Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1C=CC2N(O)N=NC=2C=1.[NH:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:29]([C:31]([NH:33][C@H:34]([C:38](O)=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:38](=[O:39])[C@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:29]([CH3:30])[NH:28][C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42]
Reactant: OC(c1nc2ccccc2s1)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
36 (0.43 g, 1.23 mmol), HOBt (0.183 g, 1.35 mmol), WSCD (0.259 g, 1.35 mmol), Boc-Ala-Val-OH (0.35 g, 1.23 mmol), TEA (0.172 ml, 1.54 mmol)
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:18]2[C:13](=[C:14]([NH:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc3c(NC4CCN(C(=O)OC(C)(C)C)CC4)cccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(N)nccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of Intermediate 132 (270 mg) in 95% trifluoroacetic acid (5 ml) was stirred at 50° C. for 16 hours, and the solvent was evaporated under reduced pressure. The residue was added with dioxane (3 ml), 2 N aqueous sodium hydroxide (1 ml) and 2 di-t-butyl dicarbonate (393 mg) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:isopropylamine=5:5:1) to obtain the title compound (199 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:26]([CH:35]=[O:36])[CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:13](=[O:25])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[CH:35]([N:26]([CH:12]([C:13](=[O:25])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([OH:37])=[O:2])=[CH:7][CH:8]=1)[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:36]
Reactant: COC(=O)/C=C/c1ccc(C(C(=O)Nc2ccc(C(F)(F)F)cc2)N(C=O)CCN2CCOCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=CN(CCN1CCOCC1)C(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of (E)-3-{4-[[formyl-(2-morpholin-4-yl-ethyl)-amino]-(4-trifluoromethyl-phenylcarbamoyl)-methyl]-phenyl}-acrylic acid methyl ester (540 mg, 1.04 mmol) in THF (10 mL) was added aqueous 2M NaOH (3 ml) dropwise at 0 degrees Celcius, then this was stirred at room temperature overnight. The reaction was neutralized with dilute HCl solution, and the resulting precipitate filtered, and dried to obtain the desired product (216 mg, 41%). MS: calc'd 506 (MH+) exp 506 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=O.[Cl-].[NH4+]>O(CC)CC>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)[OH:17]
Reactant: CCOC(=O)CCCCBr
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 280 parts of 1-bromo-4-fluorobenzene, 34.6 parts of magnesium and 392 parts of 1,1'-oxybisethane, was added dropwise a solution of 116 parts of ethyl 5-bromopentanoate in 392 parts of 1,1'-oxybisethane. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was decomposed with a saturated ammonium chloride solution and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was triturated in hexane. The latter was decanted and the residue was crystallized from hexane. The product was filtered off and dried at room temperature, yielding 100 parts of α-(4-bromobutyl)-4-fluoro-α-(4-fluorophenyl)benzenemethanol; mp. 55° C. (int. 49).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[C-:36]#[N:37].[Na+].O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][C:36]#[N:37])=[CH:8][CH:7]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: [C-]#N
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(CC#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.000694 mol) and NaCN (0.00139 mol) in DMSO (3.5 ml) was stirred at room temperature for 2 hours, poured out into H2O, basified with K2CO3 (10%) and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.08 g (23%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzeneacetonitrile, as a white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.O>C1(C)C=CC=CC=1>[CH3:12][N:2]([CH3:1])[C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: CN(C)C(=O)Cc1ccccc1
Reactant: CN(C)CCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCC(C(=O)N(C)C)c1ccccc1
Yield: 76.8 %

Procedure:
To a mechanically-stirred, refluxing suspension of 5.85 g (0.15 mol) of NaNH2 in 150 ml of toluene, was added dropwise under N2, 50 ml of a toluene solution consisting of 16.3 g (0.1 mol) of N,N-dimethyl-phenylacetamide (prepared by reaction of phenylacetyl chloride and N,N-dimethylamine in CH2Cl2 solvent) in toluene, and the mixture was stirred at reflux for 4 hr. Then, 16.5 g (0.15 mol) of 2-(dimethylamino)ethyl chloride in 100 ml of toluene was added dropwise. The mixture was refluxed for 6 hr and then stirred at RT for 16 hr. Water (150 ml) was added to the mixture, and then the organic layer was separated and extracted with 1N HCl. The acid extract was basified in the cold with 2.5N NaOH and the basic solution extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and distilled to afford 18 g (76.8%) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide as a colorless oil, bp 108°-110°/0.2 mm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([NH:12][C:13]3[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])=[O:18])=[CH:15][C:14]=3[O:45][CH3:46])=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:47]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:47][N:1]1[C:9]2[C:4](=[C:5]([C:10]([NH:12][C:13]3[CH:44]=[CH:43][C:16]([C:17]([N:19]([CH3:42])[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=4[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])=[O:18])=[CH:15][C:14]=3[O:45][CH3:46])=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]ccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1ccn2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 4-[(indol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (160 mg) in N,N-dimethylformamide (3.0 ml) was added portionwise potassium tert-butoxide (37.3 mg) at 0° C. and the mixture was stirred at 0° C. for 1 hour. Methyl iodide (47.2 mg) was added to the mixture and the solution was stirred at 0° C. for 1 hour. The reaction was quenched with water and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; 2% methanol in chloroform) to give 4-[(1-methylindol-4-yl)-carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (65 mg) as a white syrup.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[C@@H:32]([CH2:40][CH3:41])[N:31]([CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[C:30]=4[N:29]=3)=[C:22]3[O:26][CH2:25][CH2:24][C:23]=23)=[O:17])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:42]1([N:31]2[C:30]3[N:29]=[C:28]([NH:27][C:21]4[CH:20]=[CH:19][C:18]([C:16]([NH:15][CH2:14][C@H:10]5[O:11][CH2:12][CH2:13][N:8]([CH3:1])[CH2:9]5)=[O:17])=[C:23]5[C:22]=4[O:26][CH2:25][CH2:24]5)[N:37]=[CH:36][C:35]=3[N:34]([CH3:38])[C:33](=[O:39])[C@H:32]2[CH2:40][CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H]4CN(Cc5ccccc5)CCO4)c4c3OCC4)nc2N1C1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H]4CN(C)CCO4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 8 h
Yield: 18.5 %

