Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[C:9]([C:17]#[N:18])[C:10]([NH:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:18][C:17]1[C:3]2[C:2](=[C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:6]=[CH:5][CH:4]=2)[N:7]=[N:8][C:9]=1[C:10]([NH:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)=[O:11]
Reactant: N#CC(=NNc1ccccc1-c1ccccc1)C(=O)NCC1CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)NCC2CC2)nnc2c(-c3ccccc3)cccc12
Temperature: 70 °C
Yield: 26.2 %

Procedure:
To a suspension of 2-(biphenyl-2-yl-hydrazono)-2-cyano-N-cyclopropylmethylacetamide (1.9 g, 6.0 mmol) in anhydrous toluene (30 mL) was added aluminum chloride (1.72 g, 13.0 mmol). The mixture was heated at 70° C. for 1 hour, cooled to room temperature, and diluted with ethyl acetate (150 mL). Water was added dropwise until no further precipitate formed. Aqueous 10% sodium hydroxide (150 mL) was added and the layers were separated. The organic layer was washed with 10% sodium hydroxide (100 mL), water (100 mL), and brine (100 mL) and dried over sodium sulfate, filtered, and concentrated to a semisolid. The material was dissolved in chloroform and purified on silica gel to give 500 mg of material which was then recrystallized from ethyl acetate/hexanes and then from hot toluene (two times) to afford the pure product as a solid (117 mg, 6.2%). 1H NMR (500.133 MHz, CDCl3) δ 9.23 (t, J=5.3 Hz, 1H), 9.13 (bs, 1H), 8.43 (d, J=8.4 Hz, 1H), 8.17 (bs, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.81 (td, J=7.7, 1.2 Hz, 1H), 7.71 (d, J=7.5 Hz, 2H), 7.49 (t, J=7.3 Hz, 2H), 7.43 (td, J=7.2, 0.9 Hz, 1H), 3.23 (t, J=6.3 Hz, 2H), 1.12 (t, J=5.6 Hz, 1H), 0.45 (dd, J=6.5, 1.5 Hz, 2H), 0.29 (d, J=4.4 Hz, 2H). MS APCI, m/z=319 (M+H). HPLC 1.83 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:3]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c2c(=O)c(-c3ccccc3O)coc2c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O)COc1cc(Cl)c2c(=O)c(-c3ccccc3O)coc2c1
Yield: 63.6 %

Procedure:
In 100 ml of dried dichloromethane was dissolved 1.7 g of ethyl {[5-chloro-3-(2-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxy}acetate, and the solution was cooled with dry ice-acetone. Three milliliters of boron tribromide were added to the cooled solution in small portions, and the resulting mixture was refluxed for 3 hours. After cooling, the solvent was removed by distillation under reduced pressure, and to the residue was added dilute hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, air-dried, and recrystallized from ethanol to obtain 1.0 g of the entitled compound having a melting point of 188°-189° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:22]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c(C)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4,6-trimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([NH2:24])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(Cl)nc2)n1
Reactant: N
Product: Nc1ccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
70 mg (80%, 0.16 mmol) of the compound of Example 23A is mixed with ammonia solution (14 N, 1.5 ml) and kept in the microwave in a sealed tube for 13 hours at 150° C., whereby a pressure of 20 bar develops. After cooling to room temperature, the ammonia solution is removed i. vac., and the residue is purified via preparative HPLC (mobile solvent: acetonitrile/water gradient). 20 mg (38% of theory) of the title compound is obtained.
Reaction SMILES: [Na].[C:2]1([CH3:17])[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[C:2]1([CH3:17])[CH:3]=[CH:4][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=Cc2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccc(C)cc2)cc1
Yield: 61.8 %

