Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxyethoxy)-amide (1.33 g, 3.05 mmol) in methanol (40 mL) was added aqueous hydrochloric acid (6.7 mL, 1M, 6.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes then concentrated in vacuo to remove the methanol. The resultant residue was dissolved in 1:1 diethylether:ethyl acetate (30 mL) and aqueous saturated sodium hydrogen carbonate solution (30 mL) added. The resultant mixture was sonicated until a precipitate formed, the precipitate collected by filtration and washed with water then diethyl ether to yield the title compound as a yellow solid (1.12 g, 90%). LCMS (method A): RT=5.22 min, [M+H]+=409/411. 1H NMR (DMSO-d6, 400 MHz) 9.20 (1 H, s), 8.07 (1 H, s), 7.51 (1 H, dd, J=10.86, 2.22 Hz), 7.44 (1 H, s), 7.40 (1 H, d, J=9.33 Hz), 7.16 (1 H, ddd, J=8.61, 2.20, 1.07 Hz), 6.89 (1 H, d, J=9.31 Hz), 6.50 (1H, t, J=8.84 Hz), 4.63 (1 H, s), 3.65 (2 H, t, J=4.79 Hz), 3.46 (3 H, s).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([O:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[N:5]([CH3:12])[S:4]1(=[O:14])=[O:13])=[O:19]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Yield: 80.3 %

Procedure:
A mixture of 2-chloromethyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g; 2.08 mmol), 2,6-dichlorobenzoic acid (0.4 g; 2.09 mmol), and triethylamine (0.3 mL; 2.08 mmol) in 20 ml of toluene was allowed to react at 90°-100° C. for 15 hours and at 100° C. for 19 hours, and then cooled. The mixture was concentrated in vacuo and the residue was purified by flesh chromatography to afford 0.66 g (80%) of 2-(2,6-dichlorophenylcarbonyloxy-methyl)-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =methyl) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]([O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)OC1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)OC1(c2ccc(CC[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 96.2 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-isopropoxycyclopropyl)-benzene (Intermediate 64, 240.0 mg, 0.94 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (18.0 mg, 0.094 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (66.0 mg, 0.094 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (250.0 mg, 98%) was isolated by chromatography (0-3% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11](=[O:12])[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCOCCO)OCc1ccccc1
Yield: 67.5 %

Procedure:
2-(2-Aminoethoxy)ethanol (5.26 g, 50 mmol) and sodium hydroxide (2.1 g, 52.5 mmol) were dissolved in water (200 mL). The resulted solution was cooled in ice bath, followed by the dropwise addition of benzyl chloroformate. After the addition, the reaction mixture was continuously stirred in ice bath for another hour. The desired product was extracted with ethyl acetate (EtOAc, 200 mL). The EtOAc layer was washed with water (3×100 mL) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield the crude product. The product was further purified by flash column chromatography (SiO2, 1:2 Hexane:EtOAc) to give [2-(2-hydroxy-ethoxy)-ethyl]-carbamic acid benzyl ester as a clear oil (8.07 g, 67.5% yield). 1H-NMR (CDCl3, ppm) 7.35 (m, 5H), 5.34 (b, 1H), 5.10 (s, 2H), 3.71 (m, 2H), 3.56 (m, 4H), 3.41 (m, 2H), 2.20 (b 1H),. ESMS 240.0 (M+1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:38])[CH:34]=[CH:35][CH:36]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([C:37]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[O:38])[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1cccc(C(=O)N2CCOCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(=O)N4CCOCC4)c3)nn12
Yield: 12 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (3-Amino-phenyl)-morpholin-4-yl-methanone (0.179 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 22.40 mg of {3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-morpholin-4-yl-methanone as a lyophilized powder. (M+H)=430.8. 1H NMR (400 MHz, DMSO, d6) δ 9.58 (s, 1H), 8.95 (s, 1H), 7.78 (m, 2H), 7.71 (m, 1H), 7.48 (m, 1H), 7.26 (m, 1H), 7.18 (m, 1H), 7.07 (t, 1H, J=7.48 Hz), 6.94 (m, 2H), 6.89 (m, 1H), 3.96 (s, 3H), 3.73 (m, 2H), 3.36 (m, 4H), 3.17 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].N1CCNCC1.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: C1CNCCN1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Yield: 90.6 %

Procedure:
4-Methoxy-3-(2-phenylethoxy)benzaldehyde (51.26 g), dimethyl malonate (26.43 g), piperazine (1.70 g) and acetic acid (1.20 g) were refluxed by heating in 300 ml of benzene under azeotropic dehydration conditions for 8 hours. After the reaction solution was cooled to room temperature, it was washed with water, 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-dichloromethane to obtain 67.15 g of methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylacrylate.
Reaction SMILES: [N+:1]([C:4]1[C:13]([O:14][C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:28])([O-])=O.CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[Fe].CO.C(Cl)Cl.CCOC(C)=O.O>[NH2:1][C:4]1[C:13]([O:14][C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:28]
Reactant: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 5 h
Yield: 75.9 %

