Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:16][CH3:17])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=1.[Br:18][C:19]1[C:20]([O:26][C@H:27]([CH3:31])[C@H:28]([OH:30])[CH3:29])=[N:21][C:22](Cl)=[N:23][CH:24]=1.Cl>C(#N)C.O1CCOCC1>[Br:18][C:19]1[C:20]([O:26][C@H:27]([CH3:31])[C@H:28]([OH:30])[CH3:29])=[N:21][C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:16][CH3:17])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: CCOC(=O)N=S(=O)(CC)c1ccc(N)cc1
Reactant: C[C@@H](O)[C@@H](C)Oc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CCOC(=O)N=S(=O)(CC)c1ccc(Nc2ncc(Br)c(O[C@H](C)[C@@H](C)O)n2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
128 mg (0.51 mmol) of (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-ethyl sulfoximide and 150 mg (0.53 mmol) of (2R,3R)-3-[(5-bromo-2-chloropyrimidin-4-yl)oxy]-butan-2-ol in 2 ml of acetonitrile are mixed with 0.12 ml of a 4N solution of HCl in dioxane. The batch is stirred for 2 days at 60° C. The solvent is removed, and the residue is purified by chromatography (DCM/EtOH 95:5). 43 mg (0.09 mmol, corresponding to 17% of theory) of the product is obtained.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[N:6][C:7]=1[Br:8].N([O-])=O.[Na+].[ClH:18]>O.Cl[Cu]>[Br:8][C:7]1[N:6]=[C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:4]=[CH:3][C:2]=1[Cl:18]
Reactant: COC(=O)Nc1ccc(N)c(Br)n1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(Cl)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of methyl 5-amino-6-bromopyridin-2-ylcarbamate (100 mg, 0.41 mmol) and CuCl (120 mg, 1.6 mmol) in HCl (28%, 10 mL) was added and NaNO2 (29 mg, 0.41 mmol) at 0° C. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-chloropyridin-2-ylcarbamate (80 mg, 75%). 1H NMR (400 MHz, CDCl3) □ 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (brs, 1H), 3.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Reactant: C1CNCCN1
Product: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Yield: 52.1 %

Procedure:
Beginning with 3,5-dichlorobenzotrifluoride (500 mg, 2.32 mmol) and piperazine (1 g, 11.6 mmol), 320 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C[Si]([O:29][Si](C)(C)C)(C)C.[K].[Si](O[K])(C)(C)C>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:5]3[N:6]([C:8](=[O:11])[NH:9][N:10]=3)[NH:7][C:2](=[O:29])[C:3]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:13][CH:14]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccncc3)c(Cl)nn12
Reactant: C[Si](C)(C)O[Si](C)(C)C
Agent: C[Si](C)(C)O[K]
Agent: [K]
Solvent: C1CCOC1
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 32 %

Procedure:
To the solution of 6-Chloro-8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (29 mg, 0.081 mmol), prepared as described in Example 9, in THF (3 ml) was added potassium trimethylsilyloxide, TMSOK, (36 mg, 0.28 mmol). The solution was heated to refluxed for 15 min. After this time, the solution was cooled to RT. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound, 8-(4-chlorophenyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (12 mg, 32%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH:6]([CH2:21][CH:22]=[NH:23])[S:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3.N[C:25]1[CH:30]=CC=[CH:27][CH:26]=1>C(O)C>[OH:1][CH2:2][CH:3]1[CH:8]2[C:9]3[C:14]([CH2:15][CH2:16][N:7]2[CH:6]([CH:21]2[CH:27]=[CH:26][CH:25]=[CH:30][C:22]2=[NH:23])[S:5][CH2:4]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3
Reactant: Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C1C(CO)CSC(CC=N)N1CC2
Solvent: CCO
Product: COc1cc2c(cc1OC)C1C(CO)CSC(C3C=CC=CC3=N)N1CC2
Yield: 62 %

