Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[N:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncnc2cc(N)ccc12
Reaction time: 8 h
Yield: 71.6 %

Procedure:
A mixture of 600 mg of tert-butyl 7-nitroquinazolin-4-ylcarbamate and 150 mg of 10% Pd—C in 15 ml each of THF and MeOH was stirred overnight under a hydrogen balloon, filtered through a Celite® pad, concentrated and purified by chromatography eluting with 5% methanol in dichloromethane to provide 385 mg of tert-butyl 7-aminoquinazolin-4-ylcarbamate (Compound 98-4). MS m/e=261.1 (MH+)
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[OH:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[OH:23])[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Oc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Product: CCOC(=O)N1CCc2nc3ccccc3c(O)c2CC1
Yield: 20 %

Procedure:
11-Hydroxy-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared analogous to Example 101 from 3-benzyl-11-hydroxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:46])[C@@H:13]([CH3:45])[NH:14][C:15](=[O:44])[C@@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([C:40]([O:42][CH3:43])=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:6][CH:5]=1)([O-])=O.C(O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C1COCC1>[C:7]1([CH2:10][O:11][C:12](=[O:46])[C@@H:13]([CH3:45])[NH:14][C:15](=[O:44])[C@@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([C:40]([O:42][CH2:43][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:41])[NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of N-[N2 -[(1,1-dimethylethoxy)carbonyl]-N6 -[(phenylmethoxy)-carbonyl]-(R)-6-[(methoxy)carbonyl]-L-lysyl]-D-alanine 4-nitrophenylmethyl ester (40a, Kolodziejczyk, et. al., Int. J. Pept. Prot. Res., 1992, 39, 382; 683 mg, 1.06 mmol), 4 molecular sieves (2.15 g, crushed), THF (10.5 mL), and benzyl alcohol (11.0 mL, 105.6 mmol) is stirred for 30 min and then treated with titanium(IV) isopropoxide (82 μl, 0.27 meq). The resulting mixture is heated for 24 h at 85°-90° C. The solids are filtered through diatomaceous earth and the solvent removed. The excess benzyl alcohol is removed by distillation on a Kugelrohr apparatus (approx. 1000μ pressure, 50°-75° C.) The crude orange oil is chromatographed (2.5×31 cm column), gradient of 4:1-2:1 hexane/EtOAc) to provide 40b (633 mg, 88% yield): NMR δ1.39 (d, J=7.2, 3H), 1.43 (s, 9H), 1.40-1.67 (m, 4H), 1.84 (br s, 2H), 4.07 (br s, 1H), 4.40 (m, 1H), 4.58 (apparent quintet, 1H), 5.0 (br d, 1H), 5.07-5.25 (m, 6H), 5.43 (br d, J=7.9, 1 H), 6.68 (br d, 1H), 7.33 (m); MS (HR-FAB) m/z 676.3232 (M+H, calcd. for C37H46N3O9, 676.3234).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[N:61]1[CH2:66][CH2:65][C:64](=O)[CH2:63][CH2:62]1>>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:64]3[CH2:63][CH2:62][N:61]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][N:55]=4)[CH2:66][CH2:65]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=C1CCN(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 51 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (300 mg, 0.6 mmol), acetic acid (45 mg, 0.72 mmol), sodium triacetoxyborohydride (200 mg, 0.91 mmol) and 1-(2-pyridinyl)-4-piperidinone (120 mg, 0.66 mmol) (preparation 37). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (96:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (199 mg) as a foam. MS: 653 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])[CH3:21].C(Cl)(Cl)Cl>O>[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH:25][CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:21]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Reactant: CCOC(=O)[C@H](C)N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To 5 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, was added 22 g of L-alanine ethyl ester and the reaction was continued for 30 minutes at 100° C. After cooled to room temperature, the reaction mixture was added with 100 ml of chloroform and 100 ml of water and stirred. The chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from chloroform-n-hexane to obtain 5.9 g of the titled compound having the melting point of 101° to 102° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](Cl)=[O:9])[CH3:6].[F:15][C:16]1[C:17]2[CH2:23][S:22][CH2:21][C:18]=2[S:19][CH:20]=1>C(Cl)Cl>[CH2:5]([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([C:20]1[S:19][C:18]2[CH2:21][S:22][CH2:23][C:17]=2[C:16]=1[F:15])=[O:9])[CH3:6]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: Fc1csc2c1CSC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)C(=O)c1sc2c(c1F)CSC2
Temperature: 0 °C
Yield: 70 %

