Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[NH:16])[O:18][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[O-]
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 0.08 h

Procedure:
A mixture of 10.7 (0.05 ml) of 5-(4-nitrophenyl)-2-furonitrile and 500 ml of anhydrous methanol was heated on a steam bath until a solution resulted. After slight cooling, a catalytic amount (0.1 g) of powdered sodium methoxide was added with stirring. The solution turned quite dark and in about 5 minutes, solid started to separate. The mixture was allowed to stir for an hour and then was filtered. The solid was washed with anhydrous methanol and air dried. The yield was 10.0 g (81%). Recrystallization from 200 ml of ethyl acetate gave 6.0 g of analytically pure methyl 5-(4-nitrophenyl)-2-furancarboximidate, m.p. 184°-188°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:51][CH:52]1[C:61]2[C:56](=[C:57]([CH2:62]O)[CH:58]=[CH:59][CH:60]=2)[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:53]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[N:14]([CH2:62][C:57]3[CH:58]=[CH:59][CH:60]=[C:61]4[C:56]=3[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:65])[CH2:53][CH:52]4[F:51])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1Cc2c(CO)cccc2C(F)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CN(C(=O)OC(C)(C)C)CC5F)c3cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask containing N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3) (87 mg, 0.187 mmol), resin bound (PS) TRIPHENYLPHOSPHINE (159 mg, 0.350 mmol), tert-butyl 4-fluoro-8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-7) (89 mg, 0.316 mmol) & DI-TERT-BUTYL AZODICARBOXYLATE (97 mg, 0.421 mmol) was added THF (2 mL). The reaction mixture was then capped (not under N2) & agitated at room temperature. Followed by LC/MS. After ˜10 min at room temp r×n mixture (clear tan & resin), filtered (to remove resin), then concentrated. Purification by silica gel chromatography (0-50%; EtOAc/Hex; 24 g ISCO); desired fractions concentrated, then the resulting residue was repurified by reverse phase chromatography (10-100% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions free based (suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated) to yield tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13](=[O:26])[N:14]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:15]=1[CH3:16].C(OC([NH:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:37]COS(C)(=O)=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C(OC(C)=O)(C)C.CS(O)(=O)=O>CN(C=O)C.O>[NH2:35][C@H:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:37][N:12]1[C:11](=[O:27])[C:10]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[C:15]([CH3:16])[N:14]([CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[C:13]1=[O:26]
Reactant: COc1cccc(-c2c(C)n(Cc3c(C)cccc3F)c(=O)[nH]c2=O)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1cccc(-c2c(C)n(Cc3c(C)cccc3F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1Cl
Temperature: 50 °C
Reaction time: 17 h

Procedure:
7b (120 g, 0.271 mol), 1d (128.34 g, 0.407 mol) and K2CO3 (93.64 g, 0.407 mol) were charged to the reaction vessel under an inert atmosphere and suspended in DMF. The resulting slurry was warmed to 50° C. and stirred for 17 hours. The reaction was incomplete so additional 1d (50 g, 0.158 mol) and DMF (300 mL) were added. The reaction was complete after 32 hours and the mixture was cooled to RT. i-PrOAc (1 L) and water (1 L) were added and stirred for 30 minutes. The layers were separated and MeSO3H (52.8 mL, 0.813 mol) was added slowly to the organic layer controlling the exotherm (24.4° C. to 41.0° C.). The mixture warmed to 60° C. and was stirred for 3 hours. The mixture was cooled to RT and was added slowly to a mixture of K2CO3 (186.99 g, 1.35 mol) in water (975 mL). After stirring for 15 minutes, the organic layer was separated and extracted with a H3PO4 solution (94 g of 85% H3PO4 in 975 mL water). The aqueous layer was slowly added to K2CO3 (186.99 g, 1.35 mol) in water (975 mL), followed by i-PrOAc (1100 mL). The mixture was stirred for 10 minutes and the layers separated. The i-PrOAc layer was dried (NaSO4) and concentrated to give 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 7c as a foaming solid (145.5 g, 0.25 mol, 95% crude yield, uncorrected for purity).
Reaction SMILES: CO.B(F)(F)F.[CH3:7]COCC.[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([O:21][CH3:7])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1C(=O)CC(C(=O)O)C1c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CC(=O)N(C)C1c1ccccc1

Procedure:
To 400 ml. of methanol containing 25 ml. of boron trifluoride etherate was added 60 g of 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylic acid and the solution refluxed for 8 hours. Concentration in vacuo provided an oil which was dissolved in chloroform. The chloroform solution was washed with a saturated sodium carbonate solution, a saturated sodium bicarbonate solution, water, a saturated sodium chloride solution and dried (Na2SO4). Titration and concentration in vacuo provided 63 g. of an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Si:10]([O:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20]Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH2:18][CH:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1])([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCC(CCl)OC1CCCCO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Product: CC(C)(C)[Si](C)(C)OCC(Cn1cc([N+](=O)[O-])nc1Cl)OC1CCCCO1
Yield: 49.5 %

