Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 4.5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.23 g, 1.0 mmol), sodium hydride (60% in oil, 0.048 g, 1.2 mmol) and 1-iodopentane (0.26 mL, 2.0 mmol) to give the title compound (0.014 g). Used as is in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12](Cl)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:9][C:10]1[N:11]=[C:12]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cncc(Cl)n2)C[C@H](C)O1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
cis-2,6-Dimethylmorpholine (0.850 g, 7.38 mmol) was added to a suspension of 2,6-dichloropyrazine (1 g, 6.71 mmol) and potassium carbonate (2.78 g, 20.14 mmol) in anhydrous acetonitrile (50 mL). After addition, the reaction mixture was stirred at 90° C. for 3 hours. Crude LCMS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing the pure product were combined and concentrated under reduced pressure to give the title compound as a white solid (742 mg, 3.10 mmol, 46.1% yield). LC/MS [M+H]+=228/230.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:18]([N:25]1[C:33]2[C:32]([N:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)=[CH:31][N:30]=[CH:29][C:28]=2[C:27]([CH3:44])=[C:26]1[CH3:45])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH2:46]>C(O)(=O)C>[CH2:18]([N:25]1[C:33]2[C:32]([N:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)=[CH:31][N:30]=[CH:29][C:28]=2[C:27]([CH2:44][OH:46])=[C:26]1[CH3:45])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)cncc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC(=O)O
Product: Cc1c(CO)c2cncc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The compound (250.4 mg, 0.62 mmol) prepared in Example 35 was treated with a saturated sodium bicarbonate solution to obtain 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (216.8 mg, 0.59 mmol). A mmonium cerium (IV) nitrate (973 mg, 1.77 mmol) was added at room temperature to a solution of 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (216.8 mg, 0.59 mmol) in acetic acid (3 ml) and then stirred for 4 hours at 55° C. The reaction mixture was cooled to room temperature, added to water, and then extracted with ethyl acetate. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 ml). 2N Lithium hydroxide (2.5 ml) was added to the reaction mixture, which was then stirred for 1 hour at room temperature. The reaction mixture was neutralized with IN hydrochloride, concentrated under reduced pressure, and then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H -pyrrolo[3,2-c]pyridine, which was then dissolved in 10 ml of ethyl acetate and saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (200 mg, 76.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cc(Br)cc(OC)c1
Product: COc1cc(OC)cc(-c2ccco2)c1

Procedure:
1-Bromo-3,5-dimethoxybenzene was coupled with 2-furylboronic acid following the procedure for Example 21. 2-(3,5-Dimethoxyphenyl)furan was isolated as a colorless liquid (0.746 g, 79% yield).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[OH:21]>O>[OH:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[OH:21]
Reactant: COc1ccc(-c2coc3c(O)c(O)ccc3c2=O)cc1
Solvent: O
Product: Oc1ccc(C2COc3c(ccc(O)c3O)C2)cc1

Procedure:
As example 26, but using 7,8-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [J. Sci. Ind. Research (India) 20B, 334 (1961)] (540 mg) instead of 7-hydroxy-8-methyl-3-(4-methylphenyl)-4H-1-benzopyran-4-one. A crystalline precipitate is formed when water is added; it is filtrated off and washed with water. 3,4-Dihydro-7,8-dihydroxy-3-(4-hydroxyphenyl)-2H-1-benzopyran is obtained; m.p. 225°-226°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[ClH:21].C[O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C.Cl>C(OCC)C.O.C1(C)C=CC=CC=1>[OH2:10].[ClH:21].[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[C:24]([OH:30])=[O:23])=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)[C@@H]1CCCN1Cc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran, 0.9 g. (0.006 mole) of L-proline methylesterhydrochloride (available from the Aldrich Chemical Company) and 1.2 g. (0.012 mole) of triethylamine in 100 ml. of toluene is heated at reflux for about 100 hours. The mixture is extracted three times with 50 ml. portions of water. The organic layer is then extracted repeatedly with 50 ml. portions of 3N hydrochloric acid to remove all of the yellow product from the toluene layer. The aqueous layer is neutralized with 10 percent sodium carbonate solution. The aqueous layer is then extracted with dichloromethane until the water is colorless. The dichloromethane layer is dried, then evaporated to provide a residue which is diluted with diethyl ether to provide a brownish precipitate. The solid is removed by filtration, and the filtrate is concentrated to provide a residue. The residue is suspended in 50 ml. of concentrated hydrochloric acid diluted 1:1 with water. The mixture is heated at 90° C. for three hours. The mixture is cooled and filtered to provide a yellow precipitate. The precipitate is washed with water to provide N-[(2-nitro-3-phenylbenzofuran-5-yl)methyl]-L-proline hydrochloride hydrate, m.p. 109°-110° C., having the structure ##STR22##
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]Cl>CO>[I:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: ClI
Reactant: O=c1ccn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]1
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 2.75 h
Yield: 66 %