Procedure:
2.31 mmol of AlCl3 was added to 20 ml DCM with 2.31 mmol 2-ethylhexanoyl chloride at about 0° C. Compound 7 from the previous step was added to the mixture. The mixture was reacted at about 0° C. for about 4 hours. After reacting, the reactant was poured into ice water. The organic phase was extracted by ether 3 times. Compound 8 was purified by silica gel. The yield was about 70%.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C1CCCC(Br)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CCCC(=O)c3ccccc32)CC1
Yield: 52 %

Procedure:
9-Bromo-6,7,8,9-tetrahydrobenzocyclohepten-5-one (590 mg, 2.5 mmol), 1-t-butoxycarbonylpiperazine (500 mg, 2.7 mmol) and potassium carbonate (510 mg, 3.7 mmol) were stirred overnight in DMF. The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 450 mg (1.3 mmol, 53%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidine according to conditions described in general procedure C. Mp: 190-191° C.; 1H NMR (400 MHz, CDCl3) δ 1.52-1.63 (m, 6 H), 3.27-3.63 (m, 4 H), 3.72 (m, 4 H), 3.87 (m, 4 H), 5.81-5.83 (m, 1 H), 5.92-5.94 (m, 1 H), 6.78 (d, J=10.0 Hz, 1 H), 7.08 (d, J=6.4 Hz, 1 H), 7.33-7.35 (m, 2 H), 7.50-7.61 (m, 2 H), 7.89-7.91 (m, 1 H), 7.96-8.14 (m, 1 H), 8.12-8.17 (m, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].Br[CH2:10][C:11]#[N:12].CCN(CC)CC>C1COCC1>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[CH2:10][C:11]#[N:12]
Reactant: N#CCBr
Reactant: OCC1CCCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCCCC1CO

Procedure:
The method follows that of S3 using 2-piperidinemethanol (26.50 g, 0.230 mol), BrCH2CN (30.35 g, 0.253 mol), Et3N (35.27 mL, 0.253 mol) and dry THF (150 mL). The crude product was purified by flash chromatography using ether/CH3OH (19:1) as eluent. The title-compound was crystallised from ether yielding cream-coloured crystals (31.46 g, 89%). δH(250 MHz; CDCl3); 1.2-1.85 (m, 6H, NCH2CH2CH2, CH2CH2CH2CH and CH2CH2CH), 2.05 (s (broad), 6H, OH), 2.4 (m, 1H, NCH2CH2), 2.55 (3×d, 1H. 1×NCH2CH2), 2.95 (m, 1H, NCHCH2), 3.45 (d, 1H, J=17 Hz, 1×NCH2CN), 3.5 (2×d, 1H, J=3 Hz and 12 Hz, 1×CHCH2OH), 3.76 (2×d, 1H, J=3 Hz and 12 Hz, CHCH2OH) and 4.05 (d, 1H, J=17 Hz, 1×NCH2CN); δC (62.9 MHz; CDCl3); 23.71, 25.25, 28.69, 43.43, 54.04, 60.73, 64.46 and 115.05 (CN); FAB MS, m/z(M+H)+ 155; IR υmax/cm−1; 3400 (OH, m broad), 2350 and 2240 (CN) and 1650.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8]([O:15][CH2:16][CH3:17])=[N:9][O:10][C:11]=1[C:12]([OH:14])=[O:13])[C:3]([OH:5])=[O:4].Cl.[CH2:19](O)[CH3:20]>>[NH2:1][CH:2]([CH2:6][C:7]1[C:8]([O:15][CH2:16][CH3:17])=[N:9][O:10][C:11]=1[C:12]([OH:14])=[O:13])[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCO
Reactant: CCOc1noc(C(=O)O)c1CC(N)C(=O)O
Agent: Cl
Product: CCOC(=O)C(N)Cc1c(OCC)noc1C(=O)O

