Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1cnccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cnccc1CO
Temperature: 15 °C
Reaction time: 8 h

Procedure:
3-Aminoisonicotinic acid (1 g, 7.24 mmol) was carefully added in 3 aliquots to a slurry of LiAlH4 (0.99 g, 26.1 mmol) in dry tetrahydrofuran (40 ml). The resulting mixture was stirred at 15° C. overnight. After cooling in an ice bath, the reaction mixture was quenched with careful addition of water (1 ml) dropwise, followed by 15% aqueous NaOH (1 ml), and then water (3 ml). The resulting solid was filtered, and washed several times with tetrahydrofuran. The filtrate was concentrated to give oil, which was purified by flash chromatography on silica gel using 5% CH3OH(NH3)/ethyl acetate as eluent to yield the title compound as a yellow oil. 610 mg.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[C@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][NH:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(Cl)Cl>[C@H:8]([NH:12][C:13]1[N:18]=[C:17]2[CH2:19][N:20]([C:2](=[O:1])[CH3:4])[CH2:21][CH2:22][C:16]2=[N:15][C:14]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1)([CH2:10][CH3:11])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@H](C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(C)=O)C2
Reaction time: 1 h

Procedure:
A solution of (R)—N-(sec-butyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (136.4 mg) in DCM (2.57 mL) at 0° C. was treated with pyridine (0.062 mL, 0.770 mmol), followed by acetic anhydride (0.048 mL, 0.513 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH, filtered through a Millipore® 0.45 μm syringe filter, and purified by HPLC Method A to give title compound, as a TFA salt, as a yellow solid (52.0 mg, 32.2% over two steps). 1H NMR (500 MHz, methanol-d4) δ ppm 0.98 (m, 3H), 1.26 (m, 3H), 1.67 (m, 2H), 1.96 (m, 2H), 2.13 (m, 2H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.73 (td, J=5.9, 1.5 Hz, 0.7H), 2.84 (td, J=5.9, 1.5 Hz, 1.3H), 3.08 (m, 2H), 3.43 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (m, 0.7H), 3.97 (m, 1H), 4.49 (m, 1H), 4.59 (m, 0.7H), 4.63 (s, 1.3H), 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.17 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 460.0.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:11]([CH2:13][NH2:14])[OH:12]>CC(C)=O>[C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:12][CH2:11][CH2:13][NH:14][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: NCCO
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)NCCO

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].S(O[CH2:22][CH2:23][S:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:4]1([CH2:3][CH2:2][O:1][CH2:22][CH2:23][S:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CC[C@H](SCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 69.8 %

Procedure:
To a solution of 0.21 g of 1-(2-hydroxyethyl)pyrrolidine in 5 ml of dimethylformamide, 0.076 g of NaH (60% dispersion in mineral oil) were added and the mixture was kept at reflux for 2 hrs, then 0.35 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml of dimethylformamide was added, the mixture was kept at reflux temperature for 4 hrs and 5 ml of water were added. The residue was extracted with methylene chloride, the organic layer was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.22 g of the title compound (I-bz) as a white pasty solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[H-].[Na+].CI.[C:15](OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:15])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CCOC(C)=O
Reactant: OCc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COCc1cc(Cl)nc(Cl)c1
Reaction time: 2 h

Procedure:
0.18 g of 2,6-dichloro-4-pyridinemethanol were dissolved into 5 ml of tetrahydrofuran (hereinafter referred to as “THF”), the solution was cooled by ice, and thereafter 0.04 g of sodium hydride (oil base, 60%) were added. To this, a solution of 0.15 g of methyl iodide dissolved in 2 ml of THF was added dropwise, and stirring was conducted for 2 hours at room temperature. Ethyl acetate was added to the reacted solution, and after the organic phase was washed by water, the organic phase was dried by adding sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 0.06 g of 2,6-dichloro-4-methoxymethylpyridine (Compound No. 1).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])([O-:3])=[O:2]
Reactant: Nc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Product: N#Cc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Yield: 37.4 %

