Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32]1([C:64]3[C:55](=[CH:56][C:57]4[O:62][CH2:61][CH2:60][O:59][C:58]=4[CH:63]=3)[O:54][CH2:53]1)[C:33](=[O:52])[N:34]2[CH:39](C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:39][N:34]1[C:35]2[C:31](=[C:30]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:38]=[CH:37][CH:36]=2)[C:32]2([C:64]3[C:55](=[CH:56][C:57]4[O:62][CH2:61][CH2:60][O:59][C:58]=4[CH:63]=3)[O:54][CH2:53]2)[C:33]1=[O:52]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3cnn(C)c3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to replace quinolin-3-ylboronic acid, and 4′-bromo-1-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (58%) as a colorless solid: mp 220-222° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (dd, J=7.9, 7.9 Hz, 1H), 7.16 (s, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.48 (d, J=9.1 Hz, 1H), 4.23-4.09 (m, 4H), 3.75 (s, 3H), 3.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.6, 144.8, 144.2, 138.7, 138.0, 130.8, 129.3, 129.1, 127.8, 125.2, 122.7, 119.0, 111.5, 107.0, 99.4, 76.7, 64.6, 64.0, 58.3, 38.9, 26.8; MS (ES+) m/z 390.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([C:12]#[N:13])[C:3]=1[Cl:14].[OH-:15].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([Cl:14])=[C:4]([C:12]#[N:13])[C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[C:8]([NH2:9])=[O:15]
Reactant: N#Cc1c(Cl)c(Cl)c(C#N)c(Cl)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(Cl)c(Cl)c(C(N)=O)c(Cl)c1Cl
Yield: 58.1 %

Procedure:
Tetrachloroterephthalonitrile (26.6 g, 0.1 mol) and ethanol (532 g) were mixed, and the resultant mixture was heated to 79° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (16 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 16.5 g of 2,3,5,6-tetrachloro-4-cyanobenzamide (yield 58%).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3C=C(C([O-])=O)S[C:11]=3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.[Na+].ClC1C2C(=CC=CC=2)[O:28]C(C2C=CC=CC=2)C=1C=O>CO>[O:8]1[C:9]2[C:10](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11](=[O:28])[CH2:12][CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])c1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Na+]
Solvent: CO
Product: O=C1CC(c2ccccc2)Oc2ccccc21

Procedure:
Analogously, (-)-sodium 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxylate, [α]43625 =-89° (c=0.5, methanol), is prepared starting from the pure enantiomeric 4-chloro-3-formyl-flav-3-ene which is obtained by chloroformylation of (-)-flavanone [(-) at 436 nm]. The preparation of (+)- and (-)-flavanone is described e.g. in Tetrahedron Lett. 26, 2305 (1970) and Acta Chim. Acad. Sci. Hung. 86, 161 (1975).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][O:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][O:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C1c2ccccc2C(=O)N1OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 2,4-dihydroxy-benzoic acid methyl ester (1.42 g, 8.45 mmol) and 2-(3-bromo-propoxy)-isoindole-1,3-dione (2.00 g, 7.04 mmol) ) in acetone (50 mL) was added cesium carbonate (6.88 g, 21.1 mmol). The mixture was heated to reflux for 3 hours and allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using chloroform to give 4-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-2-hydroxy-benzoic acid methyl ester (0.76 g, 30%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 10.86 (s, 1H), 7.76 (m, 2H), 7.68 (m, 3H), 6.40 (m, 2H), 4.35 (t, 2H), 4.21 (t, 2H), 3.85 (s, 3H), 2.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26]([OH:28])[OH:27].CCN(C(C)C)C(C)C.C/C(/[O:46][Si](C)(C)C)=N\[Si](C)(C)C.C1C=C(SSC2N=CC=CC=2)N=CC=1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26](=[O:46])([OH:27])[OH:28]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous acid mono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester (27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12 mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at room temperature for 3 hours. To the reaction solution was added 2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowed to stir for an additional 2 hours at room temperature. The reaction mixture was diluted by addition of H2O and the solution was stirred for 2 more hours when it was concentrated. The residue was dissolved in a solution of 10% TFA/CH2Cl2 and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse-phase