Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34].C(O)COCCO.O.NN.[OH-].[K+]>>[CH3:36][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[P:3]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[C:12]=1[C:21]1[C:26]([CH:27]([CH3:28])[CH3:29])=[CH:25][C:24]([CH:30]([CH3:32])[CH3:31])=[CH:23][C:22]=1[CH:33]([CH3:35])[CH3:34]
Reactant: COc1ccc(OC)c(P2C(C)(C)CC(=O)CC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(OC)c(P2C(C)(C)CCCC2(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 210 °C
Reaction time: 7 h
Yield: 26.5 %

Procedure:
A round bottom flask was charged with 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphinan-4-one (1.03 g, 2.02 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (10.6 mL, 111 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The flask was charged with hydrazine hydrate (0.892 mL, 10.1 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (918 mg, 10.1 mmol, 5 equiv). The mixture was immersed in an oil bath at 170° C. The temperature of the bath was gradually increased to 210° C. over 1 hour and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen. Reaction material that had condensed on the Claisen adapter was washed down into the reaction flask with ethyl acetate (5 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (2×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. Purification of the crude material by silica gel column chromatography on an Isco CombiFlash system (40-g column; gradient: 2 column volumes heptane, ramp up to 85:15 heptane:ethyl acetate over 8 column volumes, hold at 85:15 for 4 column volumes) afforded the title compound as a white solid (266 mg, >99 area % by HPLC, 27% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.95 (s, 2H), 6.85 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.56 (s, 3H), 2.95 (hept, J=6.9 Hz, 1H), 2.49 (hept, J=6.7 Hz, 2H), 2.10-1.89 (m, 2H), 1.71-1.51 (m, 2H), 1.45-1.26 (m, 8H), 1.21 (d, J=6.8 Hz, 6H), 1.14 (s, 3H), 1.08 (s, 3H), 0.93 (d, J=6.7 Hz, 6H), 0.80 (d, J=8.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 154.3, 151.9 (d, J=11 Hz), 146.3, 145.5 (d, J=2 Hz), 140.1 (d, J=42 Hz), 132.5 (d, J=9 Hz), 127.7 (d, J=46 Hz), 119.7, 110.6, 107.1, 54.3 (d, J=62 Hz), 40.8 (d, J=4 Hz), 34.0 (d, J=5 Hz), 33.4, 30.7, 30.3 (d, J=24 Hz), 30.1 (d, J=3 Hz), 25.5, 24.2 (d, J=13 Hz), 20.8. 31P NMR (CDCl3, 202 MHz) δ ppm −6.0 (br s). HRMS (TOF-ESI+) calcd for [M, C32H49O2P]+ 496.3470, found 496.3465.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[CH2:8][CH:9]([CH:13]2[CH2:18][CH2:17][CH2:16][S:15][CH2:14]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26][O:27][NH2:28].C(=O)(O)[O-].[Na+]>CO>[OH:12][C:11]1[CH2:10][CH:9]([CH:13]2[CH2:18][CH2:17][CH2:16][S:15][CH2:14]2)[CH2:8][C:7](=[O:19])[C:6]=1[C:1](=[N:28][O:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][O:21]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: NOCC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCC(=NOCC1CCCO1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 81 %