Procedure:
A solution of 1-nitro-2-naphthylamine (875 mg, 4.65 mmol), 3-bromobenzonitrile (846 mg, 4.65 mmol), cesium carbonate (3.03 g, 9.30 mmol), tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.23 mmol) and (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (217 mg, 0.35 mmol) in toluenene (10 mL) was heated at 110° C. for 16 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound (503 mg, yield 37%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Cl)=[CH:15][CH:14]=2)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:15][CH:14]=2)[C:11](=[O:24])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCCl)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2-ethyl-3-[4-(3-chloropropoxy)phenyl]-4(3H)-quinazolinone (19 g, 55.6 mmol), piperidine (23.7 g, 278 mmol), potassium carbonate (11.5 g, 83.4 mmol) and potassium iodide (13.8 g, 83.4 mmol) were mixed in dimethylformamide (400 mL) and stirred at 80° C. for 24 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([OH:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[N:8]([OH:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2
Reactant: O=c1[nH]c2cc(F)ccc2n(O)c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2n(O)c1=O
Temperature: 0 °C
Yield: 15.8 %

Procedure:
In 22 ml of sulfuric acid was dissolved 1.6 g of 6-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione followed by addition of 0.9 g of KNO3. The mixture was reacted at room temperature for 3 hours, after which it was poured in ice-water. The resulting crystals were recovered by filtration to provide 310 mg of 6-fluoro-1-hydroxy-7-nitroquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]([CH3:50])([CH3:49])[C:31]([NH:33][C@H:34]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:48])[CH:40]=1)[C:35](O)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:35](=[O:36])[C@H:34]([NH:33][C:31](=[O:32])[C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:50])[CH3:49])[CH2:38][C:39]4[C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:41]([CH3:48])[CH:40]=4)[CH2:13]3)[C:11](=[O:18])[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3cn(C)c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture comprising 4-(4-fluorophenyl)-2-isopropyl-2,7-diazaspiro[4.5]decan-1-one (ASW MedChem) (243 mg, 0.744 mmol), (R)-2-(2-(tert-butoxycarbonylamino)-2-methylpropanamido)-3-(1-methyl-1H-indol-3-yl)propanoic acid (Intermediate 3D) (300 mg, 0.744 mmol) and DIPEA (0.519 ml, 2.97 mmol) in acetonitrile (3 ml) was treated with ®T3P (50% in DMF, 0.868 ml, 1.487 mmol) and stirred at RT for 19 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic portion was dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 2% MeOH in DCM afforded the title compound;
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH2:15][CH2:16][CH2:17]Br.O>CO>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:14][CH2:15][CH2:16][CH2:17][O:2][CH3:1]
Reactant: C[O-]
Reactant: COc1ccc(C=O)cc1OCCCBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCOc1cc(CO)ccc1OC
Temperature: 25 °C

Procedure:
A 30% solution of sodium methanolate in methanol (0.86 liter, 4.64 mol) is added dropwise at 61°-64° C. to a solution of 4-methoxy-3-(3-bromopropoxy)-benzaldehyde (844 g) in methanol (4.15 liters). The batch is stirred under reflux for a further 1.5 hours, then allowed to cool to room temperature, and water (150 ml) is added. The methanol is removed in a rotary evaporator (30° C. bath temperature) and the residue is then partitioned between diethyl ether (3×3 liters) and ice-cold 4N hydrochloric acid. The combined organic phases are washed with water and saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. The residue is purified by FC on silica gel (ethyl acetate/hexane 1:3) and the title compound is obtained in the form of an oil (498 g): Rf (ethyl acetate/hexane 1:2)=0.18.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)/[CH:3]=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)/[CH2:3][OH:4]
Reactant: C/C(C=O)=C\c1ccc(C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(C)cc1)CO
Reaction time: 3 h
Yield: 93.7 %

