Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[CH:10])=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1/[C:19](=[CH:27]/[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34])/[C:20](=[O:26])[NH:21]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:11])[C:9]#[C:10][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2/[C:19](=[CH:27]/[C:28]2[NH:29][CH:30]=[CH:31][C:32]=2[O:33][CH3:34])/[C:20](=[O:26])[NH:21]3)=[C:4]([O:12][CH2:13][S:14][CH3:15])[CH:3]=1
Reactant: C#CC(O)c1ccc(Cl)cc1OCSC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(Cl)cc3OCSC)c21

Procedure:
Using Method D above, 3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propyne (158 mg, 0.65 mmol) (from Example 53 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (152 mg, 0.48 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (40 mg) (Aldrich) and CuI (22 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, yielding rac-(Z)-4-[3-(4-chloro-2-methylsulfanylmethoxy-phenyl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 132 mg, 57%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH2:31](OB(C=C)OCCCC)[CH2:32]CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([CH:31]=[CH2:32])=[CH:22][C:20]=2[CH:21]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB(OCCCC)OCCCC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(Br)ccc2o1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=Cc1ccc2oc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a mixture of 2027 mg (4.7 mmol) {2-[(5-Bromo-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (56) and 289 mg (0.25 mmol) Pd(Ph3)4 in 40 ml toluene were added 1.84 ml of a 5.4M solution of sodium methoxide in methanol and 957 mg (5.2 mmol) vinylboronic acid dibutyl ester and the solution was heated at 90° C. for 3 h. The reaction mixture was poured on 5% aqueous citric acid. Extraction with ethyl acetate, washing of the organic phase with brine. The organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethylacetate 2:1) to give 1530 mg (4.04 mmol) {2-[(5-Vinyl-benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (57).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:15]3[CH:7]([CH2:8][N:9]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[C:10]=3[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][C:3]1=[O:24].Cl>CCOC(C)=O>[CH3:1][N:2]1[C:14]2[C:15]3[CH:7]([CH2:8][N:9]([CH2:16][C:17]([OH:19])=[O:18])[C:10]=3[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CCCC2CN(CC(=O)OC(C)(C)C)c3cccc1c32
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)CCCC2CN(CC(=O)O)c3cccc1c32
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl (7-methyl-6-oxo-2a,3,4,5,6,7-hexahydroazocino[4,3,2-cd]indol-1(2H)-yl)acetate, enantiomer A, from Step G (18 mg, 0.057 mmol) in EtOAc (1 mL) was saturated with HCl (g), aged at ambient temperature for 10 min, then resaturated with HCl (g). After a further 10 min, the mixture was concentrated in vacuo to give the title compound. MS: m/z=275 (M+1).
Reaction SMILES: O[C@@H:2]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH2:3][CH3:4].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].O.[N:17]1[CH:22]=CC=C[CH:18]=1>C(OC(=O)C)(=O)C>[CH3:18][N:17]([CH3:22])[C@@H:2]([C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)[CH2:3][CH3:4].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: CC[C@@H](O)[c-]1cccc1
Reactant: c1ccncc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC[C@H]([c-]1cccc1)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g (38.6 mmol) of crude (R)-(1-hydroxypropyl)ferrocene in 10 ml of pyridine and 10 ml of acetic anhydride was stirred at room temperature for 18 hours. The reaction mixture was admixed with 50 ml of water and extracted three times with 200 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated on a rotary evaporator. The formation of the acetylated (R)-(1-hydroxypropyl)ferrocene can be followed by 1H NMR spectroscopy (δCHOAc =5.72-5.66, "dd", 1H). The crude (R)-(1-acetoxypropyl) ferrocene was stirred overnight at room temperature with 100 ml of isopropyl alcohol and 75 ml of dimethylamine (50% in water). The mixture was subsequently subjected to an aqueous work-up and extracted three times with 200 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH3:17])=[O:13])=[N:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>O1CCCC1>[Br:1][C:2]1[C:7]([C:8](=[S:27])[NH2:10])=[CH:6][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH3:17])=[O:13])=[N:4][CH:3]=1
Reactant: CCCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A suspended mixture of 5-bromo-2-(3-propylureido)isonicotinamide (Intermediate 43, 123 g, 407 mmol), Lawesson's Reagent (131.6 g, 326 mmol), and tetrahydrofuran (1.55 L) was stirred at 70° C. for 18 h. Stirring was stopped and a bright yellow precipitate was allowed to settle. The precipitate was then vacuum filtered and washed with methyl tert-butyl ether (2×500 L). This solid was then dried in the vacuum oven at 50° C. for 12 hours to give 50 g of product solid. The mother liquor was concentrated and the residue was suspended in toluene (300 mL). The solid thus obtained was filtered and combined with the previous solid. The combined totaled 110 g (85%) of 5-bromo-2-(3-propylureido)pyridine -4-carbothioamide as an off white solid
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:16][CH3:15])=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: C[O-]
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(OC(C)C)c1
Temperature: 65 °C
Yield: 94.3 %

