Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=S)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1>CC(C)=O.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A suspension of Raney® 2800 nickel (3 big spatula, pre-washed with H2O, MeOH and acetone) in acetone (50 mL) was stirred at refluxing for 1 h. Triacetate 88 (0.93 g, 2.03 mmol) was subsequently added into the above suspension at reflux. The mixture was stirred for 5 min, cooled to room temperature over 30 min. The reaction was quenched by bubbling H2S (g) into the mixture for 2 h. The resulting mixture was filtered through a short pad of Celite® and washed with EtOH. The filtrate was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3=1-2%) to afford 0.52 g (60%) of 89 as a white solid: mp 121-123° C.; 1H (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 6.93 (s, 2H), 6.03 (d, J=3.6 Hz, 1H), 5.93 (dd, J=6.4, 3.6 Hz, 1H), 5.58 (t, J=6.0 Hz, 1H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.26 (m, 1H), 4.11 (q, J=6.0 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 427.2. Elemental Analysis calc'd for C16H18N4O8S.0.5 CH3OH.0.25H2O: C, 44.34; H, 4.62; N, 12.54; S 7.17. Found: C, 44.54; H, 4.88; N, 12.16; S, 7.17.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][C:49]=1[F:57].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[C:49]([F:57])[CH:50]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (74 mg, 0.05 eq.) and 4-chloro-3-fluoro-phenylboronic acid (825 mg, 2.5 eq.). 30 mL of MeOH and 3 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (480 mg). The reaction mixture was heated at 55° C. for 3 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 261 mg (33%) of the title product as a light yellow oil. ES-MS m/e: 332.1 (M+H+).
Reaction SMILES: [H-].[Na+].CS(C)=O.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:21][CH2:22][CH2:23]Br>CC(OC)(C)C>[F:7][C:8]([F:18])([F:19])[C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
The mixture of sodium hydride (1.312 g, 54.7 mmol) and DMSO was stirred for about 10 minutes at room temperature. Then a solution of 2-(3-(trifluoromethyl)phenyl)acetonitrile (5 g, 24.86 mmol) and 1,3-dibromopropane (5.02 g, 24.86 mmol) in MTBE (80 mL) was added dropwise via dropping funnel. After addition, the mixture was stirred for about 12 hours, and quenched with 60 mL of water. The aqueous phase was extracted with MTBE (3×30 mL). The combined organic layers were washed with water (3×30 mL) and brine (3×30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel column (20:1 Hexanes/ethyl acetate) to obtain the title compound as a transparent liquid (3.8 g, 63.4%). LC-MS: m/z (M+H) 226.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=O)[CH3:11].B>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH3:11])[CH3:12]
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O
Agent: B
Solvent: C1CCOC1
Product: Cc1ccsc1C(Cc1ccccc1N)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A stirred solution of 5.79 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 400 ml of tetrahydrofuran was treated dropwise under nitrogen with 90 ml of a 1M solution of borane in tetrahydrofuran. The solution was stirred overnight at room temperature and then quenched with 60 ml of a 10% sodium hydroxide solution. The aqueous mixture was extracted with dichloromethane (2×100ml), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was treated with 15 ml of glacial acetic acid and 35 ml of concentrated hydrochloric acid. After stirring at room temperature overnight, the solution was decanted over 200 g of ice, basified with 20 ml of 50% aqueous sodium hydroxide, and extracted with dichloromethane (3×100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification was accomplished by means of HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). Concentration of the appropriate fraction afforded a solid which was recrystallized from diethyl ether to afford 3.7 g of 2-amino-N,N-dimethyl-α-(3-methyl-2-thienyl)benzeneethanamine, mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:10]3[CH2:9][C:8](=O)[NH:7][C:6]=2[CH:24]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NC(=O)CC2C1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NCCC2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 15B (168 mg, 0.435 mmol) in tetrahydrofuran (1.5 mL) was added borane in tetrahydrofuran (1.74 mL, 1 M solution). The resulting mixture was heated to 80° C. overnight. Methanol was then added, and the mixture was heated at 80° C. for 1 hour to destroy excess borane. The reaction was then cooled to room temperature and 1 M HCl was added. The mixture was allowed to stir for another 30 minutes. Aqueous sodium bicarbonate was slowly added to the mixture until the solution was basic (pH=8). Ethyl acetate was then added, and the water layer was separated and washed two times with additional ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0% to 30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.88 (s, 1 H), 6.70 (s, 1 H), 5.75 (d, J=5.55 Hz, 1 H), 3.61-3.79 (m, 1 H), 3.36-3.58 (m, 2 H), 2.95-3.23 (m, 5 H), 2.82-2.94 (m, 1 H), 1.80-1.97 (m, 1 H), 1.56-1.74 (m, 1 H), 1.41 (s, 9 H); MS (DCI+) m/z 372.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][C:29]=5[CH3:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[CH3:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:28]=1[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: ClCCl
