Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42](O)=[O:43])=[CH:35][CH:34]=1.[N:55]1[CH:60]=[CH:59][C:58]([CH2:61][NH2:62])=[CH:57][CH:56]=1.[C:63]([O-:66])(O)=[O:64].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:66][C:63]([C:51]([F:54])([F:53])[F:52])=[O:64].[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42]([NH:62][CH2:61][C:58]2[CH:59]=[CH:60][N:55]=[CH:56][CH:57]=2)=[O:43])=[CH:37][CH:38]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: NCc1ccncc1
Reactant: O=C([O-])O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NCc2ccncc2)cc1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (0.071 g, 0.18 mmol) and (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.062 g, 0.14 mmol) in DMF (5 mL) were stirred at RT for 45 min, then (4-pyridinylmethyl)amine (0.030 g, 0.28 mmol) was added. The solution was stirred at RT for 16 h, then saturated NaHCO3 solution (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with saturated NaHCO3 solution (50 mL), water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The crude material was partially dissolved in dichloromethane (10 mL) and diethyl ether was added (10 mL). The solid was filtered, washed with diethyl ether, and dried to give the title compound as an orange residue. The solid was dissolved in CH2Cl2 (5 mL) and trifluoroacetic acid (1 mL) was added. The solution was concentrated to dryness to give the title compound as a TFA salt. 1H NMR (400 MHz, DMSO) δ 8.80 (t, J=5.9 Hz, 1H), 8.71 (d, J=5.7 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.64 (d, J=5.9 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 6.54 (d, J=8.2 Hz, 2H), 4.47 (bs, 2H), 4.41 (s, 2H), 2.43 (s, 3H), 2.15-2.10 (m, 1H), 1.81-1.77 (m, 1H), 1.28-1.23 (m, 1H), 1.14-1.09 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[N:23]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:38])[N:24]=[N:25][C:26]=4[C:27]([F:30])([F:29])[F:28])=[CH:16][C:15]=3[CH3:39])=[CH:11][CH:12]=2)[N:7]([CH:40]([CH3:42])[CH3:41])[N:6]=1)=[O:4].C1COCC1.[Li+].[OH-].Cl>O.CO>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]4[CH:40]([CH3:41])[CH3:42])=[CH:12][CH:11]=3)=[C:15]([CH3:39])[CH:16]=2)=[C:26]([C:27]([F:28])([F:30])[F:29])[N:25]=[N:24]1
Reactant: COC(=O)c1nn(C(C)C)c2cc(-c3ccc(OCc4c(C(F)(F)F)nnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2c(C(F)(F)F)nnn2-c2c(Cl)cccc2Cl)ccc1-c1ccc2c(C(=O)O)nn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 6-{4-[3-(2,6-dichloro-phenyl)-5-trifluoromethyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-1-isopropyl-1H-indazole-3-carboxylic acid methyl ester (0.13 g, 0.21 mmol) in a 1:1:1 mixture of THF, methanol, water (4.5 mL) is added LiOH (0.09 g, 2.10 mmol). The reaction is stirred for 18 h at room temperature. The reaction is adjusted to pH 3 with 1N HCl and extracted with EtOAc to yield the title compound (0.12 g, 92%). LC-ES/MS m/e 602.0 (M−1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O)#[N:21].N1C=CC=CC=1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Reactant: N#Cc1ccccc1O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3C#N)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-cyanophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evaporated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (40%); mp: 181-183° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2].C(O)(=O)C.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:30][C:29]2[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](N)C[C@@H]1C)CCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
To a solution of cis-4-amino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 3) (0.35 g, 1.28 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added acetic acid (0.73 mL, 1.28 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (0.21 mL, 1.28 mmol) and sodium triacetoxyborohydride (0.406 g, 1.92 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was then diluted with chloroform and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10% ethyl acetate/hexanes as eluent afforded the title compound (approximately 300 mg). 1H NMR (CDCl3) δ1.1 (d, 3H), 1.3 (t, 3H), 2.6 (m, 1H), 3.6 (dd, 1H), 4.5 (m, 1H), 7.30 (s, 1H), 7.35 (s, 1H), 7.8 (s, 1H), 8.0 (s, 2H).