HPLC to provide the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H), 5.50-5.61 (m, 1H); 31P (121.4 MHz, CD3OD) δ 0.50; MS (m/z) 357 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>C1COCC1>[CH3:29][O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: COC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 32.7 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.21 g, 0.84 mmol) in 5 mL of THF was added potassium tert-butoxide (0.19 g, 1.68 mmol) in one portion and stirred for 1 minute. To the suspension was added methyl thioglycolate (0.15 mL, 1.68 mmol) dropwise over 1 minute. The mixture was stirred for 12 h then poured into ice water and the solids collected. Purification by trituration using ethyl acetate/hexanes gave 88 mg (33%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H), 8.90 (m, 1H), 8.11 (m, 1H), 7.74 (m, 2H), 7.48 (m, H), 7.17 (m, 2H), 4.10 (s, 2H), 3.63 (s, 3H); MS (EI) m/z 319.13 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][C@@H:17]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][OH:19].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:22]([O:21][CH2:20][C@H:17]([NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][OH:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: N[C@H](CO)COCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
4-Chloro-3-nitroquinoline (41.0 g, 197 mmol) was added to a mixture of (2R)-2-amino-3-(benzyloxy)propan-1-ol hydrochloride (43.0 g, 197 mmol) and triethylamine (69.0 mL, 494 mmol) dissolved in 985 mL of CH2Cl2 at 0° C. The resulting yellow mixture was stirred for 18 hours at ambient temperature. The solvent was then removed under reduced pressure to afford a yellow solid. The solid was stirred in H2O (100 mL) and filtered to give 57 g of (2R)-3-(benzyloxy)-2-[(3-nitroquinolin-4-yl)amino]propan-1-ol as a bright yellow solid.
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].Cl>CO>[NH:1]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O

Procedure:
9.98 g of BOC-Met-Leu-Gly-OEt are dissolved in 300 ml of methanol. 57 ml of 0.59 N sodium hydroxide solution are added over the course of 45 minutes at room temperature and the mixture is stirred for a further hour. Thereafter the pH-value is adjusted to 7 with 0.68 N hydrochloric acid and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate and water and the pH-value is brought to 2 by means of 0.68 N hydrochloric acid. The aqueous phase is extracted by shaking with ethyl acetate. The combined ethyl acetate phases are washed with sodium chloride solution, dried and evaporated. The residue is crystallised from ethyl acetate-hexane. Melting point 137°- 138° C.; [α]D = -31° (c = 2 in dimethylformamide); Rf7 = 0.74 (on silica gel).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][N:16]3[C:21]=2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+]>ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([Br:22])[N:16]3[C:21]=2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@@H](NC(=O)c1ccn2c1CCCC2)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(Br)n2c1CCCC2)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide (9i) (9.7 g, 34.35 mmol) in dry dichloromethane (200 ml) at −78° C. was added N-bromo-succinimide (6.11 g, 34.35 mmol) in several portions (over 2 min) and the mixture was stirred for 1 h min at −78° C., 1 h at 0° C. and 30 min at 25° C. Then 500 ml aqueous 2% sodium hydroxide was added, and the mixture was extracted 3 times with dichloromethane, the combined organic layers were dried over sodium sulfate, evaporated and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 5.24 g (42%) of 3-bromo-5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ((R)-1-phenyl-propyl)-amide. LC/MS (method 4): Rt=1.33 min; m/z=361.21 (M+H+).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:25]1[O:29][N:28]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1.Cl>C(O)C.O1CCOCC1>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:6]=1[C:25]1[O:29][N:28]=[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1
Reactant: CCOC(=O)c1cc(-c2c(OCOC)cc(OCOC)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2c(O)cc(O)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
