Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.P(Cl)(Cl)([Cl:16])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:16][C:7]1[N:6]=[C:5]([CH3:9])[C:4]([C:10]([O:12][CH3:13])=[O:11])=[N:3][C:2]=1[Cl:1]
Reactant: COC(=O)c1nc(Cl)c[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)c(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6 mmol) in toluene (100 mL) at 0° C. was added phosphorus oxychloride (10 ml, 109 mmol) and DMF (1 ml, 12.91 mmol). The reaction mixture was stirred at room temperature for 1 h, and then was heated to 85° C. fort 8 h. The mixture was cooled to RT and concentrated. The residue was diluted with EtOAc and washed with saturated NaHCO3 solution. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified with ISCO (0% to 10% EtOAc/Hexanes) to afford the desired methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate (6.51 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.00 (3H, s), 2.83 (3H, s)
Reaction SMILES: [CH:1]1([N:6]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]3[C:7]2=[N:8][C:9]([NH:19][C:20]2[CH:42]=[CH:41][C:23]([C:24]([NH:26][CH:27]4[CH2:33][CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)=[O:25])=[CH:22][C:21]=2[O:43][CH3:44])=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH:27]([NH:26][C:24](=[O:25])[C:23]2[CH:41]=[CH:42][C:20]([NH:19][C:9]3[N:8]=[C:7]4[C:12]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][CH2:16][N:6]4[CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][N:10]=3)=[C:21]([O:43][CH3:44])[CH:22]=2)[CH2:28]1
Reactant: COc1cc(C(=O)NC2CCCCN(C(=O)OC(C)(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 3-[[4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoyl]amino]azepane-1-carboxylate (Example 348; 149 mg, 0.25 mmol) in DCM (2 mL) was treated with TFA (1 mL) The resulting solution was stirred at ambient temperature for 5 hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[CH2:5][C:6]1[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([I:24])[CH:18]=2)=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)[CH3:27]
Reactant: CCN(CC)C(=O)Cc1c(-c2ccc(O)c(I)c2)nn2c(C)cc(C)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC)C(=O)Cc1c(-c2ccc(OC)c(I)c2)nn2c(C)cc(C)nc12
Reaction time: 8 h
Yield: 952.4 %

Procedure:
To a solution of 4 (30 mg, 0.063 mmol) in DMF (5 mL) was added K2CO3 (300 mg, 2.2 mmol) and MeI (100 μL×2M, 0.2 mmol). The reaction was stirred overnight and the solvent was removed under vacuum and the residue was purified by silica gel column chromatography (EtOAc as eluent) to give 1 (29 mg, 0.60 mmol, 95%). 1H NMR (CD3OD, 400 MHz) δ 1.15 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 2.57 (s, 3H), 2.77 (s, 3H), 3.43 (q, J=7.2 Hz, 2H), 3.58 (q, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.97 (s, 2H), 6.80 (s, 1H), 7.06 (d, J=8 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 8.09 (s, 1H). ESI MS m/z: [M+H]+ C21H26IN4O2: calculated 493.1. found 493.1.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].[ClH:25]>>[ClH:25].[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[N:11]=[CH:12][C:7]=2[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C=O)CC3)nc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21

Procedure:
A mixture containing, 2.0 g of 5,8-dihydro-8-ethyl-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid and 30 ml of 10% aqueous hydrochloric acid was heated at 90° - 95°C for 1 hour. The reaction mixture was concentrated to dryness and addition of ethanol to the residue resulted in the separation of a solid, which was collected and washed with ethanol to yield 1.7 g of the product, m.p. above 300°C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11]COC)[CH:5]=[C:4]([O:15]COC)[C:3]=1[C:19](=[O:32])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]COC)=[CH:24][CH:23]=1.Cl.CO>CO>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][C:19]([C:3]2[C:4]([OH:15])=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[OH:1])=[O:32])=[CH:27][CH:26]=1
Reactant: CCCc1c(OCOC)cc(OCOC)c(C(=O)CCc2ccc(OCOC)cc2)c1O
Agent: Cl
Solvent: CO
Product: CCCc1c(O)cc(O)c(C(=O)CCc2ccc(O)cc2)c1O
Yield: 69.2 %

Procedure:
Then, 20.9 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-n-propylphenyl]-3-(4-methoxymethoxyphenyl)-1-propanone was dissolved in 40 ml of methanol, and 20 ml of a 5-15% hydrochloric acid/methanol reagent was added to the solution and the mixture was heated and refluxed for 2 hours. The temperature was lowered to room temperature, 200 ml of a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The solvent was removed from the ethyl acetate layer by distillation and the obtained residue was subjected to the polyamide column chromatography (diluting solvent=methanol) and recrystallized from benzene to obtain 10.2 g (yield=69.1%) of 3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxy-3-n-propylphenyl)-1-propanone in the form of a yellow prism.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].C(OCC)(=O)C.CO.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([C:32]#[N:33])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ncc(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 99.8 %

