Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1>>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH:7]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Clc1cccnc1Cl
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCNC(c2ncccc2Cl)C1
Yield: 70 %

Procedure:
Following the modus operandi described in Example 1, by reaction of 4-acetamidopiperidine with 2,3-dichloropyridine, 4-acetamido-2-(3-chloropyridyl)piperidine is obtained, with a yield of 70%, which, after crystallization in ethyl acetate, melts at 118° to 120° C. By hydrolysis of the product thus obtained with 6 N hydrochloride acid, the monohydrochloride of 4-amino-1-(3-chloropyridyl)piperidine (CM 57375) is obtained which is crystallised in 90% ethanol; m.p. 258° to 260° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.O.[NH2:26][NH2:27].CCOC(C)=O.CCCCCC>CCO>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:27][N:26]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(NCc3ccccc3)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(NCc2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To 4-{2-amino-6-[(phenylmethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (367 mg, 1.15 mmol) in EtOH (10 mL) was added hydrazine monohydrate (1.0 mL, 20.4 mmol) and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford crude product (280 mg). This material was dissolved in EtOH. Hexane was added until a precipitate began to form (a spatula was used to scratch the walls). The mixture was decanted and the solid was dried under vacuum to afford the title compound (150 mg, 39%) as a tan solid. LC-MS (ES) m/z=332 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 4.59 (s, 2H), 6.29 (s, 1H), 7.23 (m, 1H), 7.28-7.38 (m, 4H), 7.41 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.75 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[S:30]>C(#N)C>[NH2:12][C:8]1[C:9]([NH:11][C:29]([NH:28][C:22]2[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])=[S:30])=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH:7]=1
Reactant: CCOC(=O)c1cc(N)c(N)cc1OCC(F)(F)F
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(N)cc1OCC(F)(F)F

Procedure:
Prepared analogously to example 583h from ethyl-4,5-diamino-2-(2,2,2-trifluoro-ethoxy)-benzoate (synthesis described at example 575) and 2,6-dichloro-1-isothiocyanato-benzene in acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[CH:8]N(C)C)[C:5](=O)[CH3:6].Cl.[C:14]([NH:18][NH2:19])([CH3:17])([CH3:16])[CH3:15].C([O-])(=O)C.[Na+].ClCCl>C(O)C>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[N:19][N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=1[CH3:6])=[O:12]
Reactant: CC(C)(C)NN
Reactant: COC(=O)C(=CN(C)C)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 43.40 mmol) in absolute ethanol (70 mL) was treated with tert-butylhydrazine hydrochloride (5.52 g, 44.29 mmol) and sodium acetate (4.42 g, 53.88 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C. The reaction was poured onto ice using dichloromethane to assist the transfer (50 mL). The mixture was transferred to a separatory funnel at which time the layers were shaken and separated. The aqueous layer was further extracted with dichloromethane (1×50 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. ISCO CombiFlash (120 g column; 0-10% ethyl acetate/hexanes) afforded 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (6.04 g, 71%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:13]=2)[C:9](=[O:27])[C:8]([C:28]([O:30]CC)=[O:29])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([OH:26])=[O:25])=[CH:16][CH:17]=2)[C:9](=[O:27])[C:8]([C:28]([OH:30])=[O:29])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound is prepared from 2-butyl-3-(2'-carboxybiphen-4-yl)methyl-5-ethoxycarbonylpyrimidin-4(3H)-one similarly to that in Example 9 by ester hydrolysis. The t-butyl ester is hydrolyzed in neat trifluoroacetic acid to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1([O:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:18]([CH2:19][CH:20]=[CH:21][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCOc1ccccc1
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1C=CCOc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 14.6 %