Procedure:
(a) To 50 ml of absolute ethanol is added 0.58 g of sodium, and 4.2 g of 4-[N-(p-tolyl)formimidoyl]phenol and then 7.84 g of ethyl 2-bromo-2-methylpropionate are added to the solution at room temperature with stirring. The mixture is refluxed under heating and with stirring for 5 hours on an oil bath. After distilling off the ethanol from the reaction mixture, the residue is dissolved in ether. The solution is washed with 5% aqueous solution of sodium hydroxide and then with water. After drying the solution, the ether is distilled off, and the residue is further concentrated under reduced pressure on an oil bath at 100° C. to give 4.0 g of ethyl 2-[4-{N-(p-tolyl)formimidoyl}phenoxy]-2-methylpropionate as an oily product.
Reaction SMILES: [Si]([C:5]#[CH:6])(C)(C)C.Br[C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].C(NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[C:5]([C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14])#[CH:6]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: N#Cc1ccccc1
Product: C#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of bis(benzonitril)dichloropalladium(II) (53 mg, 0.14 mmol) and copper (I) iodide (26 mg, 0.14 mmol) in 6 mL dry THF was purged with argon for 3 minutes, then was added tri(tert-butyl phosphine) (69 ul, 0.28 mmol), TMS acetylene (0.77 ml, 5.5 mmol), 3-bromo-4-fluoronitrobenzene 505 mg, 2.295 mmol), and di-isopropylamine (0.77 ml, 5.5 mmol). The mixture was stirred at room temperature for 5 hours under argon. To the reaction mixture was added 7 mL 1 M TBAF/THF and the mixture was stirred at room temperature for 10 minutes. Workup and purification by column chromatography (silica, 5%-35% EtOAc/hexane) give 2-ethynyl-1-fluoro-4-nitro-benzene.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[CH3:1][N:2]([CH3:31])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C(=O)CCl
Reactant: CN(C)c1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5cccc(N(C)C)c5)cccn4n3)cc2)CC1

Procedure:
2-(4-{4-[8-(3-Dimethylamino-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(3-dimethylamino-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.100 g, 0.242 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.037 mL, 0.364 mmol) in a manner analogous to Example 313 to give product (0.060 g, 50%). MP=100-104° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.75 (d, 1H), 7.82 (d, 1H), 7.62 (d, 2H), 7.50 (s, 1H), 7.32 (m, 2H), 7.15 (m, 3H), 6.80 (d, 1H), 3.15 (s, 2H), 3.05 (s, 3H), 3.00 (s, 6H), 2.95 (m, 2H), 2.82 (s, 3H), 2.45 (m, 1H), 2.15 (m, 2H), 1.65 (m, 4H). MS=498 (MH)+.
Reaction SMILES: C([CH:4]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:5]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:6])C=C.[O:32]1CC[CH2:34][CH2:33]1.O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([CH:4]([C:5](=[O:6])[CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH2:34][CH2:33][OH:32])[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: C1CCOC1
Reactant: C=CCC(C(=O)Cc1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(CC(=O)C(CCO)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 27.5 g of the compound prepared in (d) above in 640 ml of a mixture of tetrahydrofuran and water (in a 2:1 ratio) was added 9 ml of a 2.5% solution of osmium tetraoxide in tert.-butanol. The reaction mixture was then allowed to stir at room temperature until it darkened to a black opaque mixture, after which time 82.07 g of sodium metaperiodate was added. The resultant mixture was then stirred at room temperature for 20 hours, after which time it was filtered and the solvent was removed by evaporation to yield a residue that was extracted with a mixture of ethyl acetate and water. The organic layer was evaporated and the resultant residue was chromatographed on silica gel employing a mixture of methylene chloride and ethyl acetate in a ratio of 8:1 as the eluent to yield a solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11](O)=O)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O

Procedure:
unsaturated D-glucuronic acid:D-glucuronic acid:D-mannose=2:1:1:2 (two
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:11][C:9]1[S:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=2[N:8]=1)=[O:16]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1cccc2sc(N)nc12
Product: Cc1cccc2sc(NC(=O)c3cccnc3Cl)nc12