Procedure:
N-[[(2R)-4-Benzylmorpholin-2-yl]methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 15b (370 mg, 0.59 mmol) was dissolved in 30 mL of methanol. The reaction solution was hydrogenated with H-Cube (column of catalyst: 10% palladium/carbon; the pressure of hydrogen: 10 atmosphere; temperature: 40° C.) for 8 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[[(2R)-4-methylmorpholin-2-yl]methyl]-2,3-dihydrobenzofuran-4-carboxamide 15 (60 mg, yield: 18.5%) as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C@H:15]([OH:18])[CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)(OCC)[O:20]CC.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][C@@H:15]([CH2:16][OH:17])[O:18][C:19]3=[O:20])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)OCC
Reactant: OC[C@@H](O)CNc1ccc(C2CCCCC2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1O[C@H](CO)CN1c1ccc(C2CCCCC2)cc1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of 1.40 g (5.6 mmol) of (S)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol in 50 ml of toluene was treated with 0.73 g (6.2 mmol) of diethyl carbonate and 0.5 ml of a 1 molar sodium methylate solution and stirred overnight at an oil bath temperature of 110°. After distilling off the solvent the residue was treated with water and 5 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over magnesium sulfate and the solvent was distilled off. 1.35 g of (S)-3-(4-cyclohexylphenyl)-5-hydroxymethyl-oxazolidin-2-one were obtained in the form of colorless crystals from ethyl acetate/hexane. M.p.: 166°-168°. [α]D =+51.25° (c=0.8/CH3OH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][Cl:39])[C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][Cl:39])[C:34]([O:26][CH2:25][C:23]1[CH:22]=[CH:21][C:20]([N+:27]([O-:29])=[O:28])=[C:19]([CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:24]=1)=[O:35]
Reactant: O=C(Cl)N(CCCl)CCCl
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1cc(CO)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1cc(COC(=O)N(CCCl)CCCl)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Fex, et al., U.S. Pat. No. 3,299,104), tert-butyl(3R)-4-[5-[bis(2-chloroethyl)carbamoyloxymethyl]-2-nitro-phenyl]-3-(tert-butoxycarbonylamino)butanoate (20b) is prepared through carbamoylation of tert-butyl(3R)-3-(tert-butoxycarbonylamino)-4-[5-(hydroxymethyl)-2-nitro-phenyl]butanoate (20a) (731 mg, 2.0 mmol) with commercial N,N-bis(2-chloroethyl)carbamoyl chloride (439 μL, 614 mg, 3.0 mmol) in anhydrous pyridine (15 mL) at about 0° C. The reaction mixture is stirred with gradual warming to room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Excess of the carbamoyl chloride is destroyed with crushed ice. Aqueous work-up followed by purification through silica gel column chromatography afford the title compound (20b).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[NH2:13][C:14]1[CH:28]=[C:27]([Cl:29])[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:16]([Cl:30])[CH:15]=1>C(#N)C>[Cl:29][C:27]1[CH:28]=[C:14]([NH:13][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:8])[CH:15]=[C:16]([Cl:30])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Solvent: CC#N
Product: O=C(O)CCCCCOc1c(Cl)cc(NC(=O)NC(=O)c2ccccc2Cl)cc1Cl
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 7.5 g (41.1 mmol) of 2-chlorobenzoyl isocyanate in 300 ml of acetonitrile was added to a suspension of 10.0 g (34.2 mmol) of 6-(4-amino-2,6-dichlorophenoxy)hexanoic acid in 700 ml of dry acetonitrile under a protective gas atmosphere at room temperature. The mixture was boiled under reflux for 2 hours and cooled to room temperature. The resulting precipitate was filtered off with suction and washed with 50 ml of acetonitrile. The residue was stirred with 100 ml of methanol, filtered off with suction, washed with a little methanol and dried at 40° C. under vacuum overnight. 13.7 g (28.9 mmol, 85%) of the required product were obtained. Melting point: about 171-173° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[CH3:11][C:3]1[C:2]([C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: Cc1c(Br)ccc2[nH]ncc12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Product: Cc1c(C(=O)O)ccc2[nH]ncc12

