Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:64][N:65]([CH3:69])[CH2:66][CH2:67][NH2:68]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:68][CH2:67][CH2:66][N:65]([CH3:69])[CH3:64])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Yield: 20 %

Procedure:
4-((2S,4R)-1-Acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 35) (90 mg, 0.225 mmol) was dissolved in anhydrous DMF (3 ml and HATU (103 mg, 0.270 mmol) added. DIPEA (0.118 ml, 0.674 mmol) was added to the mixture and after a further 5 min of stirring at r.t. N1,N1-dimethylethane-1,2-diamine (0.030 ml, 0.449 mmol). The reaction mixture was stirred at r.t. overnight, concentrated and partitioned between EtOAc and water. The Organic phase was separated, dried (Na2SO4) and concentrated. The yellow residue was purified by chromatography a silica cartridge (10 g), eluting with MeOH/DCM (1-6% over 120 mls, followed by 6-20% over 120 mls) to give 4-((2S,4R)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2(dimethylamino)ethyl)benzamide (24 mg, 0.05 mmol, 20% yield) as a light brown solid. LCMS (Formic, 2 min), Rt=0.79 min, MH+=471.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C([Li])(CC)C.Cl.[C:26](OCC)(=[O:28])C>C1COCC1.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:26]=[O:28])=[C:12]([F:16])[C:11]=2[F:17])=[C:6]([F:18])[C:5]=1[F:19])[CH3:2]
Reactant: CCOc1ccc(-c2cccc(F)c2F)c(F)c1F
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C=O)c(F)c2F)c(F)c1F
Reaction time: 2 h

Procedure:
4-Ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl (s-7) (28.0 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00M; n-hexane and cyclohexane solution; 109 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. N,N-Dimethylformamide (8.0 g) in a THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The resulting reaction mixture was poured into a vessel containing a 1N-HCl aqueous solution (300 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The resulting solution was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent and further purified by recrystallization from a mixed solvent of THF and heptane (THF:heptane=1:5 by volume) and dried to give 4′-ethoxy-2,2′,3,3′-tetrafluoro-1,1′-biphenyl-4-carboxaldehyde (s-8) (28.0 g). The yield based on the compound (s-7) was 90.6%.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.C(Cl)(=O)C>[CH3:22][C:21]([O:11][C@@H:10]1[C@@:2]2([CH3:1])[CH2:3][CH2:4][C@@H:5]3[C@@H:20]4[C:14](=[CH:15][C:16]([CH2:18][CH2:19]4)=[O:17])[CH2:13][CH2:12][C@H:6]3[C@@H:7]2[CH2:8][CH2:9]1)=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C

Procedure:
In an apparatus supplied with a drierite drying tube, a solution of 19-nor-testosterone (6) (100 g; 0.365 mole) in acetic anhydride (200 ml), pyridine (32 ml) and acetylchloride (320 ml) was heated at reflux under magnetic stirring, for 3 h and then concentrated to dryness under vacuum. The dry residue was triturated in absolute ethanol, filtered and washed with little portions of absolute ethanol. After drying, 19-nor-testosterone acetate 3-enolacetate was obtained as a white powder (121.4 g, yield 93%) mp. 176°-177° C. The structure was confirmed by spectroscopic means.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.C(O)(=O)C.[OH-].[K+]>O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-n2cccc2)c([N+](=O)[O-])c1

Procedure:
100 g (0.75 mole) of 2,5-dimethoxytetrahydrofuran are added to a solution of 84.1 g (0.5 mole) of 4-methoxy-2-nitroaniline in 500 ml. of glacial acetic acid. The solution is refluxed for 30 minutes, poured into 2500 ml. of water, and neutralized with potassium hydroxide. A solid precipitates and is filtered, dried, and recrystallized from ether to give 1-(4-methoxy-2-nitrophenyl)pyrrole, m.p. 75.5°-76.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a solution of N-(4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.80 g, 5.57 mmol) in DMF (35 mL) was added potassium tert-butoxide (1.87 g, 16.7 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (1.046 g, 6.68 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (1.8 g, 73%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[C:33]([N:36]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][CH2:42][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(=O)N1CCCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCN(C(C)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with N-acetylhomopiperazine. A yellow solid 112 was obtained (0.0246 g, 50%). 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.10 (m, 2H), 2.08 (s, 3H), 3.55 (t, J=5.9 Hz, 1H), 3.59 (t, J=5.5 Hz, 1H), 3.79 (t, J=6.2 Hz, 1H), 3.83 (s, 3H), 3.84-3.92 (m, 3H), 4.05 (t, J=5.3 Hz, 1H), 4.15 (t, J=5.5 Hz, 1H), 6.86 (s, 1/3H), 6.89 (s, 2H), 6.92-7.08 (m, 4H), 7.45-7.53 (m, 3H), 7.84 (s, 1/3H), 7.85 (s, 2/3H), 8.26-8.30 (m, 1H), MS (APCI) m/z 502 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([C:7]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCOC(=O)C(O)(C=Cc1ccccc1)c1ccccc1

