Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.C[O:21][CH2:22][CH2:23]OCCOC>>[OH:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:17][OH:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: C1CO1
Reactant: COCCOCCOC
Agent: [Na+]
Agent: [OH-]
Product: OCCOc1ccc(-c2ccc(OCCO)cc2)cc1

Procedure:
1.5 mol (280 g) of 4,4'-dihydroxybiphenyl is dissolved in 1,263 g of diethylene glycol dimethyl ether and, after adding catalytic amounts of sodium hydroxide, oxethylated with ethylene oxide in the manner described in Example 2.1 at 170° C. to obtain 4,4'-bis(2-hydroxyethoxy)biphenyl. After subjecting the reaction mixture to an analogous working up step, the diol is obtained, mp 201°-202° C. (from tetrahydrofuran/cyclohexanone). The 1H NMR spectrum confirms the constitution of the diol.
Reaction SMILES: [C:1]([N:8](C1C=CC=CC=1O)[C@H:9]([C:12]([OH:14])=O)[CH2:10][SH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCO[CH2:25][CH2:24]1.ClC(OCC)=O.[BH4-].[Na+].[O:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>O>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][S:11][C:24]1[CH:25]=[CH:38][CH:39]=[CH:40][C:41]=1[OH:37])[CH2:12][OH:14])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(c1ccccc1O)[C@@H](CS)C(=O)O
Reactant: C1CCOC1
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CSc1ccccc1O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
74.45 g (0.237 mol) of N-Boc-(2-hydroxyphenyl)-L-cysteine (VIII) and 300 ml of distilled tetrahydrofuran are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to −10° C. and then 26 ml (0.236 mol) of N-methylmorpholine are added dropwise. After stirring for 15 minutes at −10° C., 22.7 ml (0.237 mol) of ethyl chloroformate are introduced dropwise. The mixture is stirred at −10° C. for 30 minutes and then the precipitate formed is filtered off under cold conditions. The filtrate is recovered directly in a round-bottomed flask and cooled to −10° C. 13.45 g (0.35 mol) of sodium borohydride in solution in 50 ml of water are then introduced in such a way that the temperature of the mixture does not exceed −10° C. At the end of the addition, the mixture is reheated to ambient temperature and stirred for 12 hours. The mixture is concentrated under reduced pressure, acidified using 250 ml of an aqueous potassium hydrogensulfate solution (2N) and extracted with dichloromethane. The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. 61.41 g (0.205 mol) of the title compound (IXa-1) are obtained in the form of a yellow oil, which is used without additional purification in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1>ClCCl.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ccncc1
Reactant: COc1cccc(C2CCCN2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(C2CCCN2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.5 %

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)pyrrolidine (5.42 g) in dry dichloromethane (153 ml) was added sodium hydride (97%, 1.69 g) followed by 4-picolyl chloride hydrochloride (5.26 g), under nitrogen, at 0° C. The reaction mixture was stirred for 15 hrs at ambient temperature and diluted with water and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (4 times). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/ether). The appropriate fractions were collected and evaporated to afford 5.70 g (70%) of 2-(3-methoxyphenyl)-1-(4-pyridinylmethyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].[ClH:5].[NH2:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:18](Br)=[CH:17][N:16]=[C:15]3[NH:20][CH:21]=[C:22]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=4)[C:14]=23)[CH2:9]1>>[ClH:5].[Cl:5][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH2:8][C@@H:7]([NH:6][CH:2]([CH3:3])[CH3:1])[CH2:9]2)=[C:14]2[C:22]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=3)=[CH:21][NH:20][C:15]2=[N:16][CH:17]=1
Reactant: NC[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: CC(C)=O
Agent: Cl
Product: CC(C)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 64 %

