Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:26]1[C:30]([C:31]([O-])=[O:32])=[N:29][N:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].C1(N=C=NC2CCCCC2)CCCCC1.Cl>N1C=CC=CC=1>[CH2:19]([N:26]1[C:30]([C:31]([NH:11][C:10]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:32])=[N:29][N:28]=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Reactant: COc1cc(C)cc(N)c1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(C)cc(NC(=O)c2nnnn2Cc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
A mixture of 2-benzyloxy-3-methoxy-5-methylaniline (2.6 g), potassium 1-benzyl-1H-tetrazole-5-carboxylate (2.5 g) and dicyclohexylcarbodiimide (2.1 g) in dry pyridine (100 ml) was stirred at room temperature overnight. The mixture was then poured into a mixture of ice (250 g) and concentrated hydrochloric acid (100 ml), and the mixture was allowed to stand for 1 hour. The precipitate was filtered off and recrystallised from ethanol to give 1-benzyl-2'-benzyloxy-3'-methoxy-5'-methyl-1H-tetrazole-5-carboxanilide (0.16 g), m.p. 181°-183° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]#[N:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].CCOC(C)=O>CC(O)C>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14](=[N:18][OH:19])[NH2:15])[CH:8]=[CH:7][C:6]=2[CH:5]1[OH:16])=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: [N-]=[N+]=NC1CCc2cc(C(N)=NO)ccc2C1O
Temperature: 25 °C
Yield: 94.7 %

Procedure:
Racemic (5S*,6R*)-6-azido-5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (400 mg, 1.9 mmol) and hydroxylamine hydrochloride (260 mg, 3.7 mmol) were mixed in 2-propanol (7.5 mL). To this suspended solution was added sodium bicarbonate (627 mg, 7.5 mmol) and the solution was heated at reflux for 2 hr. Then the reaction mixture was cooled to room temperature and diluted by EtOAc (50 mL) and washed with water and brine. The combined aqueous layers were extracted again by EtOAc. The combined organic layers were dried (MgSO4) and concentrated to afford pure racemic (5S*,6R*,E/Z)-6-azido-N′,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-2-carboximidamide (445 mg, 1.8 mmol, 96% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:49])[CH2:30][CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH:38]C(OCC3C=CC=CC=3)=O)[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:50][CH3:51])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:49])[CH2:30][CH:31]2[CH2:32][CH2:33][CH:34]([CH2:37][NH2:38])[CH2:35][CH2:36]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:25])[CH3:26])[O:16]2)[C:8]=1[O:50][CH3:51])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CC(NC(=O)CC2CCC(CNC(=O)OCc3ccccc3)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COc1c(CC(NC(=O)CC2CCC(CN)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reaction time: 6.5 h
Yield: 101.6 %

Procedure:
A solution of 3-[2-{2-[4-(Benzyloxycarbonylamino-methyl)-cyclohexyl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (1.56 g, 2.18 mmol) in MeOH (22 mL) was purged with Argon for 5 minutes. Palladium on carbon (10%, 0.153 g) was added, flask evacuated, and the reaction stirred under hydrogen atmosphere for 6.5 hr. The reaction was filtered through a Celite-plugged filter frit, washed with MeOH and DCM, and concentrated to provide 1.29 g of crude product that was carried to the next step without purification. ESI-MS m/z 583 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Reactant: N
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1c(F)cccc1Cl
Reaction time: 40 h

Procedure:
A mixture of N-[3-(2-fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2 g, 0.0047 mol), yellow mercuric oxide (2.56 g, 0.012 mol) and methanolic ammonia solution (40 ml) was stirred for 40 hours. The solvent was removed in vacuo and the black residue was treated with chloroform and filtered through celite. Evaporation of the solvent and recrystallisation from chloroform/ether gave the desired product. Yield 0.96 g (50%), m.p. 168°-170 ° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]4[CH2:36][CH2:35]4)=[O:33])[N:30]=3)[CH:27]=2)[CH:37]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
3-(1-Cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (2.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (75 mg, 0.233 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and diisopropyl ether to give the title compound (40.8 mg, 35%) as a colorless powder.
Reaction SMILES: [ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([N:8]=[CH:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([NH:16][C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C>[ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:33][CH:34]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC1CCc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCc2ccc(NC(=O)c3ccc(C=NN4CCOCC4)cc3)cc2C1
Reaction time: 8 h
Yield: 63.7 %

