Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C@@H:13]([C@H:15]1[CH2:19][S:18][C:17](=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[CH3:30])[N:16]1[CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:14])(C)(C)C>>[OH:12][C@@H:13]([C@H:15]1[CH2:19][S:18][C:17](=[N:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[CH3:30])[N:16]1[CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H]([C@@H](C)OC(C)(C)C)N1CC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H]([C@@H](C)O)N1CC(C)C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
A solution of TFA (8 mL) was cooled to 4° C. and added to solid (4S)-4-(1 (R)-tert-butoxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (Method C5b; 0.16 g, 0.42 mmol) via cannula. The resulting solution was warmed to 20° C. and stirred at that temp. for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between Et2O (100 mL) and a saturated NaHCO3 solution (100 mL). The ether layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; gradient from hexane to 10% EtOAc/hex) to yield (4S)-4-(1(R)-hydroxyethyl)-3-isobutyl-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (0.13 g, 90%): TLC (25% EtOAc/hex) Rf0.13.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=O)[C:15]=2[CH3:29])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:30]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[NH2:30])[C:15]=2[CH3:29])=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: N
Reactant: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1C(=O)O
Product: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccccc1C(N)=O

Procedure:
In a manner similar to that described for Examples 1B-C, the title compound was prepared from 2-[3-(4-methanesulfonyl-phenylcarbamoyl)-2,5-dimethyl-pyrrol-1-yl]-benzoic acid and ammonia. 1H-NMR (DMSO-d6): δ 9.82 (1H, s), 8.08 (2H, d, J=9.1), 7.90 (2H, d, J=9.1), 7.67 (4H, m), 7.39 (1H, s). 7.34 (1H, m), 6.63 (1H, s), 3.23 (3H, s), 2.27 (3H, s), 2.00 (3H, s); MS (ESI): 412 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18](=[C:27]=[O:28])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:21]1([N:20]([CH2:19][C:18](=[C:27]=[O:28])[O:17][CH2:15][CH3:16])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=C=O)CNc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=C=O)CN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitro-benzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxy-carbonylethyl)-aniline in 300 ml of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 ml of water with stirring. The mixture was extracted 3 times with 200 ml of dichloromethane, the organic extract was washed twice with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried over sodium sulphate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory), Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)=[O:14])=[CH:11][C:6]=2[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.O>[OH:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([NH:12][C:10]2[CH:9]=[CH:8][C:7]3[C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:25])([CH3:24])[C:6]=3[CH:11]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc21
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(CO)cc3)ccc21
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of Am-80 (320 mg, 0.912 mmol) and triethylamine (152 μl, 1.09 mmol) in tetrahydrofuran (5 ml) was cooled to −20° C., and added dropwise with a solution of methyl chloroformate (82 μl, 1.06 mmol) in tetrahydrofuran, and the mixture was stirred for 1 hour. The reaction mixture was filtered through Cerite, and then washed with tetrahydrofuran (3 ml). The filtrate was cooled on ice, and added with NaBH4 (208 mg, 5.47 mmol), then the mixture was slowly added dropwise with water (4 ml) with vigorous stirring, and stirring was further continued over 18 hours until the reaction mixture became 26° C. The reaction mixture was added with saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was treated in a conventional manner. The residue was separated by silica gel chromatography [eluted with hexane-ethyl acetate (2:1)], and recrystallized to obtain 4-hydroxymethyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide (290 mg, 94%) as colorless prisms.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[N:17]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:20]2[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:16][N:17]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:19]=2)=[N:4][CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: C#Cc1ncncc1CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-ethynylpyrimidin-5-yl)acetate (I110) (0.146 g, 0.766 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.250 g, 0.547 mmol) in dry DMF (15 mL) were added triethylamine (0.305 mL, 2.19 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.016 g, 0.055 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.019 g, 0.027 mmol) and Cu(I)I (0.010 g, 0.055 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated in vacuo to give a brown gum. The crude material was purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I111) (0.093 g, 27% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.50 (s, 1H), 9.23 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.14-4.04 (m, 4H), 3.96 (s, 2H), 2.81 (br s, 2H), 2.70-2.61 (m, 1H), 1.75 (d, J=11.9 Hz, 2H), 1.53-1.37 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: it 6.64 min; m/z 609.2 [M−H]−.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]([CH3:35])([CH3:34])[C:8]([NH:10][CH2:11][CH:12]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH:13]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)=[O:9])(=O)C.O>C(O)C>[Cl:33][C:28]1[CH:27]=[C:26]([CH:13]2[CH:12]([CH2:11][NH:10][C:8](=[O:9])[C:7]([OH:6])([CH3:35])[CH3:34])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(=O)OC(C)(C)C(=O)NCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)C(C)(C)O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
2 M Aqueous sodium hydroxide solution (0.3 mL) was added dropwise to a solution of tert-butyl (6SR,7RS)-7-({[2-(acetyloxy)-2-methylpropanoyl]amino}methyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)([CH3:17])[O:13][C:12]2=[O:26])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[OH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C@@:14]2([CH3:17])[O:13][C:12](=[O:26])[N:11]([C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:10])[CH2:16][CH2:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc([C@H](C)N2CCC(C)(c3ccc(C=O)cc3)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([C@H](C)N2CC[C@@](C)(c3ccc(CO)cc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.0163 g of 4-(3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,3-oxazinan-6-yl)benzaldehyde isomer 2, obtained as described above, and 0.100 g of NaBH4 in MeOH (3 mL) was stirred at room temperature for 24 h. After the solvent was evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-6-(4-(hydroxymethyl)phenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.43 min, m/z 356 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.42-7.25 (m, 4H), 7.14 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 5.50 (q, J=7.3 Hz, 1H), 4.53 (s, 2H), 3.69 (s, 3H), 2.70-2.65 (m, 2H), 2.36-2.30 (m, 1H), 1.98-1.87 (m, 1H), 1.50 (s, 3H), 1.19 (d, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:8]([C:6]1[CH:5]=[N:4][C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:2]([CH3:1])[N:7]=1)[CH3:9])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(C)n1
Product: Cc1nc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 68 %

Procedure:
The title compound is prepared in 68% yield (347 mg, a pale brown oil) from 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone (350 mg, 1.50 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (217 mg, 1.79 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N:11]2[C:19]3[CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][C:15](=[O:22])[C:14]=3[C:13]([CH:23]([F:25])[F:24])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC([O-])(C)C.[Na+].[NH2:32][CH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.N1C=CC=N1.[OH-].[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2].CS(C)=O.C1(C)C=CC=CC=1>[F:24][CH:23]([F:25])[C:13]1[C:14]2[C:15](=[O:22])[CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][C:19]=2[N:11]([C:9]2[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:32][CH:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH:10]=2)[N:12]=1
Reactant: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C(N)=O)c(Br)c3)c2C1
Reactant: NC1CCSCC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C(N)=O)c(NC4CCSCC4)c3)c2C1
Temperature: 120 °C

Procedure:
2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide (300 mg, 0.76 mmol), Pd(OAc)2 (8.7 mg, 5 mol %), DPPF (44.5 mg, 10 mol %) and NaOtBu (153 mg, 1.52 mmol) were added to a microwave vial. Toluene (1 mL) and 4-aminotetrahydrothiopyran (116 mg, 1.3 mol eq) were added and the vial was evacuated and back-filled with N2. The reaction mixture was heated at 120° C. for 15 min (microwave). The reaction mixture was filtered and the solids washed with CH2Cl2. The product was purified using flash chromatography eluting with hexanes and EtOAc. Product was recovered as an off-white solid (70 mg, 21%). The preceding product pyrazole (70 mg, 0.16 mmol) was dissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 65 mL, 2 eq) was added and the reaction mixture was heated at 70° C. for 12 hours. The reaction mixture was washed with H2O and EtOAc. The product was purified using flash chromatography eluting with hexanes and EtOAc. The title compound was obtained as an off-white solid (40 mg, 56% yield), LC/MS (m/z): M+H=449.2.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:18]([C:26](O)=[O:27])[NH:17][C:16]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:53]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C=O)C.O>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]1[C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:18]([C:26]([N:56]2[CH2:55][CH2:54][N:53]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57]2)=[O:27])[NH:17][C:16]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1[nH]c(=O)n([C@@H]2CCCC[C@H]2OCc2ccccc2)c1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n([C@@H]3CCCC[C@H]3OCc3ccccc3)c2-c2ccccc2)CC1
Yield: 74.7 %

Procedure:
Dissolved 15E (1.5 g, 3.82 mmol) in 15 mL of DMF and added EDC (1.28 g, 6.68 mmol) and HOBt (0.88 g, 6.49 mmol). The mixture was stirred for at least 15 minutes. Next, DIEA (2.0 mL, 11.4 mmol) was added along with tert-butyl piperazine-1-carboxylate (0.85 g, 4.58 mmol). This reaction mixture was then stirred overnight at RT. After the disappearance of 15E, this mixture was poured into 150 mL of water. The white solid was filtered, rinsed with water and dried under vacuum to provide tert-butyl 4-(1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate (15Ga) (1.6 g, 75%). ESI-MS: m/z 561.6 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1)[CH3:2].[BH4-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cccc(CO)c1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2′,6′-diethylbiphenyl-3-carbaldehyde (3.48 g, 14.6 mmol) in a mixture of methanol (35 mL) and tetrahydrofuran (35 mL) was added sodium borohydride (0.28 g, 7.3 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid, diluted with ethyl acetate, washed successively with water and saturated brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (2.82 g, yield 80%) as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:34])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:13]=1)[CH3:9]>C(Cl)Cl>[NH:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[C:11]([O:10][CH2:8][CH3:9])=[O:34])[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1cccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(OCCC2CCNCC2)c1
Reaction time: 8 h
Yield: 163.9 %

Procedure:
TFA (25 ml) was added to a solution of N-Boc-3-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester (8.5 g, 22 mmol) in DCM (100 ml). Stirring overnight followed by evaporation of the solvents afforded 10 g of the title compound as the TFA salt. LC-MS (m/z): 279 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15]1)[C:6]([O:8][CH3:9])=[O:7].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][CH2:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:19]=2[CH:20]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Yield: 98.9 %

Procedure:
Palladium-on-carbon (10% w/w, 0.2 g.) was added to a solution of (G) (0.69 g.) in ethyl acetate (50 ml.) in a hydrogenation bottle and the mixture hydrogenated at a pressure of 3.17 bars of hydrogen. When the uptake of hydrogen had ceased, catalyst was removed by filtration through diatomaceous earth. The filter pad was washed with ethyl acetate and the filtrate and washings were evaporated to give methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (0.625 g., 91%) as a foam; NMR: 3.1 (br s,2 H, NH2), 3.3 (t,2 H, OCH2CH2N), 3.85 (m,6 H, OCH3 +CO2CH3), 4.2 (t,2 H, OCH2CH2N), 4.45 (s, 2 H, CH2 --Ar), 6.0 (m,2 H), 6.55 (d,1 H), 7.3 (d,1 H), 7.55 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[CH:19]([C:22]1[N:23]=[C:24]([C:27](O)=[O:28])[S:25][CH:26]=1)([CH3:21])[CH3:20].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C:3]1[C:2]([NH:1][C:27]([C:24]2[S:25][CH:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[N:23]=2)=[O:28])=[C:7]([Cl:8])[C:6]([O:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl)OC
Temperature: -10 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
1-[2-amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone (1.89 g, 6.92 mmol) and 4-isopropyl-thiazole-2-carboxylic acid (1.77 g, 10.38 mmol) was dissolved in pyridine (20 mL) and was cooled to −10° C. POCl3 (0.823 mL, 8.99 mmol) was added dropwise. The reaction was stirred at −10° C. for 2 hours. The reaction was quenched with CH3OH (5 mL). After 15 minutes, the reaction was taken up in EtOAc and extracted with 2N HCl(aq). The organic layer was dried with Na2SO4, filtered and was concentrated. 4-Isopropyl-thiazole-2-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (2.84 g, 96%) was isolated by silica gel chromatography as a white solid.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:18]([OH:21])[CH:19]=[CH2:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH2:20][CH2:19][CH:18]=[O:21])=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CCC=O)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 92.3 %

Procedure:
To a solution of 20 g (69.9 mmol) of ethyl 4-iodobenzoate, 0.47 g (2.1 mmol) of palladium acetate, 14.7 g (175 mmol) of sodium bicarbonate, and 22.5 g (70 mmol) of tetrabutylammonium bromide in 200 mL of dimethyl formamide were added, under nitrogen, 6.89 g (118.8 mmol) of allyl alcohol. The reaction mixture was stirred at room temperature for 42 hours. The dimethyl formamide was then removed by evaporation under reduced pressure and the residue was dissolved in 300 mL of ethyl acetate. This was washed with water (3×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 7:3 hexane:ethyl acetate to give 13.3 g (98%) of 3-(4-ethoxycarbonylphenyl)-1-propanal as a light yellow oil. 1H NMR (CDCl3) δ 10.02 (1H, s), 8.18 (2H, d, J=7.3 Hz), 7 47 (2H, d, J=7.3 Hz), 4.56 (2H, q, J=6.5 Hz), 3,21 (2H, t, J=6.5 Hz), 3.02 (2H, t, J=6.5 Hz), 1,59 (3H, t, J=6.5 Hz), Taylor, E. C. et al., J. Org. Chem., 57, 3218 (1992); J. Org. Chem., 60, 6684 (1995).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[C:16]1C=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1C=O>N1CCCCC1>[C:1]([C:9]1[C:10](=[O:11])[O:12][C:13]2[C:17]([CH:16]=1)=[CH:20][CH:21]=[C:22]([O:24][CH3:25])[CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Solvent: C1CCNCC1
Product: COc1ccc2cc(C(=O)c3cccnc3)c(=O)oc2c1

Procedure:
A mixture of 0.65 g ethyl nicotinoylacetate, 0.5 g 2-hydroxyanisaldehyde and 10 ml alcohol was heated on a steam bath until solution was attained. Five drops of piperdine were added and heating was continued. After several minutes the reaction mixture solidified. An additional 10 ml of alcohol were added and the reaction mixture heated another 15 minutes. After cooling, the solid was collected and recrystallized twice from a mixture of alcohol and acetonitrile.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
1-Benzyl-4-piperidone (635 mg), 5-aminoindazole (532 mg), and acetic acid (0.20 ml) were dissolved in methanol (10 ml), and a borane-pyridine complex (0.51 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (1.00 g, yield 82%).