Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[C:11]([Br:14])[CH:12]=2)[N:7]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(Cl)c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-6-chloro-1H-indole-3-carboxylic acid methyl ester (80.0 g, 277 mmol) in N,N-dimethylformamide (600 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 16.6 g, 416 mmol) portion-wise over 20 minutes. The reaction was stirred at 0° C. for 60 minutes followed by the addition of 4-methylbenzenesulphonyl chloride (63.4 g, 333 mmol), which was added portion-wise to the stirring solution. The reaction was allowed to stir for 2 hours at 0° C. and the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into water (1200 mL) and stirred for 12 hours. The suspension was filtered and the filter cake was washed with a further portion of water (700 mL) then heptane (2×300 mL), 160 g of crude material was recovered. The material was placed in a 3 L round bottom flask and placed on rotorary evaporated with a 40° C. bath under vacuum overnight to remove residual water. This afforded 116 g of pink solid which was suspended in acetone (600 mL) and heated to reflux for 1 hour, then removed from the heat, cooled to room temperature, and stirred for a further hour. The suspension was filtered and the filter cake was washed with acetone (˜500 mL) until the filtrate was colorless. The filter cake was dried to afford desired product (108.7 g, 89% yield). 1H NMR (CDCl3, 400 MHz) 5=8.39 (s, 1 H) 8.24 (s, 1 H) 8.11 (s, 1 H) 7.82 (d, J=8.59 Hz, 2 H) 7.32 (d, J=8.20 Hz, 2 H) 3.93 (s, 3 H) 2.40 (s, 3 H); MS (ES+) 441.9 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)C(O)=O)CCCC1.C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:84][N:85]=[CH:86]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:84][N:85]([CH3:86])[C:8](=[O:9])[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: N
Agent: O=C(O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Product: CN(O)C(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
The desired material was prepared according to the procedures described in Example 4 substituting 2-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for 2-cyclopentyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid and Example 6 substituting 2-cyclohexyl-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]-phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 0.7 (m, 1H), 1.0 (m, 1H), 1.15 (m, 4H), 1.55(m, 2H), 1.65 (m, 2H), 1.85 (m, 1H), 3.03 (s, 3H), 3.86 (d, 1H, J=7Hz), 4.84 (s, 2H), 7.0 (d, 2H, J=7Hz), 7.2 (d, 2H, J=7Hz), 7.62 (d-t, 1H, J=8Hz and 2Hz),7.68 (d, J=8Hz, 1H), 7.8 (dt, J=8Hz, 2Hz, 1H,), 8.0 (t, J=8Hz, 2H), 8.43 (d, J=8Hz, 1H), 9.8 (s, 1H). IR (CDCl3):3520, 1610 cm-1. MS (DCI/NH3) m/e 405 (M+H)+. Analysis calcd for C25H28N2O3 : C, 74.23; H, 6.98; N, 6.93. Found: C, 73.96; H, 7.04; N, 6.74.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:12]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 87.7 %

Procedure:
To a solution of L-tyrosine methyl ester (Sigma Chemical Company) (10.0 g, 51.3 mmol) and diisopropylethylamine (25.9 g, 200.0 mmol) in CH2Cl2 (400 mL) was added t-butyldiphenylsilyl chloride (TBDPS-Cl; 35.2 g, 128.2 mmol) at 23° C. The resultant mixture was stirred at 23° C. for 14 hours. The crude reaction mixture was dried over (MgSO4) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography. The polarity of the eluting solvent mixture was adjusted according to the Rf value of the product. The eluted fractions were combined, dried over MgSO4, concentrated and dried to give 19.5 g (87.8% yield) of O-(tert-butyldiphenylsilyl)-L-tyrosine methyl ester as a colorless syrup. Rf (hexanes/ethyl acetate (AcOEt)/methanol (MeOH) 20:20:1)=0.38.
