Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([CH3:11])[CH:10]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:11][N:9]1[CH:10]=[C:6]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])[N:7]=[CH:8]1
Reactant: Cn1cnc(I)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reaction time: 2 h

Procedure:
3 M Ethyl magnesium bromide in THF (11.0 ml, 33.0 mmol) was added dropwise to a solution of 4-iodo-1-methyl-1H-imidazole (5.61 g, 27.0 mmol) in THF (50 ml) at −78° C. After stirring for 2 h, tributyltin chloride (8.0 ml, 29.5 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed (hexane:ethyl acetate) to yield 1-methyl-4-(tributylstannyl)-1H-imidazole. Method [7] Retention time 7.34 min by HPLC (MH+ 373).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH2:10])[CH2:6][CH2:7][S:8][CH3:9].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=1[CH2:25]Br.C(N(CC)CC)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:10]1[CH2:25][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][C:17]=2[C:21]([F:24])([F:22])[F:23])[C:14]1=[O:13])[CH2:6][CH2:7][S:8][CH3:9]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1cccc(C(F)(F)F)c1CBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 115 °C
Yield: 39.4 %

Procedure:
A mixture of (S)-2-amino-4-methylsulfanyl-butyric acid methyl ester hydrochloride (Aldrich, 199 mg, 1 mmol) and 2-bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (prepared as in Example 1, 297 mg, 1 mmol) in acetonitrile (5 mL) and triethylamine (280 μL, 2 mmol) was placed in a microwave reaction vessel and sealed. The reaction mixture was then placed in a microwave reactor and heated at 115° C. for 15 min. After this time, the reaction mixture was cooled and concentrated with silica gel (2 g) in vacuo. The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (137 mg, 40%) as a colorless viscous oil: HR-ES(+) m/e calcd for C15H16NO3SF3 [M+H]+ 348.0876, observed 348.0874; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07 (d, J=7.46 Hz, 1H), 7.83 (d, J=7.67 Hz, 1H), 7.64 (t, J=7.67 Hz, 1H), 5.25 (dd, J=4.69, 10.44 Hz, 1H), 4.79 (d, J=17.47 Hz, 1H), 4.53 (d, J=17.47 Hz, 1H), 3.77 (s, 3H), 2.38-2.62 (m, 3H), 2.16-2.31 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: [OH-:1].[Na+].BrBr.[C:5]([C:8]1[O:9][C:10]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([Br:19])=[CH:13][C:11]=2[CH:12]=1)(=[O:7])C.Cl>O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:10]2[O:9][C:8]([C:5]([OH:7])=[O:1])=[CH:12][C:11]=2[CH:13]=1
Reactant: COc1cc(Br)cc2cc(C(C)=O)oc12
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(Br)cc2cc(C(=O)O)oc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 107.6 ml of 5N sodium hydroxide aqueous solution was added dropwise 26.8 g of bromine at a temperature of -5° C. or below. To this was further added dropwise and slowly a 100 ml dioxane solution containing 15.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran obtained in the above step a). After completion of the dropwise addition, the temperature of the resulting reaction solution was increased gradually to 60° C. and then stirred for 30 minutes. After cooling, the resulting reaction solution was adjusted to pH 2 with concentrated hydrochloric acid and then extracted with ethyl acetate. The resulting organic layer was concentrated to dryness, and crystals thus precipitated were collected by filtration to obtain 5-bromo-7-methoxy-2-benzofurancarboxylic acid. The thus obtained crystals were suspended in 200 ml of ethanol, and 10 ml of thionyl chloride was added dropwise to the suspension with stirring at room temperature. The resulting reaction solution was refluxed under heating for 2 hours. After cooling, the thus treated reaction solution was neutralized with saturated sodium bicarbonate aqueous solution, and then mixed with water to collect precipitated crystals by filtration. The crystals thus collected were purified by silica gel column chromatography using chloroform as an eluant to obtain 11.33 g of ethyl 5-bromo-7-methoxy-2-benzofurancarboxylate.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=1)[NH2:4].[CH3:14][C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19].C([O-])(=O)C.[Na+].C(OCC)C>C(O)(=O)C>[CH3:19][C:18]1[N:4]([NH:3][C:5]2[N:6]=[N:7][C:8]([N:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=2)[C:15]([CH3:14])=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CN(C)c1ccc(NN)nn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(C)n1Nc1ccc(N(C)C)nn1
Yield: 47 %

