Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N([CH2:18][CH3:19])CC)C.[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][CH:31]([C:35]([OH:37])=O)[C:32]([OH:34])=[O:33])[CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C:31]2[C:32](=[O:33])[O:34][C:25]([C:24]3[CH:23]=[C:20]([CH3:22])[CH:21]=[C:18]([CH3:19])[CH:29]=3)=[CH:26][C:35]=2[OH:37])[CH2:21][CH2:22]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3CC3CC3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3,3'-dimethyl acetophenone (2 g, 13.51 mmol), trimethylsilyl triflate (3 g, 13.1 mmol), triethylamine (2.73 g, 27.02 mmol), methylene chloride (20 mL), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio]propanedioic acid (2.18 g, 6.76 mmol). m.p. 168° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 2H), 0.39 (dd, 2H), 1.13 (m, 1H), 2.36 (s, 6H), 2.67 (d, 2H), 6.85 (s, 1H), 6.92 (m, 1H), 7.11 (m, 2H), 7.22 (s, 1H), 7.33 (m, 1H), 7.47 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:10])[CH3:9].[CH3:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH2:28][CH:29]=[C:30]([CH3:33])[C:31]#[CH:32]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:8]([O:11][CH2:12][CH:13]=[C:14]([CH3:18])[C:15](=[O:16])[C:32]#[C:31][C:30]([CH3:33])=[CH:29][CH2:28][C:21]1[C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][CH2:25][C:20]=1[CH3:19])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC=C(C)C(=O)Cl
Reactant: C#CC(C)=CCC1=C(C)CCCC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC=C(C)C(=O)C#CC(C)=CCC1=C(C)CCCC1(C)C
Reaction time: 0.08 h

Procedure:
Under nitrogen atmosphere 59.9 mg (0.308 mmol) of copper(I) iodide and 110.3 mg (0.154 mmol) of bis(triphenylphosphine)palladium(II) dichloride [(PPh3)2PdCl2] were added to a 100 ml four-necked flask. At 23° C., 42.0 ml of anhydrous THF was added and the yellow suspension was stirred for 5 min. When 2.15 ml (15.4 mmol) of triethylamine were introduced drop wise via syringe an orange solution was obtained. Within 1 minute 3.10 g (15.4 mmol) of 4-chloro-3-methyl-4-oxobut-2-enyl acetate (compound of formula (Ia)) were added and the solution turned dark orange. Upon drop wise addition of 2.92 g (14.0 mmol) of 1,3,3-trimethyl-2-(3-methylpent-2-en-4-ynyl)cyclohex-1-ene (compound of formula (III))
Reaction SMILES: [CH2:1]([O:3]C(=O)CP(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)[CH3:2].N12CCCN=C1CCCCC2.[Na+].[I-].[NH2:36][C:37]1[C:42]([CH:43]=O)=[C:41]([CH:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:40]=[C:39]([C:58]2[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)=[CH:62][CH:61]=[CH:60][C:59]=2[O:74][CH2:75][CH:76]2[CH2:78][CH2:77]2)[N:38]=1>C1COCC1>[CH:76]1([CH2:75][O:74][C:59]2[CH:60]=[CH:61][CH:62]=[C:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][CH3:73])=[CH:68][CH:67]=3)[C:58]=2[C:39]2[CH:40]=[C:41]([CH:45]3[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:46]3)[C:42]3[CH:43]=[CH:2][C:1](=[O:3])[NH:36][C:37]=3[N:38]=2)[CH2:78][CH2:77]1
Reactant: CCOC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C=O)c(N)n2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3ccc(=O)[nH]c3n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
To a solution of ethyl(diphenoxyphosphoryl)acetate (1.090 g, 3.403 mmol) in THF (15 mL) were added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.520 g, 3.403 mmol) and NaI (0.510 g, 3.403 mmol) followed by a solution of tert-butyl 3-(2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (1.000 g, 1.701 mmol), obtained in the step (1) of Example 25-2, in THF (5 mL). The mixture was stirred at 0° C. for 1.5 hrs and quenched with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate, and the extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:2) to give tert-butyl 3-(2-{2-(cyclo-propylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as an amorphous solid (0.276 g, 27%).
Reaction SMILES: [CH3:1][C:2]12[CH2:12]CCC[CH:3]1[C:4]([O:6][C:7]2=[O:8])=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH:17]2[C:20]([O:22][C:23](=[O:24])[CH:16]2[CH2:15]1)=[O:21].[OH:25]CCOC(=O)C(C)=C>CN(C)C1C=CN=CC=1>[CH3:13][CH:14]1[CH2:19][CH2:18][C:17]([CH2:3][CH2:4][O:6][C:7](=[O:8])[C:2]([CH3:12])=[CH2:1])([C:20]([OH:25])=[O:21])[CH:16]([C:23]([OH:22])=[O:24])[CH2:15]1
Reactant: CC12CCCCC1C(=O)OC2=O
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Reactant: C=C(C)C(=O)OCCO
Agent: CN(C)c1ccncc1
Product: C=C(C)C(=O)OCCC1(C(=O)O)CCC(C)CC1C(=O)O
Temperature: 95 °C
Reaction time: 5 h