Procedure:
2.82 g (10 millimoles) of 2-butyryl-3-hydroxy-5-(tetrahydrothiopyran-3-yl)-cyclohex-2-en-1-one was stirred together with 1.69 g (11 millimoles) of tetrahydrofur-2-ylmethoxyamine hydrochloride and 0.93 g (11 millimoles) of sodium bicarbonate in 20 ml of methanol for 12 hours at 25° C. The mixture was evaporated down, the residue was taken up with dichlorbmethane and the solution was extracted by shaking with water. The dried dichloromethane solution was evaporated down to give 3.1 g (8.1 millimoles) of 3-hydroxy-2-(1-tetrahydrofur-2-ylmethoxyiminobutyl)-5-(tetrahydrothiopyran-3-yl)-cyclohex-2-en-1-one as a viscous oil. ##STR9##
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:11][CH:12]=1)#[N:6]>C(O)CCC>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:19][CH2:5][CH2:7][CH2:8][CH3:9])=[O:18])=[N:11][CH:12]=1)#[N:6]
Reactant: N#Cc1ccc(NC(=O)CCC(=O)O)nc1
Solvent: CCCCO
Solvent: O=S(Cl)Cl
Product: CCCCOC(=O)CCC(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of butan-1-ol (3 mL) was added dropwise thionyl chloride (2.73 mmol, 0.200 mL 3 eq). After 5 min, 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (prepared as described before, 200 mg, 0.912 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was washed with a saturated solution of sodium hydrogenocarbonete and dried on magnesium sulfate, then concentrated under vacuum. The residue was first washed with cyclohexane and the solid obtained was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give butyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A66 (10%) and the by-product butyl 6-[(4-butoxy-4-oxo-butanoyl)amino]pyridine-3-carboxylate A67 (9%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:23])([F:22])[C:9]1[CH:10]=[C:11]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Cl)[CH:12]=[CH:13][CH:14]=1.[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:19][CH2:18][CH2:17][CH2:16][C:15](=[O:21])[C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:23])([F:22])[F:7])[CH:10]=3)[CH2:37][CH2:36]2)[CH:30]=1)=[O:27]
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(C(F)(F)F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-[3-(trifluoromethyl)phenyl]-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16](I)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>C1COCC1>[Si:5]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:17]=[C:16]([B:28]3[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Temperature: 0 °C

Procedure:
To a stirred THF (30.00 mL) solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-4-iodo-1H-pyrazole (Compound 137B, 1.1400 g, 2.8053 mmol) was added 2.00 M of isopropylmagnesium chloride in THF (2.31 mL, 4.63 mmol) dropwise under an atmosphere of Nitrogen in 5 min at 0° C. The reaction mixture was stirred at 0° C. for another hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9577 mL, 5.610 mmol) was added at 0° C. and then the mixture was stirred at room temperature for another hour. The mixture was treated with saturated NH4Cl (10 ml), extracted with EtOAc (20 ml×3). The extracts were washed with water (10 ml), brine (15 ml), dried over Na2SO4. Solvent was removed under reduced pressure to give a residue which was purified by flash chromatography (10% EtOAc/hexane). MS (ES+): m/z=407.18 [MH+]. HPLC: tR=3.21 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.OS(O)(=O)=O.[C:17](OC(C)=C)(=[O:19])[CH3:18]>>[C:17]([O:10][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]=1)(=[O:19])[CH3:18]
Reactant: C=C(C)OC(C)=O
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Product: CC(=O)OC1=CCCc2ccccc21
Temperature: 25 °C
Yield: 112.3 %

Procedure:
A mixture of α-tetralone (200 mL, 1.5 mol) and conc. H2SO4 (4 mL) in isopropenyl acetate (1.0 L, 9.08 mol) was heated to reflux overnight. It was cooled to r.t. and filtered through a mixture of celite, NaHCO3 and silica (approx. 1:1:0.2) with EtOAc and concentrated to yield 317.1 g of the crude title product; bp: 90° C./0.5 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2Cl.[CH3:20][NH:21][CH3:22].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[N:21]([CH3:22])[CH3:20]
Reactant: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Reactant: CNC
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 60 °C

Procedure:
6-Bromo-4-chloro-2-(3-fluorophenyl)-quinoline (20 g, 59.4 mmoles) was placed in a 500 mL three-neck round-bottom flask equipped with magnetic stirrer, nitrogen inlet, gas outlet, condenser and heating bath and dissolved in 150 mL of N-methylpyrrolidinone. 250 mL of a 40% aq. solution of dimethylamine was added with stirring. The mixture was warmed to 60° C. for 48 hrs. At the end of this time the mixture was cooled, added to 3 L of water in a 4 L Erlenmeyer flask and the mixture stirred until solids formed. The solids were collected by vacuum filtration and dried in a vacuum oven. The product was recrystallised from ethanol in a −20° C. freezer to give 19.6 g (95%) yield of the desired product.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C.O>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:4]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Fc1ccccc1CBr
Reactant: Ic1n[nH]c2ncncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Cn1nc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
569 mg (2.313 mmol) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 828 mg (2.544 mmol) of caesium carbonate were initially charged in 10 ml of DMF, and 481 mg (2.544 mmol) of 2-fluorobenzyl bromide dissolved in 2 ml of DMF were added. The reaction mixture was stirred at RT overnight, diluted with 50 ml of water and filtered with suction, and the residue was dried under high vacuum. 733 mg of the target compound were obtained (purity 83%; 74% of theory).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.C(N(CC)CC)C.O>CN(C)C=O>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(OS(=O)(=O)c1ccc(C)cc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: -70 °C
Yield: 51.6 %

