Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)O>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:24]([C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OC(c1ccccc1)c1ccc2ccccc2c1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: CC1(c2ccccc2)C(=O)C(C(c2ccccc2)c2ccc3ccccc3c2)=C1O

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with naphthalen-2-yl-phenyl-methanol to give the title compound as a colorless solid. MS: 389.5 ([M−H]−).
Reaction SMILES: BrC1C=C(NS(C)(=O)=O)C=C(C(C2C=NC=CC=2)=O)C=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:29]2[CH:30]=[C:31]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:32]=[C:33]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[CH:37]=[CH:38][N:39]4[Si](C(C)C)(C(C)C)C(C)C)[CH:34]=2)=[O:28])[CH:22]=1>>[NH:39]1[C:40]2[C:36](=[C:35]([C:33]3[CH:32]=[C:31]([NH:54][S:55]([CH3:58])(=[O:56])=[O:57])[CH:30]=[C:29]([C:27]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)=[O:28])[CH:34]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(NS(C)(=O)=O)cc(C(=O)c4cccnc4)c3)cccc21
Agent: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Product: CS(=O)(=O)Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1

Procedure:
N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide was converted to N-[3-(pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-methanesulfonamide, and the triisopropylsilyl group was removed with tetra n-butylammonium fluoride to give N-[3-(1H-indol-4-yl)-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide as described in Example 75. 1H NMR (400 MHz, methanol-d4/CDCl3): δ 8.97 (s, 1H), 8.71 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.87 (t, J=1.8 Hz, 1H), 7.78 (t, J=1.5 Hz, 1H), 7.56 (t, J=1.9 Hz, 1H), 7.44 (dd, J=7.8, 4.9 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H), 6.60 (d, J=3.3 Hz, 1H), 3.00 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(N(CCCC)CCCC)CCC.C[O:19][C:20]1[CH:21]=[C:22](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=2)[CH:23]=[C:24]([O:26]C)[CH:25]=1>>[C:22]1(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH:23]=[C:24]([OH:26])[CH:25]=[C:20]([OH:19])[CH:21]=1
Reactant: COc1ccc(/C=C/c2cc(OC)cc(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4.5 g of anhydrous aluminium chloride (33.7 mmol) are introduced, under a nitrogen atmosphere, at ambient temperature and with stirring, into 10.37 g of tributylamine (56 mmol) in a three-necked round-bottomed flask. The medium is brought to 60° C. and is maintained at this value for 4 h. 1 g of (E)-3,5,4′-trimethoxystilbene (3.7 mmol) is then introduced and the reaction medium is brought to 80° C. for 2 h and to 100° C. for 2 h. It is brought back to ambient temperature and then 10 g of a 50/50 water/ice mixture are added. It is maintained at 0-5° C. with stirring for 3 h and extracted 4 to 5 times with 10 ml of methyl ethyl ketone. The combined organic phases are washed with 10 ml of a saturated aqueous sodium bicarbonate solution and then with 10 ml of water. After concentrating the organic phase, an HPLC quantitative determination (external calibration) gives an (E)-resveratrol yield of 75%.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[I-].[K+].O>CS(C)=O>[CH2:16]([C:7]1([CH2:7][CH2:8][CH2:9][CH3:10])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC1(CCCC)c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 15 °C
Reaction time: 2 h
Yield: 158.7 %

Procedure:
12.66 g of 2-nitrofluorene (1) (60 mmol), 21.0 g of potassium hydroxide (0.3 mol, purity: 80%), and 1.01 g of potassium iodide (6 mmol) were dissolved in 200 ml of anhydrous dimethylsulfoxide under nitrogen atmosphere, and a reaction temperature was maintained at 15° C. Then, 33 ml of n-bromobutane (0.3 mol) was slowly added thereto for 2 hours, followed by stirring at 15° C. for 1 hour. Thereafter, 200 ml of distilled water was added to the reaction mixture and stirred for about 30 minutes, a product was extracted with 300 ml of dichloromethane, and the extracted organic layer was washed with 100 ml of distilled water three times. Then, the recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. The obtained product was purified using a silica gel column chromatography (eluent: dichloromethane:n-hexane=20:1), thereby obtaining 15.4 g of 9,9-di-n-butyl-2-nitrofluorene (5) (79.5%) as a light yellow product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNCCCC
Reactant: Cc1ccc2nc(-c3ccc(OCCCCl)cc3)cn2c1
Product: CCCCN(CCCC)CCCOc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 25 °C