Procedure:
(2E)-2-methyl-3-(4-methylphenyl)-2-propenal (320 g, 2 mol, described in Tet. Let., 28, 1987, 1263) was dissolved under nitrogen in dry THF (1 liter). The solution was cooled in an ice-water bath and solid lithium aluminum hydride (25 g, 0.63 mol) was added portion-wise at a rate such as to maintain the internal temperature below 20° C. The cooling bath was removed and the reaction stirred for 3 hours. It was then recooled in an ice-water bath. Water (25 ml) was added slowly to the reaction, followed by 5% aqueous NaOH (75 ml) and more water (25 ml). The cooling bath was removed and the reaction stirred until a white slurry was obtained (30 minutes). Solid anhydrous sodium sulfate (100 g) was added to the reaction. After stirring for an additional 15 minutes, the solid was filtered off and thoroughly rinsed with diethyl ether. The filtrate was then concentrated under vacuum. The product was purified by distillation through a 20-cm Widmer column. 304 g of the desired alcohol were obtained (1.78 mol, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21]O)=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1.CS([Cl:29])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([CH2:21][Cl:29])=[C:16]([CH3:23])[C:15]=3[CH:24]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(CCl)CCCc2ccc(NC(=O)c3ccc(Cl)cn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.3 %

Procedure:
To a solution of 5-chloro-N-(8-(hydroxymethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide from step 3B (52 mg, 0.15 mmol) in dichloromethane (1 mL) was added methanesulfonylchloride (0.015 mL, 0.20 mmol) and DIPEA (0.048 mL, 0.27 mmol). The mixture was stirred at rt for 20 h. The mixture was subjected to chromatography (hexanes-100% EtOAc) to give 5-chloro-N-(8-(chloromethyl)-9-methyl-6,7-dihydro-5H-benzo[7]annulen-2-yl)picolinamide (30 mg, 0.083 mmol, 55% yield). LCMS (M+H)+=361.2. 1H NMR (500 MHz, chloroform-d) δ 9.81 (br. s., 1H), 8.58 (dd, J=2.3, 0.6 Hz, 1H), 8.27 (dd, J=8.4, 0.6 Hz, 1H), 7.90 (dd, J=8.4, 2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.1, 2.3 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.37 (s, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.21 (s, 3H), 2.17 (quin, J=7.1 Hz, 2H), 2.05-1.98 (m, 2H)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C@@H:3]([CH2:11][OH:12])[C@@H:2]1[CH2:13][OH:14].[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:18][O:12][CH2:11][C@@H:3]1[O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][C@H:2]1[CH2:13][OH:14]
Reactant: CI
Reactant: OC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
(2S,3S)-1,4-dioxaspiro[4.5]decane-2,3-diyldimethanol (65 g, 321.4 mmol) was dissolved in DMF (500 mL) and cooled in an ice bath. 60% Sodium hydride (15.43 g, 385.7 mmol) was added slowly and the reaction was stirred for 30 minutes in an ice bath then warmed to ambient temperature for 2 hours. Iodomethane (20.05 ml, 321.4 mmol) was added and the reaction was stirred at ambient temperature overnight. The majority of the DMF was removed on a rotary evaporator, and the residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified over 1 Kg of SiO2 (20 to 40% EtOAc in hexanes) to afford ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)methanol (31.3 g, 144.7 mmol, 45.03% yield) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH:27][NH:28][C:29](=[O:37])[CH:30]([CH3:36])[CH2:31][C:32]([F:35])([F:34])[F:33])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.CC#N>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]3[O:37][C:29]([CH:30]([CH3:36])[CH2:31][C:32]([F:34])([F:35])[F:33])=[N:28][N:27]=3)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2
Reactant: CC(CC(F)(F)F)C(=O)NNC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CC(CC(F)(F)F)c1nnc(C23CCC(c4nnc(-c5ccccc5C(F)(F)F)n4C)(CC2)CC3)o1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To 13-B in toluene (3 mL) was added thionyl chloride (2 mL) and, fitted with a reflux condenser, the solution was heated to 85° C. under a nitrogen atmosphere. After 1 hour the solvent was stripped off in vacuo. The residue was dissolved in CH3CN (4 ml) and product was purified by Masslynx reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed and the product lyopholyzed from CH3CN and water to afford 13-C as a white solid. MS (ESI+)=514.22 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.85-7.83 (m, 1 H), 7.72-7.68 (m, 2 H), 7.52 (t, 1 H), 3.48 (s, 3 H), 3.46 (m, 1 H), 2.86-2.74 (m, 1 H), 2.51-2.39 (m, 1 H), 2.28 (m, 6 H), 2.14 (m, 6 H), 1.50 (d, 3 H) ppm.
Reaction SMILES: NC1C=C(C=CC=1)C([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=O.C(N(C(C)C)CC)(C)C.C(C1C=CC(C(C2C=CC(CC(C)C)=CC=2)Cl)=CC=1)C(C)C>CN(C)C=O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Nc1cccc(C(=O)c2c[nH]c3ccccc23)c1
Agent: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Reaction time: 14 h
Yield: 210.1 %