Procedure:
To a solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (940 mg) in dimethylformamide containing 10% tetrahydrofuran (5 ml) is added toluene-p-sulfonyl chloride (456 mg). After cooling to -70° C., the solution is mixed with triethylamine(0.3 ml). The reaction mixture is allowed to warm slowly up to room temperature, poured into water, and extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated. The obtained residue is chromatographed over silica gel containing 10% water using benzene containing 5% ethyl acetate to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-toluene-p-sulfonyloxyethylidene)acetate (644 mg). IR: νmaxCHCl3 1785, 1735 cm-1. NMR: δCDCl3 2.45s3H, 4.75+4.20ABq (14 Hz)2H, 5.15s2H, 5.77s2H, 8.30-6.60 ml 3H.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@@H](N)CC1CCCC1)C(=O)OCc1ccccc1
Yield: 102.7 %

Procedure:
A solution of benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550 mg) in TFA/CH2Cl2 (10 mL, 20% v/v) was stirred for 2 h at 5° C. The mixture was neutralized with sat'd aq NaHCO3 and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4 and evaporated to give benzyl (S)-2-amino-3-cyclopentylpropylmethylcarbamate (420 mg) that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.Cl.[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][SH:17])[NH2:15].CCN=C=NCCCN(C)C.CN1CCOCC1>CC#N.CCOC(C)=O>[SH:17][CH2:16][C@H:14]([NH:15][C:4](=[O:6])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: COC(=O)[C@@H](N)CS
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)/C=C/C(=O)N[C@@H](CS)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Separately, mono methyl fumarate (100 mg, 0.77 mmol) was taken up in 4 mL of CH3CN along with L-cysteine methyl ester hydrochloride (132 mg, 0.77 mmol), EDCI (245 mg, 0.77 mmol) and N-methylmorpholine (85 μl, 0.77 mmol). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford crude (R,E)-methyl 4-(3-mercapto-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate. This material was then taken up in 3 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)—N—(2-(2,5-dioxo-2H-pyrrol-1(5H)-yl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (173 mg, 0.38 mmol) and stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 60 mg of (E)-methyl 4-((R)-3-(1-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2,5-dioxopyrrolidin-3-ylthio)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobut-2-enoate (22%). MS (EI) calcd for C37H51N3O8S: 697.34; found: 698 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
4'-Hydroxyacetophenone (10 g, 73.4 mmole) was suspended in 200 ml dichloromethane in a 500 ml one neck round bottom flask under nitrogen at 0° C. The suspension was treated with diisopropylethylamine (14.7 ml, 84.5 mmole) followed by acetyl chloride (6.0 ml, 84.5 mmole) in 1×50 ml dichloromethane slowly dropwise. The reaction mixture was stirred 30 minutes at 0° C. and then for 1 hour at room temperature. The mixture was washed with 1×100 ml 10% hydrochloric acid and the organics were dried over magnesium sulfate. The dried organics were conentrated in vacuo to a yellow oil. The oil was distilled via kugelrohr (high vacuum, 165° C.) to give 12.25 g (94%) of 4'-acetoxy-acetophenone as a white solid. Melting Point: 47°-49° C. 4'-Acetoxy-acetophenone (10 g, 56.2 mmole) was dissolved in acetic anhydride (10.6 ml, 112.2 mmole) in an oven dried 50 ml two neck round bottom flask under nitrogen. The solution was cooled to 0° C. and boron trilfuoride gas was bubbled into the reaction mixture until it was saturated. The reaction was stirred 1 hour at room temperature and was poured into 600 ml diethyl ether. The orange precipitate was collected, washed with fresh diethyl ether, and was dried to afford 6.6 g (43%) of a boron difluoride complex. Melting Point: 130°-132° C.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2=[N:19][S:20][N:21]=[C:17]2[CH:16]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:19]1[S:20][N:21]=[C:17]2[CH:16]=[C:15]([CH2:14][N:37]3[CH2:38][CH2:39][N:35]([C:27]4[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=4)[C:36]3=[O:40])[CH:23]=[CH:22][C:18]=12
