Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>O>[ClH:1].[CH2:21]([NH:24][C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:18]([O-:20])=[O:19])[CH:8]=2)[N:3]=1)[CH:22]=[CH2:23]
Reactant: CCCCCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NCCCCC)c2cc([N+](=O)[O-])ccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 170 mg (0.61 mmol) of 2-chloro-6-nitro-4-pentylaminoquinazoline was added 1.52 g (26.66 mmol) of allylamine, followed by stirring at room temperature overnight. To the reaction solution was water added, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 160 mg (yield: 83.6%) of a free base compound of the title compound.
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][C@@H:8]([CH2:10][N+:11]([O-])=O)[CH2:7][C@@H:6]1[CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(=[O:3])[CH3:2].C(OCC)(=O)C.C(O)C>O1CCCC1.[Ni]>[C:1]([NH:4][C@@:5]1([C:26]([NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:9][C@@H:8]([CH2:10][NH2:11])[CH2:7][C@@H:6]1[CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:24])([CH3:25])[O:18]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](C[N+](=O)[O-])C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)C[C@@H](CN)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
To a stirring solution of (1S,2S,4S)-1-acetamido-N-(tert-butyl)-4-(nitromethyl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)cyclopentanecarboxamide (0.907 g, 2.0 mmol) in a mixture of tetrahydrofuran (20 mL), ethyl acetate (15 mL), and ethanol (5 mL) under nitrogen was added Raney nickel (1.2 g). The reaction mixture was then purged with hydrogen and stirred under an atmosphere of hydrogen at room temperature for 6 h. At the end of this period, the mixture was purged with nitrogen, then carefully through Celite®. After rinsing the filter cake with ethyl acetate the combined filtrate was concentrated in vacuo to afford the subject compound (0.841 g, 99%) as a white solid. NMR (CDCl3): δ 6.98 (br s, 1 H), 6.93 (br s, 1 H), 2.55-2.70 (m, 3 H), 2.44 (m, 1 H), 2.24 (m, 1 H), 1.91 (m, 3 H), 1.50-1.65 (m, 3 H), 1.20-1.45 (m, 4 H), 1.26 (s, 9 H), 1.66 (s, 12 H), 0.60-0.75 (m, 2 H). MS (M+1): 424.4.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=O)[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:45][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:26])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)CC
Yield: 87.1 %

Procedure:
2.47 g (0.007 mol) of N-[(9-fluorenyl)methoxycarbonyl]-L-isoleucine, 1.89 g (0.007 mol) of octadecylamine, 85.5 mg (0.0007 mol) of 4-(N,N-dimethylamino)pyridine (DMAP), and 1.61 g (0.0084 mol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) was dissolved in 45 ml of dichloromethane, and the resultant solution was stirred for 4 days at room temperature. Then, the obtained reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure, the resultant residue was subjected to re-crystallization treatment using ethyl acetate, and gel-like substance was subjected to a suction filtration, thereby obtaining 3.69 g of N-[(9-fluorenyl)methoxycarbonyl]-L-isoleucylaminooctadecane (hereinafter also referred to as “Intermediate product (1)”) at the yield of 87%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH2:65])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:52])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH:65][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of hexadecandioic acid mono t-butyl ester (100 mg, 0.29 mmol) in dry DCM (2 ml), HOAt (44 mg, 0.29 mmol) and DCC (72 mg, 32 mmol) was added. The mixture was stirred at 50° C. for 1 h. The oil bath was removed. 5-Amino-isophthalic acid mono t-butyl ester (69 mg, 0.29) and DIPEA (0.07 ml, 0.32 mmol) was added. The mixture was stirred at RT over night under nitrogen. The yellow suspension was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc and extracted with 0.1N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a white solid, which was purified twice by flash chromatography using EtOAc/Hept 1:2+5% AcOH. The title compound was obtained in 86% yield (0.140 g) as an oil containing an impurity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:42][N:43]([CH:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:44](=[O:59])[CH:45]([NH:57][CH3:58])[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][O:15][CH2:16][C:17](=[O:19])[N:57]([CH3:58])[C@@H:45]([C:44](=[O:59])[N:43]([CH3:42])[C@@H:60]([C:68](=[O:71])[NH:69][CH3:70])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1COCC(=O)O
