Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(Cl)cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Li].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Cl-:13].[Cl-].[Cl-].[Cr+3:16]>O1CCCC1>[Cl-:13].[Cl-:13].[N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][Cr+2:16])[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1cccc2cccnc12
Reactant: [Cr+3]
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: [Cr+2]Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.01 moles of the lithium salt of 8-hydroxyquinoline (prepared as described in Example 3) in 50 mL of tetrahydrofuran is added dropwise to a solution of 0.01 moles of chromium trichloride in 50 mL of tetrahydrofuran at −78° C. After warming to room temperature and stirring overnight, the suspension is filtered and the solvent evaporated under vacuum. The product is recovered from the solids by extraction with toluene and then isolated by evaporating the toluene. Polymers may be produced using this catalyst by following the procedure of Example 4.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccccc1C(F)(F)F
Product: O=c1cc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nc[nH]1

Procedure:
6-[4-(2-Trifluoromethyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=339.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH2:2][CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CN(C=O)C.CCOCC>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][N:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH3:21]
Reactant: C=CCCN[C@@H](C)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCCN(CC(=O)OCC)[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of But-3-enyl-((S)-1-phenyl-ethyl)-amine (6.37 g, 36.4 mmol) in 150 mL of DMF at 0° C. is added K2CO3 (10.0 g, 72.8 mmol) in small portions. After stirring at 0° C. for 10 min, ethylbromoacetate (8.35 g, 54.6 mmol) is added slowly. The reaction mixture, a white suspension, is stirred at r.t. overnight/16 hrs. The solution is diluted with 200 mL of ether, and washed with 3×100 ml of water. The crude product is purified by chromatography (hexane/CH2Cl2: 50/50) to give a pale liquid (8.5 g, 94.5%). (NMR and MS data confirmed, U-4117-58).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(CCCC)C(Cl)=O)C.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[C:1]1([N:7]2[C:11](=[O:12])[C:10]([C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)[nH]n1-c1ccccc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: CCCCC(CC)C(=O)Cl
Product: CCCCCCCCCCCC(=O)c1c(-c2ccccc2)[nH]n(-c2ccccc2)c1=O

Procedure:
Following the procedure of example 18 with the same proportions but replacing 2-phenyl-5-methyl-(3H)-pyrazol-3-one by 2-phenyl-5-phenyl-(3H)-pyrazol-3-one (MW=136.3 g; mp=136° C.) and 2-ethylhexanoyl chloride by lauroyl chloride a solid product is obtained which after recrystallisation in hexane has a melting point of 69° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25]>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]>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(=O)Nc1cccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)c1
Temperature: 110 °C
Yield: 35 %

Procedure:
A mixture of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 1.0 equivalent), 3-acetamidophenylboronic acid (2.0 equivalents), and PdCl2(dppf) (0.08 equivalent) in 1:2 saturated NaHCO3/dioxane (0.15 M with respect to 2D) was heated at 110° C. for 15 minutes in the microwave. After cooling to room temperature, the crude mixture was filtered and the filtrate was purified by preparatory LC-MS to give the titled compound (35%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 2.09 (s, 3H) 5.20 (s, 1 H) 6.60 (d, J=2.27 Hz, 1 H) 7.52-7.57 (m, 1 H) 7.60-7.64 (m, 2 H) 7.73-7.77 (m, 1 H) 7.84-7.89 (m, 1 H) 7.99-8.07 (m, 2 H) 8.20 (d, J=2.27 Hz, 1 H) 8.28 (t, J=1.77 Hz, 1 H) 10.24 (s, 1 H) 11.28 (s, 1 H). ESI-MS: m/z 430.3 (M+H)+.