Procedure:
3.4 g (0.01 mole) of 1-(hydroxymethyl)-4-(iminoethyl)-9,10-dimethoxy-1,6,7,11b-tetrahydro-2H,4H-[1,3]thiazino[4,3-a]isoquinoline are refluxed with 1.86 g (0.02 mole) of aniline in 30 ml of ethanol for 5 hours. The excess of ethanol and aniline is distilled off and crystallized from ethanol to yield the desired compound, melting at 187° to 189° C. Yield: 62%.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(O)(=O)C.[O:8]1[CH:13]2[CH:9]1[C:10](=O)[CH2:11][C:12]2([O:25][Si](C)(C)C)[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CO.C(N(CC)CC)C>[CH3:1][S:2][C:10]1[C:9](=[O:8])[CH2:13][C:12]([OH:25])([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1
Reactant: C[S-]
Reactant: C[Si](C)(C)OC1(CCCCOc2ccccc2)CC(=O)C2OC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a solution of 25 mg of sodium thiomethoxide dissolved in methanol, 51 μl of acetic acid was added, and the mixture was stirred for 10 minutes. Triethylamine (170 μl ) was then added, and after the mixture was stirred for 10 minutes, a solution of 16 mg of 2,3-epoxy-4-trimethylsilyloxy-4-(4-phenoxybutyl)cyclopentanone obtained in Example 51 in 3 ml of methanol was added and the mixture was stirred for 5 hours. Then saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to obtain 7.1 mg (yield 51%) of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=2)(=[O:24])=[O:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1

Procedure:
Starting from compound D1 and 3-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as described for compound D4.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>CN(C)C=O>[O:1]([CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCOc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCOc1ccccc1

Procedure:
252.3 g (1.40 mole) of 4-phenoxybutyric acid, 154 ml (2.1 mole) of thionyl chloride and a few drops of dimethylformamide are heated under reflux with exclusion of moisture. After evolution of gas has ceased (about 2 hours), the mixture is fractionated under water pump vacuum. The acid chloride distils at 149°-151° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25])[C:16](O)=[O:17].C(OCC)C>[OH-].[K+].O>[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25])[CH2:16][OH:17]
Reactant: CCCOc1ccc(C(=O)O)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc(CO)cc1N
Yield: 86.2 %

Procedure:
The preparation of part I of Example 1 was repeated with two major changes. The amounts of material employed were increased by a factor of about 10. The reduction in step (e) was carried out differently. To a solution of 1.1 g of lithium aluminum hydride (Alfa Inorganics-Ventron) in 50 ml of scrupulously dried tetrahydrofuran was added dropwise with stirring 2 g of 3-amino-4-n-propoxybenzoic acid in 100 ml of scrupulously dried tetrahydrofuran. The mixture was refluxed for 20 minutes, cooled, diluted with 1 ml of 15% potassium hydroxide and 3 ml of water. Then 150 ml of diethyl ether was added to extract the product. The ether extract was separated, dried and evaporated to yield 1.6 g of the 3-amino-4-n-propoxybenzyl alcohol product, mp 94°-95°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[C:31]([O:33]COC)[CH:30]=[CH:29][C:10]=1[C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:10]=1[C:11]1[CH2:12][O:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Agent: Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Oc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 85.7 %