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 2-(carboxymethoxymethyl)piperidine-1-carboxylic acid tert-butylester (225 mg, 0.82 mmol) in 5 ml of dichloromethane was added 1-hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg, 0.90 mmol) and the mixture was to stirred for 30 min. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(2-naphthyl)propionamide (332 mg, 0.82 mmol) in dichloromethane (5 mL) was added followed by diisopropylethylamine (0.14 ml, 0.82 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (20 g) with ethyl acetate to give 416 mg of 2-([N-methyl-N{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)piperidin-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:25])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C)cc3s1)n2C
Yield: 83.5 %

Procedure:
1-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.47 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 2-amino-6-methyl-benzothiazole (0.82 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 354.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=[O:21])[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]([C:38]1[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=1)[C:15](=[O:21])[CH:14]=[CH:13]2)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(ccc(=O)n2-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 120 h
Yield: 86.1 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (23 mg, 0.05 mmol) and 4-chlorophenylboronic acid (16 mg, 0.10 mmol) in dichloromethane (2 mL) was added copper (II) acetate (9 mg), followed by molecular sieve 4 Å and pyridine (82 μL). The mixture was stirred for 5 days, and filtered and washed with ethyl acetate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (25 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36Cl2NO4: 580.2. Found: 580.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([F:23])=[CH:11][C:10]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:31]([CH3:34])[CH2:32][CH3:33].[OH2:35]>O1CCCC1>[C:32]1([NH:31][C:34]([N:27]2[CH2:26][CH2:25][CH:24]([C:10]3[CH:11]=[C:12]([F:23])[C:13]([O:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:29][CH2:28]2)=[O:35])[CH:4]=[CH:3][CH:2]=[CH:1][CH:33]=1
Reactant: Fc1cc(C2CCNCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O
Reactant: CCN(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
65 μl (0.45 mmol, 1.2 eq) of (S)-(−)-phenylethyl isocyanate are added to a solution of 147 mg (0.37 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine in 3 ml of tetrahydrofuran in the presence of 64 μl (0.37 mmol, 1 eq) of dimethylethylamine. The reaction medium is stirred at ambient temperature for 50 minutes. The reaction is stopped by adding ml of water, and then extracted with ethyl acetate. The organic phases are combined and dried over magnesium sulphate. The solvent is evaporated off and the residue is chromatographed on silica gel, elution being carried out with 60/40 heptane/ethyl acetate. 178 mg of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid phenylamide are obtained. Yield=89%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:29]3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CCCN1CCN(CCCCl)CC1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCN(CCCOc2ccc3nc(C#N)nc(NCC(C)(C)C)c3c2)CC1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesium carbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 102-104° C., Rf=0.4 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [CH3:1][C:2]1O[C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[NH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C>[CH3:7][C:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[C:2]([CH3:1])=[C:3]([CH3:8])[N:4]=1
