Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])C.CCCCCC>>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:1][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1c(N)cccc1Cl
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Nc1cccc(Cl)c1C#N

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 (Method B) from 2-amino-6-chlorobenzonitrile. m.p.: 144.5-145.1 (ethyl acetate/hexane) 1H-NMR (CDCl3) δ: 8.21 (1H, d, J=8 Hz), 7.49 (1H, t, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.17 (1H, br s), 4.27 (2H, q, J=7 Hz), 1.35 (3H, t, J=7 Hz)
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:28]([CH3:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH:28]2[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
A solution of ethyl 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenyl carbonate (0.45 g, 1.02 mmol) in methanol (5.0 mL) was treated with a 1 N sodium hydroxide (5.1 mL) solution, and heated at 75° C. for 14 hours. After cooling to room temperature, the methanol was evaporated in vacuo. The resulting aqueous mixture was acidified with a 1 N hydrochloric acid solution, diluted with a saturated, aqueous, sodium chloride solution (100 mL), and extracted with dichloromethane (5×15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a white solid. The solid was purified by filtration through a short column of silica gel, eluting with ethyl acetate, to yield the title compound as a homogeneous, white, crystalline, solid (0.34 g, 89%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11]OS(C)(=O)=O)[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:11][C:8]1[CH:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:10][N:9]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cc(-c2ccco2)on1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(-c2ccco2)on1
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of 2.21 g of methane sulfonic acid 5-furan-2-yl-isoxazol-3-ylmethyl ester in 45 mL of DMF was added 0.61 g of sodium azide. After stirring for 15 hrs, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride and distilled water, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.50 g of 3-azidomethyl-5-furan-2-yl-isoxazole. This concentrate was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:27]4[CH2:26][CH2:25][CH2:24][C:23]([C:28]([O:30]C)=[O:29])=[CH:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[C:27]4[CH2:26][CH2:25][CH2:24][C:23]([C:28]([OH:30])=[O:29])=[CH:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cccc(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)c2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(c3cccc4c3CCCC(C(=O)O)=C4)CC2)cc1
Reaction time: 13 h
Yield: 58.4 %

Procedure:
To a solution of methyl 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1.0 g) in ethanol/THF (20/40 ml) was added at room temperature 1N sodium hydroxide solution (2.7 ml), and the mixture was stirred for 13 hours. Under reduced pressure, the mixture was concentrated. To the mixture was added water, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate/THF. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting colorless crystals were collected by filtration, which were washed with hexane to give colorless crystals of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (565.4 mg).
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([C:34](=[O:36])[CH3:35])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[Cl:8][CH2:35][C:34]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:27]=1)=[O:36]
Reactant: O=I(=O)Cl
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCl)cc1OC1CCCC1
Yield: 36.5 %

Procedure:
Under a N2 flow, a solution of benzyltrimethylammonium dichloroiodate (78 g) in THF (250 ml) was added to a mixture of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]-ethanone (26.3 g) in THF (250 ml) while stirring. The resulting reaction mixture was stirred for 16 hours at RT. The solvent was evaporated and the residue was redissolved in diethyl ether (300 ml). The mixture was added dropwise to a 5% Na2S2O4 solution (400 ml). The aqueous layer was extracted twice with diethyl ether (100 ml). The combined organic layers were washed twice with water (500 ml), dried (MgSO4), filtered and the solvent evaporated. The crude oil was crystallized from hexane. The precipitate was filtered off, washed with hexane and dried, yielding 11 g of 2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone. The filtrate was evaporated and the residue was crystallized from hexane. The precipitate was filtered off and dried, yielding 7.4 g (24.6%) of 2-chloro-1-[3(cyclopentyloxy)-4-methoxyphenyl]ethanone (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(C=O)c1ccc(C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(CO)c1ccc(C(=O)OC)cc1
Temperature: 0 °C

Procedure:
4-(1-Formyl-heptyl)-benzoic acid methyl ester (3.17 g, 12.1 mmol) is dissolved in ethanol (50 mL) and allowed to stir under nitrogen in an ice bath at 0° C. Sodium borohydride (0.457 g, 12.1 mmol) is added to the mixture in one portion. The reaction is allowed to stir at 0° C. for one hour, then warmed slowly to room temperature for several hours and is monitored by TLC. Upon complete consumption of starting material, the reaction is carefully quenched with water and the ethanol is removed in vacuo. The remaining mixture is diluted with ethyl acetate. The two phases are separated, and the organic layer washed, dried, and concentrated. The title compound is used in the next step without further purification. MS (ES): 265.2 [M+H]+.
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CO.Cl>C(Cl)Cl>[O:23]=[C:20]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:5]2[C:4](=[O:24])[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:2]2[S:1][CH2:21]1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate prepared by the method of Example 4.--III(2) (70 mg) in a mixture of methylene chloride (2 ml), methanol (2ml), and 10% hydrochloric acid (0.3 ml) is stirred at room temperature for 2 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-oxo-7-phenoxyacetamidocepham- 4-carboxylate (44.5 mg), identical with the product of Example 4.--III(3). Yield: 74%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1(Br)[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].CCN(C(C)C)C(C)C>C(#N)C.C(OC(=O)C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCC1(Br)Br
Reactant: Oc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCC=C1Oc1ccc(Br)cc1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 4-bromophenol (500 mg, 2.9 mmol) in ACN (14.5 mL), 2,2-dibromo cyclopentanone (1.4 g, 8.7 mmol) and DIPEA (500 mg, 2.9 mmol) were added. The resulting mixture was stirred at r.t overnight. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL), washed with water (50 mL) and brine (50 mL) successively. The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1:9 EtOAc:hexane) to provide title compound (461 mg, 63%) as pale brown liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>CN1CCC(=O)CC1.ClCCl.[Cu]>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([C:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH:4]=4)[CH:16]=3)[CH:12]=[CH:13]2)=[CH:26][CH:25]=1
Reactant: CN1CC=C(c2ccc3cc[nH]c3c2)CC1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]
Agent: CN1CCC(=O)CC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CN1CC=C(c2ccc3ccn(-c4ccc(F)cc4)c3c2)CC1
Yield: 51.8 %