Procedure:
Using 4-methyl-benzothiazol-2-ylamine and 2-chloronicotinic acid chloride the title compound was obtained as a yellow solid (50% yield), MS: m/e=304 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[N:8]=[N:9][N:10]([CH3:12])[N:11]=2)=[CH:4][CH:3]=1.FC1C=CC(CC2N(C)N=NN=2)=CC=1.[Li]CCCC.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:35]=1>CCOCC.O1CCCC1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([C:7]2[N:8]=[N:9][N:10]([CH3:12])[N:11]=2)[C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[OH:41])=[CH:4][CH:3]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Reactant: Cn1nnc(Cc2ccc(F)cc2)n1
Agent: Cn1nnnc1Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1nnc(C(c2ccc(F)cc2)C(O)(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To a 1:1 mixture of 5-(4-fluorobenzyl)-2-methyl-2H-tetrazole and 5-(4-fluorobenzyl)-1-methyl-1H-tetrazole, (0.209 g, 1.09 mmol) in 10 mL of 1:1 ether:tetrahydrofuran at −78° C. was added dropwise n-BuLi (0.434 mL of 2.5 M in hexane, 1.09 mmol). After stirring for one hour, a solution of dipyridin-3-ylmethanone (200 mg, 1.09 mmol) in 3 mL of tetrahydrofuran was added dropwise. Afterh 30 minutes, the reaction was quenched by transferring it via cannula to a −78° C. solution of 100 mL of ether containing 1 mL of concentrated aqueous HCl solution. After concentrating the mixture in vacuo, the resulting residue was taken up in EtOAc and extracted with 10% aqueous Na2CO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the titled compound, along with a regioisomer (Example VII-4). 1H NMR (500 MHz, d6-DMSO): δ 8.91 (br s, 1H), 8.66 (br s, 1H), 8.36 (d, J=4.4 Hz, 1H), 8.24 (d, J=4.4 Hz, 1H), 8.07 (br d, J=8.3 Hz, 1H), 7.82 (br d, J=8.0 Hz, 1H), 7.51 (dd, J =8.7 and 5.6 Hz, 2H), 7.29 (dd, J=8.3 and 4.9 Hz, 1H), 7.16 (dd, J=8.0 and 4.6 Hz, 1H), 6.95 (t, J=9.0 Hz, 2H), 6.16 (s, 1H), 6.05 (s, 1H), 4.23 (s, 3H). HRMS [M+H] C20H18FN6O calcd 377.1521 , found 377.1527.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH-:11].[Na+].OO.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]([OH:11])=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (810 mg; 4.0 mmol), 15% NaOH (aq.) (3 mL), MeOH (5 mL), and 30% H2O2 (5 mL) was stirred at r.t. for 2 hrs., then acidified with 10% HCl (aq.). The resulting white solid was collected, rinsed with water, and dried to give the desired product (670 mg; 77%).
Reaction SMILES: I[C:2]1([O:9][CH3:10])[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH2:3]1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]#[C:17][C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[O:19].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[O:8][C:6]2[CH:7]=[C:2]([O:9][CH3:10])[CH:3]=[CH:4][C:5]=2[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: COc1cc(C(=O)C#Cc2ccco2)cc(OC)c1OC
Reactant: COC1(I)C=C(O)C=CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3ccco3)oc2c1
Temperature: 102.5 °C
Yield: 12 %

Procedure:
5-Iodo-5-methoxyphenol (125 mg, 0.5 mmol), 3-(2-furyl)-1-(3,4,5-trimethoxyphenyl)-prop-2-yn-1-one (172 mg, 0.6 mmol), LiCl (21.2 mg, 0.5 mmol) and Na2CO3 (265 mg, 2.5 mmol) were added to anhydrous DMF (3 ml) and flushed with N2 three times. Pd(OAc)z was added to the reaction mixture and again flushed with N2. The reaction mixture was heated to 100-105° C. for 6 h and then reaction was cooled to room temp. Quenched by addition of aqueous NH4Cl solution and extracted with EtOAc. 2-(2-Furyl)-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan was isolated in 12% yield by silica gel column chromatography using 20 to 40% EtOAc in hexane. 1H NMR (300 MHz, CDCl3) δ: 3.75 (s, 6H, OMe), 3.86 (s, 3H, OMe), 3.90 (s, 3H, OMe), 6.44-6.46 (m, 1H), 6.87 (dd, J=2.1, 8.7, 1H), 6.97 (d, J=3.6, 1H), 7.07 (d, J=2.1, 1H), 7.15 (s, 2H), 7.36 (d, J=8.7, 1H), 7.41 (d, J=1.2, 1H). MS (ES) m/z: 408.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>>[CH3:7][C:3]1([CH3:8])[C:4](=[O:5])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][CH2:2]1
Reactant: Nc1ccccc1S
Reactant: CC(C)(CBr)C(=O)O
Product: CC1(C)CSc2ccccc2N(c2ccccc2)C1=O
Yield: 71 %