Procedure:
The compound (0.15 g) obtained in Example 1 was suspended in ethanol (10 ml), a 1N aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, a 3N aqueous hydrochloric acid solution was added, and the formed precipitate was filtered, washed with water, and dried under reduced pressure to obtain the entitled compound (0.09 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: CCCNCCC
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CCC)C(=O)CN(CC)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethylglycine and dipropylamine: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=9.0 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 6.65 (dd, J=8.8, 2.5 Hz, 1H), 4.14 (s, 2H), 3.51 (m, 2H), 3.31 (t, J=7.5 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H), 1.63 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.00 (t, J=7.3 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:46])([CH3:45])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:9]=1.[F:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1B(O)O.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[CH3:1][Si:2]([CH3:46])([CH3:45])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[F:47])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:9]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5F)nc4)c3n2)CC1
Temperature: 100 °C
Yield: 93 %

Procedure:
To tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (2.25 g, 3.3 mmol) in Dioxane (24 ml) and H2O (6 ml) was added the 2-fluorophenylboronic acid (0.92 g, 6.6 mmol), PdCl2(dppf)2.CH2Cl2 (0.32 g, 0.39 mmol) and K3PO4.H2O (1.7 g, 8.2 mmol). The reaction was heated at 100° C. for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, H2O (100 ml) and EtOAc (100 ml) were added and organics were extracted with EtOAc (4×50 ml), dried (Na2SO4) and concentrated in vacuo to give a crude product. Gradient column chromatography on silica eluting with 0% to 100% EtOAc/hexanes gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-(2-fluorophenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (2.3 g, 95%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([NH:15][NH:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])=O)=[CH:11][N:10]=[C:9]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C(#N)C>[CH:1]1([NH:6][C:7]2[C:8]3[CH:24]=[N:23][N:22]([CH2:25][CH3:26])[C:9]=3[N:10]=[CH:11][C:12]=2[C:13]2[S:36][C:17]([CH:18]([CH3:20])[CH3:19])=[N:16][N:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)NNC(=O)C(C)C)cnc21
Solvent: CC#N
Product: CCn1ncc2c(NC3CCCC3)c(-c3nnc(C(C)C)s3)cnc21
Temperature: 65 °C

Procedure:
Intermediate 10 was dissolved in acetonitrile (5 ml) then treated with Lawesson's reagent (0.125 g) and heated under nitrogen at 65° C. for 66 h. Volatiles were removed in vacuo and the residue was purified by mass directed autoprep HPLC to afford Example 6. LCMS showed MH+=357; TRET=3.59 min.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[C:8]([N+:11]([O-:13])=[O:12])[C:7](Cl)=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1Cl)([O-:3])=[O:2].[CH2:19]([CH2:21][NH2:22])[OH:20]>CO>[N+:1]([C:4]1[C:9]([NH:22][CH2:21][CH2:19][OH:20])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([NH:22][CH2:21][CH2:19][OH:20])=[C:6]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:22][CH2:21][CH2:19][OH:20])([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=[N+]([O-])c1c(Cl)c([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Product: O=[N+]([O-])c1c(NCCO)c([N+](=O)[O-])c(NCCO)c([N+](=O)[O-])c1NCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of 7.2 g (0.0227 mole) of 2,4,6-trinitro-1,3,5-trichlorobenzene and 70 ml of methanol was stirred in an ice bath while a solution of 9.9 g (0.162 mole) of ethanolamine in 70 ml of methanol was added over 10 min. Stirring at room temperature gave a solution from which yellow solid precipitated until the mixture became too thick to stir. After standing for 2 hr., the mixture was filtered to give 7.6 g (86%) of 2,4,6-trinitro-1,3,5-tris(2-hydroxyethylamino)benzene; 1H NMR (DMSO-d6): 3.48 (m, 6H), 3.72 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24](SC)=[N:25][CH:26]=2)[CH:15]=1>O>[Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:24]2[NH:23][C:22](=[O:29])[C:21]([CH2:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: Cc1ccnc(CSCCN)c1Br
Solvent: O
Product: Cc1ccnc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1Br

