Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:9]=1[Cl:10])[C:5]#[N:6].C(O)(C(F)(F)F)=O.NC1C=CC=CC=1.Cl[C:36]1[N:41]=[C:40]([N:42]([CH:52]2[CH2:54][CH2:53]2)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:39]2=[N:55][CH:56]=[C:57]([C:58]#[N:59])[N:38]2[N:37]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:10][C:9]1[C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:36]1[N:41]=[C:40]([N:42]([CH:52]2[CH2:54][CH2:53]2)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:39]2=[N:55][CH:56]=[C:57]([C:58]#[N:59])[N:38]2[N:37]=1
Reactant: CN1CCN(CCCc2cc(C#N)cc(N)c2Cl)CC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(CCCN4CCN(C)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C

Procedure:
3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile, TFA (104 mg) was converted to the free base by dissolving in MeOH and passing through an SCX column, first rinsing with MeOH, then 2N NH3 in MeOH to release the material. To this aniline (38.8 mg, 0.132 mmol) in a 2 dram vial was added 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (47 mg, 0.132 mmol), palladium(II) acetate (8.92 mg, 0.040 mmol), DPPF (7.34 mg, 0.013 mmol), Xantphos (7.67 mg, 0.013 mmol), cesium carbonate (86 mg, 0.265 mmol) and dioxane (Iml). The vial was evacuated and backfilled with N2 3×, then heated at 100° C. for 1 h. The reaction was cooled to room temperature and filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material purified by flash column chromatography (0-10% MeOH/DCM; 24 g column). 2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (48 mg) was obtained as a yellow glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>CN(C)C=O.O>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=[CH:6][CH:5]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a suspension of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (150, mg, 0.33 mmol) in N,N-dimethylformamide (5 mL) was added pyridine (40 μL, 0.49 mmol). The reaction mixture was cooled to 0° C. under nitrogen, then methanesulfonyl chloride (28 μL, 0.36 mmol) was added dropwise. After stirring at room temperature for 18 hours, the reaction mixture turned clear. Ethyl acetate and water were added and the phases separated. The organic phase was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (95:5 chloroform:methanol) gave N-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)methanesulfonamide (170 mg, 96%) as a yellow syrup. 1H NMR (CDCl3): δ 7.93 (d, 1H), 7.66 (d, 1H), 7.42 (m, 1H), 7.35–7.25 (m, 5H), 6.25 (m, 1H), 5.99 (m, 2H), 5.62 (broad, 1H), 4.29 (m, 1H), 3.96 (m, 1H), 2.94 (s, 3H), 2.10–1.99 (m, 4H), 1.77–1.49 (m, 12H). MS m/z 532 (M+1).
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].[OH-].[K+].[O:13]=[C:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH:15]1[C:25](OCC)=[O:26]>O>[NH2:9][C:8]1[O:13][C:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][C:15]=2[C:25](=[O:26])[N:10]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)C1CCC(c2ccccc2)C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(o1)C(c1ccccc1)CC2
Yield: 61.2 %

Procedure:
2-Methyl-2-thiopseudourea sulfate (1.336 g, 9.61 mmol) was dissolved in water (10 mL) and KOH (1.128 g, 20.10 mmol) was added. Under stirring, ethyl 2-oxo-3-phenylcyclopentanecarboxylate (2.03 g, 8.74 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and ether, and dried over anhydrous sodium sulfate to afford 2-amino-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazin-4(5H)-one (1.22 g, 5.35 mmol, 61.2% yield) as white solid. LC-MS (M+H)+=229.1. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ ppm 7.57-7.85 (2H, m), 7.08-7.47 (5H, m), 4.25-4.38 (1H, m), 1.72-2.73 (3H, m), 1.09-1.31 (1H, m).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[OH:30][CH2:31][CH2:32][NH:33][NH2:34].O>O1CCCC1>[OH:30][CH2:31][CH2:32][N:33]1[CH2:28][CH2:27][C:26]([CH2:25][CH:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)=[N:34]1
Reactant: NNCCO
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC4=NN(CCO)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 57.9 %