Procedure:
2-Methyl-hexahydrophthalic anhydride (Also known as 4-methyl-1,2-cyclohexanedicarboxylic anhydride; 210.0 g, 1.25 mol, CAS #19438-60-9, Alfa Aesar, lot B04w039), 4-(dimethylamino)pyridine (DMAP, 7.5 g, 0.06 mol, CAS #1122-58-3, Alfa Aesar, lot L125009), 2-hydroxyethylmethacrylate (HEMA, 162.5 g, 1.25 mol, and butylated hydroxytoluene (BHT, 0.380 g) were charged into a 1-liter 3-neck reaction flask equipped with a mechanical stirrer, a thermocouple connected to a temperature controller, a dry air stream running through a T-shape connection into the reactor then to an oil bubbler, and a heating mantle. The mixture was continuously stirred at 95° C. for 5 hours. The heat was turned off and the flask contents were allowed to cool to room temperature to give 4-methyl-(2-methacryloyloxyethyl)hexahydrophthalic acid intermediate as a colorless viscous liquid. Structure was confirmed by NMR.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[C:28]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:13])=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].C1(OC)C=CC=CC=1>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[C:16]1([CH2:15][O:14][C:12]([NH:11][CH2:10][CH2:9][NH2:8])=[O:13])[C:28]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)OCc1cccc2c1Cc1ccccc1-2

