Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH2:4]([O:6][P:7]([C:12]([F:26])([F:25])[CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:5]>C(Cl)Cl>[CH2:4]([O:6][P:7]([C:12]([F:26])([F:25])[CH2:13][NH2:14])(=[O:11])[O:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCOP(=O)(OCC)C(F)(F)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrazine monohydrate was added to a methylene chloride solution of diethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate, for stirring at ambient temperature for one hour, to obtain diethyl(2-amino-1,1-difluoroethyl)phosphonate.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Brc1ccc(Br)nc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Yield: 18.2 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (3 g; 7.3 mmol) in 7 ml of dioxane was treated under nitrogen with 2,5-dibromopyridine (1.9 g; 8.1 mmol) and DIEA (1.4 ml; 8.1 mmol) and heated in a pressure tube for 2 days at 210C. Upon cooling, additional DIEA (1.4 ml) was added and heated 2 more days. Upon cooling, the reaction mixture was partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl and saturated brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography using an ethyl acetate-hexane gradient (5–60%) afforded the title compound (0.75 g; 18% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:18][N:17]=1)([O-])=O.C(O)(=O)C>ClCCl.[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([N:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Yield: 83.2 %

Procedure:
Into a 100-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridin-4-yl(3-(trifluoromethyl)benzyl)carbamate (760 mg, 1.37 mmol, 1.00 equiv) in dichloromethane (10 mL), and Zn (500 mg). This was followed by dropwise addition of acetic acid (0.7 mL) with stirring. The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The solids were removed by filtration. The solution was adjusted to pH 8-9 with NaHCO3 (aq). The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The product was obtained as 600 mg (83%) of a black solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([N+:12]([O-])=O)[CH:7]=[CH:8]2)=[N:3]1.[Sn](Cl)(Cl)(Cl)Cl.Cl.CCOCC>COCCOCCOC>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH2:12])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Cc1c2ccc(N)cc2nn1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2,3-dimethyl-6-nitro-2H-indazole (0.48 g, 2.5 mmol, 1 equiv) was dissolved in 2-methoxyethylether (4.3 ml) with heating then cooled down to 0° C. Tin chloride (1.6 g, 7.1 mmol, 2.8 equiv) was added under nitrogen. Concentrated HCl (3.2 ml) was added dropwise keeping the temperature below 5° C. When all the HCl was added, the reaction was allowed to warm up to room temperature and stirred for 45 min. Ether (14 ml) was added and a precipitate was collected too yield the desired product as an hydrochloride salt (0.35 g, 86.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 6-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.330 g (37%) of a colorless foam. FDMS m/e=407 (M+ of free base).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([CH2:10][OH:11])=[N:8][N:9]=1.O.[C-]#[N:20].[Na+]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[C:3]=1[CH2:4][C:5]1[N:6]([CH3:12])[C:7]([C:10]([NH2:20])=[O:11])=[N:8][N:9]=1
Reactant: Cn1c(CO)nnc1Cc1c(F)cccc1F
Reactant: [C-]#N
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(Cc2c(F)cccc2F)nnc1C(N)=O
Reaction time: 4 h

Procedure:
1.43 g (6 mmol) of 5-(2,6-difluorobenzyl)-3-hydroxymethyl-4-methyl-4H-1,2,4-triazole and 5.22 g (60 mmol) of manganese dioxide are heated under reflux in 40 ml of toluene for 3 hours using a water separator. The reaction mixture is then cooled and filtered over Hyflo, and the filtrate is concentrated by evaporation. The residue is added to 90 ml of isopropanol saturated with ammonia. At 0°, 1.47 g (30 mmol) of sodium cyanide and 10.44 g (120 mmol) of manganese dioxide are added. The reaction mixture is stirred for 4 hours at 0° and filtered over Hyflo. The filtrate is concentrated by evaporation. Recrystallisation of the residue from ethanol yields the pure 5-(2,6-difluorobenzyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>C(Cl)Cl>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Reactant: C=C(C)OC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S, 2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2Cl2 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2Cl2 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+260.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5](Br)[CH2:6][N:7]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:8][CH:9](Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:34]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(Br)CN(CC(Br)C(=O)OCC)S(=O)(=O)c1ccccc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccccc2)CC(C(=O)OCC)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
To a solution of (SR)-3-[benzenesulfonyl-((SR)-2-bromo-2-ethoxycarbonyl-ethyl)-amino]-2-bromo-propionic acid ethyl ester (CAS 58661-68-0) (13.8 g, 26.8 mmol) in toluene (54 ml) was added benzylamine (8.81 ml, 80.4 mmol) and the mixture was stirred at 90° C. for 1.5 h. Cooled to 23° C., filtered the solid off, washed with toluene and the filtrate was evaporated to leave a crude product which was purified by silica gel column chromatography with tert-butyl methyl ether and n-heptane 3:7 to give the title compound as light yellow crystals (7.0 g, 57%), MS (ISP) m/e=461.2 [(M+H)+].
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:40]=[CH:39][CH:38]=[CH:37][C:31]=1[CH:32]=[CH:33][C:34](O)=[O:35])([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][CH:39]=[CH:40][C:30]=1[N+:27]([O-:29])=[O:28])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1ccccc1[N+](=O)[O-])C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 42 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 2-nitrocinnamic acid under the conditions described in example 86 to yield 42% of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:13]2[C:14]([CH3:20])([CH2:17][CH2:18][CH3:19])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:35]4[C:31](=[O:37])[CH2:32][CH2:33][C:34]4=[O:36])[CH2:6][CH2:7]3)[N:12]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: CCCC1(C)C(=O)N(C2CCN(C(=O)CCl)CC2)N=C1c1ccc(OC)c(OC)c1
Reactant: O=C1CCC(=O)N1
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)CN3C(=O)CCC3=O)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4-methyl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound A8) and succinimide as starting compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8]1=[O:25].[CH:31]1[N:35]=[CH:34][N:33]([C:36](N2C=NC=C2)=O)[CH:32]=1>C(#N)C>[CH3:34][N:33]([CH3:36])[CH2:32][CH2:31][NH:35][C:17]([C:15]1[C:14]2[N:13]=[C:12]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:11]3=[CH:10][C:9]=2[C:8](=[O:25])[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=1)=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cn2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Solvent: CC#N
Product: COc1ccc(Cn2cc(C(=O)NCCN(C)C)c3nc4c(C)cccc4cc3c2=O)cc1OC
Yield: 85 %

