Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@:3]([O:8][Si](C)(C)C)([CH3:7])[C:4](Cl)=[O:5].[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[NH2:22])(=[O:17])[CH3:16]>C(Cl)Cl.C(N(CC)CC)C>[C:15]([NH:18][C:19]1[C:20]([Cl:34])=[C:21]([NH:22][C:4](=[O:5])[C@:3]([OH:8])([CH3:7])[C:2]([F:14])([F:13])[F:1])[CH:23]=[CH:24][C:25]=1[S:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)(=[O:17])[CH3:16]
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(N)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (1.179 g) in DCM (10 ml) was added dropwise to a stirred and ice-cooled suspension of 3-acetamido-2-chloro-4-(4-fluorophenylsulphanyl)aniline (Method 18) (1.315 g) in DCM (20 ml) and triethylamine (1.72 ml). The mixture was allowed to warm to ambient temperature overnight. More triethylamine (0.8 ml) followed by (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (0.6 g) in DCM (5 ml) was added. After a further 6 hours the mixture was concentrated by evaporation. MeOH (50 ml) and 2M aqueous HCl (5 ml) were added, the mixture was stirred overnight, and then diluted with water (20 ml). The MeOH was removed by evaporation and 2M aqueous HCl (30 ml) was added. The mixture was then extracted with ether (2×80 ml). The extracts were washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Biotage cartridge (40 g silica), eluting with 50% EtOAc/isohexane to give the title compound (1.104 g) as a foam. NMR: 1.6 (s, 3H), 2.05 (s, 3H), 7.0 (d, 1H), 7.26 (t, 2H), 7.38-7.48 (m, 2H), 7.8-7.9 (m, 2H), 9.76 (brs, 1H), 9.9 (brs, 1H); m/z: 449.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br-].[Cl-].[NH4+].[CH2:19]1COC[CH2:20]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]([OH:13])[C:19]#[CH:20])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C1CCOC1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-yl)-benzaldehyde (28.9 mmol) in THF (100 ml), ethnylmagnesium bromide (0.5M solution in THF) (43.4 mmol) is added at −78° C. The solution is then stirred at room temperature for 18 h. The reaction mixture is treated with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. CH2Cl2 is added to the residue to afford a precipitate, which is collected by filtration. yield 84.2%, Rf=0.23 (CH2Cl2:MeOH=9:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.[C:15](Cl)(=[O:19])[C:16]([Cl:18])=[O:17]>C1COCC1>[O:19]=[C:15]([C:14]1[N:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[CH:7][C:6]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:16]([Cl:18])=[O:17]
Reactant: c1csc(-c2cc3ccccn3c2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(-c2cccs2)cc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To an ice-cold solution of 2-thiophen-2-yl-indolizine (0.5 g, 2.51 mmol) in THF (8 ml) was added oxalyl chloride (0.3 ml, 3.48 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under vacuum. The crude product was recrystallized from dichloromethane-hexane to give oxo-(2-thiophen-2-yl-indolizin-3-yl)-acetyl chloride (0.3 g, 41%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10]OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].[CH2:30]([OH:32])C.O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:30]([NH:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26])=[O:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Product: C[C@H](NC(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
The title compound is prepared by the procedure of Example 255 using 5.3 g of product from Example 254, 1.48 g of L-alanine, 4.6 ml of triethylamine,and 200 ml of 80/20 ethyl alcohol/water. The resulting oil is purified by chromatography (3X, silica gel: 50% ethyl acetate/hexane) to give 3.39 g of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:29](=[O:30])[N:11]2[CH:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:14][C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](N(C(C)C)CC)(C)C.CI>CN(C=O)C.ClCCl>[CH2:1]([C:8]1[N:9]=[C:10]2[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:12][N:11]2[C:29]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cc2ccccc2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(Cc2ccccc2)nc2c(Cc3ccccc3)nc(-c3ccccc3)cn12
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of 2,8-dibenzyl-6-phenyl-7H-imidazo[1,2-a]pyrazin-3-one (0.25 g, 0.6 mmol) in dry DMF (10 mL) at ambient temperature under argon was added diisopropylethylamine (1.1 mL, 6.0 mmol) all at once, followed by dropwise addition of methyl iodide (0.4 mL, 6.0 mmol). After stirring for 1 h the reaction was complete by TLC analysis. The reaction mixture was diluted with dichloromethane (75 mL) and washed twice with water. The organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to provide a brown oil. The crude oil was purified by flash chromatography on silica gel (30 g) using dichloromethane as mobile phase. Appropriate fractions were pooled and evaporated to afford 200 mg (77%) of the desired compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:4].C[Si](C)(C)C(CC1C=CC([N+]([O-])=O)=CC=1)C.[H][H]>[Pd]>[CH3:16][Si:2]([CH3:1])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:4]
Reactant: [H][H]
Reactant: CC(Cc1ccccc1[N+](=O)[O-])[Si](C)(C)C
Agent: [Pd]
Agent: CC(Cc1ccc([N+](=O)[O-])cc1)[Si](C)(C)C
Product: CC(Cc1ccccc1N)[Si](C)(C)C