Procedure:
A mixture of (RS)-2-amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionic acid (2.0 g, 8.2 mmol) and a solution of HCl in ethanol (35 mL) was boiled under reflux for 3 h to give ethyl (RS)-2-amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionate. Ethyl (RS)-2-Amino-3-(5-carboxy-3-ethoxyisoxazol-4-yl)propionate (0.6 g) was added a dilute solution of NaOH, and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was dissolved in acetone (6 mL) and added a solution of oxalic acid (0.14 g, 1.6 mmol) in acetone (6 mL), and the formed precipitate was collected by filtration (110 mg, 10%): mp 159-161° C.; 1H NMR (DMSO-d6) δ1.11 (t, 3 H), 1.32 (t, 3 H), 1.36 (t, 3 H), 3.02 (dd, 1 H), 3.11 (dd, 1 H), 3.98-4.16 (m, 3 H) 4.32 (q, 2 H), 4.37 (q, 2 H); MS ((M+H)+) m/z 301. Anal. calcd, C, 46.15; H, 5.69; N, 7.18; found, C, 46.38; H, 5.69; N, 7.36.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].[CH2:16]([N:18](CC)CC)C.CN>C(Cl)(Cl)Cl>[CH3:16][NH:18][S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:3]([CH:1]=[O:2])[CH2:4][CH2:5]2)(=[O:14])=[O:13]
Reactant: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc2c(c1)CCN2C=O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 31.07 g (0.126 mol) of N-formyl-5-chlorosulfonylindoline in 400 ml of ice-cold methylene chloride was added 37 ml (0.252 mol) of triethylamine and 30 ml (0.252 mol) of 40% aqueous methylamine solution, portionwise over twenty minutes. The mixture was allowed to warm to room temperature and then heated to reflux in an oil bath for one hour while stirred mechanically. Thin layer chromatography with chloroform showed the reaction was complete. The aqueous layer was removed. The methylene chloride layer was washed with water and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue allowed to air dry to give 23.74 g (0.0988 mol) (75% by weight yield) of 5-methylsulfamoyl-N-formylindoline.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([N:17]([CH:21](N(CCC)CCC)OC(C)(C)C)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:21]=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:15][CH3:16]
Reactant: CCCN(CCC)C(OC(C)(C)C)N(CCC)CCC
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Product: CCCN(C=Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-])CCC
Reaction time: 2 h
Yield: 85.8 %

Procedure:
For two hours, 5.5 g of 2,3-dinitrotoluene is heated with 13.0 g of bisdipropylamino-tert-butoxymethane to 60° C. After cooling, the reaction mixture is freed of volatile components under a high vacuum, thus obtaining 7.6 g of β-dipropylamino-2,3-dinitrostyrene as an oil.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37].C=O.[BH4-].[Na+]>C1COCC1.CC(=O)OCC>[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][C@@H:32]4[CH2:36][CH2:35][N:34]([CH3:1])[CH2:33]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCNC1)C3
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@@H]1CCN(C)C1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
TFA (15 μL) was added to a cold (0° C.) mixture of Example 80 (150 mg; 0.35 mmol; 1 eq.), formaldehyde (0.26 mL; 3.49 mmol; 10 eq.) and NaBH4 (66 mg; 1.74 mmol; 5 eq.) in THF (12 mL) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EA, washed with 0.1M NaOH, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (50 mg, 32%) as yellow foam. 1H NMR (DMSO-d6) δ 7.39-7.30 (m, 1H), 6.98 (dd, J=11.5, 2.3 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.01-4.92 (m, 1H), 4.85-4.78 (m, 2H), 4.66-4.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.70 (m, 1H), 2.62 (s, 1.5H), 2.60-2.52 (m, 2H), 2.55 (s, 1.5H), 2.35-2.2.20 (m, 2H), 2.17 (s, 1.5H), 2.16 (s, 1.5H), 1.81-1.60 (m, 1H). HPLC (max plot) 96.7%, Rt 2.74 min. UPLC/MS: (MS+) 444.5 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][N:18]=2)[CH2:12][CH2:11]1)=[O:9]>[Pd].C(O)C>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:9])[CH2:11][CH2:12]2)=[N:18][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)c2ccccc2F)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1OC1CCN(C(=O)c2ccccc2F)CC1
Yield: 68.9 %