Procedure:
(R)—N-(5-Chloro-4-(3-(isopropylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (30 mg, 64% yield) was prepared as described in Example 6, using propan-2-one (104 mg, 1.80 mmol) and substituting (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (43 mg, 0.089 mmol) for (S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride. 1H NMR (400 MHz, D2O) δ 9.20-9.19 (m, 1H), 8.88-8.83 (m, 2H), 8.17 (s, 1H), 8.05-7.80 (m, 1H), 7.44-7.43 (m, 1H), 3.86-3.73 (m, 1H), 3.50-3.44 (m, 1H), 3.41-3.31 (m, 2H), 3.18-3.10 (m, 1H), 3.06-2.98 (m, 1H), 2.04-1.95 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.47 (m, 1H), 1.35-1.25 (m, 1H), 1.14 (d, 3H), 1.10 (d, 3H); LCMS (APCI+) m/z 413.1 (M+H)+, Retention time=2.06 minutes (Method 2).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[C:9]([N:19]2[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]2)=[C:10]([F:18])C(F)=[C:12]([C:14](=O)[CH3:15])[CH:13]=1)(C)(C)C.[S].[I-].[K+].[NH3:42].C[S:44]([CH3:46])=O>O>[CH3:26][C@H:21]1[O:22][C@@H:23]([CH3:25])[CH2:24][N:19]([C:9]2[C:8]([CH2:7][OH:6])=[CH:13][C:12]3[C:14]([CH3:15])=[N:42][S:44][C:46]=3[C:10]=2[F:18])[CH2:20]1
Reactant: CS(C)=O
Reactant: N
Reactant: CC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: [I-]
Agent: [K+]
Agent: [S]
Solvent: O
Product: Cc1nsc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Temperature: 100 °C

Procedure:
A mixture of 1-[5-(tert-Butyldiphenylsilanyloxymethyl)-4-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-2,3-difluorophenyl]ethanone (Intermediate 9, 0.5 g, 0.92 mmol), sulfur powder (0.06 g, 1.8 mmol), potassium iodide (0.08 g, 0.4 mmol) and 25% aqueous ammonia solution (10 mL) in DMSO (10 mL) was heated in a sealed tube at 100° C. for 4 hours. The reaction mixture was cooled and water was added. The mixture was extracted with ethyl acetate, which was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (1:9 ethyl acetate:hexanes) to afford product as a yellow solid. Yield: 0.18 g (63%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14])([O-])=O.CO>ClCCl.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([C@@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:9]2=[O:14]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (1.3 g, 0.0050 mol) in methanol (40 mL, 1 mol) and dichloromethane (5 mL) was added palladium on charcoal (0.2 g, 0.001 mol) and stirred under hydrogen (1 atm) for 2 h. The reaction mixture was filtered over celite and the filtrate removed under reduced pressure to yield the pure product as an off white solid. MS m/z=232.5 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.O[CH2:25][CH:26]1CC1>CCO.CCO.CCO.CCO.[Ti]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH:20]3[CH2:26][CH2:25]3)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reaction time: 8 h

Procedure:
A mixture of 6.22 g (20 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 1.52 g (6.7 mmol) of tetraethyl orthotitanate and 10 g (194 mmol) of hydroxymethyl-cyclopropane is stirred at 115° overnight, evaporated to dryness, the residue is taken up in methylene chloride and stirred for 0.5 hour with about 50 ml of water. The emulsion obtained is filtered through siliceous earth, the organic phase is washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from ethyl acetate there is obtained cyclopropylmethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 189-190°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[N:6]=[CH:18][CH:13]=[CH:14]2
Reactant: Cc1cc(Br)ccc1N
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Cc1cc(Br)cc2cccnc12
Reaction time: 3 h

Procedure:
A mixture of 10 g of 4-bromo-2-methylaniline, 3.3 g of ferrous sulfate, 20.4 g of glycerol, 4.06 g of nitrobenzene and 11.5 ml of concentrated sulfuric acid was heated gently. After the first vigorous reaction, the mixture was boiled for 3 h under reflux and then evaporated to remove t nitrobenzene. The solution was added std. aq.NaHCO3 and extracted with dichloromethane, dried with Na2SO4 and concentrated to give solid. The solid was purified with flash column chromatography to return the title compound (9.5 g, 80%). 1H NMR (CDCl3, 300 MHz) δ 8.92 (m, 1H), 8.01 (m, 1H), 7.81 (d, 1H), 7.66 (m, 1H), 7.43 (m, 1H), 2.79 (s, 3H).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([O:8]C)=[O:7])#[N:4].[CH2:10]1[O:20][C:19]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=2[O:11]1.Cl>>[C:3]([C:5](=[CH:15][C:14]1[CH:17]=[CH:18][C:19]2[O:20][CH2:10][O:11][C:12]=2[CH:13]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: COC(=O)CC#N
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1ccc2c(c1)OCO2)C(=O)O
Temperature: 95 °C
Reaction time: 16 h