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:45][CH:46]([C:50]1[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=1)[CH:47]([CH3:49])[CH3:48]>CN(C=O)C>[C:1]12([C:11]([NH:45][CH:46]([C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)[CH:47]([CH3:48])[CH3:49])=[O:13])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CCOC(=O)c1ccc(C(N)C(C)C)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(NC(=O)C23CC4CC(CC(C4)C2)C3)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with 1-adamantylcarboxylic acid (0.031 g, 0.17 mmol) was added HATU (64.6 mg, 0.17 mmol), triethylamine (0.14 mL, 1.02 mmol) and DMF (1 mL). The solution was shaken at rt for 1 h then ethyl 4-(1-amino-2-methylpropyl)benzoate (0.038 g, 0.17 mmol) in DMF (1 mL) was added. The resulting mixture was shaken at rt for 16 h. Solvent was then evaporated. To the residue was added DCE (3 mL) and sat. NaHCO3 solution (1.5 mL). After separation, the aqueous layer was extracted with DCE twice. Combined organic layers were concentrated to give crude ethyl 4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate as a solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyridine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hoursafter which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL). The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3,81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[N:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 4-isocyanato-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 58a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid pyridine-4-ylamide as a white solid. (Yield 23 mg, 21.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:20]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCN(CC)c1ccc(B(O)O)cc1C(C)(C)C
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 40 °C
Yield: 15.8 %

Procedure:
To 5.6 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (17 mmol) are added 6.5 g of 3-tert-butyl-4-diethylaminophenylboronic acid (26 mmol) dissolved in 112 mL of toluene and 30.5 mL of 2M potassium carbonate (61 mmol). The reaction medium is stirred and heated to 40° C.; 2 g of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.74 mmol) are added and the medium is heated to 110° C. and stirred for 3 hours. The reaction is stopped by adding 200 mL of water and the medium is then extracted with 200 mL of ethyl acetate. The organic phases are washed with 400 mL of water and neutralized with 200 mL of saturated NH4Cl and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 9/1 heptane/ethyl acetate). 1.2 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=16%) in the form of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.CCOC(C)=O>[CH2:21]([N:20]([CH3:19])[C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCc1ccccc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a suspension of 2,4-dichloro-5-fluoropyrimidine (0.30 g, 1.80 mmol) in dioxane (3.6 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.23 g, 1.80 mmol) and N-methyl-1-phenylmethanamine (0.24 g, 1.98 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc (15 mL) and the resulting solution was washed with H2O (2×5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to a light yellow oil which was purified by flash chromatography (40 g SiO2, EtOAc/Hexanes gradient) to give a colorless oil which solidified upon cooling. The solid was dried under high vacuum at 23° C. for 16 h to give N-benzyl-2-chloro-5-fluoro-N-methylpyrimidin-4-amine (0.34 g, 76%) as a white solid: mp 47-49° C.; 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=6.4, 1H), 7.43-7.23 (m, 5H), 4.82 (s, 2H), 3.17 (d, J=3.3, 3H); MS (EI) m/z 251 (M)+.