Procedure:
Dideoxyuridine (2.122 g, 10.0 mmol) was dissolved in 30 mL of warm methanol and, after cooling to 25°, iodine monochloride (4.06 g, 25 mmol, 2.5 eq, Fisher) in methanol (20 mL) was added over 5 minutes. The dark purple reaction mixture was heated in a 50° bath under nitrogen for 20 minutes and then immediately cooled in an ice-water bath. After standing without stirring for 165 minutes, the resulting precipitate was collected by filtration and washed with cold methanol (2×10 mL). Vacuum-drying overnight afforded 2.232 g (66%) of iodide 21 as off-white microcrystals. This material was used without further purification in the next reaction, but other preparations were purified by chromatography or recrystallization from boiling methanol (30 mL/g) to give white needles (mp d 160°-164°). NMR indicated that the crude precipitate was homogeneous, but also that the 5'-hydroxyl proton was very broad due to exchange catalyzed by trace impurities. Chromatographed or recrystallized materials afforded spectra in which this proton was, as usual, a sharp triplet.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3cccc(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.5 %

Procedure:
(2R,4S)-Methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (545 mg, 1.63 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature for 23 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (286 mg, 63.5%). 1H NMR (400 MHz, dmso) δ 1.09 (q, 1H), 1.36 (dq, 1H), 1.71-1.81 (m, 2H), 2.50-2.79 (m, 5H), 2.95-3.03 (m, 1H), 5.66 (s, 1H), 6.95-7.07 (m, 3H), 7.26-7.34 (m, 1H). HRMS Calculated for [C15H17FN2O2+H]+: 277.1352. Found: 277.1343
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=S)[C:11]([C:20]([O:22]CC)=O)=[N:10]2)=[CH:4][CH:3]=1.Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH:32][NH2:33])[CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>COCCOC.[Hg](Cl)Cl.C(OCC)(=O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:33][N:32]([CH:28]4[CH2:29][CH2:30][CH2:31][O:26][CH2:27]4)[C:20](=[O:22])[C:11]3=[N:10]2)=[CH:6][CH:7]=1
Reactant: NNC1CCCOC1
Reactant: CCOC(=O)c1nn(Cc2ccc(I)cc2)c2ncccc2c1=S
Agent: Cl
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: O=c1c2nn(Cc3ccc(I)cc3)c3ncccc3c-2nn1C1CCCOC1
Temperature: 50 °C