Procedure:
To an aqueous solution containing 14.20 g of sodium hydroxide and 33.75 g of methyl cyanoacetate, 30.32 g of 3,4-(methylenedioxy)benzaldehyde was added, followed by stirring at 95° C. for 16 hours. After completion of the reaction, an aqueous diluted hydrochloric acid solution was added to obtain a pale yellow solid. The resultant solid was recrystallized from ethanol to obtain a crystal having a melting point of 233° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([O:12]C)=[O:11])[CH:7]=1.[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23]>CCOCC>[Cl:1][C:2]1[C:3]([O:21][CH2:23][CH2:22][O:24][CH2:25][CH3:26])=[CH:4][C:5]([O:19][CH3:20])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CCOCCBr
Reactant: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Solvent: CCOCC
Product: CCCCCC(CC(=O)O)c1cc(Cl)c(OCCOCC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45a-(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 56A) and 2-ethoxyethyl bromide, the corresponding. ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=1)[CH2:7][CH:6]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:5]2.C[N:43]([CH3:46])C=O>>[C:46]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:17]=1)[CH2:7][CH:6]([NH:37][S:38]([C:41]1[CH:4]=[CH:3][CH:2]=[CH:11][CH:10]=1)(=[O:40])=[O:39])[CH2:5]2)#[N:43].[C:46]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([N:37]([CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1)[S:38]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:40])=[O:39])[CH2:5]2)#[N:43]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)NC1Cc2cc(Br)ccc2N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Product: N#Cc1ccc2c(c1)CC(N(Cc1ccccc1)S(=O)(=O)c1ccccc1)CN2Cc1c[nH]cn1
Product: N#Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)CN2Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 75 %

Procedure:
The title compound (2.5 g, 75%) was obtained from compound N-[6-Cyano-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-quinolinyl]-N-(phenylmethyl)benzenesulfonamide (2.68 g, 5.3 mmol) in a manner similar to the preparation of N-[6-Bromo-1,2,3,4-tetrahydro-1-[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-3-quinolinyl]methanesulfonamide except dimethylformamide was employed instead of acetonitrile as the solvent. The white solid was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)(Cl)Cl.[W]>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(C)cc1
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1ccc(CBr)cc1

Procedure:
A solution of ethyl 4-methylphenoxyacetate, which may be prepared as set forth by S. G. Powell and R. Adams in J. Am. Chem. Soc., 42, pages 646-658 (1920), (18.21 g, 0.094 mole) in 100 ml of dry CCl4 was stirred and refluxed under a 350 watt tungsten lamp. A solution of 15 g (0.094 mole) of bromine in 100 ml of CCl4 was added by means of an addition funnel over a period of 30 minutes. The colorless reaction mixture was evaporated in vacuo and the resulting oil distilled bulb-to-bulb taking a middle cut at 120°-140° at 0.17 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C)[CH:13]=[O:14]>CO>[CH3:13][O:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(O)CCCCCCBr
Solvent: CO
Product: COCCCCCCC(=O)O

Procedure:
The title compound was prepared by the method of Example 1 using 7-bromoheptanoic acid (50 g, 239 mmol) instead of 12-bromoundecanoic acid and dimethylformamide (300 mL) instead or methanol as the solvent. Concentration afforded the title compound (30 g) as a pale yellow liquid and the structure verified by NMR.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30].O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: COc1ccc(OC)c(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 81.8 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2,5-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (200 mg, 0.48 mmol, prepared in Synthetic Example 21) in DMF (5 ml) was added hydrazine monohydrate (80%, 100 μl, 2.50 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (162 mg, 82%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12]1.[CH:24]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][C:35](O)=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:26])[CH3:25]>C(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:15][CH2:14][N:13]([C:35](=[O:36])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:29]=2)[CH2:12]1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: CC(C)Oc1cccc(CC(=O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1cccc(CC(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C

