Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[O:14]1[C:19]2[CH:20]=[CH:21][C:22](N)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1.C([O-])=O.[NH4+]>CO.[Pd]>[O:14]1[C:19]2[CH:20]=[CH:21][C:22]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)OCCO3)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A solution of 5 mmol (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (prepared as per example 47, step 1) and 1.1 eq. 2,3-Dihydro-benzo[1,4]dioxin-6-ylamine in MeOH (20 mL) was treated with ammonium formate (5 eq.) and 10% Pd/C (200 mg) and stirred at 80° C. for 2 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (24%) as a light yellow oil. MS m/e: 325.0 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[C:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]3[CH:3]=[CH:2][S:1][C:5]=3[CH2:6]2)=[O:28])=[CH:30][CH:31]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cc1

Procedure:
As described for Example 26, 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12].O>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:14][CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(NC(C)C)ncc1Br
Temperature: 60 °C
Yield: 63.6 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (1.2 g, 5.37 mmol) in THF (20 mL) was treated with TEA (1.57 mL, 10.74 mmol) and isopropylamine (0.7 mL, 8.1 mmol) and heated at 60° C. for 5 h. The mixture was cooled to RT, treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford 5-bromo-N-isopropyl-4-methoxypyrimidin-2-amine (0.84 g, 634%). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.17 (br s, 1H), 3.96-3.94 (m, 1H), 3.87 (s, 3H), 1.12 (d, J=6.5 Hz, 6H); MS (ESI) m/z: 246.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.Cl.[C:22]12([NH2:27])[CH2:26][CH:24]([CH2:25]1)[CH2:23]2.O>CS(C)=O>[C:22]12([NH:27][C:2]3[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=3)[CH2:26][CH:24]([CH2:25]1)[CH2:23]2
Reactant: NC12CC(C1)C2
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CSc1ncc(C#N)c(NC23CC(C2)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a stirred solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (3.0 g, 16 mmol) in DMSO (20 mL) was added DIEA (6.2 g, 48 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (1.9 g, 16 mmol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)). The resulting mixture was stirred at 60° C. for 2 h and then poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (3.5 g, 14.9 mmol, 93% yield). MS (ESI) m/z=233.2 [M+1]+.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([F:20])[C:13]=1[NH:21][NH2:22]>CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:21]([C:13]3[C:14]([F:20])=[C:15]([F:19])[CH:16]=[C:17]([F:18])[C:12]=3[F:11])[N:22]=[CH:4][C:3]=12
Reactant: NNc1c(F)c(F)cc(F)c1F
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Temperature: 184 °C
Yield: 104.3 %

Procedure:
To a 15 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (710 mg, 2.83 mmol), (2,3,5,6-tetrafluorophenyl)hydrazine (509 mg, 2.83 mmol), and anhydrous NMP (4 mL). The reaction mixture was flushed with argon, securely capped, and heated at 184° C. for 2.75 h. The reaction mixture was partitioned with ethyl acetate (300 mL), water (125 mL), and brine (50 mL). The organic layer was washed with water (4×40 mL) and brine (75 mL) and the combined aqueous layers were extracted with additional ethyl acetate (300 mL). The second organic layer was washed with water (4×60 mL), and brine (100 mL), and the combined organic layers were dried over sodium sulfate, and evaporated in vacuo to give 1.16 g (quantitative yield) of the title compound as a tan solid. LC/MS (Condition B): ret. T=3.92 min, (M+H)+ 393.89.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: COc1cccc(C2(c3ccncc3)N=C(N)N(C)C2=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)C(c2ccncc2)(c2cccc(O)c2)N=C1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a suspension of 2-amino-5-(3-methoxyphenyl)-3-methyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-4-one (0.75 g, 2.5 mmol) in CH2Cl2 (7.5 mL) is added BBr3 (1.0 M in CH2Cl2, 15 mL, 15 mmol) at −78° C. After addition, the reaction mixture is warmed to room temperature and stirred for 3 h. The reaction mixture is poured into ice-water (50 mL) and the two layers are separated. The aqueous is neutralized with 50% aqueous NaOH to pH˜7 and extracted with 4/1 CH2Cl2/2-PrOH (3×100 mL). The combined organic extracts are washed with brine (150 mL), dried (Na2SO4) and concentrated. The resultant residue is purified by chromatography (silica gel, EtOAc/2M methanolic NH3: 95/5) to give the title compound (0.58 g, 79%) as a solid. Mp: 245-247° C.; MS(+) ES: 283 (M+H)+.
Reaction SMILES: BrC1C=CC(Cl)=CC=1[N+]([O-])=O.C1(B(O)O)C=CC=CC=1.ClCCl.[OH-].[Na+].Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([N+:39]([O-])=O)[CH:28]=1>O1CCCC1.C(O)(=O)C.C(O)C.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].[Fe]>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][CH:27]=[CH:28][C:29]=1[NH2:39]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Fe]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 107.6 %

