Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C1COCC1>[C:36]([C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[C:3]=2[CH3:26])=[O:45])=[CH:47][CH:48]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1c(N)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 4-[6-(3-amino-2-methyl-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzonitrile (380 mg; 1.12 mmol) and diisopropylethylamine (187 mg; 1.45 mmol) in anhydrous THF (25 mL) is stirred under nitrogen at rt. A solution of 4-tert-Butyl-benzoyl chloride (230 mg; 1.17 mmol) in 5 mL anhydrous THF is then added dropwise to the stirring reaction solution. After 30 minutes, the mixture is partitioned between ethyl acetate (75 mL) and water (75 mL) and the water layer extracted with ethyl acetate (2×50 mL). The organic layers are pooled, washed with brine and dried over anhydrous sodium sulfate. The filtrate is then concentrated in vacuo and the crude oil dissolved in a minimum volume of CH2Cl2. Diethyl ether is added and the resulting precipitate is filtered and washed with diethyl ether to provide 4-tert-butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide as a light orange solid (450 mg)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][C:30]1[N:35]=[CH:34][C:33]([C:17]2[N:18]=[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)[S:28][C:15]=3[N:16]=2)=[CH:32][N:31]=1
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (104 mg) in 1,2-dimethoxyethane (10 mL) was added 2-methyl-5-tributylstannanyl-pyrimidine (180 mg) and copper(I)bromide-dimethyl sulfide (96 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (14 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 409. NMR: (CDCl3): 2.67-2.70 (4H, m), 2.82 (3H, s, Me), 2.84 (3H, s, Me), 3.30-3.32 (4H, m), 3.85 (2H, s, CH2), 3.91-3.92 (4H, m), 3.98-4.01 (4H, m), 7.01 (1H, s, Ar) and 9.58 (2H, s, Ar). MS: (ESI+): MH+=490.14
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.S([N:36]=[N+:37]=[N-:38])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:36]([C:7]1[C:2]([Cl:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1)=[N+:37]=[N-:38]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(N=[N+]=[N-])cnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (10 g, 32.5 mmol) was dissolved in THF (250 mL) and cooled to −78° C. Sec-Butyllithium ( 54.8 mL, 1.3M/cyclohexane, 71.4 mmol.) was then added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g, 81.2 mmol.) in THF (100 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and warmed to RT. This mixture was extracted with hexanes (2×200 mL) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 100% hexanes) to afford 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as a mixture with starting material (10.2 g). This mixture was directly used in next step. B. 5-Azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 4.6 mmol) was dissolved in ethyl acetate (100 mL) and Pd/C (10%, 100 mg) was added. This suspension was stirred at RT and under 1 atmosphere. of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to afford 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (730 mg, 43.5%, 2 steps). C. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (10.2 g, 31.5 mmol) was diluted in ethyl acetate (200 mL) and acetic acid (100 mL). Zinc dust (50 g, 0.8 mol.) was added in small portions at RT. After stirring the suspension at RT for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×300 mL). The combined organic layers were dried, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (6.38 g).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.CC1(C)[C@@]23C4(ON4S(=O)(=[O:34])C2)C[C@@H]1CC3.[Cl-].[NH4+]>C1COCC1.O.C(#N)C>[F:6][C:7]1[C:12]([OH:34])=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:15][C:8]=12
Reactant: CC1(C)[C@H]2CC[C@]13CS(=O)(=O)N1OC13C2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
sec-Butyllithium (27 mL, 38 mmol; 1.4M in cyclohexane) was added dropwise to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17 mmol; Example 1, Step D) in THF (200 mL) at −78° C., and the reaction was stirred for 30 minutes. (1S)-(+)-(10-Camphorsulfonyl)oxaziridine (9.4 g, 41 mmol) in THF (40 mL) was added rapidly, and the reaction was stirred at −78° C. for 30 minutes. A solution of saturated ammonium chloride (50 mL) was added, and the reaction mixture was allowed to reach room temperature. After one hour, the aqueous phase was extracted with AcOEt, dried over MgSO4 and concentrated to a solid, which was triturated in ether. The solid (most of the camphor side product) was filtered off, and the filtrate was concentrated and purified by reverse phase chromatography (Biotage SP4, C-18 40M+, water/ACN 40/60→0/100, 12 CV) to yield 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g, 49% yield) as a paste.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22])([CH3:19])[CH3:18].O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:21]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:17]([CH3:19])[CH3:18])=[O:22])=[N:6][CH:7]=1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: NNc1ccc(F)cn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C(=O)NNc1ccc(F)cn1)C(C)C