Reactant: BrCc1ccc2nsnc2c1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc4nsnc4c3)C2=O)nc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 5-(bromomethyl)benzo[c][1,2,5]thiadiazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 82% yield: MS (ES+) m/z 404.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1.CN1[CH2:30][CH2:29][O:28]CC1.O>ClCCl>[C:29]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1)(=[O:28])[CH2:30][CH2:23][CH2:2][CH2:3][CH3:4]
Reactant: CN1CCOCC1
Reactant: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Solvent: ClCCl
Solvent: O
Product: CCCCCC(=O)Nc1ccc2scc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
Hexanoyl chloridc (0.024 g.) was added to a stirred solution of methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g.), and N-methylmorpholine (0.1 ml.) in dichloromethane (3 ml.). The mixture was stirred for 1 hour and then poured into water (20 ml.). The aqueous mixture was extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05 g., 75%) as a colorless solid NMR (250 MHz, DMSO-d6): 0.87(t,3H, CH2CH3), 1.28(m,4H, CH2.CH2.CH3), 1.59 (quintet,2H, CH2CH2CON), 2.29(t,2H, CH2CON), 3.84(s, 3H, OCH3), 3.91(s,3H, OCH3), 4.11(s,2H, CH2 -Ar), 7.14 (d,1H), 7.34 (s,1H), 7.49(m,3H), 7.86(d,1H), 8.11(d, 1H), 9.95(s,1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28]>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]([C:25]([O:26][CH2:27][CH3:28])=[O:29])[CH2:2][CH2:3]1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCNc2ccccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-4-ylcarbamate (65 mg, 0.26 mmol) in DCM (1 mL) was added Na2CO3 (55.5 mg, 0.520 mmol), followed by ethyl carbonochloridate (0.028 mL, 0.29 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM, washed with 1N HCl, dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate 38A (72 mg, 0.23 mmol, 86% yield). LCMS=1.97 min [M+Na]=342.9 (Method B).
Reaction SMILES: CS(O)(=O)=[O:3].[Cl:6][CH2:7][C@@H:8]([O:12][Si](C)(C)C)[CH2:9][C:10]#N.[CH3:17][CH2:18][O:19][C:20]([CH2:22]Br)=[O:21].Cl>O1CCCC1.[Zn]>[Cl:6][CH2:7][C@@H:8]([OH:12])[CH2:9][C:10](=[O:3])[CH2:22][C:20]([O:19][CH2:18][CH3:17])=[O:21]
Reactant: CS(=O)(=O)O
Reactant: CCOC(=O)CBr
Reactant: C[Si](C)(C)O[C@H](CCl)CC#N
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C[C@H](O)CCl
Temperature: 27.5 °C

Procedure:
Mixture of zinc dust (69 grams) and methane sulfonic acid (6 ml) in tetrahydrofuran (500 ml) was heated to reflux temperature and stirred for an hour. (S)-4-chloro-3-(trimethylsilyloxy)butanenitrile (100 grams) followed by ethyl bromo acetate (147.2 grams) was added to the reaction mixture at 65-70° C. and stirred. After completion of the reaction, the reaction mixture was cooled to 25-30° C. and then added to the aqueous hydrochloric acid solution at 0° C. and stirred. The reaction mixture extracted into ethyl acetate and then washed it with sodium bicarbonate solution followed by sodium chloride solution. Ethyl acetate was distilled off from the reaction mixture under reduced pressure to get the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][CH:17]=1)[CH3:15]>O.C(OCC)(=O)C>[OH:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH3:47])=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of hydroxylammonium chloride (3.30 g), sodium hydrogen carbonate (4.80 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (2.22 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.77 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.85 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.57 g, 23%).