Procedure:
A mixture of 5-nitro-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (2.05 g, 5.43 mmol), MeOH (135 mL), H2O (30 mL) and glacial acetic acid (3.1 mL, 54 mmol) was treated at reflux with iron powder (3.01 g, 54 mmol). The reaction was monitored by mass spectrometry and was complete in 5 h. The volume of solvent was reduced under reduced pressure. EtOAc and dilute aqueous NaHCO3 were added. A brownish-green emulsion formed which was filtered through Celite. The mixture was extracted with EtOAc. The combined organic layer was washed with dilute aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. Purification by chromatography (EtOAc then 6% MeOH/CH2Cl2) gave the product as a tan solid (1.43 g, 4.12 mmol, 76%). The structure was confirmed by NMR and mass spectrometry. MS m/z 348 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.B1([C:33]2[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:9]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]=4[S:14][C:13]=3[C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5cccnc5)ccc4c23)cc1
Temperature: 110 °C

Procedure:
To a suspension of 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9) in DMF (0.1 M) were added the pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.5 equiv), 2 M Na2CO3 (3 equiv) and PdCl2dppf (0.05 equiv). The mixture was heated in the microwave reactor at 110° C. for 10 min. The reaction mixture was partitioned between EtOAc and saturated NaHCO3. The organic phase was separated, dried over MgSO4, filtered, evaporated and purified by flash chromatography (70:30 hexanes/EtOAc to 100% EtOAc) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[N:10]/[S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:17].[CH2:18]1[CH2:22]OC[CH2:19]1>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([C@H:9]([NH:10][S@@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH:18]([CH3:22])[CH3:19])=[CH:6][C:7]=1[CH3:8]
Reactant: C1CCOC1
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Product: Cc1cc([C@H](N[S@](=O)C(C)(C)C)C(C)C)cc(C)c1Cl
Temperature: 25 °C

Procedure:
In a separate flask a solution of imine INT 36 (5 g, 18.4 mmol) in THF (140 mL) was cooled in a dry ice bath under argon to −78° C. At this temperature the organozincate solution from above was added dropwise over a period of about 30 minutes. Stirring was continued for another hour before the resulting mixture was first quenched carefully with 10% ammonium chloride solution (40 mL), then water (50 mL). The reaction mixture was allowed to warm up to room temperature and was then extracted with Et2O (3×). The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:16])[C:13]([OH:15])=O)[CH2:7][CH2:6][CH2:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]1([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:16])[C:13]([N:50]1[CH2:51][CH2:52][N:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48][CH2:49]1)=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: C[C@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCN(c2ccccc2)CC1)N1CCCc2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a 0° C. solution of (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-propanoic acid (16.91 g, 57 mmol) in a (1:1) mixture of methylene dichloride and DMF (150 mL), was added HATU (21.7 g, 57 mmol). The reaction mixture was stirred at this temperature for 10 minutes. To this was added, 1-phenylpiperazine (8.7 mL, 57 mmol), followed by addition of sodium bicarbonate (4.79 g, 57 mmol). Upon completion of addition, the mixture was stirred at 0° C. for 4 hours. The reaction mixture was diluted with 250 mL of methylene chloride and washed with water (1500 mL) and 1M HCl solution (2×250 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 20-50% ethyl acetate in hexane gave (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-1-(4-phenylpiperizin-1-yl)propan-1-one as a white solid (11.84 g, 54%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=384.3; tR=3.59 min.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[N:3][CH:2]=1.[CH2:11](N(CC)CC)[CH3:12].ClC(OCC)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[N:1]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[N:3][CH:2]=1
Reactant: O=C(O)Cc1cncnc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)Cc1cncnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a stirred solution of 4.06 g of 5-pyrimidineacetic acid (F. Zymalkowski and E. Reimann, Arch. Pharm. 1966 299 362-7) and triethylamine (6.55 g) in methylene chloride (150 mL) at 0° C. was added ethyl chloroformate (6.38 g) followed by 4-dimethylaminopyridine (0.72 g). The mixture was stirred at 0° C. for 1 h, then the solution was diluted with methylene chloride (200 mL) and saturated ammonium chloride (150 mL) was added. After removal of the organic phase, the aqueous layer was extracted with methylene chloride (2×200 mL) and the combined organic extracts were dried over MgSO4 and concentrated to give 7.33 g of a crude oil. Purification by column chromatography, eluting with hexane; 50% ethyl acetate gave ethyl 5-pyrimidinylacetate (3.98 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[S:32][C:33]6[CH2:34][N:35]([CH3:40])[CH2:36][CH2:37][C:38]=6[N:39]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[S:32][C:33]6[CH2:34][N:35]([CH3:40])[CH2:36][CH2:37][C:38]=6[N:39]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: CN1CCc2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4C=O)cn(C)c3=O)sc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3cc(-c4ccnc(N5CCn6c7c(c(F)c6C5=O)CCCC7)c4CO)cn(C)c3=O)sc2C1
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
Compound 223a (160 mg, 0.27 mmol) was dissolved in methanol (30 mL), followed by addition of NaBH4 (31 mg, 082 mmol) at 0° C. The reaction mixture was stirred for 30 min and then quenched with water (10 mL). It was concentrated under reduced pressure and the residue was extracted with dichloromethane (3×30 mL). The combined organic phase was concentrated under reduced pressure and the residual was purified by reverse-phase prep-HPLC to afford 223 (56 mg, 35%) as a white solid. MS-ESI: [M+H]+ 590.2. 1H NMR (500 MHz, DMSO-d6): δ 9.92 (s, 1H), 8.64 (d, J=2.5 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.34 (d, J=5.0 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.46-4.41 (m, 2H), 4.19-4.17 (m, 2H), 4.08-4.03 (m, 1H), 3.88-3.85 (m, 1H), 3.60 (s, 3H), 3.42 (s, 2H), 2.63-2.58 (m, 6H), 2.41 (s, 3H), 2.34 (s, 2H), 1.78-1.76 (m, 2H), 1.68-1.66 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl-].[NH4+:11].[OH-].[NH4+]>O>[NH2:11][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)cc(O)c1
Temperature: 180 °C

