Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][N:14]1[C:23]2[C:22](=[O:24])[NH:21][C:20]3[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=3[NH:18][C:17]=2[C:16]([CH3:29])=[N:15]1>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:18]1[C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[NH:21][C:22](=[O:24])[C:23]2[N:14]([CH3:13])[N:15]=[C:16]([CH3:29])[C:17]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1nn(C)c2c1Nc1ccccc1NC2=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reaction time: 3 h
Yield: 65.1 %

Procedure:
2 g of chloroacetyl chloride and 2 g of triethylamine are added dropwise at the same time over the course of 40 minutes to a boiling solution of 2.3 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one in 30 ml of absolute dioxane, and the mixture is stirred for a further 3 hours. It is then allowed to cool and is filtered; the filtrate is concentrated to dryness and chromatographed over a silica gel column by means of a 1:1 mixture of petroleum ether and ethyl acetate, and the product is recrystallized from toluene to yield 2.0 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 246° to 248° C. (dec.).
Reaction SMILES: C[Si](Br)(C)C.[CH2:6]([N:8]([CH2:23][CH3:24])[C:9](=[O:22])[C:10]([CH2:12][O:13][CH2:14][CH2:15][P:16]([O:20]C)([O:18]C)=[O:17])=[CH2:11])[CH3:7]>>[CH2:23]([N:8]([CH2:6][CH3:7])[C:9](=[O:22])[C:10]([CH2:12][O:13][CH2:14][CH2:15][P:16]([OH:20])([OH:18])=[O:17])=[CH2:11])[CH3:24]
Reactant: C=C(COCCP(=O)(OC)OC)C(=O)N(CC)CC
Agent: C[Si](C)(C)Br
Product: C=C(COCCP(=O)(O)O)C(=O)N(CC)CC
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
17 g (111 mmol) trimethylsilyl bromide are slowly added dropwise to 13.5 g (51 mmol) of compound 2 and the mixture is subsequently stirred for 2 hours at 40° C. Afterwards, it is firstly concentrated in a water-jet vacuum and then in a fine vacuum (0.2 mbar), 70 ml of absolute methanol are added and the mixture is stirred overnight at room temperature. The slightly yellowish, clear solution is concentrated on the rotary evaporator and dried off in fine vacuum (0.2 mbar) at 40° C. until its weight is constant. 13.5 g (100% yield) of a bight yellow oil remain as product, which has a HPLC purity of 98.1%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
250 mg (0.74 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 143 mg (0.96 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to General Method 3. Yield: 276 mg (88% of theory)
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]=[N:20][NH:21][C:22]=2[CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])O)[N:9]=[N:8]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:19]=[N:20][NH:21][C:22]=2[CH2:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[N:9]=[N:8]1
Reactant: OC(c1ccccc1Cl)c1[nH]nnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cn2nnc(-c3nn[nH]c3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Dissolve [1′-(3,5-bis-trifluoromethyl-benzyl)-5′-phenyl-1H,1′H-[4,4′]bi[[1,2,3]triazolyl]-5-yl]-(2-chloro-phenyl)-methanol (38 mg, 0.066 mmol) and 1.5 mL CH2Cl2. Carefully add triethylsilane (23 mg, 31.4 μL, 0.197 mmol). Cool to 0° C. and add trifluoroacetic acid (452 mg, 305 μL, 3.96 mmol) and stir. After 15 hours, pour into 10 mL of (saturated aqueous NaHCO3) and 20 mL of CH2Cl2. Extract 3 times with CH2Cl2 and 1 time with EtOAc. Combine the organics, dry over MgSO4 and filter and concentrate. Apply the mixture to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a 100 mL of Hexanes, and then 200 mL each of of 10:90 EtOAc/Hexanes, 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc to provide the title compound. Exact Mass 562.1: mass spectrum (IS): m/z=563.1 (M+1), 561.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.72 (s, 1H), 7.42-7.28 (m, 5H), 7.24 (m, 1H), 7.16-6.97 (m, 6H), 5.52 (s, 2H), 4.37 (s, 2H).
Reaction SMILES: [CH2:1]([O:6][C@@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[N:15]1[C:25]2[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=2[N:17]=[CH:16]1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si](Cl)(C)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[C:31]([NH:23][C:22]1[NH:21][C:19](=[O:20])[C:18]2[N:17]=[CH:16][N:15]([C:25]=2[N:24]=1)[C@@H:8]1[O:9][C@H:10]([CH2:13][OH:14])[C@@H:11]([OH:12])[C@H:7]1[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21