Procedure:
N-tert-butyloxycarbonyl-N'-fluorenylmethyloxycarbonylethylene-diamine (20.0 g, 0.052 mol) was treated with trifluoroacetic acid and anisole in dichloromethane (10:10:1) for 1 hour at room temperatute. After evaporation to dryness the crude product was crystallized from solvent mixture of ethyl acetate-n-hexane. Yield 15.0 g (73%). NMR (300 MHz, DMSO-d6, 25° C.) d: 2.85 (m, 2H, CaH2), 3.22 (m, 2H, CbH2), 4.23-4.36 (m, 3H, Fmoc OCH2CH--), 7.37 (m, 1H, NH), 7.34-7.89 (m, 8H, Fmoc), 7.77 (br, 2H, NH2). M.p. 128-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH2:14](I)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2)[CH:15]=[CH2:14]
Reactant: C=CCI
Reactant: Cc1ccc(O)c2ccc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)ccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
5-Hydroxy-8-methylcarbostyril (6.35 g, 36.3 mmol), allyl iodide (6.07 g, 36.1 mmol), n-tetrabutylammonium bromide (1.16 g, 36.1 mmol) were dissolved in dimethylformamide (108 ml). To the solution, potassium carbonate (10 g, 72.5 mmol) was added, and stirred in a bath of 50° C. for 2 hours. The solvent was evaporated, and the residue, dissolved in chloroform, was washed with water. The washed material was dried and condensed. The resultant residue was purified by silica gel column chromatography (eluent; chloroform). Recrystallization (chloroform-n-hexane) yielded 4.98 g of 5-allyloxy-8-methylcarbostyril as colorless flakes (63.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]4[CH2:31][CH3:32])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:33]=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH3:33])[CH2:27][CH:26]4[CH2:31][CH3:32])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C=O
Reactant: CC[C@H]1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1
Product: CCC1CN(C)CCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Compound 193 was coupled with formaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 452. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H), 8.36 (d, 2H), 7.92 (d, 1H), 7.67 (m, 2H), 6.99 (d, 2H), 6.72 (s, 1H), 5.07 (d, 1H), 4.36 (s, 1H), 3.43 (m, 7H), 3.04 (m, 4H), 2.36 (s, 1H), 2.05 (m, 1H), 2.00 (s, 3H), 1.15 (t, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>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.[Cu]I.CN(C=O)C>[CH:9]1([NH:8][C:5]2[N:6]=[N:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Brc1ccc(NC2CCC2)nn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc(NC2CCC2)nn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
6-Bromo-N-cyclobutylpyridazin-3-amine (0.60 g, 2.63 mmol), trimethylsilylacetylene (TMSA) (1.29 g, 13.1 mmol), Pd(PPh3)4 (0.15 g), and CuI (0.04 mg) were placed in a vial with a rubber septum. After the mixture underwent 3 cycles of vacuum/filling with Ar2, DMF (3.0 mL) and N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.2 mmol) were added. The mixture was then stirred at 80° C. for 16 hrs. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (eluent: 30% ethyl acetate in n-hexane, ethyl acetate was added 0.5% Et3N) to give an off-white solid (0.48 g, 74.5%). 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1 H, d, J=9.0 Hz), 6.50-6.53 (1 H, d, J=9.0 Hz), 5.55 (1 H, s), 4.17-4.24 (1 H, m), 2.40-2.46 (2 H, m), 1.89-1.98 (2 H, m), 1.77-1.85 (2 H, m), 0.28 (9 H, s).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2[OH:21])([CH3:5])[CH3:4].[OH2:22]>COCCOC>[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:4][C:3]([O:6][CH2:7][CH3:15])=[O:22])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]2=[O:21])([CH3:5])[CH3:4]
Reactant: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 0.149 g of 60% sodium hydride in 20 cm3 of 1,2-dimethoxyethane, 1.23 cm3 of triethyl phosphonoacetate and 1.08 g of 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydro-isoindol-1-one. The mixture is refluxed for 5 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and the mixture is then extracted with 3 times 100 cm3 of diethyl ether. The organic extracts are combined, washed with 100 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (80 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with a mixture of cyclohexane/ethyl acetate (90/10 by volume) and then with a mixture of cyclohexane/ethyl acetate (80/20 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is thus obtained in the form of a colorless oil. (Rf=0.57, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[O:24][CH2:23][C:22]2=[O:33])[CH:14]([C:34]([O:36]C)=[O:35])[CH2:13]1.[OH-].[Na+].Cl>CO.O>[C:31]([C:28]1[CH:29]=[CH:30][C:25]2[O:24][CH2:23][C:22](=[O:33])[N:21]([CH2:20][CH2:19][CH2:18][CH:15]3[CH2:16][CH2:17][N:12]([CH2:11]/[CH:10]=[CH:9]/[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH:14]3[C:34]([OH:36])=[O:35])[C:26]=2[CH:27]=1)#[N:32]
Reactant: COC(=O)C1CN(C/C=C/c2cc(F)ccc2F)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)N(CCCC1CCN(C/C=C/c3cc(F)ccc3F)CC1C(=O)O)C(=O)CO2
Reaction time: 64 h

Procedure:
A solution of methyl 1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4H-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate (Example 64) (73 mg, 0.143 mmol) in methanol (12 mL) and water (5 mL) was treated with sodium hydroxide solution (1N, 1 mL). After 64 hours, the pH was adjusted to 6 with 1N HCl. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-10%) and trituration with diethyl ether gave the title compound as a colorless solid, mixture of diastereomers, 10 mg (14%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(Cl)(Cl)Cl>[CH2:33]([C:23]1[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of Compound 105 (1.44 g, 3.11 mmol) in chloroform (12 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (9.0 mL), followed by stirring at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12, and the mixture was extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were added with diisopropyl ether followed by stirring for 30 minutes, then the crystals were collected by filtration. The crystals were dried under reduced pressure to obtain Compound 140 (0.864 g, 2.38 mmol, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C:27](=[O:28])[N:26]2[C@@H:22]([CH2:23][C@@H:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C@@:19]2([C:41]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:42])[C@@H:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccnc4ccccc34)CN2C1=O
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(C)(=O)=O)NC(=O)[C@@H]2C[C@@H](Oc3ccnc4ccccc34)CN2C1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)NS(C)(=O)=O)NC(=O)[C@@H]2C[C@@H](Oc3ccnc4ccccc34)CN2C1=O