Procedure:
To a solution of 2′,7-dibenzyloxy-4′-methoxymethyloxy-isoflav-3-ene (0.480 g, 1 mmol) in acetonitrile:water (20 mL:1 mL) was added triphenyl phosphine hydrobromide (0.788 g, 2 mmol). The reaction was heated to 50° C. for ca. 2 hrs. After disappearance of the starting material (TLC), the solvent was evaporated at 20° C. The residue was extracted with EtOAc:water (3×10 mL:10 mL). The organic layers were combined, dried and evaporated. The residue was chromatographed over silica using hexanes:EtOAc (5:1). The organic fractions were evaporated to provide 0.374 g (78%) of product as an oil. Because of the instability of this intermediate, it was immediately used for the next step: TLC Rf0.43, in hexanes:EtOAc (5:1); 1H NMR (600 MHz, DMSO-d6) δ 9.66 (s, 1H, OH), 7.46-7.32 (m, 10H, 2×CH5), 7.14, 7.13 (d, 1H, J=8.4 Hz, Ar—H5), 7.01-6.99 (d, 1H, J=7.8 Hz, Ar—H6′) 6.57-6.55 (m, 2H, H4/Ar—H5′), 6.59-6.52 (d, 1H, J=2.4 Hz, Ar—H8), 6.48-6.47 (d, 1H, J=2.4 Hz, Ar—H3′), 6.41-6.39 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 5.07 (s, 4H, PhCH2), 4.85 (s, 2H, H2).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXVIII) (8.00 g, 30.4 mmol) was taken in neat oxalyl chloride (20 ml), 0.2 ml of DMF were added and the mixture was stirred at room temperature for 1 hour. The completion of reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. The reaction mixture was concentrated under reduced pressure to provide (R)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXIX) (8.33 g) which was directly used in the next reaction.
Reaction SMILES: CN(C)[CH:3]=[O:4].S(Cl)(Cl)=O.[Cl:10][C:11]([Cl:24])([Cl:23])[CH:12]1[NH:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13]1>O>[CH:3]([N:17]1[C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH:12]1[C:11]([Cl:10])([Cl:23])[Cl:24])=[O:4]
Reactant: CN(C)C=O
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=CN1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethylformamide (20 ml.) and thionyl chloride (5 ml.) were stirred together, 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (2.0 g.) was added in small portions over 15 minutes, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was added to water (100 ml.), stirred for 1 hour and filtered. The solid product was dissolved in toluene, and purified by column chromatography on "Kieselgel"-60 (trade mark), eluting with a mixture of 5% by volume of ethyl acetate in toluene. The solvent was evaporated, and the product was crystallised from petroleum ether (b.p. 60°-80° C.) to give 3-formyl-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 114° C.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]2[O:7][C:8]([CH3:24])([CH3:23])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([C:17](OCC)=[O:18])=[CH:13][C:12]3=[O:22])[C:5]=2[CH:4]=1)#[N:2].[BH4-].[Li+].P([O-])([O-])([O-])=O.Cl>O1CCCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]2[O:7][C:8]([CH3:23])([CH3:24])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]3=[O:22])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC1(C)C=C(n2ccc(CO)cc2=O)c2cc(C#N)ccc2O1
Yield: 52.9 %

Procedure:
In 4 ml of anhydrous tetrahydrofuran, is dissolved 350 mg of 6-cyano-2,2-dimethyl-4-(4-ethoxycarbonyl-1,2-dihydro-2-oxo-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 21. Then, 0.50 ml of 2.0M solution of lithium borohydride in tetrahydrofuran is added to the solution at room temperature and reacted at room temperature for 1.5 hours. After stopping the reaction by adding 0.2M phosphate buffer, the insoluble matter is solubilized by adding 2N aqueous hydrochloric acid. Then, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 1/20 mixture of methanol/methylene chloride as a developing solvent to obtain 163 mg of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-hydroxymethyl-1-pyridinyl)-2H-benzo[b]pyran.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Product: Fc1ccc(-n2nccc2-c2ccnc(NCc3ccccc3)c2)cc1
Temperature: 180 °C
Yield: 89 %

