Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>CC(C)=O>[OH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:24]2[CH2:25][C@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A 5 ml acetone solution of 260 mg of tert-butyl {[(3R,4S)-1-(4-hydroxybenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate obtained from tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 4-hydroxybenzoic acid, by amidation in the same manner as in Reference Example 19, was mixed with 130 mg of potassium carbonate, and then the reaction solution was mixed with 0.1 ml of ethyl bromoacetate and heated under reflux for 3 hours. After cooling down to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of ethyl (4-{[(3R,4S)-3-({(tert-butylcarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate a colorless amorphous substance. FP: 637.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([NH:17][O:18]C3CCCCO3)=[O:16])[CH:11]=2)[CH2:6]1)=[O:4]>CO.Cl>[OH:18][NH:17][C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][N:5]([C:3]([NH:2][CH3:1])=[O:4])[CH2:14][CH2:13]2)=[O:16]
Reactant: CNC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: CNC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Reaction time: 16 h
Yield: 103.3 %

Procedure:
A mixture of 110 mg N2-methyl-N6-(tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide in 4 ml methanol and 6 ml 0.1M aqueous HCl is stirred for 16 h and evaporated. The residue is dissolved in acetonitrile and water and lyophilized. 85 mg of colorless foam are obtained. MH+=250.2
Reaction SMILES: [F:1][C:2]([P:8]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:13])[O:9][CH2:10][C:11]#[CH:12])([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCCC>[F:7][C:2]([P:8]([C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])(=[O:9])[O-:13])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:21][N+:22]1([CH2:10][C:11]#[CH:12])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CCCC1
Reactant: C#CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Product: C#CC[N+]1(C)CCCC1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Propargyl bis(pentafluoroethyl)phosphinate (6.44 g; 18.9 mmol) is added to cooled (0° C.) N-methylpyrrolidine (1.60 g; 18.7 mmol) in a 25 ml glass flask. In an exothermic reaction, a yellow solid forms spontaneously. This is suspended in n-hexane (12 ml), stirred at 0° C. for 30 minutes, warmed (room temperature), diluted with further n-hexane (8 ml) and stirred at room temperature for 17 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at 50° C. 1-Methyl-1-propargylpyrrolidinium bis(pentafluoro-ethyl)phosphinate, [CH≡CCH2MPL][(C2F5)2P(O)O], (7.47 g; 17.6 mmol) is isolated as pale-beige solid in a yield of 94% and a purity of 98%.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C(OC(=O)[C@H](C(C)C)N)(C)(C)C.C([O:53][C:54](=[O:61])[C@H:55]([CH2:57][C:58](=[O:60])[NH2:59])[NH2:56])(C)(C)C>>[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33]([NH:56][C@@H:55]([CH2:57][C:58]([NH2:59])=[O:60])[C:54]([OH:61])=[O:53])(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Agent: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: NC(=O)C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-asparagine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-succinamic acid is obtained; mp 165-175° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOC(C)=O.CCCCCCC>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Yield: 90.6 %

Procedure:
A solution of lithium aluminum hydride (1.40 g, 36.9 mmol) in tetrahydrofuran (15.0 mL) and a solution of 3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.40 g, 3.82 mmol) in tetrahydrofuran (30.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give an oil. Column chromatography (silica gel, 20-30% EtOAc/heptane) afforded 1.22 g (90%) of the title compound as a white solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 7.74, 7.63-7.61, 7.48, 7.45-7.40, 7.36, 3.84, 3.00-2.92; 13C NMR (100 MHz, CDCl3) δ 142.5, 139.3, 136.9, 135.2, 134.5, 128.9, 128.6, 128.5, 128.3, 127.3, 127.0, 126.4, 119.1, 117.8, 112.8, 108.8, 60.7, 55.7, 53.8, 28.6, 23.9; IR (drift) 3385, 3371, 1467, 1344, 1328, 1120, 1027, 870, 820, 765, 756, 750, 735, 728, 698 cm−1; MS (EI) m/z 352 (M+); Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.24; H, 6.89; N, 8.05.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:15][C:11]([S:10][C:7]1[S:8][CH:9]=[C:5]([CH2:4][C:1]([N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:3])[N:6]=1)([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: CNc1ccccc1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Product: CN(C(=O)Cc1csc(SC(C)(C)C(=O)O)n1)c1ccccc1