Procedure:
A stirred solution of 2-bromo-5-chloronitrobenzene (5.00 g, 21.2 mmol) and phenylboronic acid (2.58 g, 21.2 mmol) in tetrahydrofuran (85 mL) was treated under nitrogen with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.52 g, 0.63 mmol, 3 mole %) and a 5 N sodium hydroxide solution (8.5 mL, 42.5 mmol). The reaction was heated at 60° C. for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was treated with ethyl acetate (200 mL) and a saturated aqueous sodium chloride solution (100 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent concentrated in vacuo. The resulting brown oil was filtered through a plug of silica gel (20:80 ethyl acetate:hexane). After concentration of the solvent in vacuo, the resulting, pure 4-chloro-2-nitro-biphenyl (4.66 g, 19.0 mmol, 94%) was dissolved in acetic acid (13.2 mL) and ethanol (13.2 mL). Iron granules (15.6 g, 278 mmol) were added and the mixture was stirred with a mechanical stirrer for 12 hours. The mixture was diluted with ethanol and then filtered through Celite® filter aid. The resulting solution was concentrated in vacuo, diluted with toluene and concentrated in vacuo (×3) to afford a viscous oil. The viscous oil was purified by flash column chromatography, eluting with a mixture of ethyl acetate-hexane (1:4), to afford the title compound as a homogeneous oil (3.46 g, 85%);
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1>>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=391 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cooled (0° C.) solution of 7-fluoro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (330 mg, 0.81 mmol) in DCM (10 mL) was added iodine monochloride (1M in DCM, 1.6 mL, 1.6 mmol) dropwise. On complete addition the mixture was allowed to stir at 0° C. for 1 hour then quenched by the addition of saturated sodium thiosulphate solution (10 mL). The mixture was stirred vigorously for 10 min and partitioned between ethyl acetate and water. The organic layer was separated and washed with a saturated solution of sodium hydrogenocarbonate followed by brine, dried over sodium sulphate, filtered and concentrated to give the title compound as a yellow solid (358 mg, 54%). LCMS (method B): RT=4.72 min, M+H+=461.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[S:23][CH:24]=1)([CH3:19])[CH3:18])[CH3:14].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:53])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[S:23][C:24]=1[F:53])([CH3:19])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1nc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)sc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Under anhydrous condition n-BuLi (3.6 M solution in hexane, 2.55 mL, 9.20 mmol) was added to stirred solution of N,N-Diisopropyl amine (1.29 mL, 9.20 mmol) in 10 mL dry THF at −78° C. and reaction mixture was stirred for 1 hr. A solution of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (synthesized as per preparation 44; 2.0 g, 4.60 mmol) in 10 mL of dry THF was added dropwise to above reaction mixture and continued to stir for an additional 1 hr at −78° C. N-Fluorobenzenesulfonimide (2.17 g, 6.90 mmol) dissolved in 10 mL dry THF was added to reaction mixture dropwise and resulted reaction mixture was allowed to warm 0° C. within 3 hrs. Reaction mixture was poured on aq. saturated solution of NH4Cl (50 mL), mixture was then extracted with (3×50 mL) ethyl acetate; organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and washed with ethyl acetate and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (4% ethyl acetate in hexane) to afford pure compound (0.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]([CH3:26])[C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC2C=CC=CC=2)=[CH:10][CH:9]=1>C(O)C.[Pd]>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:27])[CH3:26])=[O:25])=[CH:13][CH:12]=1
Reactant: CN(C)CCN(C)C(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN(C)C(=O)Cc1ccc(N)cc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of benzyl 4-(2-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)phenylcarbamate (0.7 g) in ethanol (10 ml) was added 10% Pd-C (0.2 g). The reaction mixture was hydrogenated under atmospheric pressure at room temperature for one hr. The catalyst was removed by filtration and the filtrate was concentrated to obtain the titled compound (0.43 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3]/[CH:4]=[CH:5]\[C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15]C2CCCCO2)=[CH:10][CH:9]=[CH:8][N:7]=1>CO.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CN(C)C/C=C\c1ncccc1OCCOC1CCCCO1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1ncccc1OCCO
Yield: 56.9 %

Procedure:
To a mixture of the cis and trans isomers N,N-dimethyl-N-((2E and 2Z)-3-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}prop-2-enyl)amine (from Example 20, Step 2; 3.1 g, 10.1 mmol) in MeOH (50 mL) was added 10% Pd/C (0.30 g) and the mixture was hydrogenated in a Parr apparatus at room temperature at 70 psi H2 overnight. The solvent from the filtered solution was removed under reduced pressure and the tetrahydropyranyl protecting group was removed using the procedure described in Example 19, Step 4, to yield 1.29 g (57%) of the title compound as a brown oil. HRMS m/z calcd for C12H20N2O2 (M)+ 224.1525. found 224.1521.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl-].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][NH+:14]=1>>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: ClCc1cccc[nH+]1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: [Cl-]
Product: Cc1cc(=O)[nH]c(SCc2ccccn2)n1
Yield: 45 %