Procedure:
A mixture of 2-chloro-4-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (Example 46; 0.56 g, 0.002 mol) and benzylamine (20 mL) was heated at 180° C. overnight (about eighteen hours). The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.63 g (89% yield) of product as a white solid: mp: 125-127° C.; Anal. Calc'd. for C22H17FN4: C, 73.24; H, 4.98; N, 16.27. Found: C, 72.89; H, 4.69; N, 15.82.
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2)[CH3:2].[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:15])[CH:5]=3)[C:10]2=[O:14])[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CCN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCN(C)c1ccc2c(c1)CCN(c1cccc(Br)c1COC(C)=O)C2=O
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
6-(Ethyl-methyl-amino)-3,4-dihydro-2H-isoquinolin-1-one (2.07 g, 10.1 mmol), acetic acid 2,6-dibromo-benzyl ester (6.25, 20.3 mmol), cuprous iodide (386 mg, 2.03 mmol) and potassium carbonate (1.40, 10.1 mmol) were deposited in a sealed vessel. 30 mL DMSO was added. Argon was bubbled through the mixture for 3 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (386 mg, 2.03 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with 300 mL ethyl acetate and 300 mL water. After stirring for 20 minutes, this was filtered through a pad of celite. The layers were separated. The ethylacetate layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield acetic acid 2-bromo-6-[6-(ethyl-methyl-amino)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-benzyl ester (1.21 g, 2.81 mmol). MS (ESI) 433.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12][C:13](=[O:18])[NH:14][CH2:15][C:16]#[CH:17])([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>CS(C)=O>[C:3]([O:7][C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12][C:13]1[O:18][C:16]([CH3:17])=[CH:15][N:14]=1)([CH3:5])([CH3:4])[CH3:6]
Reactant: C#CCNC(=O)CCCNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cnc(CCCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
Sodium hydride (60 mg, 60% dispersion) was added to a mixture of (3-prop-2-ynylcarbamoylpropyl)carbamic acid tert-butyl ester (0.5 g) and dimethylsulfoxide (10 mL) under argon. The mixture was stirred at rt for 4 h. Saturated aqueous ammonium chloride (30 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (2×). Combined ethyl acetate layers were washed with water (1×), dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (20 to 30% ethyl acetate in hexanes) to give [3-(5-methyloxazol-2-yl)-propyl]carbamic acid tert-butyl ester (150 mg). HCl in dioxane (4M, 3 mL) was added to [3-(5-methyl-oxazol-2-yl)-propyl]-carbamic acid tert-butyl ester (250 mg). The mixture was stirred at rt for 2 h and was evaporated to dryness in vacuo to give the HCl salt of 3-(5-Methyloxazol-2-yl)propylamine (228 mg). ESI-MS (m/z) 141 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: C(OC(=O)[CH:5]([C:23]#[N:24])[C:6]1[S:7][CH:8]=[C:9]([C:11]([N:13]2[C@@H:22]3[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=1)C.[Cl-].[Li+]>CS(C)=O.C(Cl)Cl>[N:13]1([C:11]([C:9]2[CH:10]=[C:6]([CH2:5][C:23]#[N:24])[S:7][CH:8]=2)=[O:12])[C@@H:22]2[C@@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C(C#N)c1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCc1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
cis-Cyano-[4-(octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-acetic acid ethyl ester (0.168 g, 0.46 mmol) and lithium chloride (0.5 mmol) were dissolved in DMSO (5 mL) and heated to 160° C. by microwave irradiation for one minute. The solution was diluted with DCM (10 mL) and washed with water. The resulting organic solution was dried and the solvent evaporated to give an oil which was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.025 g). LCMS m/z 289.25 [M+H]+ RT=10.02 min (Analytical Method 2).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][P:18]([CH3:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])=[CH:14][CH:15]=2)[C:10]([C:27]2[N:28](C(OC(C)(C)C)=O)[C:29]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:31][CH:30]=3)=[N:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:39]1([CH2:38][CH2:37][O:36][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([C:10]2[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([O:17][P:18]([CH3:26])([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:19])[CH:12]=4)[NH:8][N:9]=2)=[CH:35]3)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OP(C)(=O)c3ccccc3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(=O)(Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of 10.5 mg of 3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-5-(methylphenylphosphinoyloxy)indazole-1-carboxylic acid tert-butyl ester in a mixture of 500 μl of dichloromethane and 500 μl of trifluoroacetic acid is agitated at ambient temperature for 4 hours. The reaction medium is evaporated under a stream of nitrogen and then redissolved in 1.4 ml of DMSO. The solution obtained is stirred at 60° C. for 3 days and then purified by LC/MS to obtain 5.1 mg of methylphenylphosphinic acid 3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester.