Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:17])C=1C#N)#N.O1CCOCC1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH:11]=[O:17])=[CH:5][CH:4]=1
Reactant: CCCc1ccc(OC)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C=CC=O)cc1
Yield: 68 %

Procedure:
A mixture of 4-methoxy phenylpropane (2 g), silica gel (0.5-0.8 g), DDQ (7.5 g) and dioxane (5-8 ml) was taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was placed inside a microwave oven operating at medium power (600 W) and irradiated for 2-8 minutes. After completion of the reaction (monitored by TLC), the contents of the flask were poured into chloroform and passed through a bed of Celite and further washed with chloroform. The filtrate and washing were combined and the chloroform layers were washed with an aqueous NaOH (15%, 3×15 ml). The combined aqueous layers were further extracted with chloroform (3×15 ml). The chloroform layers were then combined and washed with saturated sodium chloride (3×15 m), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude product which was loaded on silica column and the column was first eluted with hexane (70-80 ml) and then with an increasing amount of hexane/ethyl acetate (9:1 to 1:9). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 4-methoxy cinnamaldehyde in 68% yield as a solid; mp 57-58° C.; (lit. mp 58° C.). The physical and spectral data was found to similar as reported.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:29]1([CH2:38][C:39](O)=[O:40])[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:39](=[O:40])[CH2:38][N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28 (s, 0.4H), 9.20 (brs, 1H), 8.41–8.40 (m, 1H), 8.07–7.97 (m, 2H), 7.33 (s, 0.6H), 7.26 (s, 0.4H), 4.67 (s, 1.2H), 4.48 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.58 (t, 1.2H), 3.46–3.40 (m, 2H), 3.28 (t, 0.8H), 1.75 (s, 3H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:46])[CH:5]=[C:6]([Cl:45])[C:7]=1[CH2:8][C@@H:9]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[C:32]([O:40][CH2:41][CH:42]2[CH2:44][CH2:43]2)[CH:31]=1)[O:10][C:11]([C:13]1[N:14]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:12].O.O.[Sn](Cl)Cl>C1COCC1>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:14]2[CH:15]=[CH:16][CH:17]=[C:13]2[C:11]([O:10][C@H:9]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:38])[F:39])=[C:32]([O:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:31]=2)[CH2:8][C:7]2[C:2]([Cl:1])=[CH:3][N+:4]([O-:46])=[CH:5][C:6]=2[Cl:45])=[O:12])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccn1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)n2cccc2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Temperature: 45 °C
Yield: 51.1 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(1-(4-nitrophenylsulfonyl)-1H-pyrrole-2-carbonyloxy)-ethyl)pyridine 1-oxide (Int. 6) (424 mg, 0.607 mmol) and tin(II) chloride dihydrate (548 mg, 2.428 mmol) in THF (40 ml) was heated at 45° C. for 2 hours. Additional tin(II) chloride dihydrate (1.644 g, 7.284 mmol) was added in 3 portion over 3 hours at 60° C., and the resulting mixture was heated to reflux overnight. The solvent was removed and the mixture was diluted with ethyl acetate; aqueous sat. NaHCO3 was added and the mixture was filtered through a celite pad. The filtered phases were separated and the organic layer was washed with brine and dried over sodium sulfate; the solvent was removed and the crude was purified by flash chromatography on silica gel column (DCM/MeOH=98/2) affording (S)-4-(2-(1-(4-aminophenylsulfonyl)-1H-pyrrole-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 7) (207 mg, 0.310 mmol, MS/ESI+667.96 [MH]+, [αD]=−61.24, c=1, DCM).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:16][CH:15]3[C:10]([C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CO>C(=O)=O>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:16][C@@H:15]3[C@@:10]([C:18]4[CH:23]=[N:22][CH:21]=[CH:20][N:19]=4)([N:11]=[C:12]([NH2:17])[S:13][CH2:14]3)[CH2:9]2)=[N:4][CH:3]=1
Reactant: NC1=NC2(c3cnccn3)CN(c3ncc(F)cn3)CC2CS1
Agent: O=C=O
Solvent: CO
Product: NC1=N[C@@]2(c3cnccn3)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 44.2 %

Procedure:
Racemic 6-(5-fluoropyrimidin-2-yl)-7a-pyrazin-2-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-amine (520 mg, 1.57 mmol) is separated into its constituent enantiomers by chiral SFC (Column: Chiralcel OD-H (5μ), 21.2×250 mm; eluent: 45% methanol (0.2% diethylmethylamine) in CO2; flow: 70 mL/min at UV 260 nm). The first eluting isomer is the title compound (230 mg). ES/MS (m/e): 332 (M+1).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1.[C:16]([C:18]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:20][C:21](O)=[O:22])#[N:17]>O1CCCC1>[N:11]1([C:21](=[O:22])[CH2:20][CH2:19][C:18]([CH:24]([CH3:25])[CH3:26])([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:16]#[N:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: CC(C)C(C#N)(CCC(=O)O)c1cccs1
Reactant: C1=CCNC1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCC(=O)N1CC=CC1)c1cccs1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