Procedure:
A degassed suspension of 5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid methyl ester (1.35 g, 3.82 mmol), zinc (II) cyanide (492.8 mg, 4.2 mmol, 1.1 eq.), and Pd(PPh3)4 (551.0 mg, 0.48 mmol, 0.12 eq.) in anhydrous dimethylformamide (30 mL) was subjected to microwave irradiation at 150° C. for 18 minutes. The reaction mixture was poured into ethyl acetate and then filtered through a pad of Celite®. The pad was rinsed well with ethyl acetate (2×). The combined filtrates were washed with 50% brine (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 30% ethyl acetate in hexane) to give a brown oil. Trituration with MeOH afforded the desired compound as an orange solid (1.31 g, 99.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.56 (s, 1H), 8.36 (s, 1H), 8.29 (t, J=7.82 Hz, 1H), 7.37-7.27 (m, 2H), 4.10 (s, 3H), 0.29 (s, 9H); LCMS (method D1): RT=1.28 min, [M+H]+=345.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:27])([CH2:24][CH2:25][CH3:26])[CH2:10][O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:21][CH3:22])[NH:18]2)=[C:14]([NH2:23])[N:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.CCOC(C)=O>[CH3:8][C:9]([CH3:27])([CH2:24][CH2:25][CH3:26])[CH2:10][O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:21][CH3:22])[N:18]2[CH2:35][CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:14]([NH2:23])[N:13]=1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 2-[(2,2-dimethylpentyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (252 mg) in dry DMF (3.97 mL) was added potassium carbonate (356 mg). The mixture was stirred at 60° C. for 90 mins. The reaction was cooled and 4-(bromomethyl)tetrahydro-2H-pyran (127 mg) was added. The mixture was stirred at 50° C. for 6 h. The reaction was cooled and taken up in EtOAc (40 mL). The mixture was washed with water (2×20 mL) and the organics were separated, dried over MgSO4 and concentrated in vacuo to give a viscous oil. The crude material was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (30-80%) to afford the title compound as an off-white solid (116 mg).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:14][CH2:13][CH2:12]3)[O:10][C:9](=[O:15])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:17]1[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:15]=[C:9]1[N:8]([C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:22])=[CH:19][CH:18]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2([CH2:14][CH2:13][CH2:12]2)[O:10]1
Reactant: O=C1NC(c2ccccc2)C2(CCC2)O1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cccc2cccnc12)c1ccc(N2C(=O)OC3(CCC3)C2c2ccccc2)cc1
Temperature: 90 °C
Yield: 9.9 %

Procedure:
A mixture of 8-phenyl-5-oxa-7-azaspiro[3.4]octan-6-one (0.3 g, 1.57 mmol), 4-iodo-N-(quinolin-8-yl)benzamide, (0.650 g, 1.73 mmol), Cs2CO3 (1.125 g, 3.47 mmol), X-Phos (40 mg, 0.07 mmol) and Pd2(dba)3 (73 mg, 0.07 mmol) in 1,4-dioxane (2 mL) in a 50 mL round bottom flask was purged with N2 gas for 15 minutes. The reaction mixture was then heated at 90° C. for 12 hours. After completion of reaction (monitored by TLC, TLC eluent: 30% EtOAc in hexane), the reaction mixture was cooled, and 1,4-dioxane was evaporated under reduced pressure to afford initial product. The initial product was purified by column chromatography using silica gel eluting with 20% EtOAc in hexane to yield (R+S) 4-(6-oxo-8-phenyl-5-oxa-7-azaspiro[3.4]octan-7-yl)-N-(quinolin-8-yl)benzamide (70 mg, 12%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ: 10.65 (s, 1H), 8.88 (dd, J=7.2, 1.6 Hz, 1H), 8.83-8.81 (m, 1H), 8.18 (dd, J=8.4, 1.6 Hz, 1H), 7.99-7.96 (m, 2H), 7.67-7.64 (m, 2H), 7.59-7.51 (m, 2H), 7.49-7.45 (m, 1H), 7.43-7.34 (m, 3H), 7.29-7.26 (m, 2H), 5.23 (s, 1H), 2.68-2.63 (m, 1H), 2.48-2.43 (m, 1H), 2.22-2.18 (m, 1H), 1.96-1.91 (m, 1H), 1.76-1.71 (m, 1H), 1.62-1.57 (m, 1H). m/z (ESI) 450.1 (M+H)+.
Reaction SMILES: [CH:1]1([OH:9])[CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Cl-].[NH4+].[Na]>ClCCl>[CH3:17][S:18]([O:9][CH:1]1[CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: OC1CCN2CCCC12
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN2CCCC12
Temperature: 0 °C
Yield: 66.8 %