Procedure:
2-Trimethylsilyl-3-phenylpropene (2.5 g), prepared according to J. Org. Chem. 43, 147 (1978), was dissolved in THF and was then hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent yielded an oil (2.36 g) which was chromatographed on silica gel (eluent: hexane:ethylacetate 39:1) to give 2-trimethylsilyl-3-phenylpropane (2.3 g; 92.5% pure by NMR). This compound was dissolved in acetanhydride (4 ml), cooled to −35° C. and at this temperature a pre-cooled mixture of concentrated nitric acid (0.48 ml) and acetanhydride (2.4 ml) was added slowly. After warming to ambient temperature the reaction mixture was stirred for 3 hours and then poured into ice-cold diluted ammonia. After extraction with ethyl acetate and drying over sodium sulfate the solvent was removed and the residue was chromatographed on silica gel (eluent: hexane:TBF:ethylacetate 39:4:1) added) to yield a yellow oil (1.4 g) which consisted of an approximate 1:1 mixture of 2-trimethylsilyl-3-(2′-nitrophenyl)-propane and 2-trimethylsilyl-3-(4′-nitrophenyl)-propane. This mixture was hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent and chromatography on silica gel (eluent: hexane:ethyl acetate, 4:1) yielded 2-trimethylsilyl-3-(2′-aminophenyl)-propane (0.75 g; pure according to NMR). 0.15 g of this compound was dissolved in dry THF, cooled with ice and 2-chloronicotinoylchloride (0.13 g) was added, followed by pyridine (0.01 ml). The reaction mixture was stirred at room temperature over night, poured on to water and extracted twice with ethylacetate. The organic phase was washed with water, dried with sodium sulfate and the solvent was removed. Recrystallisation of the resulting crystals from hexane yielded Compound Number 9.35 (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCN(C(=O)C5CC5)CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione (30 mg, 0.066 mmol) in THF was added cyclopropyl carbonyl chloride (5 μL, 0.04 mmol). The mixture was stirred at room temperature for ten minutes. The reaction mixture was then concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(cyclopropanecarbonyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=521)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH3:15])[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: CCI
Product: CCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 42 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and iodoethane, the titled compound was obtained as a white solid. (Yield: 42%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[N+](=C)=[N-]>C1COCC1.CCOCC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:14]=1[C:6]([O:5][CH3:1])=[O:7])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: C=[N+]=[N-]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 3 h
Yield: 159.4 %