Reaction SMILES: [CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Cl)[CH:12]=2)[C:7]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:28])[NH:21][C:22]([CH3:27])=[CH:23][C:24]=2[O:25][CH3:26])=[O:16])=[C:6]1[CH3:29])([CH2:3][CH3:4])[CH3:2].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C1(C(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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.[Pd].[Pd].O1CCOCC1>[CH:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)[CH:12]=2)[C:7]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:28])[NH:21][C:22]([CH3:27])=[CH:23][C:24]=2[O:25][CH3:26])=[O:16])=[C:6]1[CH3:29])([CH2:3][CH3:4])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(Cl)cc21
Agent: [Pd]
Agent: C1CCC(C(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCC(C)n1c(C)c(C(=O)NCc2c(OC)cc(C)[nH]c2=O)c2ccc(-c3cccnc3)cc21
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A solution of (±)-1-(sec-butyl)-6-chloro-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (Compound 185) (50 mg, 0.12 mmol), pyridine-3-ylboronic acid (22 mg, 0.18 mmol), tricyclohexylmethane (7 mg, 0.024 umol), K3PO4 (120 mg, 0.60 mmol), Tris(dibenzylideneacetone)dipalladium(0)(10 mg), water (1 mL) and 1,4-dioxane (4 mL) was stirred under N2 at 100° C. for 16 h. The reaction was then allowed to cool to rt and the mixture was diluted with water and dichloromethane, the aqueous layer was extracted with dichloromethane. The organic layers were dried with Na2SO4 and evaporated. The residue was purified by preparative-HPLC (Instrument: Gilson 215; Column: Gemini C18 10 u 150*25 mm; Mobile phase A: Water (0.0225% HCl v/v); Mobile phase B: Acetonitrile (neutral); Gradient: 42-62 (B %); Flowrate: 25 ml/min) The collected fractions were combined and lyophilized to give 1-(sec-butyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-6-(pyridine-3-yl)-1H-indole-3-carboxamide as a yellow solid (3.2 mg, yield 5.7%). LCMS (M+H+) m/z: calcd 458.23. found 459.0. 1H NMR (400 MHz, CD3OD): δ9.25 (s, 1H), 8.98 (d, J=8.4, 1H), 8.80 (d, J=5.6, 1H), 8.18 (t, J=5.6, 1H), 8.05 (s, 1H), 7.97 (d, J=8.0, 1H), 7.60 (d, J=8.4, 1H), 6.86 (s, 1H), 4.64 (m, 1H), 4.62 (s, 2H), 4.13 (s, 3H), 2.73 (s, 3H), 2.53 (s, 3H), 2.30 (m, 1H), 2.03-2.10 (m, 1H), 1.71 (d, J=6.8, 3H), 0.77 (t, J=7.6, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O:20][C:21](=O)[C:22](OCC)=[O:23])C.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:22]([OH:23])[C:21]1=[O:20]
Reactant: O=C(Cc1ccccc1)Nc1ccccc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1C(O)=C(c2ccccc2)C(=O)N1c1ccccc1Cl
Reaction time: 3 h

Procedure:
After the addition of anhydride THF (20 ml) to compound 5b (1.40 g, 7.34 mmol), the temperature was adjusted to 0° C. Diethyloxalate (1.45 g, 9.50 mmol) and potassium t-butoxide (1.35 g, 11.9 mmol) were added thereto and the agitation for 3 hours was carried out. After the identification of the reaction progress with TLC, the solution was poured into the distilled water and acidified with 1N HCL aqueous solution. Three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, crude purification was carried out by the column chromatography (EA/HX, ⅕).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:31]([NH:33][CH2:34][CH3:35])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][C:38]=1[N:39]1[CH2:40][CH2:41][N:42]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:43][CH2:44]1)[C:31]([NH:33][CH2:34][CH3:35])=[O:32]
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 26 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (154 mg, 0.613 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (179 mg, 0.735 mmol) and 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (186 mg, 0.613 mmol) and DIEA (321 μl, 1.838 mmol). The vial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (80 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 8.43 (t, J=5.6 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.6, 2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.7, 3.2 Hz, 1H), 3.40 (s, 2H), 3.18-3.30 (m, 2H), 2.90-3.16 (m, 5H), 2.67-2.85 (m, 3H), 2.52 (br. s., 4H), 2.45 (dd, J=13.5, 1.6 Hz, 1H), 1.10 (t, J=7.2 Hz, 3H). [M+H] calc'd for C24H29ClN6O2S, 501. found, 501.