Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63]Cl)=[O:61])=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:74])=[CH:47][C:48]([NH:67][CH2:68][C:69]2[O:70][CH:71]=[CH:72][CH:73]=2)=[C:49]([CH:66]=1)[C:50]([O:52][CH2:53][CH2:54][CH2:55][O:56][C:57](=[O:65])[CH2:58][CH2:59][C:60]([O:62][CH2:63][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:61])=[O:51])(=[O:43])=[O:44]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)OCCl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)CCC(=O)OCCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (920). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.ClN1C(=[O:28])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:28]
Reactant: COCCCOc1ccccc1-n1ccc2ccccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: COCCCOc1ccccc1N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
The compound of step 2 (3.09 g, 11.0 mmol) was dissolved in DCM (83 ml), and N-chlorosuccinimide (1.54 g, 11.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed, the resulting solid was dissolved in concentrated acetic acid (45 ml) and heated to 70° C. After the addition of phosphoric acid (9.35 ml, 137 mmol; 85%), the reaction mixture was heated to 120° C. for 2 h. The cooled mixture was diluted with water, extracted with EA, the organic layer separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:6). 2.38 g of the title compound was obtained.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[N:19][N:18]([CH3:21])[C:13]3=2)[N:8]=1
Reactant: Cn1nnc2ccc3nc(O)c(O)nc3c21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1nnc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c21
Yield: 65.4 %

Procedure:
Finely powdered potassium nitrate (0.71 g, 7 mmol) was added portionwise to a stirred solution of 7,8-dihydroxy-1-methyl-1H-1,2,3-triazolo[4,5-f]quinoxaline (1.52 g, 7 mmol) in 28 ml of conc. sulfuric acid at 0° C. After about 1 h the ice bath was removed and stirring was continued over night at room temperature. Then an additional amount of potassium nitrate (0.7 g) was added and the mixture was stirred for 4 h at room temperature. Now the solution was poured into 150 ml of ice/water and the precipitated yellow solid was isolated by filtration and washed with water. Recrystallization from water/ethanol (1:1) afforded 1.2 g (65%) of the pure nitro compound; m.p.>300° C.; IR (KBr): 3600-2500, 1720 cm-1 ; 1H-NMR (DMSO-d6): 4.62 (s,3H, CH3), 8.07 (s, 1H, ArH), 12.4 (broad s, 1H, OH, only one exchangeable proton could be seen).
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47].Br>>[O:47]=[C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)[CH2:45][N:33]1[C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[CH:36][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:34]1
Reactant: O=C(CBr)c1cccnc1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: Br
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)n(CC(=O)c2cccnc2)n1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(pyridin-3-yl)ethanone.HBr (purchased from Aldrich). 1H-NMR δ 9.17 (d, 1H), 8.88 (dd, 1H), 8.24 (ddd, 1H), 7.50 (td, 1H), 7.03 (s, 1H), 5.73 (s, 2H), 4.40 (q, 2H), 1.39 (t, 3H), 0.28 (s, 9H). Calculated mass for C16H21N3O3Si, 331.14, observed, 332.0 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CCOC(=NC(=O)c1ccc(Cl)cc1Cl)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,4-dichlorobenzoyl chloride, there is obtained ethyl N-(2,4-dichloro-benzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 158°-159°-C.;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(c3cc(Nc4ccc5cccnc5c4)ncn3)CC2)cc1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and 1-phenyl-piperazine in the presence of K2CO3 and DMF.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[Cl-].[NH4+].O>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:1]([OH:8])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)c1cccnc1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Nicotinaldehyde (0.500 mL, 4.83 mmol) was dissolved in THF (7.0 mL). n-Butyllithium (2.76 mol/L solution in n-hexane, 2.63 mL, 7.25 mmol) was added at −78° C. and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound A18 (597 mg, 75% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[N:3]1.[Li]CCCC.[Br:24]Br.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.CCCCCC.O1CCCC1>[Br:24][C:12]1[CH:11]=[C:10]([O:13][C:14]([F:17])([F:15])[F:16])[CH:9]=[CH:8][C:7]=1[C:4]1[O:5][CH2:6][C:2]([CH3:18])([CH3:1])[N:3]=1
Reactant: BrBr
Reactant: CC1(C)COC(c2ccc(OC(F)(F)F)cc2)=N1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)COC(c2ccc(OC(F)(F)F)cc2Br)=N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a 50 ml round bottom flask was loaded 4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]-4,5-dihydro-1,3-oxazole (0.5 g, 1.93 mmol) and 7 ml tetrahydrofuran. The resulting solution was cooled with dry ice acetone bath, and nbutyllithium (nBuLi) (2.5 M hexane solution, 0.85 ml, 2.12 mmol) was added via a syringe. The resulting reaction mixture was allowed to warm up to −20° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled back to −78° C. It was quenched by addition of bromine (0.109 ml, 2.12 mmol), followed by 10 ml saturated sodium carbonate and 10 ml sodium thiosulfate solution. The resulting mixture was diluted with 30 ml ether. The layers were separated, and the organics were dried over sodium sulfate, filtered and concentrated to give 0.60 g light yellow liquid. It was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[C:42]([CH3:43])=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=5[CH3:44])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:49])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:51][CH:52]1[CH2:55][NH:54][CH2:53]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:51][CH:52]1[CH2:55][N:54]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:49])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[C:34]([CH3:44])=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][C:42]=4[CH3:43])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:53]1
Reactant: FC1CNC1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Yield: 100.9 %

Procedure:
To a solution of methyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 50, 82 mg, 0.117 mmol) in THF (1.5 mL) was added 3-fluoroazetidine hydrochloride (39.2 mg, 0.351 mmol) and triethylamine (0.074 mL, 0.5927 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 20 minutes (BIOTAGE microwave). The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude methyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (82 mg, 0.118 mmol). LCMS (M+H)+: 698.2.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].B1C2CCCC1CCC2.[CH2:20]([O:27][C:28]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33](I)=[CH:34][CH:35]=2)[O:30][C:29]=1[C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:42]([O:56][CH3:57])[CH:41]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>O1CCCC1.[OH-].[Na+].Cl[Pd]Cl>[CH2:20]([O:27][C:28]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:34][CH:35]=2)[O:30][C:29]=1[C:40]1[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:42]([O:56][CH3:57])[CH:41]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OCc1ccccc1
Reactant: C=CCCCCCCCC
Agent: Cl[Pd]Cl
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc2c(=O)c(OCc3ccccc3)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2c1
Reaction time: 6 h

Procedure:
To a stirring solution of 1-decene (0.176 g, 1.3 mmol, 1.4 eq) in tetrahydrofuran (2 ml) under argon was added 9-BBN in tetrahydrofuran (0.5M, 2.7 ml, 1.4 mmol, 1.5 eq). The reaction was stirred for 6 hours then 35 (0.560 g, 0.9 mmol) in tetrahydrofuran (5 ml), 3M NaOH solution (1.1 ml) and dichloropalladium (dppf) (0.027 g, 0.03 mmol, 0.04 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether. The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a brown oil. Column chromatography (silica gel, DCM) yielded 40 g (0.339 g, 59%) as a pale yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=1.C1(=O)[NH:16]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.O.NN.C(OCC)(=O)C.[ClH:70]>C1COCC1.C(O)C>[ClH:70].[ClH:70].[NH2:16][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1cc(CCO)ccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(CCN)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
4-(2-Hydroxyethyl)pyridine-2-carbonitrile (2.53 g, 17.1 mmol) obtained in Step 4 was dissolved in THF (40.0 mL), then phthalimide (3.02 g, 20.5 mmol), triphenylphosphine (5.38 g, 20.5 mmol), and a DEAD-toluene solution (40.0%, 8.93 g, 20.5 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration. Ethanol (200 mL) and hydrazine monohydrate (2.57 g, 51.3 mmol) were added to the resulting solid, and the mixture was stirred at 70° C. for 2 hours. After the resulting precipitate was collected by filtration, the filtrate was concentrated under reduced pressure, and a further precipitate was collected by filtration. A hydrogen chloride-ethyl acetate solution (4.00 mol/L, 50.0 mL, 200 mmol) was added to the filtrate, and precipitated crystals were collected by filtration to give 4-(2-aminoethyl)pyridine-2-carbonitrile dihydrochloride (2.05 g, yield 55%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-morpholin-4- ylisonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and morpholine using method A. NMR; δH [2H6]—DMSO 10.32,(1H, s), 8.62,(1H, t), 8.27,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.64,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.24,(1H, s), 7.11,(1H, d), 3.71,(4H, m), 3.51,(4H, m), 3.16,(2H, t), 2.20,(3H, s), 1.05,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.31 min, MH+471.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II.[CH2:13]1COC[CH2:14]1>>[CH:2]1([C:1]([OH:10])=[O:9])[CH2:14][CH2:13][CH:5]([C:6]([OH:8])=[O:7])[CH:4]=[CH:3]1
Reactant: O=C(O)/C=C\C=C\C(=O)O
Reactant: C1CCOC1
Agent: II
Product: O=C(O)C1C=CC(C(=O)O)CC1
Temperature: 160 °C
Yield: 75 %

Procedure:
In a Parr reactor, a mixture of cis,trans muconic acid (8.18 g, 57.6 mmol), I2 (293 mg, 1.15 mmol, 2.0 mole percent), and THF (120 ml, 0.48 M) is heated to 160° C. for 25 hours under ethylene pressure (pRT=252 psi (1.74 MPa)). After cooling to room temperature, a white solid is found to be suspended in a weakly yellow solution. The solution is filtered to remove the precipitated trans,trans muconic acid and all solvent is evaporated on a rotary evaporator. The residue is suspended in hot ethyl acetate/dioxane; after cooling to room temperature, the precipitated solid is removed by filtration and the filtrate is evaporated to dryness to yield cyclohex-2-ene-1,4-dicarboxylic acid (7.22 g, 42.4 mmol, 75 percent).