Procedure:
Ethyl 1-[(4-iodophenyl)methyl]-4-thioxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (2.0 g, 4.4 mmol), (±)-tetrahydro-2H-pyran-3-ylhydrazine hydrochloride [(Example 9, Step 2), 1.0 g, 6.6 mmol, 1.5 equiv], potassium carbonate (6.1 g, 44 mmol, 10 equiv), and mercury(II) chloride (1.2 g, 4.4 mmol, 1 equiv) were combined in 1,2-dimethoxyethane (20 mL) and N,N-dimethylformamide (4 mL) and stirred at ambient temperature for 1 hour. The mixture was warmed to 50° C. for 20 minutes, treated with additional potassium carbonate (1.0 g, 7.2 mmol, 1.6 equiv) and warmed to 60° C. for 30 minutes. The mixture was heated to 70° C. for 1 hour, cooled to ambient temperature, poured into water (200 mL) and ethyl acetate (200 mL) and filtered through a pad of Celite. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organic extracts were washed with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes; ethyl acetate), providing the titled compound as a red solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C@H:36]1([NH2:46])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1.CN1CCOCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[OH:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@@H:17]([C:18](=[O:20])[NH:46][C@H:36]3[C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:39][CH2:38][CH2:37]3)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)=[CH:14][CH:13]=1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a 0° C. solution of (S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1.32 g, 4.49 mmol) in DMF (30 mL) was added EDC (1.03 g, 5.39 mmol) followed by HOAt (0.73 g, 5.39 mmol). After 10 min, (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 0.66 mL, 4.49 mmol) and NMM (1.48 mL, 13.5 mmol) were added. The resulting reaction mixture was allowed to warm to room temperature over 4 h and then poured into a separatory funnel containing EtOAc and sat. aq. NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with 1N HCl, 10% LiCl and sat. NaCl and then dried over MgSO4, filtered and concentrated in vacuo. The crude oil was then purified by flash chromatography (gradient elution from 0 to 70% EtOAc/hexanes) to afford the title compound (1.25 g, 2.96 mmol, 66% over 3 steps) as a light yellow foam. 1H NMR (CDCl3) δ 7.18-6.86 (m, 4H), 6.84-6.67 (m, 1H), 6.58-6.39 (m, 1H), 6.04-5.74 (m, 2H), 4.94 (d, J=5.7 Hz, 1H), 4.78-4.61 (m, 1H), 4.56-4.41 (m, 1H), 4.20 (d, J=15.6 Hz, 1H), 3.34 (d, J=13.4 Hz, 1H), 3.02 (d, J=12.1 Hz, 1H), 2.81-2.60 (m, 2H), 1.87-1.68 (m, 2H), 1.67-1.54 (m, 2H), 1.53-1.37 (m, 9H); MS (ESI+) m/z 423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:14][OH:15])[NH2:5]
Reactant: CS(=O)(=O)c1ccc(C#N)c(Cl)c1
Reactant: NO
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(N)=NO)c(Cl)c1

Procedure:
The nitrile from Step B was dissolved into 100 mL of 1:1 ethanol/50% aqueous hydroxylamine then heated to reflux for 12 h. After evaporation of the solvent, the residue was dissolved into 400 mL of ethyl acetate then washed with saturated aqueous brine (150 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound, which was used without further purification. LC/MS 449.05 (M+1), 451.03 (M+3).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([CH2:14][N:15]2[N:43]=[C:19]3[CH2:20][C:21](=O)[C:22]4[CH2:23][S:24][N:25]=[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]([C:18]=43)=[N:16]2)[C:8]=1[CH3:44].CO.[CH:47]1([NH2:50])[CH2:49][CH2:48]1>C(O)(=O)C.O1CCCC1>[CH:47]1([NH:50][CH:21]2[C:22]3[CH2:23][S:24][N:25]=[C:26]([N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:17]4=[N:16][N:15]([CH2:14][C:9]5[C:8]([CH3:44])=[C:7]([O:6][CH3:5])[C:12]([CH3:13])=[CH:11][N:10]=5)[N:43]=[C:19]([C:18]=34)[CH2:20]2)[CH2:49][CH2:48]1
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
Sodium cyanoborohydride (1.89 g) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (5.71 g), methanol (50 mL), tetrahydrofuran (25 mL), cyclopropylamine (1.04 mL) and acetic acid (1.72 mL) under cooling in an ice bath, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure to obtain the title compound (5.91 g, 97%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:17][C:18]3[N:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]4OC(C)C)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C(O[Na])(C)=O.O=C1C(=CC2N=C3C(=CC=2)N=CC(C#N)=C3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:17][C:18]3[N:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22]([C:28]#[N:29])=[CH:21]4)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 30.3 %