Procedure:
A mixture of 5.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 4.07 g of sodium methoxide and 200 mg of 18C6 in 100 ml of methanol is heated at 65° C. for 2 h. The mixture is then concentrated and the residue is taken up with a mixture of water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to obtain 5.0 g of 1-nitro-4-methoxy-2-(propan-2-yloxy)benzene.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccnc(Cl)c1

Procedure:
5.0 g (36.5 mmol) of 4-acetyl-pyridine N-oxide and 6.64 ml (73 mmol) of phosphorus oxychloride are stirred in 50 ml of toluene for 2 h at 100°. The reaction mixture is stirred at 50° into 500 ml of 10N sodium hydroxide solution, extracted with ethyl acetate and treated with Tonsil (Fluka; bentonite--colloidal aqueous aluminium silicate). Concentration and crystallisation (diethyl ether/n-hexane) give 4-acetyl-2-chloro-pyridine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1
Reactant: OCc1csc(-c2c(F)cccc2Cl)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=Cc1csc(-c2c(F)cccc2Cl)n1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
To a stirred solution of (2-(2-chloro-6-fluorophenyl)thiazol-4-yl)methanol (5.8 g, 24 mmol) in EtOAc (200 mL) at room temperature was added 2-iodoxybenzoic acid (12.5 g, 44.6 mmol). The resulting mixture was heated at 70° C. for 18 hours. After cooling to room temperature, the residual solid was removed via filtration and the filtrate was concentrated under reduced pressure to give the crude desired product as a white solid (5.4 g, 93% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3](C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50](OC)=[O:51])=[N:48][CH:47]=[N:46]2)=[CH:31][CH:30]=1.CNC>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([N:2]([CH3:3])[CH3:1])=[O:51])=[N:48][CH:47]=[N:46]2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CNC
Product: CN(C)C(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and dimethylamine. 1H-NMR (400 MHz, CDCl3, δ) 8.21 (d, J=6.9 Hz, 1H), 7.97 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.34 (m, 1H), 6.94 (m, 1H), 5.80 (s, 2H), 3.21 (s, 3H), 3.13 (s, 3H) ppm; m/e 241, 243.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][O:10][N:11]([CH3:23])[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([N:11]([O:10][CH3:9])[CH3:23])=[O:13])=[CH:15][CH:16]=2)=[N:3][CH:4]=1
Reactant: CON(C)C(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CON(C)C(=O)c1ccc(-c2ccc(F)cn2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
Palladium tetrakis(triphenylphosphine) (1.38 g, 1.2 mmol) was added to a degassed, ambient temperature solution of 2-bromo-5-fluoropyridine (5 g, 28.4 mmol) and (4-{[methoxy(methyl)amino]carbonyl}phenyl)boronic acid (5 g, 23.9 mmol) and potassium carbonate (4.3 g, 31.1 mmol) in toluene/methanol (9.5:1) (105 mL). After stirring at 90° C. for 1.5 hr, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded 4-(5-fluoropyridin-2-yl)-N-methoxy-N-methylbenzamide.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]([O:12]CC)=[O:11])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[OH-].[Na+].Cl>>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]([OH:12])=[O:11])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OC(C(=O)OCC)c2ccc(OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OC(C(=O)O)c2ccc(OC)cc2)ccc(C(C)=O)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
A mixture of 4.5 g of Ethyl 2-(4-acetyl-2-n-propyl-3-hydroxyphenoxy)-2-(4-methoxyphenyl)acetate and 150 ml of 1 Normal sodium hydroxide was stirred at 80° C. for 2 hours. The reaction mixture was then cooled, acidified with 1 Normal hydrochloric acid, extracted with ethyl acetate, treated with charcoal, filtered and concentrated to dryness to give an oily residue which was crystallized from EtOAc/hexane, yielding 0.9 g of product, melting point 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C(OCC)(=O)C.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]>[CH2:9]([O:8][C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(C)nc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Yield: 88 %