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[S:9]1[CH:10]=[CH:11][C:7]([C:3]([NH:2][S:20]([CH3:19])(=[O:22])=[O:21])([CH3:6])[C:4]#[N:5])=[CH:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)(C#N)c1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C#N)(NS(C)(=O)=O)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2.7 g (0.0143 mole) 2-amino-2-(3-thienyl)-propionitrile hydrochloride (the product of Example 8) in 50 ml methylene chloride, 3.6 g (5 ml [0.036 mole]) triethylamine were added, followed by 2 g (1.4 ml [0.018 mole]) methanesulfonyl chloride. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was then washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and stripped to give the above-identified product which was used in Example 10 without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O.O.C(Cl)Cl.C(O)(=O)C>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:40])[CH2:34][CH2:33]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (50 mg, 0.091 mmol) in dichloromethane (2.0 mL) was added formaldehyde solution in water (37%, 0.25 mL), and 0.1 mL of acetic acid. Then sodium triacetoxyborohydride (300 mg) was added. And the mixture was stirred at room temperature for 10 min then condensed. It was then diluted with water/DCM, neutralized with sat NaHCO3 powder, organic layer was separated washed with water, brine and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 3-butyl-4-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. This compound was dissolved in DCM (2.0 mL) and 1.0 mL of 4.0 M HCl in dioxane was added. Solvents were evaporated resulting solid was washed with ether and dried to provide the title compound (25 mg). LCMS: m/z 492 [M+1].
Reaction SMILES: C([Li])CCC.O1C=CC=C1.BrCCCBr.Br[CH2:17][CH2:18][CH2:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C1COCC1.CN(C=O)C.O>[N:25]([CH2:17][CH2:18][CH2:19][C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[N+:26]=[N-:27]
Reactant: BrCCCc1ccco1
Reactant: [N-]=[N+]=[N-]
Agent: BrCCCBr
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCc1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
At 0° C., butyllithium (70 mL, 1.6 M in hexane) was added to a solution of furan (10 g, 0.15 mol) in THF (150 mL). The mixture was stirred at 0° C. for 1h, then treated with a solution of 1,3-dibromopropane (30 g, 0.15 mol) in THF (50 mL). The mixture was allowed to warm to 25° C. over 2 h, then quenched with a saturated NH4Cl solution (50 mL). The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic extracts was dried over Na2SO4. The solvent was evaporated to give crude 2-(3-bromopropyl)furan (30 g), which was purified by silica gel chromatography (10% methylene chloride in hexanes). A mixture of 2-(3-bromopropyl)furan (7.6 g, 40 mmol) and sodium azide (10 g, 150 mmol) in DMF (200 mL) was stirred for 15 h at 90 C. Water (250 mL) was then added and the mixture was extracted by diethyl ether (3×100 mL). The combined organic extracts was washed with water (3×50 mL) and dried over sodium sulfate. The solvent was removed to give pure 2-(3-azidopropyl)-furan as an oil (5 g). A mixture of 2-(3-azidopropyl)furan (0.5 g) and Pd/C (0.05 g, 10%) in methanol (15 mL) was stirred at 25° C. for 8 h under a hydrogen atmosphere. The catalyst was filtered off and solvent was evaporated to give 3-Furan-2-yl-propylamine in quantitative yield.