Temperature: 45 °C
Yield: 50.1 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO2010022076; 200 mg, 1.57 mmol) in DCM (15 mL) was added triethylamine (328 μL, 2.35 mmol) followed by N,N-diisopropylcarbamoyl chloride (282 mg, 1.73 mmol). The reaction mixture was heated at 45° C. for 4 h then poured into water and extracted with DCM (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title compound (200 mg, 50%). 1H NMR (400 MHz, CDCl3): 1.30 (12H, d, J=6.8 Hz), 3.80-4.03 (2H, m), 6.17 (1H, s), 6.53 (1H, s), 6.67-6.81 (1H, m), 7.24-7.36 (1H, m), 8.02 (1H, d, J=3.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29].O1CCCC1>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3ccccc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (500 mg), a solution (about 7 mol/L, 20.1 mL) of ammonia in methanol, and tetrahydrofuran (6.7 mL) was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (490 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.42 (2H, s), 5.37-5.60 (1H, br), 6.77 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.24-7.29 (1H, m), 7.31-7.39 (2H, m), 7.40-7.49 (2H, m), 7.50-7.58 (2H, m), 7.69 (1H, t, J=7.8 Hz), 7.75-7.95 (1H, br), 7.97-8.03 (1H, m), 8.09 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.I[CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CCCCC(I)CC
Product: CCCCC(CC)N1C(=Nc2ccc([N+](=O)[O-])cc2C)SC[C@@H]1CC(C)C

Procedure:
(1S)-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-1-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(5-heptyl)-1,3-thiazolidine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C@H:29]([CH2:32][CH3:33])[CH2:30][OH:31]>>[CH2:32]([C@@H:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[N:20][CH:21]=1)=[O:24])[CH2:30][OH:31])[CH3:33]
Reactant: CC[C@@H](N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC[C@H](CO)NC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 83 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using (R)-(−)-2-amino-1-butanol. Then, the product was recrystallized with ethanol and petroleum ether to give a desired compound.
Reaction SMILES: C([N:10]1[CH2:29][CH2:28][C@@:17]23[C:18]4[CH:19]=[C:20]([O:25][CH2:26][CH3:27])[CH:21]=[CH:22][C:23]=4[CH2:24][C@@H:11]1[C@@H:12]2[CH2:13][CH2:14][O:15][CH2:16]3)(OC1C=CC=CC=1)=O.[OH-].[K+].CC(O)C>O>[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][C:23]2[CH2:24][C@H:11]3[NH:10][CH2:29][CH2:28][C@@:17]4([C:18]=2[CH:19]=1)[C@H:12]3[CH2:13][CH2:14][O:15][CH2:16]4)[CH3:27]
Reactant: CCOc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCOc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of XXIX (0.005 m) from Step (d) above, 6 g potassium hydroxide, 75 ml 2-propanol and 20 ml water is heated at reflux for 40 hours. The 2-propanol is removed at reduced pressure. The resultant mixture is extracted with methylene chloride. The extracts are dried (Na2SO4), filtered and concentrated to produce the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([C:17](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.O>CN(C=O)C.N1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:16]2[CH:33]=[CH:34][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1cccc(CO)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(OCc2cccc(C#N)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
In DMF (23 mL) and pyridine (23 mL), suspended were 3-hydroxymethylbenzonitrile (1.12 g, 8.38 mmol) and 4,4′-dimethoxytritylchloride (3.41 g, 10.06 mmol). The suspension was stirred for 12 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, to the suspension was added iced water (20 mL). The mixture was subjected to extraction with EtOAc and water. The organic layer was washed with sat. NaCl aq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=10:1) to give 3-(4,4′-dimethoxytrityloxymethyl)benzonitrile (4) (3.31 mg, 91%) as a colorless oil.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH2:64]([O:71][C:72](=[O:82])[C@H:73]([N:75]1[C:80](=[O:81])C=CC[O:76]1)[CH3:74])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.S([O-])([O-])=O.[Na+].[Na+].[C:89]([OH:93])([CH3:92])(C)[CH3:90]>O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[CH2:64]([O:71][C:72]([C@H:73]([N:75]1[C:80](=[O:81])[C@@H:90]([OH:22])[C@@H:89]([OH:93])[CH2:92][O:76]1)[CH3:74])=[O:82])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C[C@H](C(=O)OCc1ccccc1)N1OCC=CC1=O
Reactant: CC(C)(C)O
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)OCc1ccccc1)N1OC[C@H](O)[C@H](O)C1=O
Reaction time: 14 h
Yield: 81 %

Procedure:
A mixture of K2OsO2(OH)4 (0.0063 g, 0.017 mmol), (DHQD)2PHAL (0.032 g, 0.041 mmol), and AD-mix-β (1.41 g) was dissolved in a mixture of tert-butanol (5 mL) and water (5 mL). After dissolution of the salts, methanesulfonamide (0.0994 g, 1.04 mmol) was added and the mixture was cooled to −2˜0° C. (R)-2-(α-Benzoxycarbonylethyl)-4,5-dehydro-1,2-oxazinan-3-one (7a) (0.264 g, 1.01 mmol) was added in one portion and the heterogeneous slurry was stirred vigorously for 14 h at −2˜+2° C. Sodium sulfite (1.5 g) was added in order to quench the oxidation and stirring was continued for 1 h at RT. CH2Cl2 (10 mL) was added and the upper organic layer was separated off. The aqueous phase was extracted with CH2Cl2 (5×5 mL). The combined organic extracts were dried over MgSO4. After removal of the solvent, the yellowish semisolid residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 15% EtOAc-hexanes→EtOAc) to afford 0.158 g (81%) the product 8a as a white solid. 1H NMR (400 MHz) in CDCl3+2 drops of CD3OD (J, Hz): δ 1.53 (3H, d, 3J=7.3, α-MeCH), 3.96 (1H, dd, 2J=−11.8, 3J=2.5, 6-HA), 4.41 (1H, d, 3J=4.1, 4-H), 4.44 (1H, dd, 2J=−11.8, 3J=6.8, 6-HB), 4.55-4.51 (1H, m, 5-H), 5.11 (1H, q, 3J=7.3, α-CH), 5.13 (1H, s, CH2Ph), 7.34-7.24 (5H, m, Ph).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][CH:17]([NH:19][CH3:20])[CH3:18])[CH2:12][C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:18][CH:17]1[N:19]([CH3:20])[C:13](=[O:14])[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16]1
Reactant: CNC(C)CN(CC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(C(=O)OCc2ccccc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[(benzyloxy)carbonyl]-N-[2-(methylamino)propyl]glycine (2.42 g, 8.63 mmol) in DMF (40 mL) was treated with EDC (1.66 g, 8.63 mmol) and stirred at room temperature overnight. The reaction was diluted with EtOAc and washed once each with aqueous 1N HCl, saturated aqueous NaHCO3, and brine. The combined aqueous layers were extracted once with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was subjected to column chromatography eluting with a gradient of 50-100% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:44])(=[O:45])[NH2:43])=[CH:37][C:33]=1[C:34]([N:21]1[CH2:20][CH2:19][N:18]([C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22]1)=[O:35]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)c(Cl)cc1Cl
Reactant: COc1ccc(-c2cc(N3CCNCC3)nc(C)n2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(N3CCN(C(=O)c4cc(S(N)(=O)=O)c(Cl)cc4Cl)CC3)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(1-piperazinyl)pyrimidine (0.8 g) in chloroform (10 ml) were added triethylamine (0.39 ml) and 2,4-dichloro-5-sulfamoylbenzoyl chloride (0.74 g), and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated. The obtained mixture was chromatographed on silica gel eluting with chloroform-methanol mixture (49:1 v/v), to give 4-[4-(2,4-dichloro-5-sulfamoylbenzoyl)piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (1.03 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].N[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=CC=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][C:2]1[CH:41]=[N:40][CH:39]=[CH:38][CH:37]=1)=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: NCc1cccnc1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4cccnc4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-(aminomethyl)pyridine.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH2:26])[CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCCC1.O>[CH2:11]([O:18][C:19]([C:21]1[S:22][C:23]([CH3:27])=[C:24]([NH:26][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1sc(C(=O)OCc2ccccc2)cc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)OCc2ccccc2)cc1NC(=O)Cc1ccccc1
Reaction time: 18 h
Yield: 51.3 %

Procedure:
Phenylacetyl chloride (0.26 g, 1.7 mmol) was added to a stirred solution of 5-methyl-4-amino-thiophene-2-carboxylic acid benzyl ester (0.4 g, 1.6 mmol), prepared as described above in Step 2, and diisopropylethylamine (0.26 g, 2.0 mmol) in tetrahydrofuran (15 mL) under an inert atmosphere at room temperature. After 18 hours, the mixture was diluted with water (100 mL) and acidified with aqueous HCl. The precipitate was filtered off, rinsed with water, then ethanol, then ether, and dried to afford 0.3 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid benzyl ester. Recrystallization of a sample from acetonitrile gave product with a mp 173-174° C.
Reaction SMILES: [I-:1].[K+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)#[N:4].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C=O)C.O>[C:3]([C:5]1[CH:10]=[C:9]([I:1])[C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)#[N:4]
Reactant: [I-]
Reactant: N#Cc1ccc(O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(O)c(I)c1
Yield: 47 %

Procedure:
Potassium iodide (7.97 g, 48 mmol) was dissolved in 125 ml of DMF with stirring, and 4-cyano-2-fluorophenol (16a; 5.56 g 48 mmol) and chloramine-T in 75 ml of DMF were added dropwise with stirring. The reaction mixture was poured into 650 ml of water, acidified with 6N HCl, and extracted with ethyl acetate. The organic layer was washed with 10% NaHSO3, water and brine and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the yellow solid residue was treated with 200 ml of 1N NaOH solution, filtered through supercel, and the filtrate was acidified with conc. HCl solution. The solid product was filtered, dried, dissolved in ether, and the organic layer was dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was recrystallized from ethylene chloride to afford 5.93 g (55.6%) of the title compounds.