Reactant: Cc1cccc2cc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)ncc12
Agent: Cl
Solvent: CCOCC
Product: Cc1cccc2cc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)ncc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{4-[6-amino-5-(8-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (11.0 mg, 0.0227 mmol) in DCM (0.40 mL, 6.2 mmol) was added 1.0 M of HCl in Et2O (0.60 mL, 0.60 mmol), and the mixture was stirred at ambient temperature for 2 h. Almost immediately an off-white solid precipitated. The solvents were evaporated, and the residue was suspended in Et2O, filtered off, and dried in vacuo overnight, yielding the title compound as yellow solid. It appeared to be hygroscopic during the filtration; however, after the washing and initial drying it appeared to be non-hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.6 (very brs, 1H), 9.60 (s, 1H), 9.18-9.07 (brm, 1H), 9.05-8.92 (brm, 1H), 8.88 (d, J=2.0 Hz, 1H, 8.86 (brs, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.81 (dd, J=8.4, 6.8 Hz, 1H), 7.61 (d, J=6.8 Hz, 1H), 4.58-4.49 (m, 1H), 3.40 (brd, J=12.4 Hz, 2H), 3.12 (brq, J=12.2 Hz, 2H), 2.83 (s, 3H), 2.30-2.12 (m, 4H). MS(ES+): m/z=385.21 (43) [MH+], 302.15 (100) [MH+-piperidine]. HPLC: tR=1.80 min (polar—5 min, ZQ2).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH2:27][C:28](O)=[O:29])[CH3:26]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[CH2:27][N:25]([CH3:26])[CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)CC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and dimethylamino acetic acid to yield (3aR,4S,7aR)-4-(2-dimethylamino-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); Rt 4.592 min; LC-MS Method II
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClCCl.Cl[C:16]([CH3:24])([CH2:18][CH2:19][C:20](Cl)([CH3:22])[CH3:21])[CH3:17]>O>[OH:11][C:5]1[CH:10]=[CH:9][C:8]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:16]([CH3:24])([CH3:17])[C:7]=2[CH:6]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The AlCl3 in the reaction path stands for aluminum chloride. Into phenol (1.02 g, 10.8 mmol) were added anhydrous dichloromethane (5 mL), aluminum chloride (144 mg, 1.08 mmol), and 2,5-dichloro-2,5-dimethylhexane (2.18 g, 11.9 mmol) followed by stirring at room temperature for 19 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by recrystallization in a solvent of hexane. The yield was 1.83 g (83%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[C:12]([SiH2:16][O:17][C:18]([CH3:33])([CH3:32])[C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:19]([C:18]([CH3:33])([CH3:32])[O:17][SiH2:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:20]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)ccc1N1CCOCC1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Yield: 45.7 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.391 g, 1.41 mmol), 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenylamine (0.5 g, 1.55 mmol) and N-ethyldiisopropyl-amine (0.27 mL, 1.55 mmol) is heated at 90° C. in 2-propanol (10 mL) for 8 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and water. The aqueous phase is extracted twice with dichloromethane. The organic layers are combined, washed with brine, dried over MgSO4, filtrated and concentrated in vacuo to afford the title compound (335 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:26]([O:25][C:23]([CH2:22][N:5]1[CH2:6][CH2:7][C:2]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)([CH3:1])[CH2:3][CH2:4]1)=[O:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(C2(C)CCNCC2)CC1
Reactant: CCOC(=O)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(C)(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.53 g (4.78 mmol) tert-butyl 4-(4-methyl-piperidin-4-yl)-piperazine-1-carboxylate and 1.1 mL (5.55 mmol) ethyl oxo-acetate (50% in toluene) in 50 mL THF was stirred for 1 h at RT. The reaction mixture was cooled to 0° C., 1.25 g (5.90 mmol) sodium triacetoxyborohydride was added batchwise and after elimination of the cooling bath the mixture was stirred overnight at RT. It was combined with 10 mL 20% NaHCO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by chromatography (Alox, DCM/EtOH 100:1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26]I)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:41]([C:44]1[N:45]=[CH:46][NH:47][CH:48]=1)([O-:43])=[O:42].O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:47]3[CH:48]=[C:44]([N+:41]([O-:43])=[O:42])[N:45]=[CH:46]3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCI)c3ccccc23)cc1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc([N+](=O)[O-])c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