Procedure:
The product of Step C (8.6 g) and dibutylamine (9 mL) were heated at reflux temperature for 8 hours. The reaction was cooled to ambient temperature and evaporated in vacuo. The residue was purified via silica gel chromatography (dichloromethane/acetone) to give the title compound which was converted to a hydrochloride salt upon addition of concentrated hydrochloric acid. The salt was recrystallized (methanol/acetone/ether) to give 5.66 g of product. (m.p. 188-191° C).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH2:18]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5]
Reactant: Nc1n[nH]c2ccc(Br)cc12
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: O=C(O)C=CC(=O)Nc1n[nH]c2ccc(Br)cc12
Temperature: 110 °C
Reaction time: 12 h

Procedure:
350 mg of maleic anhydride are added to 500 mg of 5-bromo-1H-indazole-3-amine, prepared as described in U.S. Pat. No. 3,133,081, in 20 cm3 of toluene. The medium is refluxed at about 110° C. for one hour. The heating is then stopped and the mixture is stirred at about 19° C. for 12 hours. The precipitate formed is filtered off on a sinter funnel and rinsed with 20 cm3 of diisopropyl ether, 2 cm3 of ethyl acetate and 2 cm3 of dichloromethane. After drying (90 Pa; 45° C.), 448 mg of 4-[(5-bromo-1H-indazol-3-yl)amino]-4-oxo-2-butenoic acid, Z form, are obtained in the form of a yellow solid melting at 172° C.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[CH3:12][C:13]1([CH:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(C)C>S(=O)(=O)(O)O.O.CC(C)=O>[CH3:12][C:13]1([CH:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC1(C2CCC(O)CC2)CCCCC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: CC1(C2CCC(=O)CC2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 23 g of sodium dichromate in a mixture of 19 ml of concentrated sulfuric acid and 65 ml of water was added dropwise at from 15° to 20° C. to a solution of from 45.8 g (0.23 mol) of 4-(1-methylcyclohexyl)cyclohexanol in 900 ml of acetone. The mixture was stirred at room temperature for one hour, 150 ml of isopropanol were added, stirring was continued for 15 minutes, and the inorganic material was filtered off with suction. The filtrate was brought to a pH of from 6.5 to 7 with solid sodium bicarbonate and then the mixture was filtered again. The filtrate was concentrated, the residue was taken up in toluene/water, and the organic phase was dried and concentrated.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15][CH3:16]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15]([CH3:16])(=[O:6])=[O:5]
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CN(C(=O)CCS(C)(=O)=O)c1nnc(-c2cccnc2)s1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
Sodium perborate tetrahydrate (130 mg, 0.84 mmol, 2.4 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23° C. The resulting yellow suspension was heated to 60° C. for 15 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as an off-white powder (90 mg, 82% yield): mp 199-201° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.15 (d, J=2 Hz, 1H), 8.73 (dd, J=6, 2 Hz, 1H), 8.32 (dt, J=8, 2 Hz, 1H), 7.46 (dd, J=8, 5 Hz, 1H), 3.94 (s, 3H), 3.59 (t, J=7 Hz, 2H), 3.33 (t, J=7 Hz, 2H), 3.09 (s, 3H); ESIMS m/z 327 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:10][C:11]1[C:12]([CH:17]=O)=[N:13][CH:14]=[CH:15][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH2:17][NH:9][CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ncccc1Cl
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCc1ncccc1Cl

Procedure:
Using General Procedure B: Reaction of C-(3-methyl-pyridin-2-yl)-methylamine and 3-chloro-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine as a yellow oil. Using General Procedure A: Reaction of (3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 2-{[(3-chloro-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 2.12 (s, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 3.97 (s, 2H), 4.22 (s, 2H), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.13 (dd, 1H, J=7.8, 4.8 Hz), 7.32 (d, 1H, J=6.9 Hz), 7.52-7.63 (m, 2H), 7.71 (d, 1H, J=8.1 Hz), 7.94 (d, 1H, J=1.5 Hz), 8.30 (d, 1H, J=4.5 Hz), 8.42 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3]1
Reactant: O[C@@H]1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 4.86 g (55.18 mmol) of (R)-(−)-3-hydroxytetrahydrofuran in 55 mL of anhydrous DCM (1M) was cooled to 0° C. with an ice bath. Then 8.5 mL (60.7 mmol, 1.1 eq.) of triethylamine and 4.8 mL (60.7 mmol, 1.1 eq.) of methanesulfonyl chloride were added successively. The reaction mixture was stirred for 2 hours at 0° C. and quenched with a saturated solution of sodium bicarbonate (70 mL). The aqueous layer was extracted with DCM (50 mL). Then the organic layers were washed with water (2×50 mL), brine (50 mL) and dried over sodium sulfate. After filtration and concentration in vacuo, a yellowish oil (7.93 g, 86.4%) was obtained corresponding to the methanesulfonic acid(R)-(tetrahydrofuran-3-yl)ester.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=C=O)=[CH:11][C:10]=1[N:18]=C=O.B(F)(F)F.CCOCC>O>[C:9]1([CH3:8])[C:10]([NH2:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N)cc1N
Yield: 97 %