Procedure:
The title yellow resin (2.0 g) was obtained using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and N-methylaniline (0.52 ml) as starting materials and by an operation similar to that of Example 461-5.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CC[N:29]=C=NCCCN(C)C.[N+:38]([C:41]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:42]=1N)([O-:40])=[O:39].CC(C)=O.ClCCl>CN(C1C=CN=CC=1)C.ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19]([NH:29][C:46]4[CH:47]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=[CH:44][C:45]=4[O:48][CH3:49])=[O:21])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1onc2c1c(=O)n(-c1cccc(CC(=O)O)n1)c1cccc(Cl)c21
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)Cc1cccc(-n2c(=O)c3c(C)onc3c3c(Cl)cccc32)n1
Yield: 11.5 %

Procedure:
[6-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-pyridin-2-yl]-acetic acid (0.075 g, 0.2 mmol), EDCI (0.055 g, 0.3 mmol), 2-Nitro-5-methoxyaniline (0.044 g, 0.26 mmol), DMAP (0.005 g, 0.04 mmol) in dichloromethane (4.5 ml) and DMF (0.75 ml) react for 5 h in a fashion similar to that of Example 3. Column chromatography (silica gel, acetone/dichloromethane gradient) gives the title compound (0.012 g, 12%). Mass Spectrum (FIA) (m/z) 520.2 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C@@H:43]([NH2:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:53]#[C:54]Br.[C:56]1([CH3:66])[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[CH:58][CH:57]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][C@@H:43]([N:45]([C:54]#[N:53])[S:62]([C:59]3[CH:60]=[CH:61][C:56]([CH3:66])=[CH:57][CH:58]=3)(=[O:64])=[O:63])[CH3:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: N#CBr
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](C[C@H](C)N)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](C[C@H](C)N(C#N)S(=O)(=O)c4ccc(C)cc4)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 399 mg of (S)-2-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethylamine in 5 ml of dichloromethane are added 0.12 ml triethylamine and 66 mg of cyanogenbromide at room temperature. The reaction mixture is stirred for 2 hours, followed by the addition of 0.32 ml of triethylamine, 178 mg of 4-toluenesulfonyl chloride and 7 mg of 4-N-dimethylaminopyridine. The reaction mixture is heated to 50° C. for 4 hours and subsequently washed with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phases are combined, dried and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.16 (EtOAc-heptane 1:1); Rt=−5.71.
Reaction SMILES: [In:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[In+3:1].[N+:2]([O-:5])([O-:4])=[O:3].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: [In]
Product: O=[N+]([O-])[O-]
Product: [In+3]

Procedure:
Metallic indium of 4N (99.99%) purity was dissolved in hot nitric acid to obtain a solution of indium nitrate. The solution was diluted to have a concentration of In of 100 g/L. Maintaining the solution of indium nitrate at a temperature in the range of 35-40° C., ammonium carbonate as a neutralisation precipitant was added thereto in an amount 1.5 times the equivalent weight to obtain a precipitate, which was separated from the solution and washed by using a filter press, and the precipitate was dried in an air atmosphere at 150° C. for 15 hours, followed by crushing the dried product with a hammer mill.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:12])=[O:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 22 %