A mixture of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-iodoethoxy)naphthalen-1-yl)urea (J. Med. Chem., 2003, 46, 4676-4686) (400 mg, 0.704 mmol), potassium carbonate (292 mg, 2.111 mmol) and 4-nitroimidazole (88 mg, 0.774 mmol) in DMF (2.0 mL) was placed in a pre-heated oil bath at 50° C. and stirred for 16 hr. The mixture was cooled to RT, poured into water (5.0 mL) and extracted with EtOAc (5.0 mL×2). The combined organic layers were dried, filtered and evaporated and the resulting residue was subjected to column chromatography (40 g), eluting with EtOAc to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-(4-nitro-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)urea (35) as a brown solid (276 mg, 60%): m/z 554 (M+H)+ (ES+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(OC)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC(C)C(=O)c1ccc(O)cc1

Procedure:
A mixture of the ester from Example 70, Step A (8.15 g), 48% HBr (40 ml) and acetic acid (80 ml) was refluxed for 4 days, then poured into water (250 ml) and extracted with ethyl acetate. The extracts were washed with water and dried (Na2SO4) and evaporated to an oil which was treated with 10% HCl in methanol (150 ml) for 18 hours. The volatiles were removed by evaporation and the residue was taken up in CH2Cl2, washed with water, brine, dried, evaporated to dryness then purified by chromatography on silica gel to provide the title compound, mp 89°-91° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2ccc(S(=O)(=O)O)cc2c1)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 7-aminonaphthalene-2-sulfonic acid, sodium salt (3 g, 12.2 mmol) in 70 mL of water is added solid NaOH (0.98 g, 24 mmol) at room temperature. The mixture is stirred for 30 minutes, and benzyl chloroformate (3.43 mL, 24 mmol) is then added. The resulting mixture is stirred over a period of 16 hours. The crude product is treated as in EXAMPLE 9, Part A, to give 4.18 g of crude N-CBz-7-aminonaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (4.18 g, 11 mmol) in 12 mL of thionyl chloride is heated at 80° C. for 3 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted with EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to give a brown oil. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (1.76 g, 4.68 mmol) as a beige solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:31])[C:20](=[O:30])[C:21]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:31])[C:20](=[O:30])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1nccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Temperature: 0 °C
Yield: 62 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-8-methoxy-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 1.19 mmol) was dissolved in dichloromethane (1 ml), and with stirring at 0° C., boron trifluoride (1.0 M in CH2Cl2, 3.9 mL) was added thereto, then gradually heated up to room temperature, and stirred at that temperature for 20 hours. The reaction solution was diluted with ethyl acetate, and with cooling with ice, this was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=1/0 to 9/1 and its polarity was stepwise increased up to 5/1) to obtain the intended compound (300 mg, 62%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]([O:14][CH3:13])=[O:16])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:14][CH3:13])=[O:16]
Reactant: Brc1ccc2ccc(Br)cc2c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)cc3c2)c1
Yield: 72 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromonaphthalene (2.00 g, 6.99 mmol), 3-(methoxycarbonyl)phenylboronic acid (3.15 g, 17.48 mmol), CsF (4.00 g) and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen. 150 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen for 2 days. The solvent was removed on a rotary evaporator. 100 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was re-crystallized from the mixture solvent of ethyl acetate and hexane (v/v=1:9) to give a pure product with a yield of 72% (2.0 g) based on 2,7-dibromonaphthalene. 1H NMR (300 MHz, DMSO-d6): δ 3.92 (s, 6H), 7.70 (t, 2H), 7.93 (d, 2H), 8.01 (d, 2H), 8.13 (m, 4H), 8.39 (m, 2H), 8.45 (d, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22]Cl)[O:19][CH2:18][CH2:17][O:16]1>CN(C)C=O>[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:12]=[O:13])=[CH:4]2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC1(CCCCl)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(CCCn2cc(C=O)c3ccccc32)OCCO1
Reaction time: 1 h

Procedure:
A suspension of 10.6 g. (0.44 mole) of sodium hydride in 50 ml. of dry dimethylformamide is treated dropwise with a solution of 58 g. (0.40 mole) of indole-3-carboxaldehyde in 200 ml. of dimethylformamide. An exothermic reaction is observed with the temperature rising to 70° C. The resulting mixture is stirred for one hour. To the resulting mixture there is added 69 g. (0.42 mole) of 2-methyl-2(3-chloropropyl)-dioxolane, and the mixture is maintained overnight at room temperature. The solvent is evaporated and the residue is extracted with ether, washed with water and dried over anhydrous magnesium sulfate. Following the evaporation of the solvent, the residue is crystallized from ether/hexane to give 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indolecarboxaldehyde, m.p. 52°-55° C.