Reaction SMILES: Cl.[C:2]1([NH:8][C:9](=[O:27])[NH:10][C:11]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:12]=2[O:13]COC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:2]1([NH:8][C:9](=[O:27])[NH:10][C:11]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]=2[OH:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1c(NC(=O)Nc2ccccc2)cc(OC)cc1C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1cc(NC(=O)Nc2ccccc2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
Conc. hydrochloric acid (1.5 ml) was added to 30 ml of a methanol solution containing 2.2 g of [2-(3-phenyl-ureido)-4-methoxy-6-tert-butylphenoxy]methoxymethane and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the residue and the resulting crystals were collected by filtration and recrystallized from a mixed solution of ethyl acetate and hexane to give 1.6 g of 2-(3-phenylureido)-4-methoxy-6-tert-butylphenol (yield: 83%, melting point: 147°-149° C., IR: 3400, 3350, 1670 cm-1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1>CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=[O:1]
Reactant: CC(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.6 %

Procedure:
N-(4-(Hydroxymethyl)-1,3-thiazol-2-yl)acetamide (2.8 g) was dissolved in methanol (10 ml) and chloroform (200 ml). Then manganese (IV) oxide (28.3 g) was added to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 7 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The resulting solid was washed with ethyl ether to give N-(4-formyl-1,3-thiazol-2-yl)acetamide (2.01 g) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[Cl:38][C:39]1[CH:40]=[C:41]([CH:46]2[CH2:50][NH:49][CH2:48][CH:47]2[CH:51]([O:53][C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][N:55]=2)[CH3:52])[CH:42]=[CH:43][C:44]=1[Cl:45]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:49]2[CH2:50][CH:46]([C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)[CH:47]([CH:51]([O:53][C:54]3[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][N:55]=3)[CH3:52])[CH2:48]2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.165 g, 0.72 mmol) in 20 mL of CH2Cl2 was added (0.14 g, 0.94 mmol) of EDC, (0.10 g, 0.94 mmol) of HOBt and Et3N (0.11 mL, 1.1 mmol). After one hour at RT, was added 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VII-B-2, 0.26 g, 0.72 mmol). The mixture was stirred at RT over night and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1:1) yielded 0.29 g (91%) of the title compound as a white foam.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH2:14]([C:16]1[N:17]([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:28])[C:19]=2[N:29]=1)[CH3:15]>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:14]([C:16]1[N:17]([CH2:30][CH2:31][CH2:32][C:33]#[C:34][C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:28])[C:19]=2[N:29]=1)[CH3:15]
Reactant: Ic1cccs1
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.112 g, 0.03 eq.), 2-iodothiophene (3.9 g, 1.1 eq.), triethylamine (1.1 g, 3 eq.), and copper (I) iodide (0.042 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.5 mmol, 1.0 eq.) in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 6 hours at which time analysis by liquid chromatography/mass spectroscopy indicated that the reaction was complete. The reaction mixture was absorbed onto the top of a column of silica gel (30 g) and the column was eluted sequentially with dichloromethane and 3/97 methanol/dichloromethane. The product was recrystallized from 1,2-dichloroethane to provide 0.25 g of 2-ethyl-1-[5-(thien-2-yl)-4-pentynyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, mp 175.0-190.0° C. (dec.). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, J=8.3, 1.0 Hz, 1H), 7.82 (dd, J=8.3, 1.0 Hz, 1H), 7.48 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.24 (m, 3H), 6.99 (dd, J=5.1, 3.6 Hz, 1H), 5.37 (s, 2H), 4.65 (t, J=7.7 Hz, 2H), 3.01 (q, J=7.5 Hz, 2H), 2.63 (t, J=6.2 Hz, 2H), 2.23 (m, 2H), 1.49 (t, J=7.4 Hz, 3H); MS (APCI) m/z 361 (M+H)+; Anal. calcd for C21H20N4S.0.03C2H4Cl2: C, 69.88; H, 5.59; N, 15.51. Found: C, 69.59; H, 5.69; N, 15.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=c1nc(-c2ccc(F)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (15.5 g, 0.06 mol) and phosphoroxychloride (155 mL) according to the general procedure I. Obtained as a light yellow solid (16.5 g, 99%). MS (EI) 276.1 [(M)+]; mp 67° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][C@H:8]([NH:17]C(OC(C)(C)C)=O)[C:7]1=[O:25]>C(Cl)Cl>[ClH:1].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][C@H:8]([NH2:17])[C:7]1=[O:25]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous HCl was bubbled into a solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine1-acetic acid methyl ester (600a, 4.0 g, 11.4 mmol) in 20 ml of CH2Cl2 for 20 min then stirred for 1 h at RT. The reaction was evaporated to give (3S)-2-oxo-3-amino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester hydrochloride as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21].[Cl-].[NH4+]>CN(C)C=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: ClCCCN1c2ccccc2Sc2ccccc21
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
To a solution of phenothiazine (4.0 g, 0.02 mol) in dry dimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodium hydride (1.0 g, 0.025 mol, 60% dispersion in oil) was carefully added. The reaction mixture was left stirring for 15 minutes. 1-Bromo-3-chloropropane (8.0 g, 0.05 mol) was added and the mixture was left stirring overnight. Ammonium chloride (2.0 g, 0.04 mol) was added, and after continued stirring for 30 minutes the solution was poured onto water (300 ml). The mixture was extracted with dichloromethane (2×200 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent evaporated. This afforded a residue which was purified by column chromatography on silica gel (250 g) using a mixture of n-heptane and ethyl acetate (9:1) as eluent. 4.4 g (80%) of 10-(3-chloropropyl)-10H-phenothiazine was obtained as an oil. Rf : 0.55 (SiO2 ; n-heptane/ethyl acetate=1:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[CH3:18])[NH:14][C:13](C(O)=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[CH3:18])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1cc2[nH]ccc2cc1OCc1ccccc1
Temperature: 220 °C
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid (0.6 g) in quinoline (6 mL) was added copper powder (0.15 g), and this mixture was stirred at 220° C. for 20 minutes. This reaction mixture was poured into 1 mol/L hydrochloric acid, the resulting mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.21 g).