Procedure:
2-(3-Bromo-4-methyl-2-pyridylmethylthio)ethylamine (1.5 g) and 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.0 g) were fused together at 160°-170° for 1 hour. The cool mixture was taken up in water at pH 2 and extracted with chloroform. The aqueous phase was adjusted to pH 7 and extracted with chloroform, and the chloroform extract was evaporated and the residue purified chromatographically on silica gel (eluting with chloroform/ammoniacal methanol (50:1) to give the title compound, m.p. 81°-85°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:14][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[C:20]([C:24]1[O:28][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[N:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21].[F-].[Cs+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[C:20]([C:24]1[O:28][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[O:14][C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:12][CH2:13]4)[CH2:10][CH2:9]5)=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)=[N:26][N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CC12CCC(c3ccc(Br)cc3)(CC1)O2
Reactant: CC(C)(C)c1nnc(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a flask charged with methyl 2-(4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)acetate (106 mg, 0.33 mmol), 5-(tert-butyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (117 mg, 0.34 mmol), Pd(amphos)Cl2 (23 mg, 0.033 mmol) and CsF (150 mg, 0.98 mmol) under N2 was added 1,4-dioxane (2.9 mL) and water (0.33 mL). The mixture was sparged with N2 for 10 min and set to stir in a 90° C. oil bath for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous NaHCO3 solution, then water, followed by a saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 210 mg crude orange solid. The crude material was triturated with warm acetonitrile to afford 113 mg of the title compound as a white solid which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.66-1.83 (m, 4H), 1.88-2.00 (m, 2H), 2.10-2.21 (m, 2H), 2.94 (s, 2H), 3.64 (s, 3H), 7.42 (d, J=8.6 Hz, 2H), 7.55-7.71 (m, 6H), 10.52 (s, 1H). ESI-MS m/z: 462.1 [M+H]+, retention time 1.51 min (condition E).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[ClH:22].[CH3:23][NH:24][CH3:25]>>[ClH:22].[ClH:22].[CH3:23][N:24]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[CH3:25]
Reactant: CNC
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: Cl
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 12 and dimethylamine hydrochloride.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][NH2:15].N>>[CH3:14][NH:15][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: N
Product: CNS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
The title compound was prepared according to the procedure of Example 50A using 3-(chlorosulfonyl)benzoic acid (Aldrich) and methylamine (Aldrich). 1H NMR (300 MHz, CD3OD) δ 2.54 (s, 3 H), 7.70 (t, J=7.8 Hz, 1 H), 8.02-8.07 (m, 1 H), 8.23-8.28 (m, 1 H), 8.45 (t, J=1.9 Hz, 1 H) ppm; MS (DCI/NH3) m/z 233 (M+NH4)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([N:6]1[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of cis-2,6-dimethyl-piperazine (600 mg) and triethylamine (0.80 mL) in dichloromethane (10 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.43 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to afford (3S,5R)-1-methanesulfonyl-3,5-dimethyl-piperazine as a white solid (817 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19]C)[CH:16]=[CH:17]3)=[C:12]([C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([OH:19])[CH:16]=[CH:17]3)=[C:12]([C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:11]=2[CH2:28][C:29]([CH3:35])([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(OC)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 10.6 %

Procedure:
To a solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-methoxyindolizin-2-yl}-2,2-dimethylpropanoate (310 mg, 0.605 mmol) in CH2Cl2 (5.0 mL) is added aluminum chloride (363 mg, 2.72 mmol). The solution is stirred for 3 h at 23° C. then treated with ethanethiol (0.112 mL, 1.51 mmol) and allowed to stir for 18 h. The mixture is poured into cold 1M aqueous Rochelle's salt solution, extracted with CH2Cl2, washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 1:1 hexanes:EtOAc) gives ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (32 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].Cl.C1COCC1>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([N:11]([CH3:10])[CH3:21])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)NNc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloropyridazin-3-yl)hydrazine, 3-dimethylaminobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and isopropyl ether to obtain N′-(6-chloropyridazin-3-yl)-3-dimethylaminobenzohydrazide. To this, ethylene glycol was added and the mixture was stirred at 160° C. for 4 hours. After allowing to cool to room temperature, followed by purification by a standard method, 6-chloro-3-(3-dimethylaminophenyl)-1,2,4-triazolo[4,3-b]pyridazine was obtained. Dat (F:274).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1

Procedure:
(R)-4-[6-trans-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (Example 24, 0.03878 g, 0.0001016 mol) was dissolved in Ethanol (1.00 mL, 0.0171 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M of lithium hydroxide monohydrate in water (1.00 mL) was added and the reaction was refluxed overnight. TLC analysis showed that the reaction was complete. The solvent was removed under vacuum. The product was diluted in methylene chloride (5 mL) and water was added (5 mL). The layers were separated and the organic phase was then concentrated to dryness under vacuum, and purified by HPLC to give 48 mg of the title compound (13% yield). MS: m/z=339.47 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.92-0.97 (m, 9 H), 1.10-1.20 (m, 1 H), 1.23-1.35 (m, 2 H), 1.39-1.51 (m, 2 H), 1.79 (s, 3 H), 1.90-1.98 (m, 2 H), 2.29 (dd, J=12.55, 2.01 Hz, 2 H), 3.81-3.86 (m, 1 H), 3.91-3.96 (m, 1 H), 4.32-4.43 (m, 1 H), 7.19 (dd, J=8.78, 2.51 Hz, 1 H), 7.28 (d, J=2.26 Hz, 1 H), 7.53 (dd, J=8.66, 2.13 Hz, 1 H), 7.80-7.89 (m, 3 H)