Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:36]1([C@H:42]([CH2:44][OH:45])[NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[OH:45][CH2:44][C@H:42]([NH:43][C:4](=[O:6])[CH:3]=[CH:2][C:1]([O:8][CH3:9])=[O:7])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: N[C@@H](CO)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C=CC(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of monomethyl fumarate (3.0 g, 23 mmol) in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added (R)-α-phenylglycinol (3.0 g, 22 mmol) and stirring continued for 20 minutes. The volatiles were removed in vacuo (40° C.) and the residue purified by flash chromatography on normal phase silica gel using hexane:ethyl acetate (1:1) as eluant. Recovered 2.5 g (46%) of (18) as a white solid, m.p. 75°-77° C.; IR (neat) 3250 (OH), 1729 (C=O ester), 1666 (C=O amide), 1640 (C=C)cm-1 ; NMR (CDCl3) δ 7.3-7.4 (5H, m, Ph), 7.0 (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, br d, NH), 5.2 (1H, m, CH), 3.9 (2H, t, J 3 Hz, CH2), 3.8 (3H, s, CH3), 2.3 (1H, t, J 5 Hz, OH); [α]D -53° (CHCl3, 24° C., c=1); anal C13H15NO4 ; requires C 62.64% H 6.07% N 5.62%; found C 62.72% H 5.92% N 5.48%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:38]=[C:37]([C:39]([N:41]2[CH2:50][C:49]3[CH:48]=[N:47][N:46]([CH3:51])[C:45]=3[NH:44][C:43]3[CH:52]=[CH:53][CH:54]=[CH:55][C:42]2=3)=[O:40])[CH:36]=[CH:35][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33].Cl.Cl.[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:58][C:59]([CH3:69])([CH3:68])[CH2:60][CH2:61][N:62]1[CH2:63][CH2:64][N:65]([C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:35]=[CH:36][C:37]([C:39]([N:41]3[CH2:50][C:49]4[CH:48]=[N:47][N:46]([CH3:51])[C:45]=4[NH:44][C:43]4[CH:52]=[CH:53][CH:54]=[CH:55][C:42]3=4)=[O:40])=[CH:38][C:26]=2[CH3:25])[CH2:66][CH2:67]1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
HBTU (101 mg, 0.27 mmol) was added to a solution of 4-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-butyric acid from E76.2 (71 mg, 0.17 mmol) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (54 mg, 0.22 mmol) in dichloromethane (10 ml) and DIEA (0.15 ml, 0.86 mmol). The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 6% methanol:94% dichloromethane) to give a white powder identified as the title compound (52 mg, 53%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:25]=[O:26])=[C:20](B(O)O)[CH:21]=1>COCCOC.O.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([CH:25]=[O:26])=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
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: O
Solvent: COCCOC
Product: O=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
A solution of 1,4-dibromobenzene (8.3 g, 35.3 mmol), potassium carbonate (11.3 g, 81 mmol) and 5-chloro-2-formylphenylboronic acid (5 g, 27.1 mmol) in DME (150 mL) and water (30 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(PPh3)4 (0.94 g, 0.814 mmol) was added and the reaction heated to 80° C. overnight. The reaction was cooled to r.t. and evaporated on the rotovap. The residue was diluted in EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (0-15% EtOAc:Hex) to give 4′-bromo-5-chlorobiphenyl-2-carbaldehyde (4.17 g, 14.11 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.28 (m, 2H) 7.42 (d, J=2.01 Hz, 1H) 7.50 (ddd, J=8.41, 2.01, 0.88 Hz, 1H) 7.59-7.69 (m, 2H) 7.98 (d, J=8.53 Hz, 1H) 9.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:10]([CH:17]([CH3:19])[CH3:18])[NH:11]2.Cl[CH:35]([F:37])[F:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:35]([F:37])[F:36])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12
Reactant: FC(F)Cl
Product: COC(=O)COc1ccc(F)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(OC(F)F)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-fluoro-2-isopropyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=2)/[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)=[N:12][N:11]=[C:9]12)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCn1/c(=N/NC(=O)CCCc2nc(-c3ccccc3)no2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCc3nc(-c4ccccc4)no3)nnc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
The mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanohydrazide (2.78 g, 6.17 mmol) in toluene (100 ml) was refluxed for 2 hours. After cooling to room temperature, the solid was filtered, washed with ethyl acetate/Hexane (1:9) and dried to give the desired product (1.97 g, 74% yield). LCMS calculated for C22H25N8O2 (M+H): 433.2; found: 433.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:23])([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:28].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:22])([CH3:23])[C:19]([NH2:28])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)F