Procedure:
Bromopivalic acid (Example 10(a)) (59.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to the procedure for Example 1(d). Column chromatography yielded the title compound (52.3 g, 232 mmol, 71%). 1H NMR (DMSO-d6) δ 12.44 (br s, 1H); 7.22 (d, 1H); 6.99 (t, 1H); 6.63 (d, 1H); 6.47 (t, 1H); 5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da/e=226 (MH+), 208 (M-H2O), 180 (M-CO2). Calcd for C11H15NSO2 : C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:34])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:34])=[O:31])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)s5)nn34)ccnc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carboxylic acid (prepared according to general method A) (0.500 g, 1.15 mmol) in dichloromethane at 0° C. was added thionyl chloride (1.26 ml, 17.3 mmol) dropwise. Three drops DMF were added and the solution was stirred at room temp for three hours. The solution was concentrated to a brown residue and taken forward without further purification.
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1>[Pd].C(Cl)Cl>[OH:1][CH:2]([CH3:21])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1
Reactant: CC(O)C=Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [Pd]
Solvent: ClCCl
Product: CC(O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
Obtained from the title compound of Example 42 by a procedure similar to that described in Example 2, but using 10% palladium on charcoal as catalyst, as a foam. Rf 0.50 (SS 4). C,73.39; H,8.77; N,9.06. C18H26N2O; 0.125 CH2Cl2 requires C,73.28; H,8.91; N,9.43%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:63]1([CH2:66][C:67](O)=[O:68])[CH2:65][CH2:64]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:63]1([CH2:66][C:67]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:68])[CH2:65][CH2:64]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(O)CC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)CC6CC6)CC5)c4)cnn23)c1

Procedure:
A mixture of N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0310 mmol) (prepared by the procedure for Example 30, step 5), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (15.1 mg, 0.0340 mmol), cyclopropylacetic acid (4.65 mg, 0.0464 mmol, Lancaster, Cat. No. L09616) and N,N-diisopropylethylamine (30.0 μL, 0.172 mmol) in DMSO (0.5 mL) was stirred at for 3 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=567.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([Cl:26])=[O:23])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Product: O=C(Cl)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 24b), starting from (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid (Example 1a) by treatment with thionylchloride there is obtained (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carbonyl chloride as a yellowish solid which is directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14]1>CO.[Pd]>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Cc1cccc(C)c1NC(=O)CCN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CCN1CCNCC1
Reaction time: 24 h

Procedure:
To N-(2,6-dimethylphenyl)-3-(4-carbobenzyloxypiperazinyl)propanamide (1.3 g) in 10 mL of methanol was added 10% Pd/C, and the mixture was hydrogenated at 30 psi for 24 hours. The mixture was filtered, and the solvent was removed from the filtrate under reduced pressure, to afford N-(2,6-dimethylphenyl)-3-piperazinylpropanamide, a compound of formula (4),which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][C@@H:5]1[C@@H:9]([N:10]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C:11]2=[O:18])[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1>[OH-].[OH-].[Pd+2].C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[NH:4][C@@H:5]1[C@@H:9]([N:10]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C:11]2=[O:18])[CH2:8][NH:7][CH2:6]1
Reactant: COC(=O)N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)N[C@H]1CNC[C@@H]1N1CC(F)(F)CCC1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
To a solution of the product from Step 5 in a 2:1 mixture of ethanol/acetic acid (30 mL) was added palladium hydroxide on carbon powder (0.13 g, 10 wt. %). The mixture was degassed and shaken under an atmosphere of hydrogen (75 psi) at 50° C. for 12 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth and the solids washed with ethanol. The filtrate was concentrated and the residue was dissolved in saturated sodium carbonate solution and extracted with chloroform (3×50 mL). The combined organic phases were dried over sodium sulfate and concentrated to afford 0.98 g (86.6%) of the product as a foam. 1H NMR (400 MHz, Methanol-d4) δ 4.49 (q, 1H), 4.20 (q, 1H), 3.86-3.67 (m, 2H), 3.61 (s, 3H), 3.28-3.21 (m, 1H), 3.19-3.09 (m, 1H), 2.96-2.87 (m, 1H), 2.74-2.64 (m, 1H), 2.63-2.47 (m, 2H), 2.38-2.23 (m, 2H). MS 278.3 (AP+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:22]N(C)C=O>>[CH3:22][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Agent: [H-]
Agent: [Na+]
Product: Cc1nnc2ccc(-c3cccc(N(C)C=O)c3)nn12

Procedure:
A mixture of 2.5 g of N-[3-(3-methyl-1,2,4-triazolo-[4,3-b]-pyridazin-6-yl)phenyl]formamide, 0.56 g of sodium hydride (50% in oil) and 250 ml of dimethylformamide were reacted as described in example 2, giving 1.72 g of the desired product as a white powder, mp 207°-210° C.