Procedure:
The product is obtained according to the procedure of example 19 by reacting 3-hydrazino-6-dimethylamino-pyridazine dihydrochloride and 2,5-hexanedione in acetic acid in the presence of sodium acetate. Yield 47%; m.p. 165°-167° C. (from ethyl ether).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:8]=2)[NH:3]1.C(N(CC)CC)C.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CO>[C:33]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:32])[CH2:34][OH:35]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(C)N3)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(C)N3C(=O)CO)C(=O)O1
Reaction time: 0.33 h

Procedure:
The deprotected material N-{[(5S)-3-(2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.48 g, 1.66 mmol) (EXAMPLE 1, Step 6) and triethylamine (0.35 mL, 2.5 mmol) are dissolved in CH2Cl2 (10 mL). Acetoxyacetylchloride (0.233 mL, 2.16 mmol) is added along with additional CH2Cl2 (25 mL). After 20 minutes the mixture is diluted with CH2Cl2 (200 mL) and washed with water, brine and dried (Na2SO4). Removal of solvent gave a residue that is dissolved in MeOH (20 mL) and CH2Cl2 (80 mL). Potassium carbonate (200 mg) is added and the reaction is stirred for 20 minutes and evaporated to dryness. The residue is purified on silica gel with 2% MeOH/CH2Cl2 to give 0.5 g (86%) of an off white solid: mp 130-133° C.; HRMS (FAB) calcd for C17H21N3O5+H1 348.1559, found 348.1569.Anal. Calcd for C17H21N3O5: C, 58.78; H, 6.09; N, 12.10.Found: C, 58.60; H, 6.27; N, 11.53.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](CS)=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[S:8][CH2:11][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)#[N:2]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(C#N)c(SCc2ccc(OC)cc2)s1

Procedure:
To a stirred solution of 2.5 g (10 mmol) of methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (Example 139, step (a)) in dry methanol (15 mL) was added p-methoxybenzylmercaptan (3.8 mL, 28 mmol) and triethylamine (1.4 mL, 10 mmol). This solution was refluxed for 15 min and cooled. The resulting solid was collected on a buchner funnel and washed with methanol (2×25 mL) to methyl 4-cyano-5-[(4-methoxyphenyl)methylthio]thiophene-2-carboxylate (2.84 g, 89%) as a solid.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C.CC(O)=O>[C:17]1([C:15]2[N:1]([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=3)[C:6]#[N:7])[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1ccnc(-n2nccc2-c2ccccc2)c1
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (100 mg, 0.75 mmol, 1.0 eq., PREPARATION 2) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (132 mg, 0.75 mmol, 1.0 eq.) in ethanol (10 mL) was added 2-5 drops of AcOH. The reaction mixture was under reflux conditions for 12 h. After reaction completion, volatiles were removed under reduced pressure, and the resultant crude material was purified by flash column chromatography (20% EtOAc/hexane) to obtain the title compound as a yellow oil (150 mg, 81% yield). [M+H] Calc'd for C15H10N4, 247.09. Found 247.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.O.[NH4+:24]>>[CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([NH2:24])=[O:21])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: CNCc1ccc(-c2nc3cccc(C(=O)OC)c3o2)cc1
Solvent: O
Product: CNCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1
Yield: 33 %