Procedure:
A mixture of 5-methylbenzene-1,3-diol (6.0 g), ammonium chloride (3.0 g), water (9.0 mL), and ammonium hydroxide (6.8 mL, 33% in water) were sealed in a bomb and heated at 180° C. for 17 hours. The mixture was cooled to room temperature and the resulting precipitate collected by filtration. Crystallisation from water gave title compound, 1.7 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][C:8]1[CH:9]=[C:10]([S:15]C#N)[CH:11]=[CH:12][C:13]=1[OH:14]>O1CCCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:10]([SH:15])=[CH:9][C:8]=1[CH3:7]
Reactant: Cc1cc(SC#N)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml three-necked flask, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 3.5 g, 92.2 mmol) and tetrahydrofuran (THF, 50 ml) was added dropwise a solution of 3-methyl-4-hydroxy-phenyl thiocyanic acid (6.13 g, 37.1 mmol) in tetrahydrofuran (THF, 30 ml) at 0° C. After 30 min of stirring at 0° C., the mixture was warmed up to room temperature and then stirred for 1 hour at room temperature. The reaction was quenched by adding ethanol (10 ml), The value of pH of the mixture was adjusted to 3-4 by adding 6 M hydrochloric acid in an ice water bath. Then the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to give a crude product 4-hydroxy-3-methyl thiophenol as yellow oil.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:10]2=[N:11][CH:12]=1.[I:26]I>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([I:26])[N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:10]2=[N:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(F)cnc32)cc1
Reactant: II
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3cc(F)cnc32)cc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
7.54 ml of a solution of N-butyllithium at 1.6 N in hexane is added, dropwise, maintaining the temperature of the medium in the region of −75° C., to a solution, cooled to approximately −78° C., of 3.5 g of 5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 100 ml of tetrahydrofuran. After agitation for approximately one hour at the same temperature, a solution of 6.12 g of bisublimated iodine in 50 ml of tetrahydrofuran is run in dropwise. After the temperature has returned to around 20° C., the reaction mixture is diluted with 600 ml of ethyl acetate, washed three times with 100 ml of a 5% aqueous sodium thiosulfate solution, dried over magnesium sulfate, treated with vegetable black, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 30 ml of diisopropyl ether, filter-dried, washed with three times 5 ml of diisopropyl ether, and dried under reduced pressure (13 kPa). 3.6 g of 5-fluoro-2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][CH:36]=[C:23]5[C:22]([CH3:38])([CH3:37])[CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:37][C:22]1([CH3:38])[CH2:21][C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][C:25]=2[C:24]2=[N:34][NH:35][CH:36]=[C:23]12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3C(C)(C)C4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2-c2n[nH]cc21
Reaction time: 0.01 h
Yield: 63.4 %

Procedure:
tert-butyl(1-(4-(4,4-dimethyl-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (8 mg, 0.015 mmol) was dissolved in TFA (0.5 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜1 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (1 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (4 mg, 50% yield). 1H NMR (500 MHz, CH3OD) 8.18 (s, 1H), 7.63 (s, 1H), 7.47 (d, 2H), 7.41 (d, 2H), 7.19-7.33 (br m, 5H), 3.08 (s, 2H), 2.68-2.79 (br m, 2H), 2.51-2.64 (br m, 2H), 2.15-2.30 (br m, 1H), 1.87-2.01 (br m, 1H), 1.35 (s, 6H). LCMS (Method A): RT=3.03 min, M+H+=421.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-pyridyl) benzoic acid (100 mg, 0.2544 mmol) was dissolved in methylene chloride (30 ml), then p-anisidine (56 mg, 0.4552 mmol), triethylamine (75 mg, 0.7425 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (126 mg, 1.3663 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:4) to give the title compound (33 mg, 0.0963 mmol, 38%).