Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CS(C)=O>[C:23]1([C:19]2[CH:18]=[C:17]([C:10]3[N:9]=[C:8]([NH:29][C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][N:34]=[CH:33]5)[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)[CH:6]=4)[N:11]=3)[CH:22]=[CH:21][CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Temperature: 85 °C
Reaction time: 4 h
Yield: 187.5 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.040 mmole) in DMSO (2 mL) was added pyrrolidine (0.143 g, 0.16 mL, 2.00 mmole) and the reaction was stirred at 85° C. for 4 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH) to give 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (0.042 g, 0.075 mmole, 19%). MS 557 (M+1). HPLC retention time 5.34 mins.
Reaction SMILES: [O:1]([CH2:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([O:31]C)=[O:30])[C:22]=2[N:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-].[Li+]>N1C=CC=CC=1>[O:1]([CH2:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([OH:31])=[O:30])[C:22]=2[N:21]=1)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCc1nc2c(C(=O)O)cccc2[nH]1)(c1ccccc1)c1ccccc1
Yield: 87.8 %

Procedure:
To a solution of methyl 2-tert-butyldiphenylsiloxymethyl-1H-benzimidazole-4-carboxylate (500 mg) in pyridine (3 ml) was added lithium iodide (602 mg) under nitrogen at ambient temperature and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with water and brine and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (chloroform only˜50:1˜25:1˜10:1) to give 2-tert-butyldiphenylsiloxymethyl-1H-benzimidazole-4-carboxylic acid (425 mg) as a powder.
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>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.CN(C=O)C>[C:22]([O:21][C:19]([NH:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([CH3:26])[C:2]([CH:27]=[CH2:28])=[CH:17][CH:16]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Temperature: 90 °C

Procedure:
A mixture of Example 126A (1.4 g, 3.3 mmol), DMF (33 mL) and tributyl(vinyl)tin (1.1 mL, 3.8 mmol) was degassed with argon 30 minutes, treated with Pd(PPh3)4 (577 mg, 0.5 mmol), heated to 90° C. for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel (200 g) with 50% dichloromethane/hexanes to provide the desired product. MS (ESI(+)) m/e 368 (M+H)+; (ESI(−)) m/e 366 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.54 (d, 1H), 7.45 (m, 2H), 7.37 (m, 3H), 7.27 (d, 1H), 6.94 (dd, 1H), 5.64 (dd, 1H), 5.31 (dd, 1H), 5.27 (s, 2H), 2.21 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.C([O:16][C:17](=O)[CH2:18][CH:19]1[CH2:24][CH2:23][C:22]([N:31]([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:33][N:31]([CH3:32])[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:24][CH:19]([CH2:18][C:17]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([F:6])=[CH:8][CH:9]=2)=[O:16])[CH2:20][CH2:21]1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Reactant: Nc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 11.9 ml; 19 mmol) was added dropwise at 0° C. to a solution of 4-fluoroaniline (1.06 g; 9.5 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (2.5 g; 8.6 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was taken up in ether. A solid then remained (less polar diastereoisomer; 1.37 g; 45%); the supernatant was chromatographed on silica gel (eluent:ether). 315 mg (10%) of the more polar diastereoisomer were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([N:27]([CH3:44])[C:28]([NH:30][CH:31]4[C:36]([Cl:38])(C)[C:35]([O:39][CH3:40])=[CH:34][C:33]([O:41][CH3:42])=[C:32]4[Cl:43])=[O:29])[CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>[Pd].CO>[Cl:38][C:36]1[C:35]([O:39][CH3:40])=[CH:34][C:33]([O:41][CH3:42])=[C:32]([Cl:43])[C:31]=1[NH:30][C:28](=[O:29])[N:27]([CH3:44])[C:23]1[CH:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[N:26]=[CH:25][N:24]=1
Reactant: COC1=CC(OC)=C(Cl)C(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(Cc5ccccc5)CC4)cc3)ncn2)C1(C)Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCNCC4)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of 1-{6-[4-(4-benzyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-3-(2,6-dichloro-3,5-dimethoxy-6-methyl-phenyl)-1-methyl-urea (100 mg, 0.161 mmol) (Example 13), palladium on carbon (30 mg), MeOH (6 mL), and HCl (37%, 16 μL) is stirred for 5 days at RT, under a hydrogen atmosphere. The reaction mixture is filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/2N NH3 in MeOH, 95:5) affords the title compound as a beige solid: ESI-MS: 532.0/534.0 [MH]+; tR=3.39 min. (purity: 100%, system 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[H-].[Na+].[Cl-].[NH4+].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH:2]3[CH2:3][CH2:4][C:5](=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[CH2:6][CH2:10]3)[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: CCCc1nc(SC2CCC(=CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.25 h