Procedure:
(1S,4R,6S,14S,18R)-7-cis-[14-tert-butoxycarbonylamino-2,15-dioxo-18-(quinolin-4-yloxy)-3,16-diaza tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, the product of Step F in Example 30 (50 mg, 0.075 mmol) was reacted in analogous fashion with methanesulfonamide (12 mg, 0.12 mmol) as described in the preceding procedure above to give 10 mg (20%) of (1S,4R,6S,14S,18R)-7-cis-[4-methanesulfonylaminocarbonyl-2,15-dioxo-18-(quinolin-4-yloxy)-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.26 (s, 9H), 1.22-1.94 (m, 11H), 2.27 (m, 1H), 2.55 (m, 1H), 2.67 (m, 2H), 3.17 (s, 3H), 4.05 (m, 1H), 4.27 (m, 1H), 4.61 (t, J=8.1 Hz, 1H), 4.73 (d, J=11.0 Hz, 1H), 4.96-5.02 (m, 2H), 5.35 (s, 1H), 5.71 (q, J=8.8 Hz, 1H), 6.73 (d, J=5.1 Hz, 1H), 6.93 (bs, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 8.77 (d, J=5.5 Hz, 1H). LC-MS (Method A, retention time: 2.43 min), MS m/z 670 (M++1). Preparation of Example 32, 2(S)-tert-butoxycarbonylamino-3-pentenylsulfanylpropionic acid methyl ester (Example 32) for use in Example 33.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:10]([NH:13][C:14]1[CH:23]=[CH:22][C:17]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][CH:15]=1)(=[O:12])[CH3:11].[OH-].[Na+].ClCCl>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][S:18]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
A mixture of 1.25 g of 1H-imidazol-1-propanamine in 25 ml of water was stirred at room temperature then 2.34 g of N-acetylsulfanilyl chloride was added and stirring was continued for 20 hours resulting in a clear solution. With the addition of 4 ml of 5N sodium hydroxide the solution turned milky and resulted in the separation of an oil. The addition of dichloromethane resulted in the formation of a suspended precipitate which was collected by filtration and gave 2.67 g of the desired compound as tan crystals, mp 178°-180° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][C:8]([OH:10])=[O:9]>CC(C)=O>[Br-:6].[C:8]([CH2:7][N+:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([OH:10])=[O:9]
Reactant: c1cscn1
Reactant: O=C(O)CBr
Solvent: CC(C)=O
Product: O=C(O)C[n+]1ccsc1
Product: [Br-]
Reaction time: 48 h

Procedure:
Thiazole (8.5 g), 2-bromoacetic acid (15.0 g) and acetone (20 ml) were mixed together and left standing at room temperature for 2 days. White crystals deposited were collected by filtration and washed with acetone.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18](O)=[O:19])[CH:9]=2)=[CH:5][CH:4]=1.[Cl:23]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([Cl:23])=[O:19])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(Cc2cc(CC(=O)O)cc3ccoc23)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2cc(CC(=O)Cl)cc3ccoc23)cc1

Procedure:
A solution of 7-(4-methylthiobenzyl)benzofuran-5-ylacetic acid (10 g), dichloromethane (100 ml), thionyl chloride (10.0 ml) and dimethylformamide (0.2 ml) was stirred at room temperature for 6 hours. The solvent was then evaporated to give a residue which contained the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[O:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)[Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: C=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The concentrated 4-vinylphenol solution above and 10 mL (7.3 g, 0,072 mol) of triethylamine (TEA) were transferred to a 1 L 3 neck round-bottomed flask fitted with a mechanical stirrer, pressure-equalized addition funnel, reflux condenser, and argon inlet tube. A solution of 75 g (0.5 mol) Of t-butyldimethylchlorosilane and 75 mL (55 9, 0.54 mol) of dry TEA in 50 mL of methylene chloride was added through the addition funnel over 45 minutes. The reaction mixture turned pink and remained clear for quite some time. Considerable heat was evolved, particularly in the early stages of the addition, necessitating cooling the mixture in ice occasionally. The mixture was stirred at room temperature for 10 hrs., being stored in the freezer if necessary to complete the following day.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25]Br)=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(N(CC)CC)C.CN(C)C=O>[C:9]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:27])[CH2:25][N:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]2=[O:8])=[CH:22][CH:23]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(CBr)c1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.6 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (338 mg) and 4'-benzamido-2-bromoacetophenone (766 mg) in triethylamine (1 ml) and dimethylformamide (10 ml) was stirred at ambient temperature, giving a solution, quickly followed by formation of a precipitate. After 45 mins, water (100 ml) was added to the suspension. The collected solid was crystallised from glacial acetic acid to give the title pyrimidinone (439 mg,); m.p. 290°-303°; λmaxEtOH 226 nm (ε 16230), 302.5 nm (ε 20370).