Procedure:
2'-O-pentylguanosine (2.3 g) in pyridine (35 ml) was treated with trimethylsilyl chloride (4.15 ml, 5 eq) and isobutyryl chloride (3.4 ml, 5 eq) as per the procedure of Example 4 to yield the product as a foam (2.3 g). An analytical sample was crystallized from EtOAc/Hex. m.p. 178-180° C. 1H NMR (DMSO-d6) δ 0.75 (t, 3, CH3), 1.1 [m, 10, 2×CH2, CH(CH3)2 ], 1.4 (m, 2, CH2), 2.74 [m, 1, CH(CH3)2 ], 3.56 (m, 4, OCH2, H-5'), 3.93 (m, 1, H-4'), 4.25 (m, 1), 4.34 (m, 1), 5.0 (t, 1, 5'-OH), 5.17 (d, 1, 3'-OH), 5.88 (d, 1, H-1'), 8.27 (s, 1, H-8), 11.65 (br s, 1, NH) and 12.05 (br s, 1, NH). Anal. Calcd. for C19H29N5O6 : C, 53.89; H, 6.90; N, 16.54. Found: 53.75; H, 6.92; N, 16.40
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](=[O:20])(=[O:19])[NH2:18])=O)C.Cl>O>[O:19]=[S:17]1(=[O:20])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:8]([CH2:7][C:6]([OH:5])=[O:21])=[N:18]1
Reactant: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 110 °C
Yield: 71.7 %

Procedure:
Solid sodium hydroxide (3.48 g, 87 mmol) was dissolved in water to make a saturated solution. The crude N-(2-sulfamoyl-phenyl)-malonamic acid ethyl ester was added into the sodium hydroxide solution. The reaction mixture was heated at 110° C. for 2.5 h, and then was cooled down to 25° C. The reaction mixture was acidified by slowly adding a 12.0 M aqueous hydrochloric acid solution (9.67 g, 116 mmol) while cooling in an ice-water bath. The product precipitated and was collected by vacuum filtration. The solid was washed with cold water and dried under high vacuum to afford the crude product, (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (5 g, 20.8 mmol, 71.7% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (2H, s), 7.31 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J1=7.8 Hz, J2=7.8 Hz), 7.67 (1H, dd, J1=7.8 Hz, J2=7.8 Hz), 7.79 (1H, d, J=7.9 Hz), 12.18 (1H, bs), 13.03 (1H, bs). LC-MS (ESI) calcd for C9H8N2O4S 240.02, found 241.1 [M+H+].
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[S:11])=[CH:8][N:7]=1.[ClH:15]>>[CH3:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:15])=[S:11])=[CH:8][N:7]=1
Reactant: Cc1ccc(C(O)=S)cn1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=S)Cl)cn1

Procedure:
Thionylchloride (23.8 g) was added to 6-methylthionicotinic acid (15.3 g) (from the above referential example 1a). The reaction mixture was gradually heated with stirring and refluxed until the generation of hydrogen chloride ceased. 6-methylthionicotinoylchloride was stoichiometricly obtained by distilling off excess thionylchloride under reduced pressure. 6-methylthionicotinoylchloride dissolved in ether was added dropwise to 20% aqueous solution of sodium borohydride (6.5 g) at 0°~10° C. After adding, the mixture was stirred for one hour and the ether layer was separated and dried. The ether layer was evaporated under reduced pressure to give 2-methylthiopyridine-5-methanol (9.6 g). nD22 1.6084
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1)=[O:23].O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22]([CH2:21][N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:2])=[O:4])=[O:23])=[N:26][CH:27]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 2 h