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]([NH:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:36]([O:35][C:33](=[O:34])[NH:40][CH2:41][CH2:42][CH2:43][C:44](=[O:45])[NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]-undec-7-ene (1.8 g, 11.8 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.4 g, 4.5 mmol) in DMF (50 mL). After stirring for 10 minutes, 1-hydroxbenzotriazole (0.7 g, 5.4 mmol) and N—BOC-γ-aminobutyric acid (1.1 g, 5.4 mmol) were added. The reaction was initiated by addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.3 g, 6.8 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with EtOAc (50 mL) and H2O (40 mL) for 30 minutes. The mixture was filtered, and dried to give (3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl-carbamic acid t-butyl ester (1.6 g, 77%) as a white solid: mp 199-201° C.; 1H NMR (DMSO-d6) δ 1.37 (s, 9H, 3CH3), 1.58-1.66 (m, 2H, CH2), 1.99-2.16 (m, 3H), 2.36-2.49 (m, 1H), 2.58-2.64 (m, 1H), 2.86-2.94 (m, 3H), 4.31 (d, J=5.6 Hz, 2H, CH2), 4.38 (d, J=17.3 Hz, 1H), 4.46 (d, J=17.3 Hz, 1H), 5.10-5.18 (dd, J=5.0 and 13.1 Hz, 1H, CH), 6.81 (t, J=5.4 Hz, 1H, NH), 7.48-7.64 (m, 3H, Ar), 8.37 (t, J=5.7 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 25.72, 28.23, 31.18, 32.63, 38.95, 46.15, 51.56, 77.04, 121.60, 128.27, 130.55, 131.61, 134.70, 140.06, 155.55, 168.04, 170.97, 171.90, 172.82; Anal. calcd. for C23H30N4O6: C, 60.25; H, 6.59; N, 12.22. Found: C, 60.12; H, 6.55; N, 12.15.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][S@@](C(C)(C)C)=O)[CH3:8].[ClH:16].O1CCOCC1>CO>[ClH:16].[ClH:16].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH2:9])[CH3:8]
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid ((R)-1-pyridin-2-yl-ethyl)-amide (1.10 g, 4.86 mmol) in MeOH (12 mL) was added 4.0 M hydrogen chloride in dioxane (3.04 mL, 12.1 mmol). The reaction mixture was stirred at room temperature for 30 min then concentrated and dried under high vacuum to afford 1.0 g of (R)-1-pyridin-2-yl-ethylamine dihydrochloride as a light yellow solid. 1H NMR (METHANOL-d4, 300 MHz): δ (ppm) 8.80 (t, J=3.8 Hz, 1H), 8.32 (tdd, J=7.9, 4.5, 1.7 Hz, 1H), 7.88 (dd, J=7.9, 4.5 Hz, 1H), 7.72-7.83 (m, 1H), 4.78 (qd, J=6.9, 4.5 Hz, 1H), 1.73 (dd, J=6.9, 4.5 Hz, 3H). Assume 82% ee based on 10:1 dr of the starting material.
Reaction SMILES: Cl.C(O[C:5](=[NH:37])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:22][N:21]=[C:20]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])[C:19]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:18]=4[C:17]=3[N:36]=2)=[CH:8][CH:7]=1)C.[CH3:38][CH:39]1[CH2:44][NH:43][CH2:42][CH:41]([CH3:45])[NH:40]1>C(O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:18]2[C:17]3[N:36]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([C:5]([N:43]5[CH2:42][CH:41]([CH3:45])[NH:40][CH:39]([CH3:38])[CH2:44]5)=[NH:37])=[CH:7][CH:8]=4)[N:14]=[CH:15][C:16]=3[CH2:22][N:21]=[C:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:19]=2[CH:31]=1
Reactant: CC1CNCC(C)N1
Reactant: CCOC(=N)c1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)cc1
Agent: Cl
Solvent: CCO
Product: CC1CN(C(=N)c2ccc(Nc3ncc4c(n3)-c3ccc(Cl)cc3C(c3c(F)cccc3F)=NC4)cc2)CC(C)N1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
A mixture of the ethyl benzimidate (100 mg, 0.17 mmol), 2,6-dimethylpiperazine (200 mg, 8.8 mmol), and absolute ethanol (1 mL) was submitted to microwave irradiation (300 W) for 7.5 minutes at 120° C. The reaction solution was cooled to room temperature and slowly poured into a stirring saline solution (10 mL). The resulting precipitate was collected and purified by column chromatography (silica gel, 0.25% NH4OH/2% MeOH/97.75% CH2Cl2 to 2.5% NH4OH/20% MeOH/77.5% CH2Cl2) to yield I-251 as a pale yellow solid (30 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.O>CCO.[Pd]>[CH3:9][C:7]1[C:5]2[NH:6][C:14](=[O:16])[NH:10][C:4]=2[CH:3]=[C:2]([CH3:1])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Reaction time: 3 h

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10% Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 3 h, then filtered through a celite pad and concentrated in vacuo. The crude solid was dissolved in CH3CN (200 mL) and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirred for 1 h, then H2O (200 mL) was added slowly and stirring was continued for 1 h. The precipitate was isolated by filtration and dried to give the title compound. MS: m/z=163 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([OH:14])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C12CC3CC(C1)C(O)C(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A stirred solution of 4-oxoadamantane-1-carboxylic acid (4.42 g, 22.8 mmol) in MeOH (100 mL) was cooled in an ice bath and NaBH4 tablets (4×1 g, 106 mmol) were added at 15 min intervals. The ice bath was allowed to melt and the mixture was stirred overnight at rt and concentrated under reduced pressure. The residue was diluted with 5% aq HCl (100 mL) and extracted with ether (2×125 mL). The combined ether extracts were dried over MgSO4 and concentrated to give 4-hydroxyadamantane-1-carboxylic acid (4.47 g, quant) as an off-white solid which was used directly.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:14]Br>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[Br:14])([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cccc2ccccc12