Procedure:
4-t-butoxycarbonylaminobenzotrifluoride (3.90 g) was dissolved in THF. At −50° C., t-butyl lithium (30 ml) was added dropwise thereto. The mixture was stirred for 3 hours with keeping at −50° C. Carbon dioxide gas was bubbled into this mixture under stirring (the temperature increased to about −30° C.). The solvent was distilled out. The back-extractraction of the residue with 2N NaOH-ether mixture solution was carried out. The aqueous layer was acidified by adding 2N HCl, extracted with ether, washed and dried over. In addition, the layer containing ether was washed, dried over, filtered and concentrated after combining the said layer containing ether to give the crude compound. Such crude compound was dissolved in ether. A solution of diazomethane in ether was added thereto until the reaction solution became yellow. The reaction solution was concentrated and purified on silica gel column chromatography (hexane:AcOEt=20:1→10:1) to give the title compound (3.80 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]#[C:28][C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: CCCC[Sn](C#Cc1ccc(Cl)cc1)(CCCC)CCCC
Agent: [Cu]I
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: ClCCl
Product: COc1cc(-n2cnc(C#Cc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of Procedure 11 (30 mg, 0.092 mmol), tributyl((4-chlorophenyl)-ethynyl)stannane (79 mg, 0.185 mmol), copper (I) iodide (5.28 mg, 0.028 mmol), and palladiumtetrakis (16 mg, 0.014 mmol) in DMF (1 mL) was stirred under nitrogen at 55° C. for 3 hours. The reaction was cooled to RT, diluted with CH2Cl2, washed with water, sat. NaHCO3, dried (Na2SO4), and concentrated to afford the crude product. The residue was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient). The product was re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the desired product 6-((4-chlorophenyl)ethynyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one J-2 (12.4 mg, 0.028 mmol, 30.0% yield) as a yellow solid. LC/MS 425 (M+H)+, tR 0.95 min (method 5); 1H NMR (400 MHz, CDCl3) δ 8.14-8.17 (1H, m), 7.55 (2H, d), 7.39 (2H, d), 7.01 (1H, d), 6.85-6.93 (2H, m), 6.75 (1H, s), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]#[N:25])=[CH:15][CH:14]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]2[NH:33][N:32]=[N:31][N:25]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cc(COc2ccc(OCc3ccc4ccccc4n3)cc2)cc(OCc2nnn[nH]2)c1

Procedure:
α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile (8.12 mmol), sodium azide (24.4 mmol) and ammonium chloride (24.4 mmol) in dimethylformamide (10 ml) are heated at 115°-120° C. for 6 hrs. After cooling, the reaction mixture is diluted with ethyl acetate (150 ml), washed with water (6×100 ml) then dried and evaporated. The residue is chromatographed on a column of silica gel (360 g) and eluted with a gradient of isopropanol in methylene chloride to give 5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole. (M.P. 131°-132° C.)
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([NH2:6])=[S:5])#[N:2].[C:13]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].N1CCOCC1.Cl[CH2:34][C:35]([NH2:37])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:16]([O:15][C:13]([N:20]1[CH2:25][C:24]2[N:6]=[C:4]3[S:5][C:34]([C:35](=[O:36])[NH2:37])=[C:1]([NH2:2])[C:3]3=[C:7]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[C:23]=2[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CC(=Cc1cccs1)C(N)=S
Reactant: NC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)N1CCc2c(nc3sc(C(N)=O)c(N)c3c2-c2cccs2)C1
Temperature: 80 °C

Procedure:
To a mixture of 2-cyano-3-thiophen-2-yl-thioacrylamide (4.38 g, 22.5 mmol) and 1-boc-3-piperidone (4.49 g, 22.5 mmol) in 200 ml of anhydrous ethanol was added morpholine (3.94 g, 45 mmol) at room temperature with stirring. The resulting mixture was heated to reflux overnight. Then, 2-chloroacetamide (4.21 g, 45 mmol) and K2CO3 (6.23 g, 45 mmol) was added. The reaction mixture was continued to heat at 80° C. overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column (chloroform/methanol, 40:1) and recrystallized from methanol to give a yellow crystalline product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.Cl[CH2:16][C:17](=O)[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[N:9]1[C:10]2=[N:11][CH2:12][CH2:13][N:14]2[C:17]([CH3:18])=[CH:16]1
Reactant: CC(=O)CCl
Reactant: Brc1cccc(Br)c1N=C1NCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=CN(c2c(Br)cccc2Br)C2=NCCN12
Temperature: 150 °C

