Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>>[OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CO
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-hydroxy-4-methylbenzoic acid (20.0 g, 0.132 mol) in methanol (200 ml) was cooled in an ice bath. Concentrated, H2SO4 (20 ml) was added cautiously and the reaction heated to reflux and held at reflux for 48 hours. The reaction was allowed to cool to ambient temperature, the solvent evaporated and the residue purified by chromatography (eluant: CH2Cl2) to give methyl 2-hydroxy-4-methylbenzoate (19.76 g, 90%).
Reaction SMILES: C1C=CC(OP(OC2C=CC=CC=2)([N:10]=[N+:11]=[N-:12])=O)=CC=1.[Si:20]([O:27][C@@H:28]([C@H:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[N:34]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:29]([CH3:32])[CH2:30]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N:10]([CH2:30][C@H:29]([CH3:32])[C@H:28]([C@H:33]1[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[N:34]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[N+:11]=[N-:12]
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Diphenylphosphonic azide (1.3 mL, 5.9 mmol) was added to a mixture of tert-butyl (4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.2 g, 3.0 mmol), diisopropyl azodicarboxylate (1.2 mL, 5.9 mmol) and PPh3 (1.6 g, 5.9 mmol) in THF (20 mL). The mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-15% EtOAc in hexanes) to provide the sub-title compound (1.09 g, 86%). LCMS calc. for C15H33N4O2Si (M+H-Boc)+: m/z=329.2. found 329.2.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>O1CCCC1>[N+:1]([C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=1[OH:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(O)cc1
Solvent: C1CCOC1
Product: COc1ccc(O)c([N+](=O)[O-])c1

Procedure:
6.3 9 of nitric acid were added dropwise at room temperature with stirring to 12.4 g of 4-methoxyphenol in 120 ml of tetrahydrofuran. The reaction mixture was then stirred for half an hour. The solvent was subsequently evaporated and the residue remaining was purified by chromatography using dichloromethane as an eluent. 6.2 g of 2-nitro-4-methoxyphenol were obtained as a yellow powder having a melting point of 72° C.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:19])[C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c(Br)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2c(Br)csc12
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 7-bromo-3H-thieno[3,2-d]pyrimid-4-one (126, 0.94 g, 4.1 mmol) in phosphorus oxychloride (4 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 7-bromo-4-chlorothieno[3,2-d]pyrimidine (0.83 g, 82% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide, obtained in Preparation Example 1-(4), (19.06 g) was dissolved in DCM (75 mL). Pyridine (8.6 mL) was added, and the mixture cooled to 0° C. Trifluoromethanesulfonic anhydride (9.6 mL) was added dropwise and the reaction was allowed to stir at 0° C. After 90 min, the reaction was quenched by the careful addition of NaHCO3 (sat., aq., 250 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (0% to 30% EtOAc/hex) to obtain the title compound (14.52 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.76 (m, 1H), 3.07-3.24 (m, 2H), 3.32-3.52 (m, 3H), 3.99-4.11 (m, 1H), 4.53-4.63 (m, 2H), 7.09-7.56 (m, 21H), 8.08-8.30 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[OH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:12][OH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)cc1
Yield: 40.4 %

Procedure:
To a solution of 4-chloro benzonitrile (1.000 g, 7.26 mmol) in ethanol (20 mL) was added hydroxyl amine HCl (0.752 g, 10.90 mmol) and potassium carbonate (3.00 g, 21.80 mmol). The reaction mass was refluxed for 10-12 h. Excess of solvent was removed under vacuum and the residue was diluted with water, acidified with dilute HCl. Precipitate obtained was filtered off and sucked dried to afford 0.500 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.88 (br s, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 9.70 (br s, 1H); MS (m/z): 171.13 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[C:4]1([C:2]2[N:11]=[C:12]([NH2:14])[S:13][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2ccccc2)cs1
Yield: 82.4 %

Procedure:
A mixture of 2 g of phenacylbromide and 0.76 g of thiourea in 50 mL ethanol was refluxed overnight. After solvent evaporation, the residue was redissolved in 50 mL DCM and treated by 50 mL of a 2% sodium carbonate solution in water. The organic layer was dried and evaporated to yield 1.45 g (82%) of 4-phenyl-2-thiazolamine (intermediate p. Mass spectral data: m/z=177 (M+H).
Reaction SMILES: [CH3:1][C:2]1OC([Si](C)(C)C)=[CH:4][C:3]=1C=O.CI.[CH2:15]([Si:17]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:18]1[O:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=1)[CH3:16].ICCCC>>[CH2:1]([C:20]1[O:19][C:18]([Si:17]([CH2:25][CH3:26])([CH2:15][CH3:16])[CH2:27][CH3:28])=[CH:22][C:21]=1[CH:23]=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Solvent: CI
Solvent: CCCCI
Product: CCCCc1oc([Si](CC)(CC)CC)cc1C=O