Procedure:
A mixture of 6-(1-Methyl-1,2,5,6-tetrahydropyridin-4-yl)-indole (20.1 mg, 0.0945 mmol), potassium carbonate (K2CO3; 52.3 mg, 0.3787 mmol), cuprous bromide (CuBr; 6.7 mg, 0.0473 mmol), a little copper powder and 1-fluoro4-iodobenzene (42.04 mg, 0.189 mmol) in 1 ml of N-methyl-4-piperidone (NMP) was heated at 170° C., under argon, overnight. After cooling, the mixture was diluted with dichloromethane and the organic layer washed with water 10 times before being passed through a silica gel column (eluting with 1% 2M ammonia/methanol in dichloromethane) to give the title product (15 mg, 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>>[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)=[CH:3][C:4]=2[CH3:17])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)cnc1N1CCN(C(C)C)CC1
Product: CC(=O)Nc1cccc(-c2cnc(N3CCN(C(C)C)CC3)c(C)c2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1-(5-bromo-3-methyl-pyridin-2-yl)-4-isopropyl-piperazine and 3-acetylaminophenylboronic acid. 1H NMR (300 MHz, CDCl3) δ 8.35 (d, 1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.46 (d, 2H), 7.35 (t, 1H), 3.32 (t, 4H), 2.92-2.75 (m, 5H), 2.30 (s, 3H), 2.19 (s, 3H), 1.14 (d, 6H).
Reaction SMILES: [OH:1][CH:2]([CH3:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].CS(OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=O)=O.S([O-])(=O)(=O)C>>[CH3:26][S:27]([O:1][CH:2]([CH3:18])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:6][CH2:5]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(CN1CCC(NC(=O)OC(C)(C)C)CC1)OS(C)(=O)=O

Procedure:
tert-Butyl [1-(2-hydroxypropyl)piperidin-4-yl]carbamate (Intermediate 224, 1.1 g, 4.3 mmol), triethylamine (0.90 mL, 6.5 mmol) and methanesulfonyl chloride (0.37 mL, 4.7 mmol). Were reacted as described for Intermediate 6. The crude mesylate was directly used for the next step.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]([Cl:14])=[N:7][C:8]([Br:13])=[C:9]([CH3:12])[C:10]=1Br)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:13][C:8]1[C:9]([CH3:12])=[C:10]2[C:2]([CH3:3])=[CH:1][NH:4][C:5]2=[C:6]([Cl:14])[N:7]=1
Reactant: C=CCNc1c(Cl)nc(Br)c(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2c(Cl)nc(Br)c(C)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A mixture of allyl-(4,6-dibromo-2-chloro-5-methyl-pyridin-3-yl)-amine (5.0 g, 14.7 mmol), Pd(OAc)2 (0.33 g, 1.47 mmol), tetrabutylammonium bromide (5.2 g, 16.2 mmol), K2CO3 (6.1 g, 44 mmol) in DMF (50 mL) is degassed, then stirred at 80° C. overnight. The mixture is diluted with EtOAc and washed with water and brine, dried over MgSO4 and concentrated. Chromatography of the residue on silica gel (Hexane/EtOAc, 4:1) gives 3.2 g of 5-bromo-7-chloro-3,4-dimethyl-1H-pyrrolo[2,3-c]pyridine. 1H NMR: (CDCl3) 8.32 (1H, br), 7.14 (1H, q, J=1.1 Hz), 2.70 (3H, s), 2.46 (3H, d, J=1.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5].[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>[CH:22]1([O:21][C:19]2[CH:18]=[CH:17][C:3]([C:4]([C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[O:12][C:11](=[O:16])[CH2:10][CH2:9]4)=[O:5])=[C:2]([OH:1])[CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCC1
Reactant: O=C1CCc2cc(C(=O)c3ccc(O)cc3O)ccc2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(C(=O)c3ccc(OC4CCCC4)cc3O)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50.0 g of 6-(2,4-dihydroxybenzoyl)-2-chromanone, 17.6 mL of cyclopentanol, and 55.4 g of triphenylphosphine were dissolved in 500 mL of tetrahydrofuran, to which 41.6 mL of diisopropyl azodicarboxylate was added dropwise at temperatures of 15 to 32° C., and this solution was stirred for 30 minutes at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water for the separation of the organic phase therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 54.7 g of 6-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-chromanone as light yellow solid.
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:30]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=[O:41])=[CH:38][CH:37]=3)[C:31]2=[O:46])[S:28][CH:29]=1>>[CH3:24][C:25]1[N:26]=[C:27]([N:30]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:45]=[CH:44][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=3)[C:31]2=[O:46])[S:28][CH:29]=1
Reactant: COC(=O)c1ccc(CN2CCN(c3nc(C)cs3)C2=O)cc1
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Yield: 65 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with methyl 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained in 65% yield: mp 222-224° C.; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 4.52 (s, 2H), 3.98-3.93 (m, 2H), 3.45-3.40 (m, 2H), 2.19 (s, 3H); MS (ES+) m/z 318.2 (M+1).
Reaction SMILES: [C:1]([C:5]([N:7]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:15]=1)[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:10]([C:8]([N:7]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:34])=[C:16]([O:21][CH2:22][C:23]([F:24])([F:25])[F:26])[CH:15]=1)[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)C(C)(C)C)C(=O)C(C)(C)C)cc1OCC(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CBr)c(OCC(F)(F)F)c1