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(N)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoyl fluoride (1.65 g, 4.23 mmol) in anhydrous THF (30 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 1.62 g (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.O.[OH-].[Li+].O.Cl>C1COCC1.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1csc(-c2c(F)cccc2F)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate (1.72 g, 6.39 mmol) in THF (40.0 mL), lithium hydroxide monohydrate (1.51 g, 36.0 mmol) was added followed by water (10.0 mL). The mixture was stirred at 60° C. for 5 h. The reaction mixture was then cooled to 0° C., and 6 M HCl was added slowly until the pH reached 2. The mixture was diluted with EtOAc (250 mL), washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-30% MeOH in DCM) to give the title compound as a white solid (1.49 g, 97%). LCMS calc. for C10H6F2NO2S (M+H)+: m/z=242.0. found 242.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]1[CH3:29]>COCCOC>[CH3:29][C:24]1[N:23]([CH2:22][CH2:21][NH:20][C:5](=[O:7])[CH2:4][N:2]([CH3:3])[CH3:1])[C:27]([CH3:28])=[CH:26][CH:25]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: CN(C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COCCOC
Product: Cc1ccc(C)n1CCNC(=O)CN(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.2 g (0.05 mol) of N,N-dimethylaminoacetic acid and 8.1 g (0.05 mol) of carbonyldiimidazole in 20 ml of ethylene glycol dimethyl ether are stirred at 70° C. for 15 min. After addition of 5.5 g (0.04 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole, dissolved in 20 ml of ethylene glycol dimethyl ether, to the mixture it is stirred at room temperature for 5 h, then concentrated, water is added, and the mixture is extracted first when acid and then when alkaline. The product contained in the extract from the mixture which has been made alkaline is crystallized using ligroin. Yield: 4.3 g (39% of theory), Melting point: 63°-65° C. Elemental analysis: C12H21N3O (223.32) calculated: C 64.5 H 9.5 N 18.8 O 7.2 found: C 64.0 H 9.4 N 18.5 O 8.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:28]3[CH2:29][CH:30]([CH3:32])[CH2:31][CH:26]([CH3:25])[CH2:27]3)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: CC1CNCC(C)C1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Product: CC1CC(C)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Yield: 43 %

Procedure:
The condensation of with 1-(2′,4′-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 3,5-dimethylpiperidine in a similar manner as described in example 1 gave the titled product. Yield 43%, m.p 224–26° C., C23H21F3N2O3, m/z 431. (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:26][CH2:25][C:22]([C:27]([OH:29])=[O:28])([CH2:23][CH2:24]4)[CH2:21][CH2:20]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][CH:3]=1.[OH-].[Na+].[I:37]I>O.C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:20][CH2:21][C:22]([C:27]([OH:29])=[O:28])([CH2:25][CH2:26]4)[CH2:23][CH2:24]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][C:3]=1[I:37]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)cc2)c1=O
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)c(I)c2)c1=O
Yield: 18.9 %

Procedure:
To a solution of 50 mg 4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylic acid (Example 27a) (0.107 mmol) in water (10 ml) containing 1 eq. of 1N NaOH (110 μL) was added at rt a solution of 30 mg of iodine (0.107 mmol) in ethanol (1 ml). The reaction mixture was concentrated in vacuo and the crude product purified by preparative chromatography to afford 12 mg (20%) of desired product (MH+=592.89).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[CH3:12].C([O:16][C:17]([C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C@H:20]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1)=O)C>ClC(Cl)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C@H:20]2[C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:36][CH:35]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC2CCCC2)cc1
Reactant: Cc1ccc(N)cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1ccc(NC(=O)[C@H]2CCCN(C(=O)c3ccccc3C)[C@H]2c2ccc(NC3CCCC3)cc2)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Me3Al (290 μL, 0.57 mmol, 2M in toluene) was added to a solution of the 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 mL) at ambient temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) dissolved in dry dichloroethane (1 mL) was added to it. The reaction mixture was then heated to 85° C. for 3 h, cooled to r.t, diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic layer was dried (MgSO4) and concentrated. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O with 0.1% TFA as additive), the product containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to get the pure (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide in 50% yield.