Under nitrogen atmosphere, diethyl cyanophosphonate (618 mg) was added to a tetrahydrofuran solution (15 ml) of 3-pyrroline (262 mg) and 4-cyano-4-(2-thienyl)-5-methylhexanoic acid (692 mg) at room temperature, and the mixture was stirred overnight. After the reaction solution was evaporated, the crude product was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a yellow oil (440 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(CO)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1nc(C)c(C=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
In THF (20 ml) was dissolved (2,4-dimethyl-1,3-thiazol-5-yl)methanol (1.0 g). To the solution was added active manganese dioxide (6.0 g), and the mixture was stirred at room temperature for 3 hours. To the mixture was added active manganese dioxide (3.0 g), and the mixture was stirred at room temperature for 1 hour. The mixture was filtered with Celite and washed with methanol. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate/methanol=10/10/1) to give 2,4-dimethyl-1,3-thiazole-5-carbaldehyde (0.32 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
1-Nitro-4-(2,2,2-trifluoroethoxy)benzene (5.5 g) was dissolved in methanol (100 ml), 10% palladium/activated carbon (50% in water, 2.5 g) was added thereto, and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere. The palladium/activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give a dark orange oil residue. The obtained residue was dissolved in ethyl acetate (200 ml), and the solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained dark orange oil residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.5 g) as an orange oil.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.C([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH:30]=[CH:31][N+:32]([O-])=O)C1C=CC=CC=1.CO>C1COCC1>[C:26]([C:18]1[C:17]([CH2:30][CH2:31][NH:32][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:16]([OH:15])[CH:21]=[C:20]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:19]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(O)c(CCNC2CCCCC2)c(C(C)(C)C)c1
Reaction time: 0.03 h

Procedure:
To a suspension of 0.10 g (4.59 mmol) of lithium borohydride in 3 mL THF was carefully added 1.3 mL (10.2 mmol) of chlorotrimethylsilane. The reaction mixture was stirred for 2 min and then a solution of 0.367 g (1.0 mmol) of 1-(benzyloxy)-3,5-di-tert-butyl-2-[2-nitrovinyl]benzene from Step B of Example 75 dissolved in 1.5 mL of anhydrous THF was slowly added. The resulting reaction mixture was stirred overnight at room temperature then cooled using an external ice water bath and 15 mL of methanol was slowly added. The resulting mixture was evaporated in vacuo, the residue was the treated with 20 mL of 5 N aqueous sodium hydroxide and then the reaction mixture was extracted with 5 times with 20 mL portions of CH2Cl2. The combined extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted initially with 5% MeOH in CH2Cl2 followed by a 95/5/0.5 mixture of CH2Cl2—MeOH-conc. NH4OH. Combination of the purified fractions and evaporation in vacuo afforded the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][NH:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16]
Reactant: C1CC2CNC1CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 0.28 g (1 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.2 g (1.1 mmole) 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 0.45 ml (3.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10 ml of acetonitrile was heated at reflux for four hours. After cooling to room temperature, the reaction mixture was filtered and the solid washed with ethanol and dried to give 0.27 g of the title compound, mp 275°-280° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)nc3)CC2)c(C)c1
Yield: 81.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (193 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:49][N:50]([C@@H:67]([C:75](=[O:86])[N:76]([CH3:85])[CH2:77][CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][N:80]=1)[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:51](=[O:66])[C@H:52]([NH:64][CH3:65])[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:64]([CH3:65])[C@@H:52]([C:51](=[O:66])[N:50]([CH3:49])[C@@H:67]([C:75](=[O:86])[N:76]([CH3:85])[CH2:77][CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][N:80]=1)[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (2.87 g, 11.8 mmol), 1-hydroxy-7-azabenzotriazole (1.6 g, 11.8 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.26 g, 11.8 mmol) were dissolved in dichloromethane (30 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (2.0 mL, 11.8 mmol) was added. (2R)-N-Methyl-2-(methylamino)-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}-3-(2-naphthyl)propionamide (6.0 g, 11.8 mmol) dissolved in dichloromethan (10 mL) was added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 5.28 g of ((3E)-1,1-Dimethyl-4-{N-methyl-N-[(1R)1-(N-methyl-N{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamoyl}but-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Agent: [Ni]
Solvent: CO