Procedure:
Stir a mixture of (2-fluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone (3.58 g, 10 mmol) and 10% palladium on carbon (358 mg) in ethanol (100 mL) at 22° C. under hydrogen overnight. Filter to remove catalyst. Concentrate filtrate to provide a colorless oil. Subject oil to silica gel chromatography eluting with hexanes and ethyl acetate (1:1), followed by 70% ethyl acetate/hexanes to give a yellow solid (2.27 g, 50% yield). MS(ES): m/z=330.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCSc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 4-bromobenzenethiol (10.1 g), and to the solution was added at room temperature potassium carbonate (9.6 g). To the mixture was added dropwise 1-iodohexane (9.5 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 1-bromo-4-(hexylthio)benzene (14.2 g). In THF (127 ml) was dissolved 1-bromo-4-(hexylthio)benzene (14.1 g), and to the solution was added dropwise at −78° C. 1.6M n-butyllithium/hexane (35.5 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (16.1 g) in THF (32 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added 10% sulfuric acid (70.5 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-(hexylthio)phenyl borate (6.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]1([N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]([CH2:20][NH:21][C:22](N2C=CN=C2)=[O:23])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:22](=[O:23])[NH:21][CH2:20][C:18]([N:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(CNC(=O)n1ccnc1)N(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCC(=O)N(c1ccccc1)c1ccccc1)Nc1cccc([N+](=O)[O-])c1
Yield: 18 %

Procedure:
3-Nitroaniline (2.8 g) is added to a solution of N-(diphenylcarbamoylmethyl)-1-imidazolecarboxamide (3.2 g) in anhydrous toluene (35 cc). The solution obtained is stirred under reflux for 4 hours. After cooling, the reaction mixture is washed with an N aqueous solution (40 cc) of methanesulphonic acid and distilled water (2×30 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is stirred for 20 minutes in dichloromethane (25 cc). The insoluble product is separated by filtration, washed with dichloromethane (5 cc) and dried in the air. After recrystallization in ethyl acetate, 2-[3-(3-nitrophenyl)ureido]-N,N-diphenylacetamide (0.7 g), m.p. 180° C., is obtained.
Reaction SMILES: [CH:1]1([CH:6]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH:1]1([CH:6]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[N:31]3)=[CH:25][CH:24]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C=Cc1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
827 mg (1.461 mmol) of ethyl (2E)-3-{3-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]phenyl}prop-2-enoate (Example 174A) were dissolved in 28 ml of dioxane/water (3:1 v/v), and 2.2 ml of 1 N aqueous sodium hydroxide solution were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then acidified to pH 1 with 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gave 780 mg (95% of theory) of the target compound.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C>[O:15]=[C:14]1[C:13]([C:11]#[N:12])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:17][NH:16]1
Reactant: N#CCC(=O)NN
Reactant: O=CC(=O)c1ccccc1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cn[nH]c1=O

Procedure:
Phenyl glyoxal (1.0 g, 7.46 mmol) and cyanoacetohydrazide (740 mg, 7.46 mmol) were heated to reflux in 10 mL ethanol for 16 hours. After cooling, the solvent was evaporated and the crude brown mixture was purified by silica chromatography (1:9 methanol/dichloromethane). The still impure product was further recrystallized from methanol affording 70 mg pure product.