Procedure:
Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehyde but substituting 2-trimethylsilyl-4-furaldehyde and methyl iodide with 2-triethylsilyl-4-furaldehyde and 1-iodobutane, respectively, gives 5-butyl-2-triethylsilyl-4-furaldehyde. IR (neat) 1690 cm-1; 'HNMR (CDCl3) 0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz), 1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91 (s, 1H) 13CNMR (CDCl3): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6, 122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance) 266 (M+, 20) 238 (20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C15H26O2Si 266.1702, found 266.1690.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-tert-Butoxycarbonylamino-propionic acid (0.5 g, 2.64 mmol) in DCM (5 ml) under an inert atmosphere is treated with 1-hydroxy-7-azabenzatriazole (0.108 g, 0.79 mmol) followed by water soluble carbodiimide (0.491 g, 3.17 mnol) and tert-butylamine (0.305 ml, 2.91 mmol). The reaction mixture is stirred at room temperature for 3 hours and then citric acid (10 ml, 0.5 M) is added to the solution and extracted with DCM (2×10 ml). The combined organic layers are washed with brine (10 ml) and dried over MgSO4. After filtration, the solvent is removed in vacuo to yield the titled compound as an oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCOC(=O)C(C)(C)Br
Agent: [Cu]Br
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,2′-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. ECl and once with NaCl solution. The organic layer was dried over Na2SO4and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[Cl:1][C:2]1[C:7]([NH:10][NH2:11])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1nccnc1Cl
Yield: 90.9 %

Procedure:
2,3-dichloropyrazine (1000 g, 6.7 mol) and hydrazine monohydrate (700 g, 14 mol) were dissolved in absolute ethanol (2 L) and refluxed under N2 overnight. A crystalline precipitate formed, which was collected by filtration, washed with ethanol (1 L), and dried to afford the desired produced as a yellow solid (880 g, 90% yield).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:20])=[CH:14][CH:13]=1.C(OCC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[O:20])=[CH:14][CH:13]=1.[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Solvent: CCOCC
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 8 h

Procedure:
First 0.15 g (0.001 mol) of anhydrous tartaric acid and then 0.39 g (0.001 mol) of trans-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenyl)-cyclohexanol are dissolved in 7 ml of absolute ethanol. Diethyl ether is then added to the clear solution until it becomes slightly cloudy and it is then left to stand for 8 hours at +4° C. The crystalline product precipitated is suction filtered, washed with diethyl ether and dried. Melting point: 169-171° C. Yield: 0.46 g (86% of theory) C27H34ClNO8 (536.02) Calculated: C 60.50 H 6.39 N 2.61 Cl 6.61 Found: 60.37 6.38 2.65 6.73
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH:1]1([O:6][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC1CCCC1)c1ccc(OCc2ccccc2)cc1