Procedure:
To a solution of 3-(3-aminobenzoyl)indole (1.2 g) in N,N-dimethylformamide (12 ml) were added diisopropylethylamine (1.77 ml) and a solution of bis(4-isobutylphenyl)chloromethane (1.92 g) in N,N-dimethylformamide (5 ml) at 25° C., and the mixture was allowed to stand at the same temperature for 14 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (50 g) eluting with a mixture of ethyl acetate and chloroform (1:20) to give 3-[3-bis(4-isobutylphenyl)methylamino]benzoyl]indole (1.25 g) as pale yellow amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[I-:14].[K+].S(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[I:14]
Reactant: [I-]
Reactant: Cc1ccc(N)c(F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: Cc1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a suspension of 2-fluoro-4-methylaniline (2.0 g, 16 mmol) in aqueous sulfuric acid (˜7 N) was added an aqueous solution of sodium nitrite (1.10 g, 16 mmol, 10 mL water) dropwise at 0° C. and the resulting light orange solution was stirred for 30 minutes. This solution was carefully poured into an aqueous solution of potassium iodide (3.98 g, 24 mmol, 16 mL water) at 80° C. and the resulting red mixture was stirred 1.5 hours at 80° C., and overnight at 50° C. The reaction was cooled to room temperature, poured into water (300 mL), and sodium bisulfite added until the light yellow color remained constant. The aqueous was extracted with diethyl ether (2×125 mL) and the organics were combined, washed with brine, dried (sodium sulfate), filtered, and the ether evaporated to give 2.5 g (66%) of crude product as a yellow green oil. Used without further purification. 1H NMR (CDCl3) δ2.32 (s, 3H,), 6.72 (dd, 1H, J=1.28 Hz, J=8.05 Hz), 6.88 (dd, 1H, J=1.28 Hz, JH=8.97 Hz), 7.58 (dd, 1H, J=1.08 Hz, J=6.78 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:26]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:20][CH2:21][N:22]([CH3:26])[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=c1[nH]n(C2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-(4-chlorophenyl)-1-piperidin-4-yl-5-pyridin-4-yl-1,2-dihydro-pyrazol-3-one (0.12 g, 0.34 mmol) in anhydrous methanol (3 mL) was cooled to 0° C. in an ice-water bath and added formaldehyde (3 mL; 37 wt. % in water), followed by sodium borohydride (0.039 g, 1 mmol). After stirring for 1 hour, the reaction was quenched with water and diluted with methylene chloride. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The title compound was isolated as a yellow amorphous solid by preparative HPLC. MS (ES+): 369.2 (M+H)+; (ES−): 367.1 (M−H)−.