Procedure:
20 parts toluene, 1.74 parts (0.01 mole) 2,4-toluenediisocyanate, 2.8 parts (0.02 mole) boron trifluoride etherate and 0.40 part (0.02 mole) distilled water were combined and reacted as described in Example 1. The neutralization and isolation procedures described in Example 2 were conducted. 1.17 parts (97% yield) 2,4-toluenediamine were recovered having a melting point of 96° C.-98° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:16][Si:17]([CH3:27])([CH3:26])[C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[NH:11][C:18]([Si:17]([CH3:27])([CH3:16])[CH3:26])=[C:19]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:15])[CH3:2]
Reactant: C[Si](C)(C)C#Cc1ccccc1
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Product: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c([Si](C)(C)C)c(-c3ccccc3)c2c1

Procedure:
4-Amino-3-nitro-benzoic acid ethyl ester and trimethyl-phenylethynyl-silane were reacted according to the same procedures as Preparation 19 to give 7-nitro-3-phenyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:9]=2)[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.O=P(Cl)(Cl)Cl>CCO.[OH-].[Na+].O.CC#N>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:11][CH2:12][CH2:13][N:14]=[C:15]([CH3:16])[C:9]3=2)[NH:4][CH:3]=1
Reactant: CC(=O)NCCOc1ccc2c(c1)c(Cl)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CC1=NCCOc2ccc3[nH]cc(Cl)c3c21
Temperature: 75 °C
Yield: 15.6 %

Procedure:
N-(2-{[3-chloro-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 39, 1.07 g, 2.73 mmol, ca 80% pure) in EtOH (25 ml) and 2 M NaOH (5 ml) were mixed and heated at 75° C. for 1 hour. The reaction mixture was cooled, diluted with water and extracted with DCM. The organic phase was dried (MgSO4) and evaporated to give the crude material (0.287 g) as a colorless oil. The crude material (0.250 g, 0979 mmol) was dissolved in MeCN (20 ml) and POCl3 was added. The reaction mixture was heated at 120° C. for 15 minutes in a microwave heater and evaporated. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (99.7 mg) as a white solid. MS m/z 235 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1)[CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][C@@H:10]([CH3:9])[CH2:11][CH3:12])[N:22]=2
Reactant: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
N-Bromosuccinimide (1.182 g, 6.64 mmol) was added portionwise to a solution of 2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- amine (1.935 g, 6.64 mmol) in chloroform (50 ml) at 0-5° C. The resulting green solution was stirred at 0-5° C. for 1 hour during which time it turned red and the mixture was then allowed to warm to room temperature and stirred overnight. The resulting green solution was washed with water (2×20 ml), separated using a hydrophobic frit and concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (100 g cartridge) using a Flashmaster II apparatus and a 0-100% ethyl acetate-cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (1.79 g).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](C4C=C5C(=CC=4)C=C(N4C(=O)C(=C)SC4=O)C=C5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[C:43]2[CH:48]=[O:49]>>[C:1]12([C:11]3[CH:12]=[C:13]([C:38]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:39]=4[CH:40]=[CH:41][CH:42]=[C:43]5[CH:48]=[O:49])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=Cc1cccc2c(Br)cccc12
Reactant: C=C1SC(=O)N(c2ccc3cc(-c4ccc(OC)c(C56CC7CC(CC(C7)C5)C6)c4)ccc3c2)C1=O
Product: COc1ccc(-c2cccc3c(C=O)cccc23)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
The intermediate 5-[3-(1-adamantyl)-4-methoxyphenyl]-1-naphthaldehyde was prepared in a similar manner as described herein using 3-(1-adamantyl)-4-methoxyphenyl boronic acid (see Example 8) and 5-bromo-1-naphthaldehyde.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:2]2[N:3]=[C:4]([CH3:15])[N:5]([C:8]3[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=3)[C:6]=2[CH3:7])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1
Reactant: C#Cc1cccc(Cl)c1
Product: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1

