=[O:22])[N:17]([CH2:19][CH2:20]O)[CH3:18])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:11]([O:15][C:16](=[O:22])[N:17]([CH3:18])[CH2:19][CH2:20][O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])([CH3:13])([CH3:14])[CH3:12]
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(CCOc1c(Cl)nc(Cl)nc1Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 124.5 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (300 mg, 1.50 mmol), (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (300 mg, 1.71 mmol), triphenylphosphine (455 mg, 1.73 mmol) and DIAD (339 μL, 1.73 mmol) in dioxane (2.5 mL) was stirred at RT for 1.5 hours then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-50% ethyl acetate in cyclohexane) affording Methyl-[2-(2,4,6-trichloro-pyrimidin-5-yloxy)-ethyl]-carbamic acid tert-butyl ester (666 mg, quantitative). LCMS: RT=3.09 min, [M-Boc+Na]+=279.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: Nc1c(Cl)ncn2c(=O)[nH]nc12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)ncn2c(=O)n(Cc3ccc(C(F)(F)F)nc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.6 %

Procedure:
To a stirred solution of 8-amino-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.41 g, 7.6 mmol) in DMF (10 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (1.78 g, 9.1 mmol), followed by K2CO3 (2.1 g, 15.2 mmol). The resulting mixture was stirred at room temperature for 5 h. Analysis by HPLC/MS indicated that the reaction was complete. Water (50 mL) was added to the reaction mixture. The solid precipitate was collected by filtration and was washed with water (10 mL×3). After the resulting solid was dried under vacuum, the title compound (2.4 g) was obtained as an off-white solid. HPLC/MS: retention time 2.43 min, [M+H]30 =345. 1H NMR (CDCl3): δ 8.81 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.21 (s, 2H), 4.42 (s, 2H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 46.9 ppm.
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2].C1N=C[N:41](C(N2C=NC=C2)=N)[CH:40]=1>CN(C=O)C>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:40]([NH2:41])=[N:31][N:30]=3)=[CH:32][CH:33]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2nnc(N)o2)cc1
Temperature: 85 °C

Procedure:
To 4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 mL) was added C-(Di-imidazol-1-yl)-methyleneamine (0.08 g, 0.50 mmol), and the reaction was heated at 85° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc:hexane gradient) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH3:42])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOC(C)=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCNCCOc1ccc(C(=O)OCC)cc1OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(OC)c1
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (78 mg, 0.29 mmol) was added Et3 N (0.1 mL, 0.72 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed successively with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 160 mg(q.y.) ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an oil. 1H-NMR (CDCl3) δ 1.13–1.23 (m, 3 H), 1.37–1.40 (m, 3 H), 2.90–3.89 (m, 12 H), 4.09–4.28 (m, 2 H), 4.33–4.39 (m, 2 H), 6.70–8.21 (series of m, total 12 H).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2-methyl-2-[(4-{2-[(4′-nitrobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]propionic acid tert-butyl ester (3.3 g) synthesized in Example 733-1 in dichloromethane (10 mL) was added trifluoroacetic acid (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. Thereto was added diisopropyl ether, and the resulting crystals were collected by filtration to give the title compound (2.4 g) as yellow crystals.