Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Br)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Br)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 52 (1.40 g, 3.04 mmol) and pyridine hydrochloride (2.0 g, 17.30 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([I+:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:23]1([CH3:34])[CH:28]=[CH:27][C:26]([S:29]([O:32]C)(=[O:31])=[O:30])=[CH:25][CH:24]=1>COC(C)(C)C>[C:23]1([CH3:34])[CH:24]=[CH:25][C:26]([S:29]([O-:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1.[C:19]([C:16]1[CH:17]=[CH:18][C:13]([I+:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][CH:10]=2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Bis(p-tert-butylphenyl)iodonium chloride (428.8 g; 1.0 mol) and methyl p-toluenesulfonate (223.5 g; 1.2 mol) were suspended in t-butyl methyl ether (500 ml). The suspension was heated at 55° C.-58° C. and refluxed for 5 hours while being stirred. After the reaction mixture had been cooled, formed white solid was separated through filtration. The white solid was washed with t-butyl methyl ether and dried under vacuum, to thereby yield 513.7 g of bis(p-tert-butylphenyl)iodonium p-toluenesulfonate (yield: 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[N:7]=[C:8](N)[S:9][C:5]=2[CH:4]=1.N([O-])=O.[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>OP(O)(O)=O>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1
Reactant: COc1cc2sc(N)nc2cc1C
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O
Product: COc1cc2scnc2cc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-methoxy-5-methylbenzo[d]thiazol-2-amine (5A) (1.24 g, 6.42 mmol) in H3PO4 (5 mL) at 0° C., was added NaNO2 (2.2 g, 32 mmol) in minimal amount of water. The reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was then transferred to ice-cold hypophosphorous acid (50%, 5 ml) and slowly warmed to room temperature and stirred at room temperature until gas evolution ceases. Solid Na2CO3 was added to neutralize the reaction and the mixture was extracted by ethyl acetate. The organic phase was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-100% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C9H9NOS: 180.0 (M+H+). Found: 180.1 (M+H+).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[OH-:22].[Na+]>O>[C:14]1([C:13]2[NH:1][C:2]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:22])=[O:11])=[N:3][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N=C1c2ncccc2C(=O)N1CC(=O)c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccnc1-c1ncc(-c2ccccc2)[nH]1
Temperature: 25 °C