Product: O=[N+]([O-])c1cccc2c(Br)cccc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-nitronaphthalene (10.0 g, 58 mmol) and FeCl3 (0.066 g, 0.41 mmol) was heated to 90° C. To the solution was added dropwise bromine (3.0 mL, 58 mmol) (no any solvent was used for this reaction). The reaction mixture was stirred at 90° C. for 2 hrs. After cooling down to room temperature, the mixture was recrystallized from ethanol to give compound A as a yellow needle crystal (7.3 g, 50%). mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=8.7 Hz, 1H), 8.34 (d, J=8.7 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.56 (t, J=8.1 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.2, 133.6, 132.7, 131.8, 129.6, 126.4, 125.7, 124.6, 123.7, 123.0. EI-MS (m/z) Calcd. for C10H6BrNO2:251 (M+), Found: 251.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[CH2:21]([OH:26])[CH:22]([OH:25])[CH:23]=[CH2:24].I[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1>CN(C=O)C.O>[OH:26][CH2:21][C:22](=[O:25])[CH2:23][CH2:24][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1
Reactant: C=CC(O)CO
Reactant: Cc1ccc(I)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CCC(=O)CO)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
To a stirred solution of Pd (OAc)2 (40 mg, 0.18 mmol), nBu3P (71 mg, 0.35 mmol), and Et3N (232 mg, 2.29 mmol) in DMF (5 ml) was added 3-butene-1,2-diol (155 mg, 1.76 mmol) followed by 4-iodotoluene (500 mg, 2.29 mmol), and the reaction mixture was stirred at 100° C. for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (10 g) column chromatography eluting with toluene/ethyl acetate (50:1) to give 1-hydroxy-4-(p-tolyl)butan-2-one (230 mg, 73.4%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:14][C@H:15]1[CH2:21][S:20][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][N:17]([CH2:28][C:29]([OH:31])=[O:30])[C:16]1=[O:32])[C:9]([O:11]CC)=[O:10].Cl>[OH-].[Na+]>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:14][C@H:15]1[CH2:21][S:20][C@H:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][N:17]([CH2:28][C:29]([OH:31])=[O:30])[C:16]1=[O:32])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)[C@H](CCCCCCN)N[C@H]1CS[C@H](c2ccccc2)CN(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCC[C@H](N[C@H]1CS[C@H](c2ccccc2)CN(CC(=O)O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
59.0 mg rel-α-{6(R)-[7-amino-1(S)-ethoxycarbonylheptylamino]-5-oxo-3(R)-phenylperhydro-1,4-thiazepin-4-yl]acetic acid (prepared as described in Example 8) were dissolved in 1.0 ml of a 0.5N aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was adjusted to a pH value of 4.5 by the addition of 1N aqueous hydrochloric acid and was then concentrated by evaporation under reduced pressure to precipitate 45 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21]([C:23]3[S:24][C:25]([C:28]([O:30]C)=[O:29])=[CH:26][CH:27]=3)=[O:22])[CH3:18])[C:13]([CH3:32])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14](=[C:17]([NH:19][NH:20][C:21]([C:23]3[S:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)=[O:22])[CH3:18])[C:13]([CH3:32])=[N:12]2)=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C(C)(C)C)cc3)N=C2C)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=NN(c2ccc(C(C)(C)C)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)O)s1
Yield: 46.8 %

Procedure:
14.9 mg (0.033 mmol) of 5-methoxycarbonyl-2-thiophenecarboxylic acid N′-(1-(1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide in 1.5 mL of methanol was stirred with 164 μL (0.164 mmol) of 1M aqueous sodium hydroxide at room temperature for 17 hours. After the stirring, 164 μL (0.164 mmol) of 1M hydrochloric acid was added, and the precipitated solid was collected by filtration to obtain 6.8 mg of the desired product as a pale yellow solid (yield 47%).