Product: NC(=O)c1cccc2oc(-c3cccc(N)c3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a mixture of 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxamide (700 mg, 2.47 mmol) in methanol (30 mL) was added Raney Ni (2 g). The mixture was purged with hydrogen and stirred at room temperature for 5 hr. Then the mixture was filtered and washed with methanol; the filtrate was evaporated under reduced pressure and purified by silica gel chromatography to obtain 2-(3-aminophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (265 mg, yield 42%). 1H-NMR (400 MHz, DMSO-d6) δ 5.57 (s, 2H), 6.83-6.86 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.25-7.29 (t, J=8 Hz, 1H), 7.42-7.44 (d, J=8 Hz, 1H), 7.51-7.56 (m, 2H), 7.96-8.00 (t, J=8 Hz, 2H), 8.07 (s, 1H), 8.47 (s, 1H); LC-MS (ESI) m/z 254 [M+1]+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:33])[CH2:14][C:15]([O:17][CH:18]([O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)CC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl 3-methylbutanoate (558 mg, 1.77 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 46 (75 mg, 12% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 14H), 1.17-1.37 (m, 3H), 1.65-1.73 (br. m, 2H), 1.83-2.01 (br. m, 4H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.17 (d, J=6.6 Hz, 2H), 2.74-2.87 (br. m, 2H), 6.45 (d, J=4.8 Hz, 1H), 7.40 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 380.23 (M+Na)+; 356.18 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(Cl)c4Cl)cc3c2C1
Yield: 76.2 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 9.5 mg (0.051 mMol) 2,3-dichlorobenzoyl chloride, 14.1 mg (76%) of the title compound were recovered as a brown solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH:22][C:23]([NH:25][C@@H:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([O:36][C:37]4[CH:38]=[CH:39][C:40]5[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=5)[CH:42]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:20][C:19]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.N.CO>CCO.[Pd]>[C:49]([C:19]1[CH:20]=[C:21]([NH:22][C:23]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:29]([O:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=4)[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCN(C(=O)OCc5ccccc5)CC4)c4ccccc43)cn12
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: CO
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C4CCNCC4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A suspension of Intermediate 16d (165 mg, 0.234 mmol), Pd/C (10%, 16 mg), and 2M NH3 in MeOH (0.117 mL, 0.234 mmol) in EtOH (5 mL) under N2 was evacuated and purged with H2 twice, then stirred at rt for 8 h. The suspension was filtered through Celite, then the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to ˜0.5 mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH (5 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left a pale yellow solid that was triturated with diethyl ether (10 mL) to leave a buff solid (121 mg). Half of this material was purified by HPLC(XBridge C18, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound as a white solid after freeze-drying (20.0 mg, 15%). LCMS (Method 5): Rt 3.16 min, m/z 571 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.16 (9H, s), 1.33 (3H, d, J 6.8), 1.35 (3H, d, J 6.8), 1.68 (2H, m), 1.79 (2H, m), 1.91 (2H, m), 2.09 (2H, m), 2.47 (2H, m), 2.98 (2H, d, J 12.3), 3.50 (1H, sept, J 6.8), 3.92 (1H, m), 4.82 (1H, m), 5.51 (1H, t, J 4.5), 5.97 (1H, s), 6.88 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.26 (1H, m), 7.31-7.38 (3H, m), 7.65 (1H, dd, J 9.8, 0.8), 8.07 (1H, br s), 8.18 (1H, d, J 2.0).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH2:16][CH2:17][C:18]#[C:19][C:20]([O:22][CH3:23])=[O:21].CO.[Cl-].[NH4+]>CCOCC.C1COCC1.[Cu]I>[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:6]=1[CH2:16][CH2:17]/[C:18](/[CH3:1])=[CH:19]\[C:20]([O:22][CH3:23])=[O:21]
Reactant: [Li]C
Reactant: COC(=O)C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)/C=C(/C)CCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of lithium dimethylcuprate (prepared from 0.97 g (5.1 mmol) of copper-(I) iodide and 6.4 ml of a 1.6M ethereal methyllithium solution) in ether (30 ml) was cooled to -78° C. and treated dropwise with a solution of methyl 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-pentynoate (1 g; 3.4 mmol) in THF (10 ml). The mixture was stirred at -78° C. for 90 minutes, treated with 0.5 ml of methanol, warmed to room temperature and treated with saturated ammonium chloride solution. The mixture was extracted twice with ether and the combined extracts were washed with water and dried. The remaining residue was purified on silica gel with hexane/ethyl acetate (95:5), yielding 0.81 g of crystalline methyl (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenoate. M.P. 87.5°-89° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:22]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:26]=1)=[C:23]=[O:24]>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:23]([NH:22][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:26]=4)=[O:24])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C=Nc1ccnc(N2CCOCC2)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccnc(N2CCOCC2)c1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=481.6 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 4-(4-isocyanatopyrid-2-yl)-morpholine.