Procedure:
A mixture consisting of 9.6 gm (0.03 mol) of 2-(2,6-dibromophenyl-imino)-imidazoline, 2.6 ml (110% of the stoichiometrically required amount) of chloroacetone, 3 ml of triethylamine and 30 ml of absolute toluene was heated in a closed tube at 150° C. for 17 hours. Thereafter, the toluene phase was decanted, and the residue was dissolved in dilute hydrochloric acid. The resulting solution was fractionally extracted with ether at stepwisely increasing pH values (addition of 2 N sodium hydroxide). The thin-layer chromatographically pure ethereal fractions were combined, dried over anhydrous calcium sulfate and evaporated in vacuo, leaving 1.65 gm (15.4% of theory) of the compound of the formula ##STR9## which had a melting point of 144°-147° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(C)C)=O)(C)(C)C.[CH3:21][Si](C=[N+]=[N-])(C)C>C(O)C.CCOCC>[NH2:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)[C@@H](N)CCCCN

Procedure:
Nα-tert-Butyloxycarbonyl-Nε-isopropyl lysine (SennChem) was reacted with trimethylsilyldiazomethan in ethanol. The resulting methyl ester amine was reacted with 2-(pinacolborono)benzyl bromide in ether and TEA to give Nα-tert-butyloxycarbonyl, Nε-isopropyl, Nε-(2-pinacolboronobenzyl) methyl lysinate:
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C-]#N.[Na+].[CH3:37][N:38](C)C=O>CO.O>[OH:32][C@@H:13]1[C@@H:14]([N:24]2[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]2)[CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:33])[CH2:2][C:37]#[N:38])[CH2:12]1
Reactant: CN(C)C=O
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CC#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1

Procedure:
A stirred mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (500 mg), sodium cyanide (500 mg), N,N-dimethylformamide (1.25 ml) in methanol (10 ml) and water (0.25 ml) was heated under reflux for 16 h. The resulting solution was cooled and poured into water (50 ml). The mixture was extracted with dichloromethane and the organic layer was washed with water to pH 7. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure and the residue (430 mg) was chromatographed on silica gel. The purified product (208 mg) was crystallised from dichloromethane-methanol to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-11,20-dioxopregnane-21-carbonitrile (96 mg). δ (CDCl3) 0.62 (s, 3H), 1.06 (s,3H), 1.22 (s,3H), 1.26 (s,3H) and 3.38 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([CH3:20])[CH:22]=[CH:23]2
Reactant: CCOC(=O)c1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(O)c2cc(-c3ccc4c(ccn4C)c3)c(Cl)cc2[nH]c1=O
Temperature: 120 °C
Yield: 65.5 %

Procedure:
To a solution of ethyl 7-chloro-4-hydroxy-6-iodo-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Intermediate 100) (300 mg, 0.762 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL) were added (1-methyl-1H-indol-5-yl)boronic acid (Combi-Blocks, 140 mg, 0.800 mmol), cesium carbonate (373 mg, 1.143 mmol) and tetrakis(triphenylphosphine)palladium (8.81 mg, 7.62 μmol). The reaction vessel was sealed and heated to 120° C. for 20 min in a microwave. After cooling, the mixture was filtered, evaporated to dryness and the resulting residue was acidified with 1N HCl. The precipitate was filtered and dried to give ethyl 7-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydro-3-quinolinecarboxylate (198 mg, 0.499 mmol, 65.5% yield) as off-white solid. LCMS: (M+H)+=397; Rt=2.79 min. HRMS: calculated for C21H18ClN2O4 (M+H)+: 397.0955. found: 397.0927.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCC>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:20]([F:25])[CH:19]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)c(F)c3)s2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Yield: 68 %

Procedure:
In a 30 ml-round-bottomed flask, 1.07 g (3.01 mM) of 2-(4-hexylphenyl)-5-(3-fluoro-4-hydroxyphenyl)thiazole prepared in Example 29, 0.23 g (3.48 mM) of potassium hydroxide and 5 ml of butanol were placed and heated. To the solution, 0.74 g (3.49 mM) of hexyl iodide was gradually added under heat-stirring, followed by heat-stirring for 5 hours about 90° C. After the reaction, the solvent was removed from the reaction mixture and water was added to the resultant residue to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent of toluene-methanol to obtain 0.90 g of 2-(4-hexylphenyl)-5-(3-fluoro-4-hexyloxyphenyl)thiazole (Yield: 68.0%). ##STR205##