Procedure:
To a solution of methyl 2-bromobenzoate (0.206 g, 0.96 mmol) in acetonitrile (3 ml) were added allyl phenyl ether (0.65 ml, 1.09 mmol), tri-o-tolylphosphine (0.014 g, 0.045 mmol), palladium acetate (0.006 g, 0.027 mmol) and triethylamine (0.16 ml, 1.15 mmol), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was filtered through celite, and ethyl acetate was added to the filtrate. The mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-phenoxypropenyl)benzoate (0.037 g, 0.14 mmol, yield 15%).
Reaction SMILES: [H-].[Na+].C(OC([N:10]1[CH2:15][C@@H:14]([CH3:16])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C@@H:11]1[CH:24]([OH:30])[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)=O)(C)(C)C.[Cl-].[NH4+]>C1COCC1>[C:20]([O:19][C:17]([N:13]1[CH2:12][C@H:11]([CH:24]([OH:30])[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[NH:10][CH2:15][C@H:14]1[CH3:16])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C(O)c2nccs2)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CN[C@@H](C(O)c2nccs2)CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 37.3 %

Procedure:
Sodium hydride (60% in mineral oil, 0.08 g, 1.9 mmol) was added to (2R,5R)-2-(hydroxy-thiazol-2-yl-methyl)-5-methyl-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.393 g, 0.95 mmol) in THF (4.8 mL) at 0° C. (ice bath) under nitrogen. The reaction was heated to 70° C. for 18 h. The reaction was cooled to room temperature and saturated aqueous ammonium chloride was added and the mixture extracted with EtOAc (3×). The combined organic extracts were dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.111 g) MS: [M+H]+=314.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1(C2C(O)=CC3N=C(C)SC=3C=2)C2C(=CC=CC=2)NC1=O>>[C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1
Agent: Cc1nc2cc(O)c(C3(O)C(=O)Nc4ccccc43)cc2s1
Product: Cc1nc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1

Procedure:
Following the procedure as described in PREPARATION 1B, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one to replace 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (87%) as a colorless solid: MS (ES+) m/z 447.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc2n(c1=O)[C@H](C(=O)O)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl ester 1h (11.13 g, 28.9 mmol) was dissloved in 1:1 CH2Cl2/TFA. 1 mL H2O was added and the mixture was stirred overnight at rt. The mixture was concentrated and the resultant residue was co-evaporated with CCl4 (3×). The residual oil was triturated with 1:1 Et2O/hexanes (100 mL) and the solid (9.0 g, 95%) was collected and dried, to provide 1i. 1H NMR (300 MHz, CDCl3) δ8.69 (br s, 1H), MS (ESI) 330.3 (M+H+); 328.3 (M−H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[C:20]([N:24]([CH3:33])[C:25](N1C=C[N+](C)=C1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:25](=[O:26])[N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:33])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)C(C)(C)C
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(C)(C)C

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(tert-Butyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to preparative HPLC (34%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 5.17 min.
Reaction SMILES: BrC1C=C(C)C=CC=1N(C)[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)CO>[Br:19][C:20]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:21]=1[NH:22][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Cc1ccc(N(C)c2nc(C)cc(C)n2)c(Br)c1
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: OCCO
Product: Cc1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Temperature: 25 °C

Procedure:
Part A: A mixture of the product from Example 1, Part A (2.01 g, 14.01 mmoles), 2-bromo-4-(1-methylethyl)aniline (3 g, 14.10 mmoles) in ethylene glycol (20 mL) was heated to reflux for 1.5 hours. Following cooling to room temperature and partitioning between ethyl acetate (200 mL) and aqueous sodium hydroxide (1 M, 50 mL), the organic layer was washed with brine, dried, and concentrated in vacuo. The residue was chromatographed on silica gel using 5% ethyl acetate in hexanes to give 2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine (3.28 g).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:34])[C:6](=O)[NH:7][C:8]1[C:9]([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28]2)=[C:10]2[CH:16]=[CH:15][N:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[N:12][CH:13]=1)(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][C@@H:5]([C:6]1[N:26]([CH:27]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28]2)[C:9]2=[C:10]3[CH:16]=[CH:15][N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:18])=[O:19])[C:11]3=[N:12][CH:13]=[C:8]2[N:7]=1)[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)c1nc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2n1C1CCCOC1
Yield: 65.9 %