Procedure:
1.1 g of the product obtained in Stage 6 of Example 1 is introduced, 127 mg of a suspension of sodium hydride at 50% in oil is added and the reaction medium is left under agitation for 15 minutes at ambient temperature. Then 657 mg of the product obtained in Stage 1 of Preparation 1 is added and the reaction medium is left under agitation for 24 hours at ambient temperature, followed by hydrolysis with a saturated solution of ammonium chloride and extraction with ethyl acetate and after chromatography, 880 mg of the expected product (amorphous solid) is obtained.
Reaction SMILES: C([NH:4][C:5]1(C(OCC)=O)[CH2:9][CH:8]2[CH2:10][CH2:11][CH2:12][CH:13]=[C:7]2[S:6]1)(=O)C.[C:19]([O:29][CH2:30][CH3:31])(=[O:28])C=CC1C=CC=CC=1.N1CCCC1>[Pd].C1(C)C=C(C)C=C(C)C=1>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:19]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)C1(NC(C)=O)CC2CCCC=C2S1
Agent: [Pd]
Solvent: C1CCNC1
Solvent: Cc1cc(C)cc(C)c1
Product: CCOC(=O)c1c(N)sc2ccccc12
Reaction time: 21 h
Yield: 64 %

Procedure:
2 g of palladium catalyst (5% Pd/C, approx. 50% moisture content; Degussa-Hüls; E 101 RW 5%) are added to a solution of 10 g of ethyl 2-acetylaminotetrahydrobenzothiophenecarboxylate in 80 ml of mesitylene and the mixture is heated to 170° under nitrogen. 2 g of ethyl cinnamate are metered in over 30 min and stirring is continued for 21 h. The temperature is then lowered to 100° and 10 ml of pyrrolidine are added. The reaction mixture is stirred for 25 h under nitrogen. The catalyst is then filtered off and rinsed with 60 g of ethanol. The solutions are combined and the solvent is distilled off. The residue is taken up in ethyl acetate and washed twice with 1 N HCl and once with water. After distillation of the solvent and subsequent crystallization from 2-propanol, ethyl 2-aminobenzo[b]thiophene-3-carboxylate is obtained with a yield of 64%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([O:26]CC)=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24]([OH:26])=[O:25])[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
A mixture of ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylate (385 mg, 1 mmol) and NaOH (2M) (5 mL) in EtOH (15 mL) and THF (15 mL) was stirred at 60° C. for 5 h. The mixture was concentrated to a residue, to which was added aq.sat. citric acid (10 mL). The solution was extracted with EA (25 ml×2), separated, dried, filtered and concentrated to yield 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)isoquinoline-3-carboxylic acid (303 mg, 85%) as a light yellow solid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CO.COCCOC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[NH:3][C:4](=[O:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: O=C(c1ccc(F)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
In methanol (65.7 ml) was suspended 2-mercapto-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-one (2.51 g) followed by addition of 1N-sodium hydroxide (15.75 ml) for dissolution. Then, a solution of 4-(4-fluorobenzoyl)benzyl bromide (5.06 g) in DME (15 ml) was added dropwise with ice-cooling. Then, the mixture was stirred at room temperature overnight. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; ethyl acetate: hexane=1:4-1:1-ethyl acetate) to provide the title compound (2.43 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[C:9]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:16]([SH:18])=[S:17])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[C:16]([S:18][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[S:17])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reactant: C=Cc1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)SCCc2ccncc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 6.6 g (0.062 mol) 4-vinylpyridine and 14.1 g (0.05 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid in 50 ml toluene was refluxed for 6 hours. On cooling, the product (via anti-Markovnikov addition) crystallized from the reaction mixture. After recrystallization from chloroform, the product melted at 191°-193° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (33 mg, 28%). MS (ISN) 461.0 [(M−H)−]; mp 214-215° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])(=[O:4])=[O:3].Cl.[N:16]([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([NH:12][NH2:16])[C:9]([F:13])=[CH:8][C:7]=1[Cl:14])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cc(N)c(F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-5-aminophenyl methanesulfonate (24.0 g), 35% hydrochloric acid (63 g) and water (48 ml) was stirred at 60° C. for 30 minutes. Then, a solution of sodium nitrite (9.1 g) in water (55 ml) was added dropwise to the resulting mixture at -20° C. to effect diazotization reaction. The resulting mixture was added under stirring to a preformed and cooled (-20° C.) solution of 35% hydrochloric acid (52 ml) and stannous chloride hydrate (58 g) in water (100 ml) and the stirring was continued for 30 minutes under cooling. Then, the reaction solution was brought to room temperature and the pH of the solution was adjusted to 8.0 with an aqueous sodium hydroxide solution. Then, the reaction solution was extracted with toluene and tetrahydrofuran and the extract was washed with water, dried over anhydrous sodium sulfate and subjected to distillation under a reduced pressure to remove the solvent used, affording the titled compound (21.9 g) of the formula: ##STR54## as yellow crystals. Recrystallization from cyclohexane gave pale yellow crystals having melting point 75°-77° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.N>C(O)C.[Pd]>[CH3:17][C:4]1[C:5]2[N:6]([C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:9][N:10]=2)[N:7]=[CH:2][CH:3]=1
Reactant: Cc1cc(Cl)nn2c(-c3ccccc3)nnc12
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1ccnn2c(-c3ccccc3)nnc12
Yield: 85 %

Procedure:
6-chloro-8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x240 is dissolved in ethanol (300 ml), and 10% Pd/C (0.9 g) and 25% aqueous ammonia (60 ml) are added. The mixture is hydrogenated in the Parr apparatus under hydrogen pressure 2.5 atm at room temperature for 1 h 10. The reaction mixture is filtered through a Celite layer, which is washed with ethanol. The combined filtrates are evaporated, and the residue is dissolved in dichloromethane. The solution is washed with brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure to afford 2.9 g of 8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x241.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:64][C:65]1[CH:70]=[CH:69][C:68]([C:71]2[CH:75]=C(C(OCC)=O)[O:73][N:72]=2)=[CH:67][CH:66]=1>>[F:64][C:65]1[CH:66]=[CH:67][C:68]([C:71]2[CH:75]=[C:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([C:12]4[CH:11]=[C:10]5[C:15]([CH2:16][N:8]([C@@H:3]([CH:2]([CH3:1])[CH3:38])[C:4]([O:6][CH3:7])=[O:5])[C:9]5=[O:37])=[CH:14][CH:13]=4)=[CH:22][CH:21]=3)=[O:25])[O:73][N:72]=2)=[CH:69][CH:70]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)no1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(-c5ccc(F)cc5)no4)cc3)cc2C1=O

Procedure:
The compound of example 615 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 3-(4-fluorophenyl)isoxazole-5-carboxylate.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:18][CH:19]=2)=[N:13]1
Reactant: CCOC(=O)CCCCCOc1ccc(C#N)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 14.5 %