Reactant: NCCCC1CCN(C=O)CC1
Reactant: Cc1nc(C)c(C)o1
Solvent: CC(=O)O
Product: Cc1nc(C)n(CCCC2CCN(C=O)CC2)c1C
Temperature: 145 °C
Yield: 50 %

Procedure:
A mixture of trimethyloxazole (10.18 g, 0.091M), 4[3-aminopropyl]-1-piperidinecarboxaldehyde and acetic acid (0.16 g) were heated at 145° C. for 6 hrs. After the reaction, the excess of trimethyl oxazole was removed at reduced pressure and the residue was purified on silica gel column eluted with 4 to 10% of methanol by volume in CHCl3 to yield 4-[3-(2,4,5,-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (3.3 g, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[O:16]=[C:17]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([C:26]#[N:27])=[CH:22][CH:23]=2)[NH:18]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[ClH:1].[OH:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][N:7]=1)=[CH:23][CH:22]=[C:21]([C:26]#[N:27])[CH:20]=2
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Reactant: [O-][n+]1cc(CN2CCCCC2)ccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: Cl
Product: N#Cc1ccc2c(-c3ccc(CN4CCCCC4)cn3)c(O)[nH]c2c1

Procedure:
The title compound was prepared as described for Example 117. Starting material: 1-[(6-chloro-1-oxidopyridin-3-yl)methyl]piperidine (0.136 g, 0.60 mmol) and 2-oxoindoline-6-carbonitrile (0.100 g, 0.63 mmol) and sodium bis(trimethylsilyl)amide (1.4 mL, 1.4 mmol). Yield: 0.031 g, 12%: 1H NMR D2O, 400 MHz) δ 8.01 (d, J=2 Hz, 1H), 7.75 (dd, J=9, 2 Hz, 1H), 7.28 (d, J=9 Hz, 1H), 7.06 (m, 2H), 6.92 (s, 1H), 4.19 (s, 2H), 3.53 (m, 2H), 2.98 (m, 2H), 1.94 (s, 2H), 1.82 (m, 1H), 1.70 (m, 2H), 1.46 (m, 1H); MS (ESP) m/z 349 (M++1).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([SH:10])=[CH:8][CH:7]=[CH:6][C:5]=12.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12]S.[O-][CH2:19]C.[Na+]>C(O)C>[N:1]1[CH:2]=[C:3]2[N:4]3[C:9](=[CH:8][CH:7]=[CH:6][C:5]=13)[S:10][C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:19]2
Reactant: CCOC(=O)CS
Reactant: CC[O-]
Reactant: Sc1cccc2nccn12
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=Cc2cnc3cccc(n23)S1
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of imidazo[1,2-a]pyridine-5-thiol (448 mg), ethyl thioglycolate (0.36 ml), and sodium ethoxide (210 mg) in ethanol (10 ml) was refluxed with stirring for 3 hours. The mixture was then allowed to cool and concentrated. The residue was diluted with ethyl acetate (10 ml) and extracted with 1N-hydrochloric acid. The aqueous layer was neutralized with 1N-NaOH/water and extracted with ethyl acetate, and the organic layer was washed with water and concentrated. The resulting crystals were collected, rinsed with diisopropyl ether (20 ml), and dried to provide the title compound (430 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27](SC)[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C=O)C.[Hg](Cl)Cl>[NH:28]([C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:23][CH:24]=1)=[N:26][CH3:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CN=C(Nc1ccccc1)SC
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=NC)Nc3ccccc3)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
3-{4-[(4-Aminophenethyl)oxy]phenyl}-2-ethoxypropanoic acid (20 mg, 0.061 mmol) and methyl N′-methyl-N-phenylcarbamimidothioate (11.5 mg, 0.064 mmol) were mixed in 0.3 ml DMF. Triethylamine (25.5 ml, 0.183 mmol) was added. The mixture was then cooled in an ice-bath and mercury (II)chloride (18 mg, 0.066 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred overnight. Water (1 ml) and ethyl acetate (0.5 ml) were added and then hydromatrix (ca. 0.5 g) was added. After a while, the mixture was filtered. The filtrate was evaporated to dryness. Chromatography of the residue on an ISOLUTE column (SI, 500 mg/3 ml) using ethyl acetate/heptane (10:90, then 25:75, and then 50:50) as eluant gave 5 mg, yield 18% of the desired product.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(S[C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)C=C.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:26][CH:25]=[CH:24][N:23]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Reactant: C=CCSc1ncc[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nccn12