Procedure:
A solution of (2R)-1-oxo-1-(1-(phenylsulfonyl)-4-(tetrahydro-2H-pyran-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)propan-2-yl acetate (830 mg, 1.7 mmol) in acetic acid (10 mL) was stirred at 105° C. for 5 h, then the reaction was cooled down and concentrated. Purification by flash chromatography (40 to 100% ethyl acetate in heptane) afforded 525 mg (66%) of (1R)-1-(6-(phenylsulfonyl)-1-(tetrahydro-2H-pyran-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl acetate. LCMS (Method E, ESI): RT=1.49 min, m+H=469.2; 1H NMR (400 MHz, CDCl3) δ 8.25-7.99 (m, 2H), 7.84 (s, 1H), 7.61-7.35 (m, 4H), 6.58 (d, J=4.2 Hz, 1H), 5.04 (t, J=12.8 Hz, 1H), 4.02-3.82 (m, 2H), 3.80-3.55 (m, 2H), 3.47 (dd, J=11.1, 6.1 Hz, 1H), 2.86 (s, 2H), 2.11-1.93 (m, 1H), 2.17 (s, 3H), 1.80 (dtd, J=14.6, 7.2, 3.7 Hz, 1H), 1.74-1.51 (m, 3H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[O:13]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)[CH2:14]1.ON1C2C=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[CH:49]=2)[CH:42]=[CH:43][C:44]=1[CH3:45]>CN(C=O)C.O>[CH3:45][C:44]1[CH:43]=[CH:42][C:41]([NH:46][C:47](=[O:60])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([N:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)[CH:49]=2)=[CH:40][C:39]=1[NH:38][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH:15]2[CH2:16][CH2:17][O:13][CH2:14]2)[CH:20]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(O)c1cccc(OC2CCOC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCOC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.165 g) was added to a stirred mixture of 3-(tetrahydrofuran-3-yloxy)benzoic acid (0.15 g), 1-hydroxybenzotriazole (0.146 g) and DMF (5 ml) which had been cooled to 0° C. The reaction mixture was stirred at 0° C. for 5 minutes and a solution of N-(3-amino-4-methylphenyl)-3-morpholinobenzamide (0.224 g) in DMF (1 ml) was added. The reaction mixture was allowed to come to ambient temperature and was stirred for 16 hours. The reaction mixture was poured into water and the resultant solid was isolated and purified by column chromatography on silica using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd6) 1.99 (m, 1H), 2.18 (s, 3H), 2.25 (m, 1H), 3.17 (t, 4H), 3.72 (t, 4H), 3.88 (m, 4H), 5.13 (m, 1H), 7.11 (m, 2H), 7.21 (d, 1H), 7.39 (m, 5H), 7.56 (m, 2H), 7.79 (m, 2H), 9.83 (s, 1H), 10.11 (s, 1H); Mass Spectrum: M+H+502.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C)C=O>[Si:15]([O:14][C@H:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:10]([O:12][CH3:13])=[O:11])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)c1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cc(Cl)cc(Cl)c1
Yield: 96.6 %