Procedure:
Ethyl α-phenyl-α-phenylethynylglycolate (5.6 g., 0.02 mole) in 50 ml. of absolute ethanol, 0.2 g. of palladium on barium sulfate and a drop of quinoline were placed in a Parr shaker under 40 psi of hydrogen at room temperature. The required amount of hydrogen was taken up in 13 minutes. The catalyst was filtered and the filtrate stripped of ethanol in vacuo to yield 5.7 g. (100%) of crude product. Both n.m.r. and infrared spectroscopy confirmed the structure. The material was distilled to yield 4.1 g. of liquid, b.p. 130°-43° (0.16 mm.). N.m.r. analysis of the distilled material indicated that about 5 mole % of the fully saturated derivative was present as an impurity.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)(=O)[CH2:12][CH3:13].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH2:12][CH3:13])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: CCC(=O)O
Reactant: Nc1ccc(Br)c(Cl)c1N
Agent: Cl
Product: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Temperature: 140 °C
Yield: 89 %

Procedure:
4-Bromo-3-chloro-1,2-benzenediamine (0.17 g, 0.766 mmol), propionic acid (0.17 g, 2.298 mmol), and 4 N HCl (1.724 ml, 6.894 mmol) were combined and heated to 140° C. for 3 h. Treatment with 1N NaOH was followed by extraction with EtOAc (×3), and washing with brine. The dried (Na2SO4) organic portions were filtered, concentrated, and chromatographed (SiO2, MeOH/CH2Cl2) to obtain 0.177 g of the title compound: 1HNMR (400 MHz, CDCl3) δ 9.50 (broad s, 1H), 7.43 (d, J=8.31 Hz, 1H), 7.35 (broad s, 1H), 2.96 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H); MS (ESI) m/z 261 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCCCCC.C([Li:25])CCC>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Li:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: [Li]c1ccc(OCCCCCC)cc1
Temperature: 25 °C

Procedure:
24.0g (0.093mol) of 4-hexyloxybromobenzene was dissolved in 30ml of benzene and stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50ml of hexane solution including 15% of butyllithium was added drop-wise for 30 minutes and the solution was maintained under stirring for 2 hours. The produced precipitate gathered by filtration in a stream of nitrogen was dried under reduced pressure to yield 11.1g of 4-hexyloxyphenyllithium.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[C:13](Cl)[N:12]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:17]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([NH:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=1)(=[O:18])[NH2:19]
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@@H](O)CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a mixture of the (S)-methyl 3-amino-2-hydroxypropanoate hydrochloride (0.333 g, 2.14 mmol) in acetonitrile (10 mL) was added 2,6-dichloropyrimidine-4-carboxamide (0.385 g, 2.01 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then cooled. The precipitated solid was filtered off, rinsed once with 2 mL acetonitrile, and air-dried to give (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate as a pale peach-colored powder (0.421 g, 1.53 mmol, 76% yield). LC/MS: m/z=275.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H2O (18 ml), OF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99-101° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CC(N)c1ccccc1N(C)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CC(Nc1cccn2nc(Cl)nc12)c1ccccc1N(C)S(C)(=O)=O

Procedure:
N-{2-[1-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-ethyl]-phenyl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (350.0 mg, 1.506 mmol) and N-[2-(1-amino-ethyl)-phenyl]-N-methyl-methanesulfonamide (380.0 mg, 1.664 mmol) in a manner analogous to Example 2d. Product isolated as a yellow foam (0.315 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83-7.79 (m, 1H), 7.62-7.25 (m, 4H), 6.85-6.71 (m, 1H), 6.61-6.43 (m, 1H), 5.42-6.13 (m, 2H), 3.35-3.26 (m, 3H), 3.08-3.00 (m, 3H), 1.70-1.53 (m, 3H). MS=402 (M+Na)+.
Reaction SMILES: [Na+].[I-:2].ClN1C(=O)CCC1=O.[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)=[CH:20][CH:19]=2)=[O:15])[CH3:12].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O>[CH2:11]([O:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([C:24]=1[I:2])=[CH:22][C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=1)=[CH:20][CH:19]=2)=[O:15])[CH3:12]
Reactant: [I-]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2[nH]1
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(-c3ccc(C(F)(F)F)cc3)cc2c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaI (2.04 g, 14 mmol) in acetone (10 mL) was added dropwise to a stirred solution of N-chlorosuccinimide (1.83 g, 14 mmol) in acetone (10 mL) protected from light. After 15 min, a solution of 5-(4-trifluoromethylphenyl)indole-2-carboxylic acid ethyl ester (3.80 g, 11 mmol; see step (a) above) in acetone (60 mL) was added dropwise, followed by stirring for 2 h at rt. The mixture was poured into Na2S2O3 (aq, 10%, 250 mL) and extracted with EtOAc (200 mL). The combined extracts were washed with NaHCO3 (aq, sat), water and brine, dried (Na2SO4) and concentrated. The residue was treated with petroleum ether to give the sub-title compound. Yield 4.88 g (93%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([Cl:27])[N:18]=[C:17]([Cl:28])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.Cl.O1CCOCC1>[ClH:27].[ClH:27].[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:20]1[C:19]([Cl:27])=[N:18][C:17]([Cl:28])=[N:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:26]
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NC1CCNCC1