Procedure:
From acid 18r with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a yellow solid (85%), mp 213-214° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.22 [s, 6H, N(CH3)21, 2.52 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.63 (s, 3H, ArCH3), 3.62 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 5.09 (s, 2H, CH2Ph), 6.74 (d, J=8.5 Hz, 1H, H-5′), 6.90-6.92 (m, 2H, H-2′, H-6′), 7.27 (t, J=7.6 Hz, 1H, H-8), 7.49 (d, J=6.8 Hz, 1H, H-7), 7.61 (d, J=8.1 Hz, 1H, H-9), 8.55 (s, 1H, H-3), 8.99 (s, 1H, H-10), 10.70 (br t, J=5.3 Hz, 1H, CONH). 13C NMR (CDCl3) δ 18.2 (ArCH3), 37.4 (CH2CH2NMe2), 45.2 (N(CH3)2], 51.9 (CH2Ph), 55.6 (OCH3), 55.7 (OCH3), 58.6 (CH2CH2NMe2), 109.6 (C-4), 111.1 (CH, C-5′), 111.5 (CH, C-6′), 119.1 (C-10a), 120.9 (CH, C-2′), 125.4 (C-9a), 126.2 (CH, C-8), 126.9 (CH, C-9), 128.2 (C-1′), 132.4 (CH, C-7), 135.5 (C-6), 139.5 (CH, C-10), 142.3 (CH, C-3), 147.6 (C-5a), 148.2 (C-4a), 148.9 (C-4′), 149.1 (C-3′), 162.1 (C-1), 164.1 (CONH).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1)C.C(=O)(O)O.[NH2:32][C:33]([NH2:35])=[NH:34].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:34]=[C:33]([NH2:35])[N:32]=[CH:4][C:5]=4[CH2:6]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(COc2ncccc2N2CCC(=O)C(=CN(C)C)C2)cc1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ncccc2N2CCc3nc(N)ncc3C2)cc1

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (673 mg, 1.83 mmol) in ethanol (100 ml) was treated with guanidine carbonate (1.32 g, 7.33 mmol), followed by addition of sodium acetate trihydrate (1.99 g, 14.64 mmol) and the reaction mixture was refluxed for 21 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The separated organic layer was dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 6% methanol in EtOAc) gave the title compound as a light yellow, amorphous solid (477 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([CH3:28])[C:20]=1[CH2:21]Br.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:21][C:20]2[C:19]([CH3:18])=[CH:26][C:25]([F:27])=[CH:24][C:23]=2[CH3:28])[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=1
Reactant: CCOC(=O)c1c(C)nc2c(N)cc(Br)cn12
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cc(Br)cn12
Yield: 59.1 %