Procedure:
Triethylamine (22.5 ml) and 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)pyrrolidine (22 grams) are added to a solution of 16 grams of 3-isopropoxyphenylacetic acid in 500 ml of methylene chloride. The mixture is cooled to 0° C. and 42.6 grams of benzotriazolyl-N-oxytrisdimethylaminophosphonium hexafluorophosphate are then added and the reaction mixture is allowed to warm up to room temperature. After thirty minutes, the mixture is concentrated under vacuum and the residue is taken up in diethyl ether and washed successively with water, a dilute sodium hydroxide solution, a saturated sodium chloride solution, a dilute hydrochloric acid solution, a saturated sodium chloride solution, and a solution of sodium bicarbonate. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title intermediate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:29]1([CH2:28][O:27][C:15]2[CH:14]=[CH:13][C:12]([CH2:10][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:26][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)c1cc(CN2CCCC2)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Pyrrolidine (25 uL, 0.30 mmol) and acetic acid (17 uL, 0.30 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.30 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50° C. then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight then quenched with NaHCO3 solution (7 ml) and extracted with dichloromethane (5 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give a yellow solid. The residue purified by MDAP to yield the title compound as an opaque solid. 34 mg.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C>C1COCC1.CCOCC>[CH3:6][C:7]1[S:8][C:9]([B:16]([OH:17])[OH:15])=[CH:10][CH:11]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
n-BuLi (2.38M, 16 ml) was slowly added to a solution of 2-methyl thiophene (3.0 g, 31 mmol) in THF (20 ml) at -78° C. The solution was kept at -78° C. for 10 min. then warmed to 0° C. for an additional 0.5 hr. The solution was then transferred by steel canula under nitrogen into a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether (15 ml) at -78° C. The resulting milky white solution was stirred at -78° C. for 20 min. then at room temperature for 2 hours. The reaction was quenched by the addition of 10% aqueous HCl (5.0 ml) and the solution was extracted into ether. The combined ether extracts were extracted with 10M NaOH (2×30 ml), the aqueous extracts were acidified with dilute HCl to pH 2 and extracted into ether (3×25 ml). The combined ether extracts were washed once with water (10 ml), once with brine (10 ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronic acid as a light brown solid. This was used in the next step with no further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29]([OH:32])[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34]C(OCC)=O>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:34]=[CH:33][C:26]([CH2:27][CH2:28][CH2:29][OH:32])=[C:25]([CH3:24])[C:30]=2[CH3:31])=[CH:17][CH:16]=1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCCO)ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Br)cc2)c1C

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-bromophenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, (c) then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedure in Example 1, Step E, and Example 2.
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17]C>>[C:1]1([C:7](=[O:12])[C:8]([O:10][CH2:11][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCO
Reactant: COC(=O)C(=O)c1ccccc1
Product: CCCCCCOC(=O)C(=O)c1ccccc1
Yield: 87 %

Procedure:
16.42 g (0.1 mol) of methyl phenylglyoxalate is transesterified as described in example 1.1, using 1-hexanol instead of methoxyethanol. 21.33 g (87%) hexyl phenylglyoxalate are obtained as a colorless liquid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1[C:44]2[NH:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:38]=[CH:37][C:36]=1[CH2:45][CH:46]1[CH2:50][CH2:49][NH:48][CH2:47]1>CC#N.CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([C:27]([N:48]2[CH2:49][CH2:50][CH:46]([CH2:45][C:36]3[CH:37]=[CH:38][C:39]4[CH2:40][CH2:41][CH2:42][NH:43][C:44]=4[N:35]=3)[CH2:47]2)=[O:33])[CH2:3][CH2:4]1)[CH3:13]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1cc2c(nc1CC1CCNC1)NCCC2
Reactant: CCOC(=O)CC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCN(C(=O)N2CCC(Cc3ccc4c(n3)NCCC4)C2)CC1
Reaction time: 16 h

Procedure:
To a solution of 6-2 (31 mg, 0.15 mmol), DIPEA (77 μL, 0.44 mmol), and CH3CN (1.5 mL) at 0° C. was added dropwise a solution of triphosgene (15 mg, 52 mmol) in CH3CN (150 μL). Afer 30 min., a solution of 1-8 (43 mg, 0.15 mmol) and DIPEA (77 μL, 0.44 mmol) in DMF (0.8 mL) was added, followed by removal of the cooling bath. After 16 hrs, the reaction mixture was poured into EtOAc and sat. NaHCO3. The EtOAc portion was then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% ethanol/EtOAc) gave 6-3 as a colorless oil.