Procedure:
A mixture of perhydro-1-pyrrolizinol (0.5 g, 3.94 mmol) and triethylamine (0.60 g, 5.91 mmol) in dichloromethane (10 ml) was stirred at 0° C. under an atmosphere of nitrogen. Methanesulfonyl chloride (0.68 g, 5.91 mmol) was added, then the mixture was allowed to warm to ambient temperature and stirred for 8 hours. Saturated aqueous ammonium chloride (10 ml), dichloromethane (25 ml) and saturated aqueous sodium bicarboante (10 ml) were added. The organic layer was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (1:3) as an eluent yielded perhydro-l-pyrrolizinyl methanesulfonate (0.54 g): 1H NMR (DMSO-d6, 400 MHz) δ 4.96 (m, 1H), 3.61 (m, 1H), 2.9-3.3 (m, 6H), 2.35 (m, 1H), 1.55-2.25 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].[C:9]([O:13][C:14](=[O:37])[NH:15][C:16]([C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[C:28](B)[C:27]=2O)(=[O:25])=[O:24])[CH:22]=1)=[NH:17])([CH3:12])([CH3:11])[CH3:10].C(O)C.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:9]([O:13][C:14](=[O:37])[NH:15][C:16](=[NH:17])[C:18]1[S:19][C:20]([S:35][CH3:36])=[C:21]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH3:8])[CH:31]=2)(=[O:25])=[O:24])[CH:22]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1cnccc1Br
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccncc2C)c1
Yield: 41 %

Procedure:
4-Bromo-3-methyl-pyridine (100 mg, 0.219 mmol, Example 138: step b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (266 mg, 0.58 mmol, Example 140: step a) and Pd(PPh3)4 (134 mg, 0.12 mmol) were combined in aqueous Na2CO3 (2M, 2 mL), ethanol (2 mL) and toluene (4 mL) and heated to 80° C. overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo. Purification by flash column chromatography (10% DCM/MeOH) afforded the title compound (120 mg, 41%). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 504.1 (M+1); found: 503.7.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH:7]([CH3:9])[O:6][C:5]1=[O:10])(=O)[CH3:2].[OH-].[Na+].[CH:13]1(C=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>C(OC(OCC)CC)C>[CH:2]1([CH:1]=[C:4]2[CH2:8][CH:7]([CH3:9])[O:6][C:5]2=[O:10])[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)C1CC(C)OC1=O
Reactant: O=CC1CCCCC1
Agent: CCOC(CC)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(=CC2CCCCC2)C(=O)O1
Yield: 97.8 %

Procedure:
Example I was repeated using propionaldehyde diethyl acetal as the azeotroping solvent for the reaction. For the reaction 100 ml propionaldehyde diethyl acetal was charged to the reactor with 14.9 g (0.10 mole) 3-acetyl-5-methyldihydro-2(3H)-furanone. The mixture was stirred and 4 g (0.10 mole) powdered sodium hydroxide added. The mixture was allowed to stir for 10 minutes and then heated to reflux for 51/2 hours after which time 14.0 g (0.125 mole) cyclohexanecarboxaldehyde was added over a one-hour period. The mixture was heated under reflux for an additional twelve hours, cooled and worked up to recover 19 g crude 3-cyclohexylmethylene-5-methyldihydro-2(3H)-furanone (59% yield). The structure of the product was confirmed by proton and carbon nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH:33](O)=[O:34]>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH:33]=[O:34])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: O=CO
Agent: Cl
Product: O=CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1

Procedure:
In a similar manner to Example 4 except for the use of 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride and formic acid as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Br:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[C:34]([S:38]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:40])=[O:39])[CH:35]=[N:36][CH:37]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 1c using (R)-1-(4-Fluorophenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 5-bromopyridine-3-sulfonyl chloride. LCMS (Method D): 533 (M+H)+, Retention time 4.1 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:6][CH:5]=1)(O)=[O:2].B.CSC.B.CO>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C1CC(Oc2ccc(C(=O)O)cc2)N1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: O=C1CC(Oc2ccc(CO)cc2)N1
Reaction time: 8 h