Procedure:
A solution of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (223 mg) and 2-hydroxyethylhydrazine (60 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (146 mg, yield 58%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 504 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27].[Cl-].[C:29]([CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:30].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:31][C:29]#[N:30])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[N:3]1[CH2:25][CH2:26][CH3:27]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=CC#N)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (535 mg, 1.44 mmol) and (cyanomethyl)triphenylphosphonium chloride (1.2 eq, 1.73 mmol, 582 mg) in THF (30 ml) at 0° C. was added KHMDS (0.5 M in toluene, 2.2 eq, 3.16 mmol, 6.3 ml). The resulting mixture was stirred for 1.5 h at this temperature then heated at 55° C. for 5 h. The cool reaction mixture was partitioned between EtOAc (10 ml) and a saturated aqueous NH4Cl solution (20 ml) and the aqueous phase was extracted with EtOAc (20 ml). The combined organic phases were washed with a saturated aqueous NaCl solution (2×20 ml), dried (MgSO4), filtered and evaporated to give a solid residue that was purified by radial chromatography (2 mm plate) using 5% MeOH in CH2Cl2 as eluent to afford 425 mg (75%) of a brittle foam (mixture of cis/trans isomers). MS: 396 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:21])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:46][CH:47]1[CH2:54][CH:53]2[N:55]([CH3:56])[CH:49]([CH2:50][CH2:51][CH2:52]2)[CH2:48]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:56][N:55]1[CH:49]2[CH2:50][CH2:51][CH2:52][CH:53]1[CH2:54][CH:47]([NH:46][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:21])=[N:13][C:12]=13)=[O:19])[CH2:48]2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)c(C)c1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxy-2-methylphenyl)benzoxazole-4-carboxamide (24 mg, 16%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=7.2 Hz, 1H), 8.22-8.16 (m, 2H), 7.67 (dd, J=8.8, 0.8 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 6.94-6.90 (m, 2H), 4.66-4.60 (m, 1H), 3.90 (s, 3H), 3.15-3.10 (m, 2H), 2.89 (s, 3H), 2.66-2.58 (m, 2H), 2.55 (s, 3H), 2.10-1.90 (m, 3H), 1.58-1.42 (m, 3H), 1.20-1.05 (m, 2H); MS (ESI+) m/z 420 (M+H); HPLC>99% (AUC), tR=13.54 min.
Reaction SMILES: [CH2:1]([OH:12])[C@@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])O)[OH:5])[OH:3]>OS(O)(=O)=O>[CH2:1]1[O:12][C@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Product: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
D-Glucitol (Aldrich, 1150 g, 6.31 mol) was suspended in aqueous 3M H2SO4 (550 mL) and heated at reflux with stirring under N2 overnight. The dark brown solution was cooled and neutralized using Amberlite® IRA-93 resin (OH-, ~4 L) Rohm and Haas, (Phil., Pa.). The resin was removed by filtration; the filtrate was decolorized using activated carbon (4 g) which was subsequently removed by filtration.
Reaction SMILES: [BH4-].[Na+].[C:3]1([NH:9][C:10]2([CH:24]=[O:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([NH:9][C:10]2([CH2:24][OH:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Yield: 82 %

