Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])cc3)nc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2cc(CCc3ccc(N)cc3)nc2c1
Yield: 92.8 %

Procedure:
A solution of 2-[2-(4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine (3.1 g) in a solution of methanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium on carbon (1.0 g) under atmospheric pressure of hydrogen gas at ambient temperature for 3 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with n-hexane to give a precipitate, which was collected by filtration and dried to give 2-[2-(4-aminophenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (2.59 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[BrH:12].N([O-])=O.[Na+].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CO.CC(C)=O.O.[Cu-]=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:19][CH:18]([Br:12])[C:17]([O:21][CH3:22])=[O:20])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(C)c1
Reactant: Br
Reactant: C=CC(=O)OC
Agent: O=[Cu-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(C(C)=O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
1-(4-Amino-3-methylphenyl)ethanone (1.70 g, 11.39 mmol) was dissolved in methanol (15 mL)-acetone (38 mL). The solution was cooled to 0° C. 48% Hydrobromic acid (5.15 mL, 45.56 mmol) was dropwise added to the solution for 1 minute. A solution of sodium nitrite (943 mg, 13.67 mmol) in water (1.8 mL) was further added to the solution. The mixture was stirred at the same temperature for 30 minutes. The mixture was left to room temperature. Methyl acrylate (7.23 mL, 80.30 mmol) and copper(I) oxide (117 mg) were added to the mixture. The resulting mixture was stirred at 40° C. for 30 minutes. The solvent was removed under reduced pressure. Ice-cold water (150 mL) was added to the residue. The mixture was neutralized with ammonia water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the desired compound (2.79 g) as brown oil (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[C:11]4[S:18][CH:19]([CH3:21])[CH2:20][C:9]([C:10]=34)=[C:8]2[CH2:22][C:23](OCC)=[O:24])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[C:11]4[S:18][CH:19]([CH3:21])[CH2:20][C:9]([C:10]=34)=[C:8]2[CH2:22][CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1c2c3c(c(OC)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c3c(c(CCO)n2Cc2ccc(Cl)cc2)CC(C)Sc13
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of product from Step 3 (785 mg, 1.83 mmol) in THF (30 mL), cooled to 0° C. and under N2 atmosphere, there was added LiAlH4 (152 mg, 4 mmol). The resulting mixture was stirred at 0° C. for 30 minutes, then quenched carefully with ice-cold H2O, and acidified with 1N aq HCl (10 mL). The mixture was extracted twice with Et2O, and these extracts were washed 3× with brine, dried over Na2SO4, and evaporated. The residue was chromatographed, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc(Cl)ncc3F)cc2C1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-5-fluoro-N4-[2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-4-pyrimidineamine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C@H:18]2[CH2:22][NH:21][C@@H:20]3[C@@H:23]([OH:26])[CH2:24][O:25][C@H:19]23)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O.O1CCOCC1>[OH:26][C@@H:23]1[C@H:20]2[N:21]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:22][C@H:18]([O:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=3)(=[O:16])=[O:15])[C@H:19]2[O:25][CH2:24]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 0.58 h
Yield: 95 %

Procedure:
A solution of sodium carbonate (281 mg, 2.65 mmol) in water (5 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate in 1,4-dioxane (5 mL). A solution of benzyl chloroformate (0.225 mL, 1.96 mmol) in 1,4-dioxane (2.5 mL) was added over 20 minutes then the mixture stirred for 35 minutes, then water (50 mL) was added and the product extracted into dichloromethane (2×50 mL). The organic layer was washed with brine (50 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 25:75 to 50:50 gave bicyclic alcohol (34) (518 mg, 95%) as a white solid. TLC (Rf=0.25, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=17.86 min., HPLC-MS 434.2 [M+H]+, 456.1 [M+Na]+, 889.3 [2M+Na]+; [□]D16.5−23.1° (c=1.190, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.96 (0.4H, d, J=4.11 Hz, OH minor), 2.43 (1.8H, s, aryl-CH3 major), 2.44 (1.2H, s, aryl-CH3 minor), 2.59 (0.6H, d, J=3.42 Hz, OH major), 3.35 (0.4H, dd, 3.71 Hz, CbzNCH2 minor), 3.41 (0.6H, dd, 3.80 Hz, CbzNCH2 major), 3.74-3.88 (3H, m, 2×OCH2CHOH and 1×CbzNCH2), 4.29 (0.4H, s, CbzNCH minor), 4.31 (0.6H, s, CbzNHCH major), 4.37 (0.4H, brs, OCH2CHOH minor), 4.49 (0.6H, brs, OCH2CHOH major), 4.51 (0.6H, d, J=4.59 Hz, TsOCHCH major), 4.64 (0.4H, brd, J=4.44 Hz, TsOCHCH minor), 4.77 (0.4H, d, J=3.43 Hz, TsOCHCH minor), 4.79 (0.6H, d, J=3.53 Hz, TsOCHCH major), 5.06-5.13 (1.6H, m, CH2Ph), 5.21 (0.4H, d, J=12.22 Hz, CH2Ph minor), 7.30 (7H, m, aromatic-CH and CH3CCH), 7.75-7.79 (2H, m, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.658 (aryl-CH3), 51.015/51.082 (CbzNCH2), 67.511/67.622 (CH2Ph), 67.953/68.902 (CbzNCH), 74.375/74.420 (OCH2CHOH), 75.322/76.156 (OCH2CHOH), 79.944/80.600 (TsOCHCH), 83.537/84.651 (TsOCHCH), 127.791, 127.837, 127.942, 128.011, 128.382, 128.485, 128.558, 128.703 and 130.102 (aromatic CH), 133.021/133.087 (CHOSO2C quaternary), 135.895/136.018 (Cbz quaternary), 145.441 (CH3C quaternary), 153.976/154.591 (Cbz C═O).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Na].ClC[C:17]1[N:21]=[C:20]([CH3:22])[O:19][N:18]=1.[CH:23](O)(C)C>>[CH3:22][C:20]1[O:19][N:18]=[C:17]([N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH2:2][CH3:23])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:21]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CC(C)O
Reactant: Cc1nc(CCl)no1
Agent: [Na]
Product: CCn1c(=O)c2c(ncn2-c2noc(C)n2)n(C)c1=O
Reaction time: 10 h
Yield: 74.2 %

Procedure:
20.2 g. of theophylline-sodium, 300 cm3 isopropyl alcohol and 13.2 g. of 3-chloromethyl-5-methyl-1,2,4-oxadiazole are heated under stirring for 10 hours. After processing 20.5 g. (74.2% yield) of 7-(5-methyl-1,2,4-oxadiazol-3-yl)-methyl-theophylline are obtained. M.p.: 134°-135° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[K])(C)(C)C>C1COCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Dissolve 1-fluoro-2-methoxy-4-nitro-benzene (118 g, 689 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (125 g, 724 mmol) in THF (800 mL) and cool to 0° C. To the above solution under a nitrogen atmosphere, add dropwise a 1M solution of tBuOK (1 L, solution in THF). After addition is complete, stir the dark brown solution for 30 min at 0° C., then dilute with water (1 L) over a 10 min period. Stir the mixture for 5 min, then extract with MTBE twice. Combine the organic solutions and wash with brine (2×700 mL), then dry and concentrate. Dry the solid in vacuo at 45° C. for 20 h to obtain 216 g (95%) of the title compounds as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.42 (s, 9H), 3.80 (s, 3H), 4.04 (m, 2H), 4.18 (m, 2H), 4.76 (m, 1H), 6.17 (dd, 1H, J=2.4, 8.5), 6.30 (d, 1H, J=2.6), 6.47 (d, 1H, J=8.5).
Reaction SMILES: [NH2:1][CH:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28](Cl)=[O:29])[C:24]=3[CH:31]=2)[C:10]1=[O:32]>O1CCCC1.C(OCC)C>[CH3:8][N:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:12](=[O:19])[N:11]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][N:26]=[C:25]([C:28]([NH:1][CH:2]([CH2:3][OH:4])[CH:5]([CH3:7])[CH3:6])=[O:29])[C:24]=3[CH:31]=2)[C:10]1=[O:32]
Reactant: CC(C)C(N)CO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)Cl)c3c2)c1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(CO)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Yield: 86.2 %

Procedure:
To a solution of 2-amino-3-methyl-1-butanol (1.39 g, 13.5 mmol) in anhydrous tetrahydrofuran at 0° C. is added dropwise a solution of 5-[3,6-Dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid chloride (2.10 g, 5.39 mmol) in tetrahydrofuran. The resultant mixture is stirred 7.5 hours at ambient temperature, diluted with diethyl ether, washed with 1M aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexanes-ethyl acetate to afford the title compound as a solid (2.12 g, 86.2%, mp 120° C.) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1C=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1.[C:37]([Cl:41])(Cl)(Cl)Cl>>[Br:36][CH2:8][C:5]1[CH:6]=[C:37]([Cl:41])[CH:2]=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COc1cc(Cl)cc(CBr)c1

Procedure:
To a solution of 2-chloro-5-methylanisole (11) (274 g, 1.75 mol) in CCl4 (2.5 L) was added benzoyl peroxide (4.23 g, 0.02 mol) and NBS (321 g, 1.80 mol). The reaction mixture was heated to reflux for 1 h with mechanical stirring. The reaction mixture was cooled, washed with 1N HCl (2 L), satd NaHCO3 (2 L) and brine (2 L), dried over MgSO4, filtered and concentrated under reduced pressure to give the 5-(bromomethyl)-3-chloroanisole (12) as a light yellow solid (412 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.30-7.34 (d, 1H), 6.95 (s, 1H), 6.91-6.93 (d, 1H), 4.45 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:11](=[O:23])[C:10]=2[C:9]=1[CH3:24])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C>>[CH3:22][N:20]([CH3:21])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[NH:17][C:8]([CH:6]=[O:5])=[C:9]([CH3:24])[C:10]=2[C:11]1=[O:23]
Reactant: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Temperature: 40 °C
Yield: 36.8 %

Procedure:
5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 23b (774 mg, 2.3 mmol) was dissolved in trifluoroacetic acid (3.1 ml, 20 mmol) under stirring, the resulting solution was heated at 40° C. for 5 minutes in an oil bath under an argon atmosphere. The reaction mixture was cooled down to −5° C. in an ice-salt bath under stirring, added with triethoxy methane (0.5 ml, 3.0 mmol) and stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ice water (3 ml) and dichloromethane (10 ml), adjusted to pH 11 with aqueous sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (10 ml×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain a henna oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c (223 mg, yield 37%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([N+:15]([O-])=O)[CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])C.CC1C=C(C2C=NC=CN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[CH3:1][N:3]([CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[NH2:15]
Reactant: CCc1ccc([N+](=O)[O-])cc1OCCN(CC)CC
Agent: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)O)cc1
Product: CCc1ccc(N)cc1OCCN(C)C

Procedure:
The title compound was prepared from 3-(2-diethylaminoethoxy)-4-ethylnitrobenzene (D52) using a similar procedure to Description 2 as a pale yellow oil (89%)
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:8]=[C:9]([CH3:20])[C:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])=[C:11]([CH3:13])[CH:12]=1.[B:21]([O:26]C)([O:24]C)[O:22]C.Cl>C1COCC1>[CH2:18]([O:17][CH2:16][CH2:15][O:14][C:10]1[C:9]([CH3:20])=[CH:8][C:7]([O:22][B:21]([OH:26])[OH:24])=[CH:12][C:11]=1[CH3:13])[CH3:19]
Reactant: COB(OC)OC
Reactant: CCOCCOc1c(C)cc(Br)cc1C
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCCOc1c(C)cc(OB(O)O)cc1C
Temperature: 55 °C

Procedure:
A suspension of magnesium (2.36 g) in THF (100 ml) was stirred under a nitrogen atmosphere, and thereto was added dibromoethane (a catalytic amount) and was subsequently added dropwise a solution of 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) in anhydrous THF (100 ml). The resulting mixture was heated at 55° C. for 2.5 hours and was then cooled to −78° C., and thereto was added dropwise trimethyl borate (19.8 ml). The reaction mixture was brought back to the room temperature and was stirred overnight. The reaction mixture was mixed with 1 N hydrochloric acid, was concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 4-(2-ethoxyethoxy)-3,5-dimethylphenylboric acid (8.4 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:32]2[CH:31]=[CH:30][N:29]=[C:28]2[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccc(C(C)(C)C)cc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (40 mg, 0.085 mmol), 4-(tert-Butyl)-benzyl bromide (16.3 μL, 0.089 mmol, 1.05 equiv), and potassium carbonate (23.5 mg, 0.17 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 36.0 mg (79%). Mass spec.: 618.6 (MH)+.
Reaction SMILES: C(N1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.Cl.[NH2:18][C@H:19]([C:27]([NH2:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:7]1(=[O:16])[N:18]([C@@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]([NH2:29])=[O:28])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Product: NC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
By following the procedure of Example 19 but employing N-carbethoxyphthalimide and (S)-phenylalaninamide hydrochloride, there is obtained (S)-2-phthalimido-3-phenylpropionamide which can be recrystallized from ethanol to afford white crystals: mp 211-215° C.; 1H NMR (DMSO-d6)δ 7.92 (s, 5H, Ph), 7.72, 7.33 (2 s, 2H), 7.2-7.0 (m, 4H, Ar), 4.92 (dd, 1H, J=12, 4.5 Hz), 3.52 (dd, 1H, J=4.3, 13.9), 3.35 (dd, 1H, J=12, 13.9); 13C NMR (DMSO-d6)δ 169.6, 167.4, 137.7, 134.3, 131.2, 128.5, 128.1, 126.3, 122.9, 54.2, 33.7.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[N:18][CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH:30]([C:27]1[CH:28]=[CH:29][C:24]([S:21]([NH:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:15]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2cncc(N3CCN(Cc4ccccc4)CC3)c2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(S(=O)(=O)Nc2cncc(N3CCNCC3)c2)cc1
Yield: 98.4 %

Procedure:
A mixture of N-[5-(4-benzylpiperazin-1-yl)-pyridin-3-yl]-4-isopropyl benzene sulfonamide (100 mg, 0.22 mmol) and 10% palladium on charcoal (10 mg) in methanol (20 ml) was hydrogenated at atmospheric pressure until the consumption of hydrogen was complete. After filtration and evaporation of the solvent under reduced pressure the residue was dissolved in water and 0.5 ml 1N HCl and was lyophilized to give 78 mg of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:21]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][C:22]5=[O:30])[CH2:20][O:19][C:17]4=[CH:18][C:11]=3[O:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]21[C:16]1[C:17](=[CH:18][C:11]3[O:10][CH:9]([CH2:8][C:3]4[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:14][O:13][C:12]=3[CH:15]=1)[O:19][CH2:20]2
Reactant: [C-]#N
Reactant: O=C1Cc2ccccc2C12COc1cc3c(cc12)OCC(Cc1ncccc1Br)O3
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1CC1COc2cc3c(cc2O1)OCC31C(=O)Cc2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[N+](=C)=[N-].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1.CCOCC>[Br:1][C:2]1[C:10]2[N:9]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:8]3[CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=3[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)CC1CCc2c1[nH]c1c(Br)cc(F)cc21
Agent: C=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC1CCc2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
To a solution of 2.13 g of the acid from Step 3 in 10 mL of THF, a solution of diazomethane in ether was added in excess until complete consumption of the acid as monitored on TLC. Then, the solvents were removed under vacuum. To a solution of the crude methyl ester thus formed in 20 mL of DMF, 539 mg of a NaH suspension (60% in oil) was added at −78° C. The suspension was stirred for 10 min at 0° C., cooled again to −78° C. and treated with 1.70 g of 4-chlorobenzyl bromide. After 5 min, the temperature was warmed to 0° C. and the mixture was stirred for 20 min. At this time, the reaction was quenched by the addition of 2 mL of AcOH and this mixture was poured into a separatory funnel containing 1N HCl/EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The alkylated material was hydrolyzed using the procedure described in Step 2. The crude material was further purified by trituration with EtOAc/hexanes to yield 2.35 g of the title compound as a pale brown solid.