Procedure:
To a solution of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl)]-4-(4-carboxyphenoxy)-azetidin-2-one (1.04 g, 2.30 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. was added dropwise with stirring under a nitrogen atmosphere a 2.0M solution of borane-methyl sulfide in tetrahydrofuran (3.0 mL, 6 mmol). The solution was allowed to attain room temperature and stirred overnight. Excess borane was decomposed by slow addition of methanol. The solution was evaporated, and the crude product was subjected to flash chromatography on silica gel using 30% ethyl acetate in hexane as the mobile phase. (4S)-3,3-Diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl)]-4-[4-(hydroxymethyl)-phenoxy]-azetidin-2-one was obtained as a colorless oil. Triphenylphosphine (637 mg, 2.43 mmol) was dissolved in acetonitrile (11 mL) and bromine (0.12 mL) was added with stirring to give rise to a yellow-orange solution. Additional triphenylphosphine was added until a faintly yellow solution was obtained. A solution of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl]-4-[4-(hydroxymethyl)-phenoxy]-azetidin-2-one (1.0 g, 2.28 mmol) in acetonitrile (10 mL) was added dropwise with stirring. The reaction mixture was stirred ovenight at room temperature, evaporated, and the crude mixture subjected to flash chromatography on silica gel using 5% ethyl acetate in hexane as the mobile phase.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:13]
Reactant: NC(=O)c1ccc2ccccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
Naphthalene-2-carboxylic acid amide (0.8 g, 1 eq, 4.678 mmol) was dissolved in THF (80 mL) and the solution was cooled down to 0-5° C. A 1.0 M solution of Lithium Aluminium Hydride (LAH) in THF (1.42 g, 8.0 eq, 37.0 mmol) was added drop-wise at 0-5° C. The reaction mixture was stirred at RT overnight. After completion of the reaction (confirmed by TLC), ethyl acetate at 0-5° C. was slowly added to quench the excess LAH in reaction mixture followed by the addition of saturated sodium sulphate solution (2 mL). The reaction mass was filtered through a hy-flow bed and the filtrate was concentrated in vacuo to afford the crude product.
Reaction SMILES: N#N.[CH3:3]C[O-].[Na+].[CH2:7]([O:9][C:10](=[O:19])[CH:11]([C:16](=[O:18])[CH3:17])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:8].[I-]>C(O)C>[CH2:7]([O:9][C:10](=[O:19])[C:11]([C:16](=[O:18])[CH3:17])([CH3:3])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:8]
Reactant: C=C(C)CC(C(C)=O)C(=O)OCC
Reactant: CC[O-]
Agent: N#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CC(C)(C(C)=O)C(=O)OCC
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 2000 ml flask, equipped with mechanical stirring, a condenser and N2 atmosphere, is charged with 24.3 g of N2 and 400 ml of ethanol to prepare sodium ethylate. After cooling to 15° C., the ethyl-2-acetyl-4-methyl-4-pentenoate (161.4 g) is added to the solution over 30 min while maintaining the temperature at 15° C.-20° C. To this is then added, all at once, 15 g of iodide. The exothermic reaction is controlled with an ice bath to keep the temperature at 30° C. for about 90 min. Stirring is continued over 2 hrs and 30 min at 20° C., and the mixture is then taken to reflux for 4 hrs. The reaction mixture is left at rest for 56 hrs, and then the NaI precipitate is filtered. Toluene (700 ml) is added and the mixture filtered again. Toluene/ethanol azeotrope (700 ml) (rotavapor. 74° C./6× 104Pa) is distilled and 250 ml of the distillate is added to the residue. After cooling to 5° C., a new filtration is carried out. The filtrate is evaporated (74° C./2.7×104Pa). Raw product is purified on a Vigreux column, and then in a glass bolos column topped by a total reflux head, to yield ethyl-2-acetyl-2,4-dimethyl-4-pentenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>CN(C)C=O.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]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[N:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(Cl)nn1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(Cl)OC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3c(cc2F)C(c2ccc(Cl)c(Cl)c2)CNC3)nn1
Yield: 3.5 %

Procedure:
Following the procedure in Step A and Step B of Example 19, 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), 3-chloro-6-methylpyridazine (282 mg, 2.2 mmol), cesium carbonate (1.08 mg, 3.3 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed by N-de-methylation with N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (471 mg, 2.2 mmol) and 1-chlorethyl chloroformate (0.48 mL, 4.4 mmol) gave 4-(3,4-dichlorophenyl)-6-fluoro-7-(6-methylpyridazin-3-yl)-1,2,3,4-tetrahydroisoquinoline (15 mg, 3%, 2 steps) as a green solid: 1H NMR (CDCl3, 500 MHz) δ 7.95 (d, J=7.8 Hz, 1H), 7.83 (dd, J=8.8, 1.9 Hz, 1H), 7.42-7.35 (m, 3H), 7.00 (dd, J=8.3, 1.9 Hz, 1H), 6.70 (d, J=12.0 Hz, 1H), 4.23-4.09 (m, 3H), 3.42 (dd, J=12.9, 5.3 Hz, 1H), 3.06 (dd, J=12.9, 6.7 Hz, 1H), 2.77 (s, 3H); ESI MS m/z 388, 390 [M+H]+.