Reaction SMILES: CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:18]([C:21]1[C:22]([C:29]([OH:31])=O)=[C:23]([CH3:28])[N:24]([CH3:27])[C:25]=1[CH3:26])(=[O:20])[CH3:19].C(Cl)CCl.[CH3:36][O:37][C:38](=[O:58])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:44][CH:43]=1)[NH2:40]>CN(C=O)C>[CH3:36][O:37][C:38](=[O:58])[C@H:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:46][CH:47]=1)[NH:40][C:29]([C:22]1[C:21]([C:18](=[O:20])[CH3:19])=[C:25]([CH3:26])[N:24]([CH3:27])[C:23]=1[CH3:28])=[O:31]
Reactant: CC(=O)c1c(C(=O)O)c(C)n(C)c1C
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C(C)=O)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
NMM (155 mg, 169 μl, 1.54 mmol), HOBT (227 mg, 1.68 mmol), 4-acetyl-1,2,5-trimethylpyrrole-3-carboxylic acid (300 mg, 1.54 mmol) and EDC (295 mg, 1.54 mmol) were added sequentially to a stirred solution of O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloric (546 mg, 1.40 mmol) in dry DMF (15 ml). The reaction was stirred at room temperature under N2 for 18 h. The solvent was removed in vacuo and the residue partitioned between EtOAc (50 ml), and 10%aqueous Na2CO3 (40 ml). The phases were separated and the queous phase extracted with EtOac (2×25 ml). The combined organic extracts were washed consecutively with 5% aqueous hydrochloric acid (20 ml), 10% aqueous Na2SO3 (20 ml) and brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained orange foam (0.6 g) was chromatographed (silica; 50% EtOAc/Hexane→100% EtOAc) affording the title compound as a white foam (380 mg, 51%); 'Hnmr (d6DMSO) 8.53 (1H, d, J 8Hz, NH), 7.57-7.43 (3H, m's, aryl-H), 7.22 (2H, d, J 8.5Hz), aryl-H), 6.95 (2H, d, J 8.5 Hz, aryl-H), 5.18 (2H, br s, CH2-O), 4.67 (1H, m, α-tyr-H), 3.66 (3H, s, Me-O), 3.34 (3H, s, Me-N), 3.12 (1H, dd, J 4.1, 13.8Hz, CHABBAr), 2.90 (1H, dd, J 11.3 13.8Hz, CH2HBAr), 2.32 (3H, s, MeCO), 2.0 (3H, s, pyrrole-Me) and 1.94 (3H, s, pyrrole-Me). m/z (ES+60V) 531 (MH+, 100 ), 533 (MH+, 75) 553( MNz+, 15%).
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:22]C1CC(=O)NC1=O>CN(C=O)C>[Br:22]/[CH:4]=[CH:5]/[C:6]1[C:7]([O:14][CH3:15])=[N:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1
Reactant: O=C1CC(Br)C(=O)N1
Reactant: COc1ncc(/C=C/C(=O)O)c(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(/C=C/Br)c(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of E-5-(2-carboxyvinyl)-2,4-dimethoxypyrimidine (0.300 g; 1.43 mmol) in dry DMF (5 ml) was added K2CO3 (0.45 g: 5.25 mmol). After stirring at ambient temperature for 15 min. a solution of N.-bromosuccinimide (0.258 g; 1.45 mmol) in dry DMF (4 ml) was added dropwise over 10 min. The suspension was immediately filtered, the solid washed with DMF and the filtrate evaporated in high vacuum. The solid residue was purified by column chromatography by preloading on SiO2 and eluting with EtOAc-hexane (7:3, v/v). Product fractions were pooled and evaporated to give fine white crystals, yield 0.561 g (45%). FAB mass spectrum: m/z245 and 247 (M+H)+. Analysis, found: C,39.9; H, 3.6; N, 11.5% C8H9BrN2O2 requires C, 40.20; H, 3.70; N. 11.43%.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:27][N:26]([CH:28]3[CH:33]4[CH2:34][CH2:35][CH2:36][CH:29]3[CH2:30][CH:31]([C:37]([OH:39])=O)[CH2:32]4)[C:25](=[O:40])[C:24]2([CH3:42])[CH3:41])=[N:19][CH:20]=1)#[N:14].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]2[CH2:27][N:26]([CH:28]3[CH:29]4[CH2:36][CH2:35][CH2:34][CH:33]3[CH2:32][CH:31]([C:37]([NH2:4])=[O:39])[CH2:30]4)[C:25](=[O:40])[C:24]2([CH3:41])[CH3:42])=[N:19][CH:20]=1)#[N:14]
Reactant: CC1(C)C(=O)N(C2C3CCCC2CC(C(=O)O)C3)CC1COc1ccc(C#N)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CCCC2CC(C(N)=O)C3)CC1COc1ccc(C#N)cn1