Procedure:
To a stirred solution of 4-(N,N-di-(tert-butyl-carbonyl)-amino)-2-(2,2,2-trifluoroethoxy)toluene (2.0 g, 5.0 mmol) from Step 3 above in CCl4 (75 mL) was added NBS (0.90 g, 5.0 mmol) and AIBN (0.2 g, 1.2 mmol). The mixture was refluxed for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-15% EtOAc:hexanes to give 4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)benzyl bromide as a colorless gum (TLC Rf =0.50 (15% EtOAc:hexanes)).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>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.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CC1(O)CCOCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 7 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 36 mg, 75%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:13][C:14]([F:24])([F:23])[CH2:15][NH:16][C:17]([NH:19][C:20]([NH2:22])=[S:21])=[NH:18]>CCO>[F:24][C:14]([F:13])([F:23])[CH2:15][N:16]=[C:17]([NH2:18])[NH:19][C:20]1[S:21][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:22]=1
Reactant: COC(=O)CCCCC(=O)CCl
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Solvent: CCO
Product: COC(=O)CCCCc1csc(NC(N)=NCC(F)(F)F)n1

Procedure:
To a solution of methyl 7-chloro-6-oxoheptanoate (2.0 g.) in hot EtOH (20 ml.) was added a solution of 2,2,2-trifluoroethylamidinothiourea (2.1 g.) in hot EtOH (20 ml.). The resulting mixture was heated under reflux for 1 hour. The mixture was then evaporated to dryness and the residue partitioned between ether (20 ml.) and water (60 ml.). The aqueous layer was separated and basified with sodium bicarbonate and extracted with EtOAc. The EtOAc solution was evaporated to dryness and the residue crystallised from EtOAc/ether containing a small amount of acetone to give methyl 5-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]valerate which was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:33]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(Cl)c1)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) in 5 ml of dichloromethane was treated with 1.61 mmol of triethylamine. The resulting slurry was cooled to 0° C. and 0.35 mmol of 3-chlorobenzoyl chloride was added. The mixture was stirred for 1 hour at room temperature, concentrated and hydrolysed. The organic phase was dried over magnesium sulfate and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield=97%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:8]=1)[CH3:5].[C:21]([OH:30])(=[O:29])[C@@H:22]([C@H:24]([C:26]([OH:28])=[O:27])[OH:25])[OH:23]>C1COCC1>[C:26]([CH:24]([CH:22]([C:21]([OH:30])=[O:29])[OH:23])[OH:25])([OH:28])=[O:27].[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:5])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:8]=1)[CH3:19]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Solvent: C1CCOC1
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
2-Methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester (4.80 g, 17.31 mmol) was dissolved in THF (80 mL) and followed by the addition of L-(+)-tartaric acid (2.86 g, 19.04 mmol). The resulting mixture was refluxed under nitrogen for 3 h. While the mixture was still hot, the solid was collected by vacuum-filtration, rinsed with THF, and further dried to afford 7.13 g (96%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester tartrate salt as a white solid: 1H NMR (DMSO-d6) δ 1.50 (s, 6H), 1.60–1.73 (m, 2H), 1.83 (d, 2H), 2.80–2.94 (m, 3H), 3.24 (d, 2H), 3.67 (s, 3H), 3.87 (s, 2H), 6.60 (d, 1H), 6.69 (s, 1H), 6.89 (d, 1H), 7.21 (t, 1H); MS m/z (relative intensity) 277 (M+, 2), 218 (6), 176 (100).