Reaction SMILES: [H-].[Na+].[CH:3]([C:14]([O-])=O)([C:9]([O:11]CC)=[O:10])[CH2:4][CH2:5][C:6]([O-:8])=O.Br[CH:18]([CH2:24][CH2:25][CH2:26][CH2:27]CC)[C:19](OCC)=O>CN(C)C=O.CCCCC>[CH2:19]([CH:14]1[C:6](=[O:8])[CH2:5][CH2:4][CH:3]1[C:9]([OH:11])=[O:10])[CH2:18][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C(CCC(=O)[O-])C(=O)[O-]
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCCCCCC1C(=O)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
In a 1 L three necked flask fitted with a mechanical stirrer, a thermometer, a nitrogen inlet tube and a calcium chloride drying tube, is placed a suspension of 5.75 g of sodium hydride in 250 ml of dry dimethylformamide. Dry nitrogen is let in and 69 g of ethyl propane-1,1,3-tricarboxylate (G. A. Swan, J.Chem.Soc., 1039 (1955)) is added dropwise with vigorous stirring. The rate of addition is adjusted to maintain an internal temperature of about 25°C. The reaction mixture is stirred at room temperature until all the sodium hydride has reacted. 60 g of ethyl α-bromocaprylate (K. Bernhard, Helv.Chim.Acta, 29, 1462 (1946)) are added over a period of 1 hour. After the addition has been completed, the reaction mixture is stirred at 100°C for 5 hours. The reaction mixture is cooled to 10°C and added dropwise to a well stirred suspension of 5.75 g of sodium hydride in 50 ml of pentane under nitrogen atmosphere over a period of 2 hours. When the addition is completed, the mixture is stirred at room temperature for an additional 12 hours. The solvent is removed at a reduced pressure and the residue is poured into 1500 ml of cold 5% hydrochloric acid. The organic layer is separated and the water phase is extracted with ether. The combined organic layer and the ether extract are washed with water and sodium carbonate solution and dried over anhydrous sodium sulphate. After removal of the solvent, the unreacted ethyl propane-1,1,3-tricarboxylate is distilled off at 100°-105°C/0,15 mm (16 g) and the residue is boiled for 20 hours with a mixture of 750 ml of acetic acid and 750 ml of concentrated hydrochloric acid. The volatile acids are distilled off at a reduced pressure and the residue is poured onto a large excess of crushed ice. The solid product is collected on a Buchner funnel, washed repeatedly with cold water and dried. The product is recrystallized from cyclohexane-pentane to yield 21,5 g (78%) of 2n-hexyl-3-oxo-cyclopentane-carboxylic acid melting at 73°-74°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])=[O:7].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:16]1=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CNC(=O)c1ccncc1N
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 100 mg of [(3-amino-pyridine-4-carbonyl)-amino]-acetic acid methyl ester in tetrahydrofuran (4.5 mL) is added 194 mg of 1,1′-carbonyldiimidazole and 0.18 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature and the mixture is stirred at the same temperature for 2 h. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 100 mg (89%) of (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid methyl ester.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.[Br-].[CH3:32][CH:33]([CH3:36])[CH2:34][Zn+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH3:32][CH:33]([CH3:36])[CH2:34][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:21]1
Reactant: CC(C)C[Zn+]
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 18.8 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (˜5 mol %), and CuI (˜6 mol %) in dry THF (0.5 mL) followed by 2-methylpropyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 3.6 mg (15%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 417 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm 0.93 (d, 6H), 1.91-2.03 (m, 3H), 2.41 (br d, 2H), 2.58 (d, 2H), 3.23 (br t, 2H), 3.72 (br d, 2H), 3.96 (m, 3H), 5.42 (s, 1H), 6.29-6.40 (m, 1H), 6.95 (d, 1H), 7.24-7.54 (m. 8H), 7.83 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39](=O)[CH3:40]>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:39][CH3:40])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: CC=O
Product: CCN[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure F using acetaldehyde. The final product was obtained in 37% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:9]C(=O)OC(C)(C)C)[C:3]1=[O:17].[ClH:18].O1CCOCC1>ClCCl>[ClH:18].[NH2:9][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCCC[C@H](N)C1=O
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of (S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate (prepared according to Example 14; 0.152 g, 0.627 mmol) in dichloromethane (2 mL) was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol), and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated to yield (S)-3-amino-1-methylazepan-2-one hydrochloride (0.112 g, 99.9% yield) which was taken on to the next step.
Reaction SMILES: COC1C=CC(CS[C@@H:9]2[CH2:13][N:12](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:11]([C:27](O)=O)[CH2:10]2)=CC=1.O1[CH2:36][CH2:35][CH2:34]C1>C(#N)C>[CH:35]([N:12]([CH2:13][CH3:9])[CH:11]([CH3:27])[CH3:10])([CH3:36])[CH3:34]
Reactant: C1CCOC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.28 g) in anhydrous acetonitrile (19 ml), N,N'-carbonyldiimidazole (489 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (478 μl) and a solution of the compound (2.60 g), which had been obtained in (1), in anhydrous tetrahydrofuran (15 ml ) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (2.09 g) was obtained as an amorphous substance.