To a stirred solution of ethyl 5-[2,4-bis(methoxymethoxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate (25 g, 52 mmol) in ethanol (150 mL) was added 4 M HCl solution in dioxane at room temperature. The solution was set aside for 5 hours then the solvent was evaporated off and the residue taken up in diethyl ether, to provide the title compound (17.1 g, 83% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.Cl[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCC(C)C>C(#N)C.O>[CH3:8][C:9]1[N:10]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[CH:12][N:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc[nH]1
Solvent: CCCC(C)C
Solvent: CC#N
Solvent: O
Product: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
Triethylamine (11.54 mL, 82.82 mmol) was added dropwise to 2-methyl-1H-imidazole (4.0 g, 48.72 mmol) and chlorotriphenylmethane (14.94 g, 53.59 mmol) in acetonitrile (120 mL) at room temperature over a period of 20 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. Water (120 mL) and i-hexane (12 mL) were added and the slurry stirred for 30 minutes before filtering. The filtered solid was washed with water (3×15 mL) and dried under vacuum to afford 2-methyl-1-trityl-1H-imidazole (15.41 g, 97%) as a cream solid which was used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[CH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10].[Cl-].[NH4+]>O1CCCC1>[CH3:7][CH:8]([CH:12]=[CH:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:21])[CH3:22])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)C(C)C=CC1CC2CC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
66.0 g of potassium tert-butoxide dissolved in 850 ml of tetrahydrofuran was added to the solution of 140 g (0.64 mol; 70% pure) of 3-methyl-5-(1,2,2-trimethylbicyclo-[3.1.0]hex-3-yl)pent-3-en-2-one in 850 ml of the same solvent at 0° C. After 30 minutes of stirring at room temperature the reaction mixture was poured on 1 l of aqueous ammonium chloride solution. After the usual workup the crude product was purified by flash chromatography on silica gel (eluent: hexane/MTBE 19:1) to give three fractions: 5.1, 28.1 and 22.3 g containing respectivly 36, 78, and 92% of 3-methyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-4-en-2-one (˜40% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:41][CH:42]([CH3:43])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl (3S,5R)-3-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (88.4 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated to give the object product (62.7 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10]O)[N:9]=1)[CH2:2][CH2:3][CH3:4].[ClH:12].CO>CO>[ClH:12].[CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c[nH]1
Agent: Cl
Solvent: CO
Product: CCCCc1nc(CCl)c[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-n-Butyl-4-hydroxymethylimidazole (33.3 g) is dissolved in methanol (50 ml), and thereto is added 18% hydrogen chloride-methanol solution (160 ml), and the mixture is evaporated under reduced pressure to remove the solvent. To the resulting residue is added toluene (150 ml), and thereto is added dropwise thionyl chloride (52 ml) under ice-cooling. The mixture is stirred at 50° C. for two hours, and concentrated to dryness under reduced pressure to give 2-n-butyl-4-chloromethylimidazole hydrochloride (58.3 g) as oil. Separately, diethyl N-acetylaminomalonate (140.8 g) is added to a solution of sodium ethylate (44 g) in ethanol (500 ml) with ice-cooling under argon atmosphere, and the mixture is stirred at 0° C. for 15 minutes. To the mixture is added dropwise a solution of 2-n-butyl-4-chloromethylimidazole hydrochloride obtained above in ethanol (250 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure to remove the solvent, and to the resulting residue are added ethyl acetate (1 liter) and saturated aqueous ammonium chloride solution (500 ml). The aqueous layer is extracted with ethyl acetate, and the extract is combined with the organic layer, and evaporated. To the resulting residue is added 10% hydrochloric acid, and the mixture is neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate to give 2 n butyl-4-{2-acetylamino-2,2-bis(ethoxycarbonyl)ethyl}imidazole (56.8 g) as powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C1COCC1>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Yield: 96 %

Procedure:
Chlorobenzene (56 mg, 0.50 mmol) reacted with phenylboronic acid (92 mg, 0.75 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at 45° C. to give the title compound (74 mg, 96%) as a white solid.