Procedure:
Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-(2-phenylethyl)piperidine-4-carboxaldehyde (2 g) in methanol (2 g) at room temperature for 2 hours. The mixture was diluted with water, extracted with chloroform and the combined extracts washed, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, using chloroform-methanol 19:1 as eluant, to afford 4-(N-phenylamino)-1-(2-phenylethyl)-4-piperidinylmethanol (1.65 g), m.p. 98°-99° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].O.NN.[OH-].[K+]>C(O)C.C(O)COCCO>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: OCCOCCO
Product: C=CCCC[C@H]1CC[C@H](c2ccc(CC)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 0.9 g of p-[trans-4-(4-pentenyl)cyclohexyl]acetophenone in 8 ml of ethanol and 8 ml of diethylene glycol was treated with 350 ml of hydrazine hydrate while gassing with argon and the solution was then heated to reflux (bath temperature 110° C.) while stirring for 1 hour. Subsequently, the mixture was treated with 421 mg of solid potassium hydroxide, the bath temperature was increased to 210° C. and the ethanol was distilled off. After 3 hours at 210° C. the reaction was interrupted and the mixture was partitioned three times in water/petroleum ether. The organic extracts were washed twice with water, dried over magnesium sulphate and evaporated. Chromatographic separation of the residue (0.85 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.76 g (90%) of 4-ethyl-1-[trans-4-(4-pentenyl)cyclohexyl]benzene as a colourless oil; m.p. (C-I) -10.6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25](Cl)(=[O:27])=[O:26].[C:29]([NH:36][CH2:37][CH2:38][NH2:39])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([NH:39][CH2:38][CH2:37][NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Example 3, Step A (400 mg, 0.789 mmols) in 5 mL of CH2Cl2, Boc-ethylenediamine (0.137 mL, 0.868 mmol) and triethylamine (0.22 mL, 1.6 mmol) were added. The reaction stirred at room temperature for 2 days, then poured into EtOAc, washed with saturated NaHCO3 solution and brine. The solution was dried over Na2SO4 and concentrated in vac o. Purification by flash chromatograpy using EtOAc:hexane (1:3) gave the titled compound. ESI+ MS: 530 [MH-Boc]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12](I)=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:64]=[O:65]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH3:18])=[CH:13][C:12]([CH:64]=[O:65])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2ccc(C=O)cc2c1OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
A mixture of 6-iodo-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (example 9a) (0.58 g, 1.56 mmol), triethylamine (0.54 mL, 3.91 mmol), diphenylpropylphosphine (dpp, 36 uL, 0.16 mmol) and palladium(II) acetate (35 mg, 0.16 mmol) in dry N,N-dimethylformamide (16 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (1.11 mL, 3.13 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 3 h. The reaction was allowed to cool to 25° C. and then extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-40% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-ethoxy-quinoline-3-carboxylic acid ethyl ester (0.25 g, 59%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.O[C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[C:4]([Cl:10])[CH:3]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(Br)cc1Cl
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 4-bromo-2,6-dichlorophenol (1.24 g, 6.02 mmol), methyl (2S)-2-hydroxy-3-phenylpropanoate (1.30 g, 7.22 mmol) and triphenylphosphine (2.05 g, 7.83 mmol) in THF (13 mL) at room temperature was treated with DEAD (1.28 mL, 8.13 mmol), stirred for 2 hours, and concentrated. The concentrate was triturated with 10% ethyl acetate/hexanes, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% ethyl acetate/hexanes to provide 1.90 g (78%) of the desired product.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:30])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1.N1C(C)=CC(C)=CC=1C.Cl[C:41]([O:43][CH3:44])=[O:42].Cl>C1(C)C=CC=CC=1>[CH3:44][O:43][C:41](=[O:42])[N:30]=[C:3]([S:2][CH3:1])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 23.8 g of the crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]thioacetimidic acid methyl ester in 100 ml of toluene there were added 32 ml of collidine and 15 ml of methyl chloroformate, and the mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, 1N hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.98 g) as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].C(N(CC)C(C)C)(C)C.O>C1COCC1>[O:16]=[C:14]([CH3:15])[CH2:13][S:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: CC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CSc1cccc(CC(=O)O)c1

Procedure:
3-Mercaptophenylacetic acid (3.0 g, 17.9 mmol) and chloroacetone (1.5 mL, 18.8 mmol) were combined in THF (100 mL) then a solution of N,N-diisopropylethylamine (10.9 mL, 62.7 mmol) in THF (100 mL) was added by addition funnel over the course of 20 minutes at room temperature. After 2 hours H2O (100 mL) was added and the reaction mixture was worked up to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:22][CH2:21]3)[N:15]=2)[CH:3]=1.[NH3:23]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:23])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[CH2:22][CH2:21]3)[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Reactant: N
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
Ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxylate (140 mg, 439 μmol) and ammonia (7M in methanol, 9.44 g, 12 mL, 84.0 mmol) were heated at 50° C. in a sealed tube for 21 h. After cooling to room temperature, concentration in vacuo gave 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxamide (112 mg, 88%) as a yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.51 (br. s., 1H) 9.16 (s, 1H) 8.16 (br. s., 1H) 7.52 (t, J=7.74 Hz, 1H) 6.86-6.96 (m, 1H) 6.68 (d, J=7.93 Hz, 1H) 5.65 (br. s., 1H) 1.99-2.10 (m, 1H) 1.06-1.12 (m, 4H). LCMS (EI/CI) m/z: 290 [M+H]. The crude product was used directly in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[CH2:14]([O:16][C:17](=[O:24])[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:15]>CC(O)C>[CH2:14]([O:16][C:17]([CH:18]1[CH2:19][CH2:20][N:21]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:22][CH2:23]1)=[O:24])[CH3:15]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2ccccn2)CC1
Temperature: 120 °C

Procedure:
Potassium carbonate (52.5 g, 0.379 mol) was charged to a stirred solution of 2-Bromopyridine (60 g, 0.379 mol) and Ethylisonipecotate (59.7 g, 0.379 mol), at an ambient temperature before heating to 120° C. for 24 hours. The mixture was cooled to room temperature and propan-2-ol charged to the solution. The reaction mixture was then filtered and telescoped into preparation 1c.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C#Cc1ccc(C)cc1
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Product: Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)cc1
Yield: 89 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with p-ethynyltoluene to give the title compound as a black oil (55 mg, 89%). MS ESI 497.3 [M+H]+, calcd for [C26H28N2O4S2+H]+ 497.15.