Procedure:
To a solution of 1 g 5-Methanesulfonyl-1H-indole-2-carboxylic acid methyl ester in 10 ml DMF, 158 mg (60% in oil) sodium hydride were added at RT. After stirring for 10 min 985 mg 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture was stirred for 2 h. After the addition of 7 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and concentrated under reduced pressure. The residue was taken-up in 10 ml water/THF 1:2 and treated with 2 ml aqueous KOH solution (10%). After stirring for 16 h at RT the reaction mixture was acidified with hydrochloric acid (5M). The precipitate was collected by filtration and dried in vacuo to yield the product as a yellow solid. Yield: 1.1 g.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)[CH3:2].Cl.[C:17]1([C:23]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]3[CH:27]([CH2:28][NH:29][CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[C:33]1([C:23]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:31]3[CH:27]([CH2:28][N:29]([C:11](=[O:13])[CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])[CH2:30]3)[C:26](=[O:32])[CH2:25][CH2:24]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCN(CC)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
N,N'-Carbonyldiimidazole (0.86 g) is added to a solution of 2-diethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred at +5° C. for 30 minutes and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.73 g) and triethylamine (1.48 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30/80 by volume) and collecting 125 cc fractions. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (15 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-diethylaminophenyl)acetyl]-4-perhydroisoindolone (1.6 g) is obtained in the form of white crystals melting at 160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]2[NH:18][C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:2]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:18]=1
Reactant: O=c1[nH]c(C=Cc2cccnc2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc(C=Cc2cccnc2)nc2ccccc12

Procedure:
A suspension of the quinazolinone compound (2.9 g, prepared in Reference example 15) in thionyl chloride (25 mL) and a few drops of dimethylformamide was heated at reflux for three hours. The mixture was then concentrated, the concentrate poured into 150 mL portions of chloroform, dried over potassium carbonate and concentrated to obtain the title compound (1.1 g) as a red oil.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:28].CCOCC>CO>[ClH:28].[ClH:28].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[O:11])=[CH:26][CH:27]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[1-(4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinyl]carbamic acid, 1,1-dimethylethyl ester (131.6 g, 355 mmol) is dissolved in methanol (800 mL) at 0° C., and the solution is saturated with HCl gas. The mixture is stirred for 3 hr at room temperature, after which ether is added to give a turbid solution. The resulting precipitate is collected and air dried to afford the title compound.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH3:41][NH:42][CH3:43]>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:41][N:42]([CH3:43])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1
Reactant: CNC
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN(C)C)C(=O)c1cc2c(cc1-3)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.061 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (10 mL), and dimethylamine (0.023 mL, 0.408 mmol) was added dropwise. The mixture was stirred at reflux for 52 h. The mixture was diluted to a volume of 250 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting first with a gradient of 0.5% MeOH in CHCl3, and then with 1% MeOH in CHCl3, to yield the product 23 as a solid (0.009 g, 47%): mp 176-178° C. (dec). IR (film) 2922, 1698, 1650, 1483, 1306, 1032, 786 cm−1: 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H), 4.54-4.48 (t, 8.4 Hz, 2H), 4.29-4.25 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.78-3.74 (t, J=4.8 Hz, 2H), 2.57-2.53 (m, 14H), 2.27 (s, 2H), 2.03-2.02 (m, 2H); ESIMS m/550 (MH+); HRESIMS m/z 550.2558 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 97.57% (C-18 reverse phase. MeOH—H2O, 85:15).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>>[CH2:28]([CH:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(Br)CC
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Product: CCC(CC)Oc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
Using the compound obtained in Example 136 and 3-bromopentane, white powdery 3-{2-[3-(1-ethylpropoxy)-4-methoxy phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CN(C)C=O.C[Si]([C:18]#[CH:19])(C)C.CN(C)C(N(C)C)=N>Cl[Cu].Cl[Pd]Cl.O>[NH2:5][C:4]1[CH:3]=[C:2]([C:18]#[CH:19])[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cccc(N)c1
Temperature: 45 °C