Procedure:
The title compound, light brown crystalline solid, MS: m/e=324.2, 326.1 (M+H+), was prepared in accordance with the general method of example 21a from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1H-pyridin-2-one and 1-chloro-3-ethynyl-benzene.
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>C(O)C.[OH-].[NH4+].[Ni]>[NH2:2][CH2:1][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)C#N
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CN
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 2-cyano-2-methylpropanoate (0.6 g, 4.2 mmol, 1.0 equiv) in 6 mL of ethanol/ammonium hydroxide (10:1) was added Ra/Ni (20%, 0.12 g). The resulting mixture was stirred under hydrogen at r.t. for 16 h. The catalyst was filtered off, and the filtrate was concentrated to give ethyl 3-amino-2,2-dimethylpropanoate (0.43 g, yield: 70%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 4.15 (q, 2H), 2.77 (s, 2H), 1.76 (s, 2H), 1.26 (t, 3H), 1.18 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:29]=[N:30][CH:31]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)C>[CH3:17][N:15]1[CH:16]=[C:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)(=[O:34])=[O:35])[CH:29]=[N:30][CH:31]=2)=[CH:3][CH:4]=3)[CH:13]=[N:14]1
Reactant: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)cn1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (5.98 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (6.78 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.18 mmol) in 2M aqueous sodium carbonate (15 mL) and 1,4-dioxane (40 mL) was heated at 100° C. for 22 h. Additional N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.83 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.09 mmol), and 2M aqueous potassium carbonate (3 mL) were added and the reaction mixture was heated at 100° C. for 22 h for complete consumption of starting material. The reaction mixture was cooled, diluted with diethyl ether (30 mL), and filtered through a pad of Celite while rinsing with (2×30 mL) diethyl ether. The organic layer was poured into a separatory funnel containing water (100 mL) and the layers were separated. The aqueous layer was acidified with 6N aqueous HCl until the pH was approximately 7 and then further extracted with (3×200 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate with decolorizing activated carbon, filtered through a pad of Celite while rinsing with (2×100 mL) ethyl acetate, and concentrated in vacuo. The filtrate was separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the residue from hot ethyl acetate afforded the title product as an ivory solid (804 mg, 30%). Additional product was obtained from the concentrated mother liquors after purification by silica gel chromatography (70-100% ethyl acetate/hexanes) followed by precipitation from cold ethyl acetate (534 mg, 20%). MS(ES)+ m/e 443 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H](CCCCNC(OCC1C=CC=CC=1)=O)N)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C([O:48][C:49](=[O:77])[C@H:50]([CH2:62][CH2:63][CH2:64][CH2:65][NH:66]C(OCC1C=CC=CC=1)=O)[NH:51][C:52](=[O:61])[CH:53]([CH3:60])[CH2:54][CH2:55]C(OC)=O)C1C=CC=CC=1.COC(CCC(C)C(N[C@H](C(O)=O)CCCCN)=O)=O.N[C@H](C(O)=O)CCCCN>>[C:9]([CH:63]([CH2:64][CH2:65][NH2:66])[CH2:62][C@@H:50]([C:49]([OH:48])=[O:77])[NH:51][C:52](=[O:61])[CH:53]([CH3:60])[CH2:54][CH3:55])([OH:27])=[O:8]
Reactant: COC(=O)CCC(C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: COC(=O)CCC(C)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: NCCCC[C@H](N)C(=O)O
Product: CCC(C)C(=O)N[C@@H](CC(CCN)C(=O)O)C(=O)O

Procedure:
By substituting Nε -benzyloxycarbonyl-L-lysine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23 and then treating the product by the procedures of Examples 24 and 26, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-Nε -benzyloxycarbonyl-L-lysine benzyl ester, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-L-lysine and Nα -(4-carboxy)-2-methylbutanoyl)-L-lysine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(Cl)cc1C=O

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (2 g, 12.8 mmol), acetic acid 2-bromo-ethyl ester (2.57 g, 15.4 mmol), K2CO3 (5.3 g, 38.5 mmol) and KI (0.26 g, 1.54 mmol) were mixed in DMF (20 mL). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2 and the organic layer was washed with water for several times. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain a yellow solid. (2.7 g)