Procedure:
A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight. The mixture was filtered through a pad of diatomaceous earth, washing with water. The basic filtrate was acidified to pH˜1 with conc. HCl and extracted with EtOAc (3×300 mL). The combined organic layers were dried (MgSO4) and concentrated to provide the desired benzoic acid (1.22 g, 22%). MS (ESI−): mass calcd. for C7H4BrNO4, 244.9; m/z found, 244 [M−H]−. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9, 1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6]2.CC1(C)COB([C:30]2[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])OC1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C1COCC1>[CH2:15]([O:14][C:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:30]3[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[CH:4]=2)[CH2:8]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@H]1Cc2ccc(CCl)cc2C1)OCc1ccccc1
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NC(=O)OCc2ccccc2)C3)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
To (S)-benzyl 5-(chloromethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (7.09 mmol, 2.24 g) in THF (44.9 mL) was added methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (7.09 mmol, 2.242 g), Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (0.355 mmol, 0.287 g) and sodium carbonate (45.0 mmol, 22.5 mL). The reaction was heated to 80° C. for 4 hrs. DCM was added before washing with water (×1) followed by brine (×1). The organics were dried over MgSO4 before removing the solvent in vacuo. The crude material was purified by silica chromatography (5:1>2:1, hep EtOAc). The solvent was removed to give the title compound as a white solid (2.6 g, 76%). MS (ESI): m/z [M+H]+ 484.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-fluoro-benzenesulfonyl chloride (1.65 g, 0.00848 mol), (R)-2-amino-4-methyl-pentanoic acid (1.233 g, 0.009398 mol), and sodium carbonate (1.91 g, 0.0180 mol) in water (15 mL) was stirred at room temperature for 5 days. The solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH=4. The mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried (MgSO4), and rotary evaporated to a yellow oil. The oil was chromatographed on silica gel (320 g, 230-400 mesh) eluting with dichloromethane-methanol (10:1, 10×300 mL). Fractions containing product were combined and rotary evaporated to give a pale yellow oil. The oil was dried in vacuo; yield 1.44 g (59%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(OCC)(=O)C.O.[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](/[CH:26]=[CH:27]/[C:28]3[O:32][CH:31]=[CH:30][CH:29]=3)=O)=[CH:20][CH:19]=2)=[CH:13][CH:12]=1>CS(C)=O>[O:32]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:27]1[N:2]([CH3:1])[N:3]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:14]3[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=3)=[CH:19][CH:20]=2)[CH:26]=1
Reactant: CNN
Reactant: O=C(/C=C/c1ccco1)c1ccc(Oc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2ccc(Oc3ccccc3)cc2)cc1-c1ccco1
Temperature: 85 °C

Procedure:
In an open vial, 3-furan-2-yl-1-(4-phenoxy-phenyl)-propenone (0.4 g) was dissolved in dimethylsulfoxide (10 mL). Methylhydrazine (1.0 g) was added and the reaction mixture was heated to 85° C. for 3 days. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was washed twice with water (25 mL), then separated and dried over sodium sulfate. The solvent was removed after filtering away the drying agent. Purification by column chromatography (silica, eluted with ethyl acetate-hexanes, 1:9) gave the desired pyrazole in moderate yield (0.1 g).
Reaction SMILES: C(O[C:6]([N:8]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)C)=O)(C)(C)C.[ClH:19]>>[ClH:19].[CH3:6][NH:8][N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)N1Cc2ccccc2C1
Agent: Cl
Product: CNN1Cc2ccccc2C1
Reaction time: 1 h

Procedure:
To the crude N-(t-butyloxycarbonyl-N-methylamino)dihydroisoindole from the above preparation was added 25 ml of concentrated hydrochloric acid. The reaction mixture was allowed to stir for one hour. Evaporation of the mixture to dryness and recrystallization of the residue from ethanolether gave 5.6 g of the desired product as a gummy solid, mp: 79°-89°. The IR and NMR were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:26]=[N:25][CH:24]=[CH:23][C:11]=1[C:12]([NH:14][NH:15]C(OC(C)(C)C)=O)=[O:13].C(O)(C(F)(F)F)=O.C(Cl)[Cl:35]>>[ClH:35].[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:26]=[N:25][CH:24]=[CH:23][C:11]=1[C:12]([NH:14][NH2:15])=[O:13]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NNC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]isonicotinohydrazide hydrochloride was synthesized from tert-butyl 2-{3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}hydrazine-carboxylate (described earlier) by deprotection of the Boc group under acidic conditions (50:50 TFA/DCM). LC/MS [7.11 min; 373 (free base, M+1)]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+].O.CCOC(C)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a stirring solution of methyl 5-chloropicolinate (1 g, 5.8 mmol) in methanol at room temperature under argon was added sodium borohydride (440 mg, 11.57 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under vacuum to obtain a gum. Water (15 mL) and EtOAc (30 mL) were added and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to obtain 840 mg of the title compound as colorless gum. HPLC/MS: retention time=0.755 min, [M+H]+=144.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([O:8][CH3:13])[CH:7]=1
Reactant: Cc1cc(Br)cc(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(C)c1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
5.49 g of 5-bromo-2,3-dimethylphenol (3-17) was dissolved in 100 ml of DMF, to which were added 6.80 g of methyl iodide and 11.32 g of potassium carbonate, and the resulting mixture was stirred at 90° C. for 2 hours. The reaction solution was poured into water, and extracted with ethyl acetate and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=9:1) to obtain 5.35 g of 5-bromo-1-methoxy-2,3-dimethylbenzene (3-18).
Reaction SMILES: N(CCO)(CCO)CCO.Cl.[C:12]([O:20]C(=O)C1C=CC=CC=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>OCC(CO)O.O>[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: OCCN(CCO)CCO
Solvent: OCC(O)CO
Product: O=C(O)c1ccccc1