Procedure:
Ethyl (2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (750 mg, 2.90 mmol) from example 2A, 2-allylthio-1H-imidazole [U.S. Pat. No. 3,574,593; Chem. Abstr. 75, 49078] (1.20 g, 7.25 mmol) and triethylamine (293 mg, 2.90 mmol) are dissolved in dioxane (10 ml) and heated under reflux for 4 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 410 mg (41% of theory) of the desired product are obtained with 84% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH2:23])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.C(N(C(C)C)CC)(C)C.Cl[C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>CO>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[NH:23][C@@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3nc4ccccc4o3)C2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a 1 dram vial was added (1R,2R)—N1-(1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (25 mg, 0.079 mmol), DMF (1 mL), diisopropyl ethyl amine (0.069 mL, 0.393 mmol) and 2-chlorobenzo[d]oxazole (0.013 mL, 0.118 mmol). The vial was capped and the reaction was stirred at 65° C. for 1 hr. After this time, the reaction was diluted with MeOH and purified using RP prep-HPLC. Two diastereomers were separated. The desired isomer had the shorter retention time. The fractions with the desired material were concentrated to give the product (1R,2R)—N1-(benzo[d]oxazol-2-yl)-N2-((S)-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (16 mg, 0.036 mmol, 45.4% yield) as yellow solid. Anal. Calcd. for C24H29N5O3 m/z 435.5, found: 436.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.06-7.92 (m, 2 H), 7.37 (d, J=7.70 Hz, 1 H), 7.25-7.15 (m, 2 H), 7.06 (t, J=7.70 Hz, 1H), 6.65 (d, J=9.35 Hz, 2 H), 5.33-5.15 (m, 1 H), 3.67 (d, J=9.08 Hz, 1 H), 3.59 (d, J=11.28 Hz, 1 H), 3.44 (br. s., 1 H), 3.16-3.03 (m, 1 H), 2.89 (br. s., 2 H), 2.63 (br. s., 1 H), 2.40 (br. s., 1 H), 2.16 (d, J=11.28 Hz, 1 H), 2.00-1.91 (m, 1 H), 1.82 (d, J=9.63 Hz, 4 H), 1.71-1.58 (m, 3 H), 1.44 (d, J=9.35 Hz, 2 H); 13C NMR (126 MHz, CDCl3) δ ppm 162.09, 162.07, 154.71, 148.33, 126.15, 124.01, 121.2, 116.46, 112.55, 108.84, 59.37, 57.80, 53.01, 51.03, 48.07, 32.22, 31.92, 29.73, 24.84, 24.60, 22.91.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClC1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:20]([C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:5])=[O:7])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Temperature: 0 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
To 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (310 mg, 1.18 mmol) dissolved in 9 mL of chlorobenzene was added acetyl chloride (0.3 mL, 3.6 eq). The solution was cooled to <0° C. while titanium tetrachloride (0.61 mL, 4.8 eq) was added dropwise. The reaction mixture was stirred at 0° C. and below for 6 h and then heated in an 85° C. oil bath for 3.5 h. The reaction mixture was poured into ice/water, and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Removal of the solvents gave 167 mg (57% yield) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].[C:15]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:25])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]>>[CH3:10][O:9][Si:6]([O:11][CH3:12])([O:7][CH3:8])[CH2:5][CH2:4][C:3]([CH3:14])([CH3:13])[CH2:2][NH:1][C@H:16]([C:15]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19]
Reactant: CCCCOC(=O)/C=C\C(=O)OCCCC
Reactant: CO[Si](CCC(C)(C)CN)(OC)OC
Product: CCCCOC(=O)C[C@H](NCC(C)(C)CC[Si](OC)(OC)OC)C(=O)OCCCC
Yield: 93 %

Procedure:
In a manner similar to Example 2, 110.7 g (0.5 mole) of 4-amino-3,3-dimethylbutyltrimethoxysilane was allowed to react with 114.3 g (0.5 mole) of dibutyl maleate to give 209 g dibutyl N-[4-trimethoxysilyl-(2,2-dimethyl)butyl]aspartate at 97% purity.