Procedure:
2-Bromo-4-ethoxy-6-methylpyridine (108 mg, 0.5 mmol), tert-butyl piperazine-1-carboxylate (140 mg, 0.75 mmol), Pd2(DBA)3 (10 mg, 0.011 mmol), sodium tert-butoxide (80 mg, 0.825 mmol) and BINAP (20 mg, 0.032 mmol) were placed in anhydrous THF (3 ml) under argon and heated at 80° C. for 30 minutes under microwave heating. The mixture was diluted with ethyl acetate, filtered through kieselguhr and concentrated under reduced pressure. The residue was dissolve in DCM and filtered through a plug of silica. The filter was washed with a mixture of DCM and diethylether, the combined filtrates were concentrated to dryness under reduced pressure to give 141 mg (0.44 mmol, 88% yield) MS (multi-mode) m/z=322.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:41])[CH:16]=2)([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(CN)c2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(CNC(=O)OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a stirred mixture of 4-(3-Aminomethyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester (0.30 g, 0.99 mmol), methylene chloride (10 mL) and water (10 mL) was added potassium carbonate (0.28 g, 2.02 mmol) followed by benzylchloroformate (0.34 g, 2.02 mmol). The reaction stirred overnight at room temperature. The reaction was extracted with methylene chloride (3×30 mL). The organic extracts were combined, dried over sodium sulfate and evaporated to give a tan oil. Purification by flash chromatography 40% Ethyl acetate: Heptane yielded 4-[3-(Benzyloxycarbonylamino-methyl)-phenyl]-4-hydroxy-piperidine-1-carboxylic acid-tert-butyl ester (0.40 g). 1H NMR [(CDCl3: δ 7.45-7.18 (m, 9H), 5.15 (s, 2H), 5.08 (br.s., 1H, NH), 4.40 (d, 2H), 4.15-3.93 (m, 2H), 3.35-3.15 (m, 2H), 2.08-1.90 (m, 2H), 1.75-1.62 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([CH:25]([OH:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NC[C@H](NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)C(=O)O)c1cccs1

Procedure:
A solution of N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (120 mg, 0.23 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in tetrahydrofuran/methanol/water (2:2:1; 2.5 mL) was stirred at room temperature for 90 min. The solvent was evaporated, then water was added, followed by 1 M HCl (1.1 mL). The resulting solid was filtered off, washed with water, dried, and purified by
Reaction SMILES: Cl.C[O:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1.C(O)(=O)C>Br.C([O-])(O)=O.[Na+]>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)C1CCNCC1
Yield: 73.3 %

Procedure:
A solution of 4-(4-methoxybenzoyl)piperidine hydrochloride (3.0 g, 11.7 mmol), in 48% HBr (aq) (16 mL), and acetic acid (16 mL) was heated at reflux for 48 h. The reaction mixture was evaporated to dryness in vacuo to give an off-white solid which was suspended in saturated NaHCO3 (aq). The resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (1.76 g, 73%) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O>>[Cl:16][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1

Procedure:
A mixture of EXAMPLE 288A (1.69 g), phosphorus pentachloride (2.03 g), and phosphoryl trichloride (0.97 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was poured into ice, and extracted with ethyl acetate three times. The extract was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:4]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Br:1][CH2:2][C:3]([C:25]([F:26])([F:27])[F:28])([OH:24])[CH:4]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1
Reactant: COc1cccc(C(Nc2cccc3ccccc23)C(O)(CBr)C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cccc(C(Nc2cccc3ccccc23)C(O)(CBr)C(F)(F)F)c1
Reaction time: 16 h
Yield: 36.9 %

Procedure:
To 20 mg (0.04 mmol) of α-Bromomethyl-3-methoxy-β-[(naphth-1-yl)amino]-α-(trifluoromethyl)benzeneethanol in 2 ml dichloromethane at −20° C. are added 0.44 ml of a 1 M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and extracted twice with ethyl acetate. The combined organic extracts are washed with saturated NaCl solution and dried over sodium sulfate. The solvent is evaporated and the residue purified by preparative thin layer chromatography on silica gel (ethyl acetate in hexane 33%). 6.5 mg of the desired compound are isolated.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:4]([CH3:18])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(I)ccc1CCCN1CCC(C)CC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1CCCN1CCC(C)CC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[3-(4-iodo-2-methylphenyl)propyl]-4-methylpiperidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 29 mg (9% of theoretical); C29H31ClN2 (M=443.023); calc.: molpeak (M+H)+: 443/445 (Cl); found: molpeak (M+H)+: 443/445 (Cl); HPLC-MS: 8.55 minutes (method A).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:30]=[CH:29][C:17]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CCOC(C)=O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:29]=[CH:30][C:14]([S:11]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:3]3)(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:23][CH:24]=1
Reactant: C1CCNCC1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(N3CCCCC3)c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
Dissolve 4-(3-chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (91 mg, 0.20 mmol) in piperidine (1.0 mL) and stir at 90° C. overnight. Dilute the solution with EtOAc (30 mL) and wash with 1N HCl (15 mL) and satd NaHCO3 (15 mL). Dry, filter and concentrate the organic solution and purify the residue by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes, to give the title compound as a light yellow foam (7 mg, 7%). MS (ES) 493.0 (M+1)+, 491.2 (M−1)−.