Procedure:
To the suspension of 7-imino-6-(2-oxo-2-phenylethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (825 mg, 3.11 mmol) in 1N NaOH (6.22 ml) 40 ml of water were added, and the reaction mixture heated to reflux for 1.5 hours. After cooling to room temperature the mixture was diluted with 100 ml of water, and the pH adjusted to 2-3 by addition of 2N HCl. The resulting precipitate was filtered off and dried to give 414 mg of the title compound as solid; ESI-MS [M+W]: 266.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1ccccc1-c1nc(N)nc(SCCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 364 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.C[Mg+].[Br-].[CH3:19]COCC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:19][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: CCOCC
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2ncc(C)nc2cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound is prepared using an adaptation of the published method of Tamao, et al. Tetrahedron, 1982, 38, 3347-3354. To a THF solution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26 mmol) and NiCl2(dppp) (0.14 g, 0.26 mmol). The reaction mixture is cooled to 0° C., and a 3 M solution of MeMgBr in Et2O (13 mL, 39 mmol) is added portionwise. The reation mixture is allowed to warm to room temperature, stirred for 1 hour, then refluxed for 1.5 hours. The mixture is cooled, quenched with 10% HCl, stirred 10 minutes, then made basic with 5% NaOH. CH2Cl2 and H2O are added to the reaction, and the mixture stirred overnight. Additional CH2Cl2, H2O, and NaCl are then added and the mixture is filtered. The resulting solution is poured into a separatory funnel, and the aqueous layers are washed 3× with CH2Cl2. The organic layers are combined, washed with brine, dried (MgSO4), concentrated onto silica gel, and chromatographed (50%-80% EtOAc/hexanes) to provide a orange solid (49% yield).
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:5]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH:4]1[CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: CC(C)(C)OC(=O)N1CCC2(CC(N)C2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 2.05 g (8.15 mmol) of tert-butyl 2-azido-6-azaspiro[3.4]octane-6-carboxylate (isomer 2) and 0.84 g (4.08 mmol) of Lindlar catalyst (PdCaCO3), 1.11 g of product are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 67.6 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (276 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[N:26][CH:27]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:28][C:25]1[N:26]=[CH:27][C:22]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:23][CH:24]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CCOC(=O)c1cn2nccc(N3CCOCC3)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Compound 5c, 5-bromo-2-chloropyridine (12.7 g, 64.1 mmol), Pd(OAc)2 (671 mg, 2.99 mmol), PPh3 (784 mg, 2.99 mmol), and KOAc (12.6 g, 128 mmol) were placed in a 250 mL pressure vessel equipped with a stir bar and then the flask was flushed with Argon. Dry DMA (150 mL) was added and then the vessel was capped under an argon purge. The reaction was stirred at 110° C. for 8 h. The reaction was cooled to rt, diluted with water (300 mL), and filtered. The precipitate was washed with water (2×200 mL), and then the solid was dissolved in DCM (500 mL). To this solution was added 50 g SiO2 and the solvent was removed under reduced pressure. The material was dry-loaded onto a 240 g SiO2 pre-packed column and eluted with 0-60% EtOAc/DCM. The fractions containing the product were pooled and concentrated to afford a residue that was triturated with EtOAc. The solid was isolated by filtration, washed with EtOAc (2×50 mL), and then dried under reduced pressure to afford compound 20a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.65 (d, J=2.0 Hz, 1H), 8.04 (d, J=5.9 Hz, 1H), 7.97 (dd, J=8.2, 2.3 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 6.14 (d, J=5.9 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.01-4.11 (m, 4H), 3.90-3.99 (m, 4H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29][CH2:30][C:31]5[O:32][CH:33]=[CH:34][N:35]=5)[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.Cl>ClCCl>[CH3:1][NH:2][CH:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[C:28]3[C:27]4[C@@H:26]([CH2:29][CH2:30][C:31]5[O:32][CH:33]=[CH:34][N:35]=5)[CH2:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH2:14][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCc2ncco2)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCc2ncco2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl N-methyl-N-(4-[[(3S)-3-[2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (110 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrogen chloride (12 M, 1 mL) at 0° C. and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with sodium hydroxide and extracted with 2×30 mL of dichloromethane. The combine organic layers were concentrated in vacuo to give N-methyl-4-[[(3S)-3-[2-(1,3-oxazol-2-yl)ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexan-1-amine (80 mg, crude) as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:28])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridine-2-carboxylic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (328 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (361 mg, 96%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O.CCOCC>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Yield: 74.6 %

Procedure:
In this example, L-proline (11.5 g; 0.10 mole) and caustic soda (8.0 g; 0.2 moles) are dissolved in 100 ml water, and a solution of p-methylphenylsulfonyl chloride (20.9 g) dissolved in ether (80 ml) is added thereto with vigorous stirring under cooling in an ice bath (5°-10° C.). After reaction for about 5 hours, the reaction mixture is left standing, and the upper ether layer is removed. The remaining aqueous layer is admixed with 2N hydrochloric acid to adjust the pH to 3-4. After being left standing in a cool place (0°-5° C.), the deposited crystals are filtered off. The crystals are recrystallized from an aqueous 60% ethanol solution (about 200 ml), whereby p-methylphenylsulfonyl-L-proline (compound number 15; 20.1 g; m.p. 57°-59° C.) was obtained. Yield: 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][SH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.Br[S:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][S:16][S:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: BrSN1CCOCC1
Reactant: SCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CSSN3CCOCC3)n1-2
Yield: 124.1 %

Procedure:
To a solution of 8-chloro-1-(mercaptomethyl)-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.5 g) in methylene chloride (20 ml) is added a solution of 4-(bromothio)morpholine (prepared from 0.47 g of dimorpholinodisulfide) in chloroform at -13° to -20° C., and the resultant mixture is stirred for 1.5 hours. The reaction mixture is mixed with water. The methylene chloride layer is separated, dried and evaporated to remove the solvent. The residue is crystallized from ether and filtered to give 8-chloro-1-(morpholinodithio)methyl-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (1.45 g) as crystals. This material is recrystallized from ethanol to give crystals melting at 149°-155° C. (decomp.).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[OH:11][C:12]1[C:13](=[O:28])[O:14][CH:15]([CH2:18][CH2:19][C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]=1[OH:17]>C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:11][C:12]1[C:13](=[O:28])[O:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]=1[OH:17]
Reactant: O=C1OC(CCC#Cc2ccccc2)C(O)=C1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: O=C1OC(CCCCc2ccccc2)C(O)=C1O

Procedure:
Quinoline (70 μL, 0.6 mmol), 15 mg of 5% Pd/BaSO4 and 61 mg (0.25 mmol) of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone were combined in 20 mL of ethanol and hydrogenated at atmospheric pressure until 12 mL (0.5 mmol) of H2 was consumed as measured by a H2O filled burette. The catalyst was removed by filtration through two #1 fluted filter papers and the solution was concentrated to a volume of about 5 mL, taken up in SOmL of ether and washed with 3×15 mL of 5% aqueous HCl, 20 mL of H2O and 20 mL of brine, dried (MgSO4) and concentrated to provide 3,4-dihydroxy-5-(4-phenylbutanyl)-2(5H)-furanone as a brown wax: 1H NMR (acetone-d6) δ 7.28-7.13 (m, 5H), 4.66 (dd, J=3.4, 7.2 Hz, 1H), 2.62 (t, J=7.7, 2H), 2.00-1.93 (m, 1H), 1.69-1.42 (m, 5H); 13C NMR (acetone-d6) δ 170.7, 154.9, 143.3, 129.2, 129.1, 126.5, 118.6, 76.2, 36.3, 32.7, 32.1, 24.6. Anal Calcd for C14H16O4 +0.25 H2O: C, 66.52; H, 6.58. Found: C, 66.71; H, 6.75.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[CH:21]=[CH:22][S:18][CH:19]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccsc2)cc1

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and thiophen-3-ylboronic acid. MS (M+H, 302).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OCC2C=CC=CC=2)[CH2:30]1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Product: N[C@H]1CCCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)C1
Yield: 20 %

Procedure:
Following the procedures of Example 144, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl piperidin-3-ylcarbamate were reacted. The reaction mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 20.0 mg (20%) of 161 over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO): 9.30 (s, 1H), 9.21 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 8.48 (m, 1H), 7.66 (s, 1H) 7.53 (m, 1H), 7.46 (s, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.37 (m, 1H), 4.29 (d, J=12.6 Hz, 1H), 3.06-2.97 (m, 1H), 2.79 (d, J=7.6 Hz, 2H), 1.94 (m, 1H), 1.80 (m, 1H), 1.61 (d, J=9.5 Hz, 1H), 1.34 (m, 1H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH3:16])=[CH:14][C:10]2[N:11]=[CH:12][S:13][C:9]=2[C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)(=O)=O.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC.[Li+].[Cl-].C(OCC)(=O)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]2[C:9]3[S:13][CH:12]=[N:11][C:10]=3[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:26]=[CH2:27])=[CH:18][CH:19]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1cc2ncsc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ncsc2c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (5F) from above reaction was dissolved in DMF (3 ml). Tributylvinyltin (130 uL), PdCl2(PPh3)2 (27 mg, 0.039 mmol) and LiCl (49 mg, 1.17 mmol) were added. The reaction mixture was stirred at 120° C. in microwave for 30 min. The reaction mixture was diluted by ethyl acetate, washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified by silica gel column (0-50% ethyl acetate/hexanes). LCMS-ESI+: calc'd for C16H20ClNS: 286.0 (M+H+). Found: 286.1 (M+H+).
Reaction SMILES: Cl.CN.[N:4]1C=CC=C[CH:5]=1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>CN(C)C=O>[CH3:5][NH:4][C:11](=[O:12])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)Oc1ccccc1
Yield: 53.5 %

Procedure:
Methylamine hydrochloride (16.9 g, 250 mmol) was dissolved in N,N-dimethylformamide (250 ml), pyridine (44 ml, 275 mmol) was added thereto, and the reaction mixture was stirred. The reaction mixture was cooled with ice, phenyl chloroformate (35 ml, 275 mmol) was added dropwise thereto, and the reaction mixture was then stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were suspended in diethylether, diluted with hexane, filtered off, washed with the diethylether:hexane=1:1, and dried by evacuation, to yield the title compound (22.3 g, 147 mmol, 59.1%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]1[CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:5](=[O:31])[C:4]([OH:32])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)c3ccccc3c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCCn2c(=O)c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
A solution of 4-[3-(5,6-dihydro-6-oxo-5-phenanthridinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.4 g) in hot methanol (80 mL) was treated with sodium carbonate (0.118 g) in water (1.5 mL), and the reaction was stirred at room temperature for 4 hours. After the methanol was removed in vacuo, dichloromethane and water were added and the mixture was acidified with 3N hydrochloric acid. The resulting solid was filtered off, dried and crystallized from ethyl acetate-tetrahydrofuran to yield 0.321 g of 4-[3-(5,6-dihydro-6-oxo-5-phenanthridinyl)propoxy]-alpha-oxobenzeneacetic acid in two crops, mp 202°-204° C.