Reaction SMILES: COCCC(NC1C2C(=C(C(OC)=O)C=CC=2)N=CN=1)C1C=CC=C([N+]([O-])=O)C=1.N.[CH3:31][O:32][CH2:33][CH2:34][CH:35]([NH:45][C:46]1[C:55]2[C:50](=[C:51]([C:56]([NH2:58])=[O:57])[CH:52]=[CH:53][CH:54]=2)[N:49]=[CH:48][N:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([N+:42]([O-])=O)[CH:37]=1>CO.[Pd]>[NH2:42][C:38]1[CH:37]=[C:36]([CH:35]([NH:45][C:46]2[C:55]3[C:50](=[C:51]([C:56]([NH2:58])=[O:57])[CH:52]=[CH:53][CH:54]=3)[N:49]=[CH:48][N:47]=2)[CH2:34][CH2:33][O:32][CH3:31])[CH:41]=[CH:40][CH:39]=1
Reactant: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: COCCC(Nc1ncnc2c(C(=O)OC)cccc12)c1cccc([N+](=O)[O-])c1
Agent: N
Solvent: CO
Product: COCCC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reaction time: 72 h

Procedure:
To a solution of methyl 4-{[3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxylate (1.74 g; 4.40 mmol) in methanol was added methanolic ammonia (7N) (30.00 ml; 7.00 M; 210.00 mmol) and stirred for 3 days. Insoluble material was removed by filtration and concentrated. The crude 4-{[3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxamide (1.5 g) of was used for the next reaction without further purification. To a solution of 4-{[3-methoxy-1-(3-nitrophenyl)propyl]amino}quinazoline-8-carboxamide (1.5 g) in MeOH (30 mL) was added palladium on active carbon (400 mg) and the mixture was hydrogenated at 40 psi for 4 h. Filtered through a pad of Celite and the solvent was removed. The crude product (1.2 g) was used as such for amide formation. LCMS [352 (M+1)].
Reaction SMILES: [ClH:1].CO[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1.[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[S:14]>CO>[ClH:1].[NH2:11][N:12]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:4][NH2:5])=[N:16][N:15]=[C:13]1[SH:14]
Reactant: NNC(=S)NN
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CO
Product: NCCCCCc1nnc(S)n1N
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To 200 ml of methanol is added 3.6 g (0.1 mole) of gaseous HCl followed by 12.7 g (0.1 mole) of O-methylcaprolactam and then 10.6 g (0.1 mole) of thiocarbohydrazide. After heating at reflux for 2 hours, the mixture is allowed to cool to room temperature and is refrigerated. The solid product is recrystallized twice from methanol/ethyl acetate, affording 13.4 g of 4-amino-5-(5-aminopentyl)-4H-1,2,4-triazole-3-thiol hydrochloride. m.p. 192°-194° C.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)C[C:8]([C:13]1[C:22]([N:23]3[C:32]4[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:34]([O:36]C)=[O:35])[CH:19]=3)[N:14]=1)=[CH:7]2>CO.O1CCCC1>[F:33][C:29]1[CH:28]=[C:27]2[C:32](=[CH:31][CH:30]=1)[N:23]([C:22]1[C:13]([C:8]3[O:1][C:10]4[CH:11]=[CH:12][C:4]([F:3])=[CH:5][C:6]=4[CH:7]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:34]([OH:36])=[O:35])=[CH:17][CH:16]=3)[CH2:24][CH2:25][CH2:26]2
Reactant: [OH-]
Reactant: COC(=O)c1ccc2nc(C3=Cc4cc(F)ccc4C3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Sodium hydroxide (15.6 mg, 0.39 mmol) was added to a solution of methyl 2-(5-fluoro-1H-inden-2-yl)-3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)quinoxaline-6-carboxylate (59 mg, 0.13 mmol) in methanol (25 mL) and tetrahydrofuran (5 mL). The reaction was stirred overnight at room temperature, concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrogen chloride (3 N). The precipitate was collected by filtration to afford 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(5-fluorobenzofuran-2-yl)quinoxaline-6-carboxylic acid (32.5 mg, 57%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([N+:14]([O-])=O)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]>C(O)C.[Pd]>[NH2:14][C:13]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCOc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc2cccnc2c1N

Procedure:
7-Ethoxy-8-nitroquinoline (2.62 g, 12.0 mmole), in absolute ethanol (200 mL) was shaken with 10% palladium on carbon (0.10 g) under hydrogen (50 psi) for 3 hr. The catalyst was filtered off and the filtrate concentrated to 10 mL. The title compound crystallized as yellow needles (1.86 g, 82%); mp 94°-95°. Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.16; H, 6.47; N, 14.87.