Procedure:
This compound was prepared in a manner similar to the preparation of 88 using commercially available 4-bromo-2,3-dimethylaniline as starting material. After an acylation step, N-(4-bromo-2,3-dimethylphenyl)acetamide was treated with isoamyl nitrite, then 10% aqueous HCl to yield 5-bromo-4-methyl-1H-indazole. 5-bromo-4-methyl-1H-indazole was treated with t-butyl lithium and carbon dioxide to yield 4-methyl-1H-indazole-5-carboxylic acid, which in turn was treated with thiosemicarbazide and polyphorsphoric acid to form 5-(4-methyl-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 232 (100%, M++1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH2:73])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]>>[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH:73][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
HATU (328 mg, 862 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (154 mg, 862 μmol) in DMF (1.5 mL, 19.5 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. DIPEA (0.3 mL, 1.7 mmol) was added to the mixture, followed by (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (200 mg, 575 μmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography (35-80% MeCN in water with 0.05% TFA) to yield the title compound (197 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:26][O:25][C:23](=[O:24])[C:22]([C:21]1[N:18]=[C:9]([C:10]2[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=2[Cl:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH:20]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)C(C)(C)C(=O)CBr
Reactant: N=C(Nc1ccc(Br)cc1)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C(C)(C)c1cn(-c2ccc(Br)cc2)c(-c2c(Cl)cccc2Cl)n1
Temperature: 170 °C
Yield: 57 %

Procedure:
A mixture of N-(4-bromophenyl)-2,6-dichlorobenzamidine (1.03 g, 3.0 mmol), methyl 4-bromo-2,2-dimethylacetoacetate (1.78 g, 8.0 mmol) and NaHCO3 (0.76 g, 9.0 mmol) in isopropanol (12 mL) was heated in a microwave unit (Biotage Initiator™) at 170° C. for 25 min. The resulting mixture was decanted and the solids rinsed with EtOAc. The combined filtrates were concentrated and purified by chromatography (silica, EtOAc/Hex, 15:85 to 50:50) to give the title compound (0.80 g, 57%) as a pale yellow solid. 1H-NMR (DCM-d2): δ 7.44 (d, 2H), 7.27-7.34 (m, 3H), 7.09 (m, 2-1), 3.67 (s, 3H), 1.61 (s, 6H); MS (ES): 467, 469, 471 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[NH:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=[O:8])[NH:3]1
Reactant: CCOC(=O)c1noc(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
To a solution of crude ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (2.4 g, 15.14 mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL, 4 mmol) at room temperature. After stirring for 5 hours at room temperature the reaction is quenched with 1N HCl (5 mL, 5 mmol), the crude is concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (1.9 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN(C=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 20.5 %

Procedure:
A mixture of 2,5-dichlorobenzonitrile (Lancaster; 2.994 g), piperazine (Aldrich; 7.616 g), and DMF (10 mL) is stirred for 4.5 h at 100° C. After cooling, the DMF is removed under reduced pressure and the residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate. The organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (8/92) and the appropriate fractions are combined and concentrated to give 0.79 g of 5-chloro-2-(piperazin-1-yl)benzonitrile; MS m/z 221; IR (mineral oil) 1489, 802, 829, 2223, 845 cm-1, 1H NMR (CDCl3) δ 3.09, 3.18, 6.94, 7.43, 7.52.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21](I)[CH3:22]>>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:21][CH3:22])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCI
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 77 %

Procedure:
This material was prepared following the procedure of Example 4 in 77% yield from product of Example 2 and ethyl iodide as a white solid; mp 57°-59° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[CH:8]=[C:7](Cl)[N:6]=1>ClCCCl>[Cl:4][C:5]1[N:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:10]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
While stirring and within a period of 1 1/2 hours at 0° to 5° C., 293.1 g (1.692 mol) of a 30% strength sodium methylate solution was added to a solution of 434 g (1.692 mol) of 2,6-dichloro-4-trichloromethylpyrimidine in 1 liter of 1,2-dichloroethane. The mixture was stirred for 1 hour at 0° to 5° C. and for 12 hours at 25° C. The reaction mixture was then extracted with water and saturated sodium chloride solution. After drying over magnesium sulfate and evaporating down, there was obtained 423 g (95% of theory) of the title compound as an almost colorless oil of nD23 =1.5552. 1H-NMR (CDCl3) (ppm) OCH3 (s/3H) 4.1; CH (s/1H) 7.25.