Procedure:
A solution of methyl (R)-2-(3,5-dichlorophenyl)-2-hydroxyethanoate (10.485 g), tert-butyidimethylsilyl chloride (8.07 g), and imidazole (3.64 g) in N,N-dimethylformamide (50 mL) was stirred under nitrogen for 18 h. Volatiles were then removed under vacuum and the residue was chromatographed on silica gel, eluting with hexanelethyl acetate (20:1) The title compound was obtained as a colorless oil (15.05 g).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]5[CH2:61][CH2:60][CH2:59][C@@H:58]5[C:62]([O:64]C)=[O:63])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:67]=[CH:66][C:37]([C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:55]=[C:54]4[C:50]([CH2:51][N:52]([C@@H:57]5[CH2:61][CH2:60][CH2:59][C@@H:58]5[C:62]([OH:64])=[O:63])[C:53]4=[O:56])=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@H]1CCC[C@H]1N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N([C@@H]2CCC[C@@H]2C(=O)O)C3)cc1)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
The compound of example 596 was prepared analogous to compound of example 98 by hydrolysis of compound of example 595.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20].[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)(Cl)Cl>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:23]([Cl:22])(=[O:25])=[O:24])[C:9]=2[CH3:16])[CH2:7][C:2](=[O:1])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Solvent: ClC(Cl)Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(=O)(=O)Cl)c2C)CC1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (1.8 g) in chloroform (20 ml) was stirred and cooled to 0° C. during the dropwise addition of chlorosulphonic acid (10 ml). The mixture was stirred for four hours at 20° C. and then poured into ice-water and the aqueous phase was extracted with chloroform (50 ml). The organic phase was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product 3-hydroxy-5-(2,4,6-trimethyl-3-chlorosulphonylphenyl)-2-propionylcyclohex-2-en-1-one was isolated as a brown oil (2.4 g, 97%). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.16 (3H, t); 2.47 (3H, s); 2.69 (3H, s); 2.80 (3H, s); 2.7-4.0 (7H, m); 7.05 (1H, s); 18.30 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].S([O-])(O)=O.[Na+].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:6]([CH3:7])[C:4](=[O:5])[C:3]3[C:2](=[C:11]([CH3:12])[CH:10]=[CH:9][CH:8]=3)[N:1]=2)=[CH:20][CH:21]=1
Reactant: CNC(=O)c1cccc(C)c1N
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Product: COc1ccc(-c2nc3c(C)cccc3c(=O)n2C)cc1
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
2-Amino-N,3-dimethylbenzamide (4.10 g, 25.0 mmol), sodium hydrogensulfite (2.93 g, 27.5 mmol) and para-anisaldehyde (3.4 g, 25 mmol) were mixed in N,N′-dimethylacetamide (20 ml), stirred at 150° C. for 5 hours, then cooled to room temperature, and distilled water (100 ml) was added thereto and stirred at that temperature for 1 hour. The precipitated solid was taken out through filtration, dried, and recrystallized from hot ethanol to obtain the intended compound (3.42 g, 49%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:27])[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[Cl:27][C:8]1[CH:9]=[C:10]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:2]([C:33]([OH:35])=[O:34])=[CH:3][N:4]=2)[N:7]=1
Reactant: O=C=O
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To an oven dried 25 ml shlenk flask under nitrogen was added 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.5 g, 1.1 mmol) from Example XXXI step (1a) and THF (5.0 ml). The solution was cooled to −78° C. and n-butyllithium was added drop-wise over 10 minutes. The reaction was allowed to stir at the depressed temperature for 1 hour. Carbon dioxide gas was then introduced via a needle purging the solution for 2 minutes. The reaction was allowed to warm to 25° C. and stir for an additional 30 minutes. Dilute 1N HCl was added taking the aqueous portion to pH=5. Ethyl acetate was added and the layers separated. The organic layer was washed with water (20 ml), then brine (10 ml), dried over Na2SO4, filtered and concentrated to provide 0.47 g of 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (98%). m/z=(410, M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:38])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][N:37]=2)=[CH:23][CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][C:31](=[O:38])[NH:32][C:33]2[NH:37][CH2:36][CH2:35][N:34]=2)=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCN1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
200 mg of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(3-(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)-propoxy)phenyl)propionate were dissolved in 5 ml of trifluoroacetic acid/water (95/5) and the solution was stirred at room temperature for 15 min. The reaction solution was then concentrated in vacuo. The residue was dissolved in water and the solution was freeze-dried. Yield: 100%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(Cl)c1

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.27 g), 3-chloroaniline (1.5 ml) and potassium carbonate (2.2 g) in 1,4-dioxane (30 ml) was refluxed for 20 hours. The insoluble materials were removed by filtration and the filtrate was concentrated. Silica gel column chromatography (chloroform-methanol, 50:1) afforded 2-(3-chlorophenylamino)-3-nitropyridine (404 mg) as an orange solid.