Procedure:
Standard reaction conditions for the rate determinations in Table 1 are as follows: 60% glycerol/water (w/w), 120 ppm hardness (2:1 Ca:Mg), 10 mM Triethanolamine adjusted to pH 7 with HCl, and 50 umol benzoic anhydride. All incubations were at -10 deg. centigrade for 5 mins. Benzoic acid produced was measured by HPLC via an internal standard (acenaphthylene).
Reaction SMILES: C1([C@H](N)[C@H](C2C=CC=CC=2)N)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31]>C(O)(C)C>[CH:32]1([C@H:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[OH:31])[CH2:33][CH2:34]1
Reactant: Cc1ccccc1C(=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: N[C@@H](c1ccccc1)[C@@H](N)c1ccccc1
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ccccc1[C@H](O)C1CC1
Reaction time: 60 h
Yield: 71.1 %

Procedure:
To a suspension of dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II) (851 mg), (1S,2S)-(−)-1,2-diphenyethylenediamine (191 mg) and potassium-tert-butoxide (270 mg) in isopropanol (90 ml) was added cyclopropyl 2-methylphenyl ketone (9.61 g) obtained in Step 2, and the mixture was hydrogenated at room temperature and at medium pressure (3.0 kgf/cm2) for 60 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to give the title compound (6.92 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:39][S:36]([O:11][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(NC(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
Benzyl 3-(2-(tert-butyldimethylsilyloxy)-1-hydroxyethyl)phenylcarbamate (4 g) was dissolved in dry DCM (80 mL) and cooled to 0° C. under an argon atmosphere. Triethylamine (5 g) was added, followed by mesyl chloride (3.42 g) added drop-wise over a period of 2 hours. The reaction temp was maintained at 0° C. for further 2 hours. The reaction was quenched by addition of water, extracted into DCM and concentrated under vacuum at a temperature below 25° C. The crude product (3.5 g) was unstable and was used for next step as soon as possible.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1.[CH3:18][N:19]=[C:20]=[S:21].O>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:20]([NH:19][CH3:18])=[S:21])=[CH:13][CH:12]=3)[N:10]=[C:4]2[CH:3]=1
Reactant: CN=C=S
Reactant: Cc1ccn2cc(-c3ccc(N)cc3)nc2c1
Solvent: O
Solvent: CS(C)=O
Product: CNC(=S)Nc1ccc(-c2cn3ccc(C)cc3n2)cc1
Yield: 81.9 %

Procedure:
A solution of 7-methyl-2-(4-aminophenyl)imidazo-[1,2-a]pyridine (14.9 g) and methyl isothiocyanate (6.4 g) in dimethyl sulfoxide (400 ml) was stirred at 50° C. for 10 hours. The reaction mixture was poured into water (1 l) and the resultant precipitate was collected by filtration, washed with water and ethyl acetate successively and dried over phosphorus pentoxide to give 7-methyl-2-[4-(3-methylthioureido)-phenyl]imidazo[1,2-a]pyridine (16.2 g).