Reaction time: 1 h

Procedure:
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.35 g, 1.81 mmol) was added in one portion to a stirred solution of the product of Example 7F (0.50 g, 1.21 mmol), 1-hydroxybenzotriazole hydrate (0.32 g, 2.42 mmol), and diisopropylethyl amine (0.63 mL, 3.63 mmol) in dry dichloromethane (7 mL). The resulting solution was stirred at room temperature for two hours before ammonia solution (2.5 mL, 2 M in isopropanol, 4.8 mmol) was added. The resulting white suspension was stirred for one hour before it was diluted with dichloromethane (50 mL) and washed with 20% NaHSO4 solution, 1 M NaOH, water, and brine. The solution was then dried (Na2SO4), filtered, and evaporated. The residue was purified over silica gel using 1-10% methanol in dichloromethane to give the title product as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.08 (s, 3H) 1.24 (s, 3H) 1.32-1.51 (m, 2H) 1.50-2.14 (m, 8H) 2.17-2.59 (m, 3H) 2.57-2.75 (m, 1H) 3.27-3.45 (m, 1H) 3.64-3.83 (m, J=9.66, 7.63 Hz, 1H) 3.92 (s, 1H) 4.31-4.45 (m, 1H) 4.46-4.61 (m, 1H) 5.38 (s, 1H) 5.54 (s, 1H) 6.83 (dd, J=8.82, 0.68 Hz, 1H) 7.81 (dd, J=8.82, 2.37 Hz, 1H) 8.48 (dd, J=2.37, 0.68 Hz, 1H).). MS (ESI+) m/z 411.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([OH:20])[CH2:14]C(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:22][NH2:23].[CH2:24]([OH:26])C>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:13]([OH:20])[CH3:14])[C:24]([NH:22][NH2:23])=[O:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](O)CNC(=O)OCc1ccccc1
Reactant: CCO
Reactant: NN
Solvent: O
Product: CC(O)[C@H](NC(=O)OCc1ccccc1)C(=O)NN
Temperature: 5 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
In a 100 ml flask were charged 2.70 g (9.60 mmol) of the ethyl (S)-4-benzyloxycarbonylamino-3-hydroxybutyrate (optical purity: 94%e.e.) prepared in Reference Example 3, 40 ml of ethanol, and 2.40 g (48.0 mmol) of hydrazine monohydrate in a nitrogen stream, followed by heating under reflux for 20 hours. The reaction mixture was cooled to room temperature (22 to 24° C.), and ethanol was evaporated under reduced pressure. To the residue was added 30 ml of methanol and heat-refluxed to dissolve the crude crystals, followed by cooling to 5° C. After stirring for 1 hour for crystallization, the precipitated crystals were collected by filtration and washed with 10 ml of diethyl ether to afford 1.42 g (52%) of the title compound. Melting point: 135.4° C. Optical purity: >99.9%e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CS(=O)(=O)CCO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CS(=O)(=O)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[2-(methylsulfonyl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-(methylsulfonyl)ethyl alcohol following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C@H:21]([NH:25]C(OC(C)(C)C)=O)[C:22](O)=O.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:54]>C(Cl)Cl.O>[ClH:54].[ClH:54].[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:20]([C@@H:21]([NH2:25])[CH3:22])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 182.5 %

Procedure:
To a solution of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (1 g, 3.8 mmol), Boc-ala-OH (727 mg, 3.8 mmol) and HOAT (522 mg, 3.8 mmol) in DCM (20 mL) at 0° C. was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (810 mg, 4.2 mmol) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (20 mL, 4 M) and the reaction mixture heated at 75° C. for 45 min. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (1.48 g, 100%). LCMS (Method C): RT=1.95 min, [M+H]+=314.