Procedure:
A solution of 4-(2,6-dichloro-5-ethoxycarbonylmethyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.01 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 333.1 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](Cl)=[C:11]([C:16]2[C:17](Cl)=[N:18][S:19][N:20]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[SH2:23].[Na].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]2[S:23][C:17]3[C:16](=[N:20][S:19][N:18]=3)[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(c2nsnc2Cl)C1
Reactant: S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)N1CCc2sc3nsnc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydropyridine (3.4 g, 10 mmol) in dimethylformamide was added sodiumhydrogensulfide monohydrate (1.5 g, 20 mmol) and potassium carbonate (2.0 g). The reaction mixture was stirred at room temperature for 3 h. Water (500 ml) was added and the water phase was extracted with diethylether (2×15 ml). The organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography, eluent: methylene chloride/ethyl acetate: 10/1, giving the title compound in 2.1 g yield.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@@H:60]([OH:59])[CH3:65])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (230 mg, 0.5 mmol), dicyclohexylcarbodiimide (160 mg, 0.77 mmol), 1-hydroxybenzotriazole (70 mg, 0.51 mmol), and (S)-3-hydroxybutyric acid (107 mg, 1.0 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (167 mg, 61%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]([S:15]C#N)[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[NH2:12][C:10]1[S:11][C:7]2[C:8](=[C:13]([SH:15])[CH:14]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=2)[N:9]=1
Reactant: CC(C)(C)c1cc(SC#N)c2nc(N)sc2c1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: CC(C)(C)c1cc(S)c2nc(N)sc2c1

Procedure:
The title compound was prepared according to General Method 14 using 6-tert-butyl-4-thiocyanato-benzothiazol-2-yl-amine (Example L-6; 2.0 g, 7.6 mmol), dithiothreitol (4.6 g, 30 mmol), phosphate buffer of pH 7 (10 mL), and EtOH (50 mL). The crude product was used further without any purification. MS (APCI): 239 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3].S(Cl)([Cl:18])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3]
Reactant: C#CCOc1ccc(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(C(=O)Cl)cc1OC
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To 100 ml of toluene were added 12.0 g of 4-(2-propynyloxy)-3-methoxybenzoic acid, 9.0 g of thionyl chloride and 50 mg of DMF, and the resulting mixture was heated to reflux for 3 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was concentrated under reduced pressure. The resulting solid was washed with hexane, and 11.0 g of 4-(2-propynyloxy)-3-methoxybenzoyl chloride was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18](O)=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O>C1COCC1>[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:18]([SH:43])=[N:19][C:20]4[C:25]([N:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Sc1nc2ccccc2nc1CCCN1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-ol (257 mg) was dissolved in THF, and Lawesson's reagent (200 mg) was added to the solution, followed by stirring the mixture at 60° C. for 8 hours. Then Lawesson's reagent (110 mg) was further added and the mixture was stirred at 60° C. for 8 hours. Water was added to the mixture and then the mixture was extracted with dichloromethane. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium: sulfate and the residue was purified by (ethanol:ethyl acetate=10:1) to obtain 103 mg of 3-(3-(4-(diphenylmethyl)piperidyl)propyl)quinoxaline-2-thiol. Yield: 39%.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:13][C:12]1[C:7]([Cl:6])=[C:8]2[C:9]([CH:2]=[C:1]([CH3:3])[NH:14]2)=[CH:10][CH:11]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2ccc(Cl)c(Cl)c2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1600 ml of isopropenylmagnesium bromide at 0.5 M in THF are introduced under nitrogen and cooled to −20° C., 51.2 g of 2,3-dichloronitrobenzene in 250 ml of anhydrous THF are added and then the mixture is left with stirring at −20° C. for 1 hour. The reaction mixture is poured at −20° C. into 1 liter of saturated NH4Cl solution and diluted with Et2O and then the aqueous phase is washed twice with Et2O. The organic phases are combined and concentrated to dryness. The product is extracted with DCM and washed twice with water and then with saturated NaCl solution. It is dried and then evaporated and the residue is chromatographed on a hexane/AcOEt (95/5; v/v) mixture. This gives 24.27 g of the expected compound, m.p.=70–71° C.