Procedure:
Cyclopentanol (2.58g.; 0.03 m) was dissolved in pyridine (50 ml), 4-benzyloxybenzoyl chloride (6.76g; 0.03 m) was added and the mixture was boiled under reflux 6 hours. The resulting mixture was added to iced-water, extracted with ether, the organic extract washed with 2×100 ml. of 2N hydrochloric acid, 2×100 ml. saturated sodium bicarbonate solution and 1×100 ml. of water, dried (MgSO4) and evaporated. The ester was purified by elution from a column of silica in toluene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH2:21][CH2:22][CH3:23]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:21]([C:20]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:22][CH3:23]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Yield: 102.3 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (10.0 g, 38.6 mmol) was treated according to a modification of the method described in Part B of Example 8. After the addition of trimethyl orthobutyrate (7.71 mL, 48.2 mmol) and pyridinium p-toluenesulfonate (0.200 g, 0.796 mmol), the reaction was heated at reflux for one hour and subjected to the work-up procedure to provide 12.3 g of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].C(N(CC)CC)C>ClCCl>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1)[CH3:31]
Reactant: CCOC(=O)CCN
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26) (37 mg, 0.099 mmol) was combined with 1-hydrobenzotriazole hydrate (23.0 mg, 0.149 mmol), N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (29.0 mg, 0.149 mmol), and beta-alanine ethyl ester hydrochloride (18.0 mg, 0.119 mmol). Anhydrous dichloromethane (5 mL) was added followed by triethylamine (0.027 mL, 0.198 mmol). The solution was stirred at room temperature for 3 d before partitioning between ethyl acetate and aq. sat. ammonium chloride. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (37.9 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.2 Hz, 2H) 7.59 (t, J=3.9 Hz, 2H) 7.46-7.52 (m, 3H) 7.37-7.45 (m, 1H) 7.11-7.19 (m, 1H) 6.75 (t, J=5.8 Hz, 1H) 5.32 (dd, J=9.7, 6.7 Hz, 1H) 4.75 (d, J=6.6 Hz, 1H) 4.10-4.21 (m, 2H) 3.70 (q, J=6.0 Hz, 2H) 2.55-2.74 (m, 3H) 2.29 (s, 3H) 1.96 (ddd, J=11.1, 8.2, 2.9 Hz, 1H) 1.75-1.84 (m, 1H) 1.64-1.73 (m, 2H) 1.26 (m, 3H) 1.16 (s, 3H) 1.09 (s, 3H); MS (M+1): 474.7.
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[C:6]([OH:18])(=[O:17])[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>O>[C:6]([O-:18])(=[O:17])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[Sr+2:5].[C:6]([O-:18])(=[O:17])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C([O-])CNC(=O)c1ccccc1

Procedure:
Strontium carbonate (0.5 g, 3.39 mmol) and hippuric acid (1.215 g, 6.77 mmol) in water (30 ml) were stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was evaporated to dryness and dried in vacuo at ambient temperature. Yield 1.25 g (83%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:19])[C:5]=2[CH2:3][OH:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole-4-carboxylic acid methyl ester (0.80 g, 2.6 mmol) is dissolved in 8 mL of THF and is cooled in an ice bath. To the solution is added 1M DIBAL solution in toluene (5.66 mL) and the reaction is stirred one hour. Additional 1M DIBAL solution in toluene (5.66 mL) is added and the reaction is stirred for an additional hour. Upon completion, the reaction is quenched with methanol and acidified with aqueous HCl solution (1M). The reaction mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (0.68 g, 93%). MS m/z: 284.0 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.[CH3:10][S:11]SC.N(OC(C)(C)C)=O.O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([S:11][CH3:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClCCCl
Solvent: O
Product: CSc1ccc(C)c(F)c1
Reaction time: 2 h
Yield: 525.5 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (25 g), dimethyl disulphide (375 g) and t-butyl nitrite (30 ml) in 1,2-dichloroethane was warmed to start the reaction. A solution of 3-fluoro-4-methylaniline (225 g) in 1,2-dichloroethane was added dropwise, simultaneously with t-butyl nitrite (241 ml) at such a rate as to maintain the temperature below 60° C. The mixture was stirred for 2 hours, then water was added. The organic layer was washed with water, hydrochloric acid, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 2-fluoro-4-(methylsulphenyl)toluene (164 g) as a yellow oil; NMR (acetone-d6); 2.2 (3H,d), 2.5 (3H,s), 7.05 (3H,m).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:12][C:5]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Yield: 53 %

Procedure:
To a suspension of NaH (88 mg, 60% in mineral oil, 2.2 mmol) in DMF (1 mL) was added 4-chloro-1H-pyrrolo[2,3-b]pyridine (305 mg, 2 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) at room temperature with stirring. The mixture was stirred for 5 min and trimethylsilylethyl chloromethyl ether (350 mg, 2.1 mmol, Aldrich) was added. The mixture was stirred at room temperature for 1 h, poured onto ice, and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product, which was purified by flash chromatograph (5% ethyl acetate in hexanes) to afford the title compound (300 mg, 1.06 mmol, 53%) as a liquid. 1H NMR (CDCl3) δ 8.28 (d, 1H, J=5.5 Hz), 7.45 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=5.5 Hz), 6.69 (d, 1H, J=3.6 Hz), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8 Hz), 0.96 (t, 2H, J=6.8 Hz), 0.07 (s, 9H); MS(ESI+) m/z 283 and 285 (M+H, 1 Cl)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccncc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Temperature: 85 °C
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80-90° C. overnight. The reaction mixture was poured into water (200 ml)/NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191-192° C.