Procedure:
The title compound is prepared from 6-methyl-2-thiouracil and 2-chloromethylpyridinium chloride by using the process described in Example 12. After recrystallization from 2-propanol the title compound is obtained as a yellowish crystalline substance in a yield of 45%, m.p.: 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/c (%): 503.4 (M+H+).
Reaction SMILES: [SH:1][C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:19][CH:20]=1>C(O)C>[C:21]1([C:18]2[S:19][CH:20]=[C:16]([CH2:15][S:1][C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[N:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: Sc1nc2cccc3c2n1CCC3
Solvent: CCO
Product: c1ccc(-c2nc(CSc3nc4cccc5c4n3CCC5)cs2)cc1
Yield: 93.1 %

Procedure:
A solution of 5,6-dihydro-2-mercapto[4H]imidazo [4,5,1-ij]quinoline (2.04 g, 10.7 mmol) in 1 N-sodium-hydroxide (10.7 ml) and ethanol (10 ml) was treated with 4-chloromethyl-2-phenylthiazole (2.25 g, 10.7 mmol) and the resulting solution heated under reflux for 5 mins. The mixture was concentrated in vacuo and the aqueous mixture extracted with ethyl acetate (2×50 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give a yellow oil which crystallised on trituration with diethyl ether (50 ml) to give the title compound (3.62 g, 93%), mp 116°-118° (Found: C, 66.4; H, 5.0; N, 11.3 C20H17N3S2 requires C, 66.1; H, 4.7; N, 11.6%).
Reaction SMILES: CC(C)([O-])C.[K+].O[C@@:8]([CH3:37])([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:33]3[S:34][CH:35]=[CH:36][C:32]=3[O:31][N:30]=2)[CH:24]=1)[CH2:9][O:10]S(C1C=CC(C)=CC=1)(=O)=O.C>O1CCCC1>[CH3:37][C:8]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:33]4[S:34][CH:35]=[CH:36][C:32]=4[O:31][N:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:9][O:10]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)COc2cccc(-c3noc4ccsc34)c2)cc1
Agent: C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(COc2cccc(-c3noc4ccsc34)c2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add potassium t-butoxide (0.67 g, 0.006 mol) in small portions to a chilled (0° C.) stirred solution of toluene-4-sulfonic acid (S)-2-hydroxy-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl ester (2.45 g, 0.00533 mol) and tetrahydrofuran (40 mL). Stir one hour at 0° C. and partition between ethyl acetate and water. Separate the organic phase, dry (MgSO4), filter, and concentrate in vacuo. Recrystallize the residue from ether-hexane to give the title compound (1.33 g, 87% yield), m.p. 84–85° C., MS (chemical ionization, CH4) MH+ 288.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C[Li].[CH2:14](OCC)C.Cl[Si](C)(C)C>C1COCC1>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8](=[O:10])[CH3:14])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CCOCC
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)CC1
Reaction time: 2 h

Procedure:
To a clear solution of 4,4-difluorocyclohexanecarboxylic acid (2.00 g, 12.18 mmol) in 100 mL THF at 0° C. was added slowly dropwise methyllithium, 1.6M solution in diethyl ether (30.5 mL, 48.7 mmol) from an addition funnel. The resulting cloudy mixture was allowed to stir 2 h, then was treated with chlorotrimethyl silane (24.74 mL, 195 mmol) dropwise over 10 min. The bath was removed and the clear solution allowed to stir 1 h. 5 mL 1M HCl aq. Was added and the reaction mixture stirred an additional hour. The reaction mixture was then concentrated in vacuo to a small volume, diluted with Et2O, and the organic layer was washed with water, sat'd aq. NaHCO3, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give impure 1-(4,4-difluorocyclohexyl)-ethanone as a clear/colorless oil, which was used without further purification.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=CC=1)([O-])=O.[NH2:28][C@H:29]([C@H:37]([OH:49])[C@@H:38]([OH:48])[C@@H:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:14]([NH:13][C@H:12]([C:11]([NH:28][C@H:29]([C@H:37]([OH:49])[C@@H:38]([OH:48])[C@@H:39]([NH:47][C:11](=[O:27])[C@H:12]([CH:24]([CH3:25])[CH3:26])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH:24]([CH3:26])[CH3:25])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@@H](N)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 5 %

Procedure:
Cbz-valine p-nitrophenyl ester was coupled to (2S,3S,4S,5S)-2,5-diamino-3,4-dihydroxy-1,6-diphenylhexane using the procedure of Example 172B to provide the desired compound (Rf 0.42, 5% methanol in chloroform) as a white solid, m.p. 239°-242° C. in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Cl:1][C:2]1[C:7]([N:8]([CH3:21])[C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:19])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN(C(=O)c1ccccc1C(F)(F)F)c1cccnc1Cl
Temperature: 25 °C
Yield: 99.2 %

Procedure:
8.0 g N-(2-chloro-pyridin-3-yl)-2-trifluoromethyl-benzamide (26.6 mmol), 1.1 g potassium carbonate (K2CO3) (80 mmol), and 100 mL ethanol were added and stirred in a round-bottomed flask. 5.7 g methyl iodide (MeI) (40 mmol) was then added and reacted for 12 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 8.3 g white solid was obtained, with a yield of 88%.