Procedure:
A 250 ml round bottomed flask, fitted with refrigerator, under a nitrogen stream, is loaded with 3-bromoaniline (2 ml), dimethylformamide (10 ml), trimethylsilylacetylene (3.4 ml), 1,1,3,3-tetramethyl guanidine (2.5 ml), CuCl (3.6 mg), PdCl2 (9.7 mg) triphenyl phosphine (58 mg), in this order. The mixture is heated to 55°-57° C. keeping this temperature until completion of the reaction. H2O (50 ml) and ACOEt (50 ml) are added at a temperature of 35°-30° C. The organic phase is evaporated to dryness and the residue is dissolved in CH3OH (10 ml) and 50% HCl (10 ml) is heated to 40-50° C. for two hours. Methanol is evaporated off and the residual mixture is treated with NaOH, extracted with toluene. The organic phase is dried, and the solvent removed under vacuum affording 3-amino-phenyl acetylene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[CH2:22]([O:29][C:30]([NH:32][CH2:33][CH2:34]Br)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:34][CH2:33][NH:32][C:30]([O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCNC(=O)OCc1ccccc1

Procedure:
15.0 G. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester are reacted with 25.8 g. of 2-[(benzyloxycarbonyl)amino]ethyl bromide in a manner analogous to that described in Example 14. Thereafter, there is obtained an oily crude product, which is chromatographed on 250 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. From the uniform fractions there is obtained 2-{2-[(benzyloxycarbonyl)amino]ethyl}-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 102°-104° C. Recrystallization from ethanol increases the melting point to 104°-105° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23].[Br:24]Br>>[Br:24][C:19]1[C:18]([F:23])=[C:17]([Cl:16])[CH:22]=[CH:21][N:20]=1
Reactant: Fc1cnccc1Cl
Reactant: BrBr
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Product: Fc1c(Cl)ccnc1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (25 g, 190 mmol) in hexanes (100 mL) cooled over dry ice acetone bath for 5 minutes was added 1.6M n-butyl lithium in hexanes (121 mL, 194 mmol) over 5 minutes. After the addition was complete, the reaction mixture was placed in an ice bath and the mixture was allowed to stir at 0° C. for 20 minutes as a white solid formed. The suspension was re-cooled over dry ice/acetone bath for 5 minutes and then treated with a solution of 4-chloro-3-fluoropyridine (25 g, 190 mmol) in hexanes (50 mL) over 5 minutes and this mixture was stirred over dry ice/acetone bath for additional 10 minutes. After this time, this mixture was treated with bromine (30.4 mL, 190 mmol) and stirred over dry ice/acetone bath for 15 minutes. After this time, the reaction mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature. The reaction mixture was re-cooled over wet ice bath and quenched with water (200 mL) and extracted with ether (3×300 mL). The combined organic extracts were washed with water, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by chromatography using 330 g silica gel cartridge and eluting with a gradient of 20-100% CH2Cl2 in hexanes to provide the title compound. 1H NMR (CDCl3) δ=8.13 (d, 1H, J=5.1 Hz) and 7.35 (dd, 1H, J=5 Hz) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.FC1C=C(N[C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[S:67])C=CC=1OC1C=CN=C2C=C(C3C=CC=C(OCCN4CCOCC4)C=3)SC=12>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]5[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=5)=[S:67])=[CH:30][CH:31]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Yield: 30 %

Procedure:
Starting from the compound 202 and following the procedure described above for the compound 163a (scheme 31), title compound 203 was obtained in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.38 (s, 1H), 11.73 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 1H), 7.79 (s, 2H, J=9.0), 7.36 (d, 2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63 (d, 1H, J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H, J=4.6 Hz), 2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+1) 625.2 (100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.[H-].[Na+].F[C:11]1[CH:12]=[C:13]([CH3:20])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C>[CH3:20][C:13]1[CH:12]=[CH:11][C:16]([N+:17]([O-:19])=[O:18])=[C:15]([CH:14]=1)[O:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: OCc1cncs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCc2cncs2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a solution of 5-(hydroxymethyl)-1,3-thiazole (1 g, 8.68 mmol) in DMF (15 mL) was added NaH (0.413 g, 9.47 mmol) under an argon atmosphere. The reaction mixture was stirred for 20 min at 0° C. 3-Fluoro-4-nitrotoluene (1.2 g, 7.89 mmol) was added. The resulting mixture was stirred for 1 h at RT, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with AcOEt. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2; hexane/AcOEt 60:40→40:60) to afford 936 mg of the title compound as an orange solid. TLC: RF=0.35 (hexane/AcOEt 1:1); HPLC: LtRet=4.26 min; LC-MS: m/z 251.2 [M+H]+.