Procedure:
Methyl 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (25 mg, 0.06 mmol) in ammonium water (2 mL) was stirred at 30° C. for 17 hr, then the solvents were evaporated and purified by pre-HPLC to obtain 2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (25 mg, yield 33%). 1H-NMR (400 MHz, MeOH-d4) δ 2.07 (s, 1H), 2.30 (s, 3H), 3.78 (s, 2H), 7.45-7.49 (t, J=8 Hz, 1H), 7.57-7.59 (d, J=8 Hz, 2H), 7.79-7.81 (d, J=8 Hz, 1H), 7.86-7.95 (m, 3H), 8.24-8.26 (d, J=8 Hz, 2H); LC-MS (ESI) m/z 282 [M+1]+.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([NH:29][C@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=4)[CH3:31])=[O:28])=[CH:24][CH:25]=3)[C:20]([CH3:41])=[C:19]2[CH3:42])=[CH:13][CH:12]=1)=[O:4])[NH2:2].CCN(C(C)C)C(C)C.CN([CH:55]=[O:56])C>>[CH:38]([C:34]1[CH:33]=[C:32]([C@@H:30]([NH:29][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:3]4[O:4][C:55](=[O:56])[NH:2][N:1]=4)=[CH:16][CH:15]=2)[C:19]([CH3:42])=[C:20]3[CH3:41])=[O:28])[CH3:31])[CH:37]=[CH:36][CH:35]=1)([CH3:39])[CH3:40]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NN)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3-c3n[nH]c(=O)o3)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of (S)-1-((2′-(hydrazinocarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide (0.062 g, 0.11 mmol), N,N′-carbonyldiimidazole (0.027 g, 0.16 mmol) and DIEA (0.03 mL, 0.16 mmol) in DMF was stirred at room temperature for 1 h, and then stirred at 50° C. for 1 h. The reaction mixture was poured on to ice-water, and then extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solvent was remove and the residue was purified with preparative-HPLC to obtain the title compound. ESI-MS (m/z): 585 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 2-(4-Chloro-phenyl)-thiazole-5-carbaldehyde (5.59 g, 25 mmol) in methanol (65 ml) at 0° C. was added sodium borohydride (1.04 g, 27.5 mmol) portionwise over a period of 5 minutes. The reaction was then allowed to warm to room temperature and stirred under nitrogen for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and stirred for 5 minutes, before the methanol was removed under reduced pressure. The resulting heterogeneous mixture was then extracted with ethyl acetate (2×100 ml), the combined organics dried over magnesium sulphate and the solvent removed under reduced pressure to give [2-(4-Chloro-phenyl)-thiazol-5-yl]-methanol (5.27 g).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:41][CH:40]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1ccc(F)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(F)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-fluorobenzylamine. Purification was performed using HPLC with a normal phase column. Elution with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) gave the title compound in 80% yield, m.p. 214-215° C.; MS [(+)ESI, m/z]: 558 [M+H]+
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([C:16]2[C:17]([CH3:28])=[N:18][O:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)[OH:15])[CH:11]=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:38]=[CH:39][C:40]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[O:19][N:18]=[C:17]([CH3:28])[C:16]=4[CH:14]([C:10]4[CH:11]=[N:12][CH:13]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:9]=4)[OH:15])=[CH:26][CH:25]=3)=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cncc(Cc2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cncc(Cc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using (5-benzyl-pyridin-3-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH:18]1[NH2:33])[C:12]([O:14]CC)=[O:13].C(O)(=O)C>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH:18]1[NH2:33])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)[C@@H](CCCCCCCN)[C@@H]1C(=O)N(CC(=O)O)c2ccccc2SC1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCCCCC[C@H](C(=O)O)[C@@H]1C(=O)N(CC(=O)O)c2ccccc2SC1N
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
In 10 ml of 1N aqueous sodium hydroxide solution is dissolved 0.35 g of 3(R)-[8-amino-1(S)-ethoxycarbonyloctyl]-amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride, and the solution is left standing at room temperature for 30 minutes. Acetic acid (2.5 ml) is added to the solution and the resulting mixture is purified by Amberlite XAD-2 column chromatography (methanol:water=1:2). The eluate is concentrated under reduced pressure and lyophilized to give 0.24 g of 3(R)-[8-amino-1(S)-carboxyoctyl]-amino-4-oxo-2, 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13]12[O:19][C:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])([CH:17]=[CH:18]1)[CH:15]([C:29](O)=[O:30])[CH2:14]2.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][NH:9][C:29]([CH:15]1[CH2:14][C:13]2([O:12][CH3:11])[O:19][C:16]1([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[CH2:17][CH2:18]2)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC12C=CC(S(=O)(=O)c3ccccc3)(O1)C(C(=O)O)C2
Reactant: NOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC12CCC(S(=O)(=O)c3ccccc3)(O1)C(C(=O)NOCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Added the O-benzylhydroxylamine·hydrochloric acid (0.387 grams, 2.43 mmol) to a stirred solution of 3-(4-methoxy-phenylsulfonyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid in methylene chloride (5 ml). Added 4-dimethylaminopyridine (0.306 grams, 2.51 mmol) and stirred approximately one-half hour (until solids dissolved), then added the 1,3-dicyclohexylcarbodiimide (0.250 grams, 1.21 mmol) and stirred at room temperature overnight. The reaction was filtered through a pad of Celite and the filtrate concentrated in vacuo to give 1.06 grams of 3-(4-Methoxyphenylsulfonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid benzyloxyamide. Took this up in methanol and decanted filtrate from fine needle crystals. Concentration of filtrate gave 0.82 grams of 3-(4-Methoxyphenylsulfonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid benzyloxyamide.
Reaction SMILES: C[Si]([NH:5][C:6]1[N:11]=[C:10]([O:12][Si](C)(C)C)[N:9]=[CH:8][N:7]=1)(C)C.C(O[C@@H:21]1[O:43][C@H:42]([CH2:44][O:45]C(=O)C2C=CC=CC=2)[C@@H:32]([O:33]C(=O)C2C=CC=CC=2)[C@H:22]1[O:23]C(=O)C1C=CC=CC=1)(=O)C.CC#N.S(O)(C(F)(F)F)(=O)=O>CS(C)=O>[CH:8]1[N:9]([C@@H:21]2[O:43][C@H:42]([CH2:44][OH:45])[C@@H:32]([OH:33])[C@H:22]2[OH:23])[C:10](=[O:12])[N:11]=[C:6]([NH2:5])[N:7]=1
Reactant: C[Si](C)(C)Nc1ncnc(O[Si](C)(C)C)n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 55 °C
Reaction time: 0.58 h
Yield: 71 %

Procedure:
A mixture of 2-[(trimethylsilyl)amino]-4-[(trimethylsilyl)oxy]-s-triazine (4.5 Kg), 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (8.8 Kg), anhydrous MeCN (34.6 Kg) and TfOH (600 g) were heated at 55° C. for 12.5 hours. The reaction mixture was cooled to 45° C., DMSO (29 Kg) was added, and the MeCN was evaporated at an internal temperature of <50° C. under vacuum until about 54 L of the solution. The solution was cooled to 23° C. MeOH (13.9 Kg) was added followed by a solution of 30% NaOMe in MeOH solution (2.5 Kg) that was pre-diluted with MeOH (7.0 Kg). The solution was stirred at 23° C. for 35 minutes. When the reaction was complete MeOH (90.4 Kg) was added and the resulting slurry was stirred at 22° C. for 3 hours and 10 minutes and was then filtered and washed three times with MeOH (7.0 Kg each). The cake was dried under vacuum at below 70° C. for 9 hours and 20 minutes to give 3.2 Kg of 98.89% purity crude azacitidine (71% yield based on 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[Cl:11])[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[Cl:11])[C:7]([Cl:17])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Br)c(Cl)c1C(=O)O
Solvent: ClCCl
Product: COc1ccc(Br)c(Cl)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4B (1.2 g, 4.6 mmol), dichloromethane (15 ml) and oxalyl chloride (1 ml) is stirred at room temperature for 2 hours. The mixture is concentrated and the resulting benzoylchloride is used without further purification.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(OCC)(=O)C>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([S:38]([C:35]5[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=5)(=[O:40])=[O:39])[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (27.6 mg, 0.085 mmol, 1.0 equivalent, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. Triethylamine (43 mg, 0.425 mmol, 5.0 equivalents) was added followed by 4-(trifluoromethyl)benzene-1-sulfonyl chloride (27 mg, 0.11 mmol, 1.3 equivalents) as a solution in dichloromethane (0.1 mL). The reaction was stirred for 15 minutes. The mixture was loaded directly onto a 4 g silica gel column and with 0:100 to 50:50 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (25 mg, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=1.4 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 5.53-5.25 (m, 1H), 4.17 (td, J=9.4, 3.0 Hz, 1H), 4.12-4.00 (m, 1H), 3.97 (d, J=13.4 Hz, 1H), 3.79 (d, J=3.5 Hz, 2H), 2.99-2.55 (m, 5H), 2.14-1.92 (m, 2H), 0.95 (ddt, J=12.1, 7.0, 2.0 Hz, 4H); MS (ESI+) m/z expected 497.1; found: 497.0 (M+H)+; [α]D24.1=0.19 (c=0.12, CH3OH).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:36][CH2:37][N:38]([C:41](Cl)=[O:42])[CH2:39][CH:40]=2)=[CH:31][CH:30]=1.O>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([N:19]3[CH2:18][CH2:17][N:16]([CH2:15][C@:4]4([CH3:3])[O:8][C:7]5=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]5[CH2:5]4)[CH2:21][CH2:20]3)=[O:42])[CH2:37][CH:36]=2)=[CH:31][CH:30]=1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C(Cl)N1CC=C(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCN(C(=O)N3CC=C(c4ccc(Cl)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (401 mg, 1.5 mmol), DMF (8 ml) and potassium carbonate (750 mg, 5.4 mmol) was stirred at room temperature for 10 minutes. To the reaction mixture, a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (400 mg, 1.56 mmol) in DMF (3 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford (S)-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]methanone (380 mg, yield 53%) as a light yellow powder.