Procedure:
A mixture of methyl thiosalicylate (0.71 g, 4.2 mmol), ethyl 6-(5-cyanopyridin-2-yl)oxyhexanoate (1.00 g, 3.8 mmol), triethylamine (0.63 ml, 4.5 mmol) and toluene (12 ml) was refluxed under nitrogen atmosphere for 30 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.22 g, 14%).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[N:25][CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:44][S:45][CH2:46][CH2:47][CH2:48]O>C1COCC1>[Br:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([O:27][CH2:48][CH2:47][CH2:46][S:45][CH3:44])[CH:22]=1
Reactant: CSCCCO
Reactant: Oc1cncc(Br)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCOc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of PPh3 (20 g, 76 mmol) in THF (20 mL) is added a solution of 5-bromo-pyridin-3-ol (5.0 g, 29 mmol) in THF (10 mL). Then a solution of di-tert-butyl azodicarboxylate (16 g, 69 mmol) in THF (10 ml) is added. The mixture is stirred at room temperature for 30 min and 3-methylsulfanyl-propan-1-ol (3.3 g, 31 mmol) is added. The mixture is stirred at room temperature for 16 hrs. Then the solid is filtered and the filterate is concentrated. The residue is purified by flash column chromatography to give 4.5 g of 3-bromo-5-(3-methylsulfanyl-propoxy)-pyridine.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(c1)NCCO2
Reaction time: 5 h

Procedure:
To a solution of dichloromethane (10 mL) containing N-(tertbutoxycarbonyl)-2,3-dihydro-benzo[1,4]oxazine (0.438, 1.86 mmol) at 0° C. was added slowly trifluoroacetic acid (1.0 mL, 7.44 mmol). The reaction mixture was stirred at this temperature during 5 h, then the solvent was removed in vaccuo. The crude product was dissolved in EtOAc (15 mL) and washed successively with 10% Na2CO3 solution and water. The organic layer was dried over MgSO4 and the solvent was removed under reduce pressure. The title compound was obtained pure as brown oil (0.245 g, 98%). Rf=0.31 (petrol/ether 5/5); LCMS m/z 136 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 3.43 (4H, m); 3.54 (1H, s); 4.27 (4H, m); 6.60-6.82 (4H, m); 13C NMR (75 MHz, CDCl3): δ 43.4; 67.7; 118.1; 119.2; 121.3; 123.7; 136.1; 146.6. IR (film): 3375; 1498; 741 cm−1.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.[Br:25][C:26]1[CH:31]=[CH:30][C:29](O)=[C:28]([F:33])[CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:5][C@H:6]2[CH2:10][CH2:9][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:7]2=[O:24])=[C:28]([F:33])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)cc3F)C2=O)CC1
Temperature: 70 °C
Yield: 83 %

Procedure:
(R)-tert-Butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.7 g, 4.7 mmol) was dissolved in dry DMSO (30 mL) and 4-bromo-2-fluorophenol (1.1 g, 5.6 mmol) and K2CO3 (0.78 g, 5.6 mmol) was added and the reaction heated to 70° C. under nitrogen. The reaction became purple then black. The reaction was cooled to ambient temperature after 3 hours and partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.8 g, 3.9 mmol, 84% yield) as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])[CH2:12][CH2:13]C.C(Br)C=C.Cl>O1CCCC1.CCCCCC.CCOCC.O>[O:4]=[C:3]([CH2:5][CH2:13][CH:12]=[CH2:11])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: O
Product: C=CCCC(=O)CC(=O)OC
Reaction time: 0.17 h

Procedure:
Methyl acetoacetate (34.8 g) is added dropwise to a suspension of 16.2 g of 50% sodium hydride in 750 mL of anhydrous tetrahydrofuran cooled to 0°. To this solution is added dropwise 141 mL of a 2.3M solution of n-butyllithium in hexane over 40 minutes keeping the temperature of the THF solution at 0°. To this solution is then added 36 g of a solution of allyl bromide in 150 mL of THF. After 10 minutes the reaction is worked up by pouring into a mixture of 60 mL of aqueous concentrated HCl, 150 mL of water and 500 mL of ether. The ether layer is separated, washed with water, dried over magnesium sulphate, filtered and evaporated to give methyl 3-oxo-hept-6-enoate.