Procedure:
A mixture of 8-amino-6-bromo-3-carboethoxy-2-methylimidazo[1,2-a]pyridine (2.06 g, 6.91 mmol), 2,6-dimethyl-4-fluorobenzylbromide (1.05 g, 4.48 mmol), sodium iodide (0.45 g), sodium carbonate (2.2 g) and acetone (40 ml) was refluxed for 22 h. The reaction mixture was filtered. The filtered material was washed with CH2Cl2. The methylene chloride solution was washed with water, dried and evaporated in vacuo. The residue was suspended in ethanol/ether and filtered to give 1.15 g (56%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].ON1C2C=CC=CC=2N=N1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=3)=[O:17])[CH:13]=2)=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCc3ccc(Cl)cc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A flask was charged with 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (48.9 mg, 0.18 mmol), 1-hydroxybenzotriazole (HOBT, 39.7 mg, 0.294 mmol), 2.00 mL of tetrahydrofuran, 4-chlorobenzylamine (28.2 mg, 0.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (66.2 mg, 0.353 mmol). The reaction was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed sequentially saturated aqueous NaCl, saturated aqueous sodium carbonate, 1.0 M aqueous hydrochloric acid, and saturated aqueous sodium bicarbonate The organic layer was dried over sodium sulfate, filtered, and concentrated on a rotary evaporator under reduced pressure. The crude product was purified by chromatography on silica gel using EtOAc as the eluent. After concentration, the product was triturated in 5% ethyl acetate in hexanes. The solid product was filtered, and after drying afforded 3-amino-6-[3-({[(4-chlorophenyl)methyl]amino}carbonyl)phenyl]-N-methylpyrazine-2-carboxamide (39.8 mg, 50% yield). 1H NMR (400 MHz; DMSO-d6): 9.15 (m, 1H); 8.87 (s, 1H); 8.80 (m, 1H); 8.50 (s, 1H); 8.35 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.37 (m, 2H); 4.51 (d, 2H); 2.83 (s, 3H): MS (EI) for C20H18N5O2Cl: 396 (MH+).
Reaction SMILES: [C:1]12([C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][C:4]([C:9]([O:11][CH3:12])=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+]>CO.O>[CH3:12][O:11][C:9]([C:4]12[CH2:7][CH2:8][C:1]([C:13]([OH:15])=[O:14])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:10]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Yield: 56 %

Procedure:
A solution of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (58.0 g, 0.25 mol) in methanol (600 mL) was heated to reflux and then a solution of potassium hydroxide (9.8 g, 0.175 mol) in methanol (100 mL) and water (12 mL) was added over 30 min. The reaction mixture was refluxed for 24 h and concentrated. The residue was diluted with water and extracted with ethyl acetate (200 mL×2) to recover some starting material (22.0 g). The resulting aqueous layer was acidified to pH=3 by addition of hydrochloric acid and extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the titled product (30.0 g, 0.14 mol, yield 55%). 1H NMR (400 MHz, CDCl3) δ ppm 3.65 (s, 3H), 1.81 (s. 12H); MS (ESI) m/z=211.3 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][NH:10][C:4]=2[C:3]=1[I:11].[H-].[Na+].S(OC)(O[CH3:18])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH3:18])[C:4]=2[C:3]=1[I:11]
Reactant: Clc1ncc2cc[nH]c2c1I
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cnc(Cl)c(I)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 6-chloro-7-iodo-1H-pyrrolo[3,2-c]pyridine (600 mg, 2.15 mmol) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride (130 mg, 3.25 mmol) under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0° C., and then thereto was added dropwise dimethyl sulfate (250 μL, 2.64 mmol). Then, the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and then the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→75:25) to give 6-chloro-7-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (540 mg, 86%) as a colorless powder.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][CH3:6]>C(Cl)(Cl)Cl>[Br:1][C:9]1[S:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CCCCc1cccs1
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Bromine, 5 ml (15.63 g or 0.0977 mol), was added to a solution of 15.2 g (0.108 mol) of 2-butylthiophene in 400 ml of chloroform. Following the addition, the mixture was stirred for 10 minutes at room temperature and was then washed with 10% aqueous sodium carbonate solution. The organic layer was separated, dried and evaporated and the remaining oil was distilled under high vacuum to yield a colorless oil. Nmr (CDCl3): 0.89 ppm (t, 3, J=7.5 Hz, CH3). 1.2-1.7 (m, 4, CH2CH2), 2.7 (t, 2, J=7.5 Hz, CH2). 6.47 (d, 1, J=4 Hz. C4-H), 6.78 (d, 1, J=4 Hz. C3-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C@@H:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:25][C@H:26]([C:31](O)=[O:32])[C@H:27]([CH2:29][CH3:30])[CH3:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([NH:25][C@@H:26]([C@@H:27]([CH3:28])[CH2:29][CH3:30])[C:31]([NH:17][C@H:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:32])([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC(C)C[C@H](N)C1(c2ccc(Cl)cc2)CCC1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
By similar method as example 2, resolved (S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II-S) (250 mg) was condensed with Boc-L-isoleucine (210 mg) to give the title compound (2S,3S)-2-(Boc-amino)-N-{(S)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]>O>[OH:4][C@@H:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Product: CCOC(=O)C[C@H](C)O
Yield: 80 %

Procedure:
Ethyl acetoacetate (130 mg, 1 mmol) was reacted with yeast (2 g) and water (2 ml) according to method I. Extraction of the yeast gave the pure product in 80% yield. The reaction was repeated following the general procedure of Method II outlined above to yield a pure product in 78% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(O)c1cccc(O)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)c1cccc(OCCCBr)c1

Procedure:
A solution of ethyl 3-hydroxymandelate (10.0 g), 1,3-dibromopropane (41.16 g) and potassium carbonate (8.08 g) in dry DMF (150 mL) was stirred at 40° C. overnight. The reaction mixture was partitioned between ethyl acetate and 1.0 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was then filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel, using a gradient of 100% hexane to methylene chloride-hexane to yield the titled compound.