Reaction SMILES: [N:1]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH:2]1[C:14]([O:16][CH3:17])=[O:15].C[Si](C)(C)N[Si](C)(C)C.[K].FC(F)(F)S(O[CH2:44][CH3:45])(=O)=O>C1COCC1>[CH2:44]([C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH2:5][CH2:6][N:1]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH3:45]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
Following the procedure according to WO 2005/079799 (the disclosure of which is hereby incorporated by reference with respect to this synthesis), 1-benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (II-JJ, 1.1 g, 2.9 mmol) was dissolved in 6 mL of dry THF and cooled to −78° C. Potassium hexamethyldisilazane (0.5M solution in toluene, Aldrich, 10 mL, 5.0 mmol) was added by syringe, and the reaction mixture stirred at −78° C. for 75 min. Ethyl trifluoromethanesulfonate (0.65 mL, 5.0 mmol) was added dropwise by syringe to this mixture, and then the reaction was allowed to warm to rt for 5 h. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organics were dried with MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (0-10% methanol/DCM gradient elution) gave 1-Benzyl 4-tert-butyl 2-methyl 2-ethylpiperazine-1,2,4-tricarboxylate (compound III-JJ) as a yellow oil, approximately 5:1 ratio of methyl and ethyl esters (1.06 g): LCMS: [M+Na]+=429.2 (60%); [M-Boc+H]+=307.1 (100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([O:19]C)=O)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:7]=1.O.[NH2:22][NH2:23].C(Cl)(Cl)Cl>CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]([NH:22][NH2:23])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cnc(C)cn2)s1
Reactant: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cnc(CNC(=O)c2ccc(C(=O)NN)s2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Methyl 5-(5-methylpyrazin-2-ylmethylcarbamoyl)thiophene-2-carboxylate (304 mg, 1.04 mmol) in methanol (3 mL) was stirred with hydrazine monohydrate at 60° C. for 12 hours. After addition of chloroform, it was stirred at room temperature for 5 hours. The precipitated solid was recovered by filtration to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid (5-methylpyrazin-2-ylmethyl)amide (yield 72%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])O[C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+:27]=[N-:28])[CH:17]=2)=[CH:3]1.[OH-].[NH4+:32]>CN(C=O)C.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:32][C:14](=[O:29])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]=[N+:27]=[N-:28])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)OC2=O)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cccc(OCCCN=[N+]=[N-])c3)C(=O)NC2=O)c2ccccc21
Temperature: 140 °C

Procedure:
To a solution of 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]furan-2,5-dione (1.0 g) in DMF (7 mL) was added and ammonium hydroxide (50 mL). The reaction mixture was heated at 140° C. for 3.5 h, then cooled to room temperature and diluted with water. The precipitates were filtered and dried to give 3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione (0.58 g). MS (EI): M+ 401.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:8]([O:10]C)=[O:9].N.Cl>O.C(OCC)(=O)C>[NH2:1][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[N:4]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: N#CBr
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of cyanogen bromide (5.0 mL, 5 M in acetonitrile, 25 mmol) was added to a mixture of methyl 3,4-diaminobenzoate (3.0 g, 18 mmol) in water (50 mL). The reaction was stirred at room temperature overnight. Aqueous ammonia (20 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the layers were separated. The organics were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added 2 N aqueous hydrochloric acid (18 mL, 36.0 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to give the title compound (2.90 g, 97%). 1H NMR (400 MHz, DMSO-d6, δ): 8.75 (s, 2H), 7.84 (s, 1H), 7.77 (dd, J=1.2, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][C@H:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:11]([CH3:23])[CH2:10]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:26]=O.C[O-].[Na+]>>[CH3:23][C@@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:26])=[CH:3][CH:4]=2)[CH2:14][C@H:13]([CH3:15])[N:12]1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: C=O
Reactant: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2R,6S)-4-[(4-aminophenyl)methyl]-2,6-dimethyl-1-piperazinecarboxylate (D28) using a method similar to that described for D23 in Description 23A although the reaction was heated at 50° C. for 48 h prior to addition of sodium borohydride then for 1 h after addition. Further paraformaldehyde (1 eq) and sodium methoxide (1 eq) were added; the reaction was heated at 50° C. for 12 h; further sodium borohydride (1 eq) was added and the reaction heated at 50° C. for 1 h. δH (CDCl3, 400 MHz) 7.16 (2H, d), 6.57 (2H, d), 4.05 (2H, m), 3.70 (1H, br s), 3.36 (2H, s), 2.82 (3H, s), 2.59 (2H, d), 2.06 (2H, dd), 1.49 (9H, s), 1.27 (6H, d). MS (ES): 356.3, (MNa+), 234.3, no molecular ion (MH+) observed.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:25](O)[CH3:26]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15])=[C:11]([Cl:17])[N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of ethanol was dissolved 6.53 g of 1-benzyl-2-phenyl-4-chloroimidazole-5-acetic acid and under ice-cooling, hydrogen chloride was introduced until saturation. The solution was further stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and the concentrate was run onto a column of 200 g silica gel, elution being carried out with benzene-chloroform (1:1). By the above procedure was obtained 2.28 g of 1-benzyl-2-phenyl-4-chloro-5-ethoxycarbonylmethylimidazole as crude crystals, which were then recrystallized from diethyl ether-hexane. Colorless needles, m.p. 72°-73° C.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])C1C=CC=CC=1C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:29]([F:39])([F:38])[F:28])[O:6][C:7]=1[CH3:8]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccccc2C(F)(F)F)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyl-oxazole, diacetylmonoxime and 2-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(2-trifluoromethylphenyl)oxazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=[O:8])[CH3:2].ClC1C=C(C=C(Cl)N=1)C(O)=[O:21].N1CCOCC1>>[CH3:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N:3]2[CH2:1][CH2:2][O:21][CH2:15][CH2:14]2)[N:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: C1COCCN1
Product: Cc1cc(C(=O)O)cc(N2CCOCC2)n1

Procedure:
The title compound is prepared in analogy to 2-diethylamino-6-methyl-isonicotinic acid starting from 2,6-dichloro-isonicotinic acid and morpholine; LC-MS: tR=0.47 min, [M+1]+=223.08.