Procedure:
To a mixture of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (40.9 mg, 0.17 mmol) (see Example 7) AcONa (160 mg, 1.95 mmol), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (33.6 mg, 0.18 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. (oil bath) for 2 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-{2-[2-(3-fluoro-phenyl)-ethylamino]-4-oxo-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a dark brown solid (20.8 mg, 30.1%). HR-ES (+) m/e calcd for C21H14FN5OS (M+H)+ 404.0976. found 404.0977.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:14]([N:19]([CH2:24][CH:25]4[CH2:27][CH2:26]4)[CH2:20][CH:21]4[CH2:23][CH2:22]4)=[C:15]([S:17][CH3:18])[N:16]=3)[CH:11]=[CH:12][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.C(OCC)(=O)C.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH:21]1([CH2:20][N:19]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:14]2[N:10]3[CH:11]=[CH:12][N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:28][CH3:29])[C:9]3=[N:16][C:15]=2[S:17][CH3:18])[CH2:23][CH2:22]1
Reactant: COc1cc(Br)ccc1-c1nccn2c(N(CC3CC3)CC3CC3)c(SC)nc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1-c1nccn2c(N(CC3CC3)CC3CC3)c(SC)nc12
Temperature: 95 °C
Reaction time: 4 h

Procedure:
N-[8-(4-Bromo-2-methoxyphenyl)-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dicyclopropylmethylamine (53 mg) was dissolved in N,N-dimethylformamide (0.22 mL), then zinc cyanide (23 mg) and tetrakistriphenylphosphine palladium complex (13 mg) were added thereto. After that, the mixture was heated under stirring at 95° C. for 4 hours and cooled to room temperature, and then ethyl acetate was added thereto. The precipitated insoluble matters were filtered off, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water, dried over magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (26 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]3[CH2:17][N:16]([C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[C:4]([F:24])[CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B(O)O)[CH:32]=2)[CH:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[CH:20]1([C:18]([N:16]2[CH2:17][CH:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[C:33]6[C:28]([CH:27]=[CH:26][NH:25]6)=[CH:29][CH:30]=5)=[CH:3][C:4]=4[F:24])[C:9](=[O:23])[NH:10][N:11]=3)[CH2:15]2)=[O:19])[CH2:22][CH2:21]1
Reactant: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc[nH]c4c3)cc2F)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
In a microwave vial purged with nitrogen, a mixture of 4-(4-bromo-2-fluorophenyl)-5-{[1-(cyclopropylcarbonyl)-3-azetidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (64 mg, 0.162 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.018 mmol), and 1H-indol-6-ylboronic acid (30 mg, 0.186 mmol) in 1,4-dioxane (1.5 mL) and 2M aq potassium carbonate (0.5 mL, 1.000 mmol) were stirred at 100° C. in an oil bath for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL), and then the layers were separated. The aqueous layer was neutralized using 1N aq HCl and then extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/ethyl acetate) provided the title compound as an impure solid. Subsequent purification of this solid by reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) followed by dessication in a vacuum oven over the weekend provided the title compound as a white solid (16 mg, 23%). MS(ES)+ m/z 432.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(=O)=O>CN(C=O)C>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (285 mg, 1.0 mmol), as prepared in step d, in DMF (5 mL) was added NaH (95%, 26 mg, 1.1 mmol). The reaction was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-4-piperidinemethanol methanesulfonate (293 mg, 1.0 mmol), as prepared in the preceding step, was added and the reaction mixture was stirred at 50° C. under nitrogen for 3 h. The reaction mixture was then partitioned between water (50 mL) and ethyl acetate (150 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (325 mg, 69%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.78 (d, 2H), 1.91 (m, 1H), 2.74 (t, 2H), 3.72 (d, 2H), 4.13 (m, 2H), 6.69 (m, 2H), 6.76 (dd, 1H), 7.16 (m, 1H), 7.37 (t, 1H), 7.62 (m, 2H), 7.95 (dd, 1H).