Procedure:
Similar to Example 28, the objective compound was synthesized from 2-chloro-4-nitroimidazole (2.15 g) and 1-(tert-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane (12 g), there was obtained 1-[3-(tert-butyldimethylsilanyloxy)-2-(tetrahydropyran-2-yloxy)propyl]-2-chloro-4-nitroimidazole (3.03 g, yield: 74.3%) as colorless liquid product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][C@@H:5]([CH:7]=O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[ClH:15].[N+:16]([C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]([N:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[ClH:15].[ClH:15].[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]([N:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:7][CH:5]3[CH:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:3][C:2](=[O:1])[CH2:6]3)[CH2:33][CH2:32]2)[CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:37][CH:38]=1)([O-:18])=[O:17]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: O=C[C@@H]1CC(=O)C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(CC2CC(=O)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
To a solution of (+−)-trans-4-oxo-2-phenylcyclopentanecarboxaldehyde from Step D (327 mg, 1.74 mmol) in 1,2-dichloroethane (20 mL) was added 4-(N-(4-nitrobenzyloxycarbonyl)(N-allyl)amino)piperidine hydrochloride (667 mg, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol). After 5 min, sodium triacetoxyborohydride (740 mg, 3.5 mmol) was added and the reaction was stirred at rt for 4 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC eluting with a gradient of 35 to 75% ethyl acetate in hexanes to give the title product (365 mg) as the free amine. This was taken up in ether and IM hydrogen chloride in ether (0.5 mL) was added to form the di-hydrochloride salt. The volatiles were removed in vacuo to give the title salt.
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9]([CH3:12])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrC[C:28]1[C:29]([C:35]([F:38])([F:37])[F:36])=[N:30][N:31]([CH3:34])[C:32]=1[F:33]>CN(C)C=O.O>[CH3:3][C:4]1([CH3:13])[O:8][N:7]=[C:6]([S:9][CH2:12][C:28]2[C:29]([C:35]([F:38])([F:37])[F:36])=[N:30][N:31]([CH3:34])[C:32]=2[F:33])[CH2:5]1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1F
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reaction time: 1 h
Yield: 77.4 %

Procedure:
19.3 g of sodium hydrosulfide (purity: 70%, 344.6 mmoles) was added to a solution of 21.3 g (120.3 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 16.7 g (121.0 mmoles) of anhydrous potassium carbonate and 18.6 g (120.7 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 31.4 g (120.3 mmoles) of 4-bromomethyl-5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 29.0 g (yield: 90.3%) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:30]3[CH2:35][O:34]C(C)(C)[O:32][CH2:31]3)[CH:29]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(=O)(O)[O-].[Na+]>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:29]=[C:28]([CH:30]([CH2:35][OH:34])[CH2:31][OH:32])[CH:27]=[N:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccc4)c4c(-c5ccccc5)ccn4n3)c2)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC(CO)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of N-benzyl-2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.122 mmol) in methanol (15 mL) was added p-toluenesulfonic acid monohydrate (12.0 mg, 0.0610 mmol) and stirred at ambient temperature for 2 h. Reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted into DCM (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-73 as described in general methods) to get 2-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)propane-1,3-diol (35.0 mg, 63.5%). LCMS Condition B-12: retention time 2.00, [M+1]=452.2. HPLC Condition B-4: retention time 7.22, purity 97.89%. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.93-2.96 (m, 1H), 3.68-3.77 (m, 4H), 4.69 (br s, 2H), 4.80 (d, J=5.6 Hz, 2H), 6.69 (t, J=5.6 Hz, 1H), 6.79 (d, J=2.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.32-7.41 (m, 5H), 7.46-7.55 (m, 4H), 7.90 (d, J=2.8 Hz, 1H), 8.36 (t, J=2.4 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.0 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N([O-])=O.[Na+].S(=O)(=O)(O)N.C1(C)C=CC=CC=1.[ClH:38]>C(O)(=O)C.O>[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:6]2[CH:5]=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([Cl:38])[CH:7]=2)=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: Cl
Reactant: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2)cc1

Procedure:
A solution of 2-amino-4-(4-acetamidophenylsulphanyl)nitrobenzene (Method 15) (2.4 g) in warm glacial acetic acid (15 ml) was poured onto ice (24 ml). Concentrated hydrochloric acid (4.5 ml) was added and the mixture was stirred and cooled to <5° C. A solution of sodium nitrite (0.601 g) in water (5 ml) was added over 7 minutes and the mixture was stirred for 2 hours at 0-5° C. Aqueous sulphamic acid solution (10% w/v) was added until a negative starch iodide test was observed. In a separate flask toluene was added to a solution of cuprous chloride (0.852 g) in water (1.2 ml) and concentrated hydrochloric acid (1.3 ml) and the mixture was cooled to <0° C. The first preparation (diazonium salt) was then added to the cold cuprous chloride mixture over 5 minutes and the resultant mixture was stirred at ambient temperature for 18 hours. The organic layer was separated and the aqueous layer was extracted with toluene (3×10 ml). The organic extracts were combined, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane to give the title compound (0.789 g). NMR: 2.1 (s, 3H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.5 (d, 2H), 7.7 (d, 2H), 7.95 (d, 1H), 10.2 (brs, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.Cl.C(OCC)(=O)C>CS(C)=O.O.[Cl-].[Na+].O.C(OCC)C>[OH:30][CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4]
Reactant: C=C(CCl)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C=C(CO)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (100 g) in dimethylsulfoxide (800 ml) and water (200 ml) were added cuprous oxide (57.6 g) and p-toluenesulfonic acid (107 g), and the resultant mixture was stirred at 50° C. for 1.5 hours and then cooled down with ice-cooling. Brine (3 liters), 2N hydrochloric acid (1 liter), ethyl acetate (2 liters) and diethyl ether (2 liters) were poured into the reaction mixture, followed by stirring for 0.5 hour. The aqueous layer was extracted with a mixture of ethyl acetate (1 liter) and diethyl ether (1 liter). The combined extracts were washed successively with brine (2 liters), 5% sodium bicarbonate (2 liters) and brine (2 liters) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1ccc(O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 4-bromobenzoic acid in DMF (0.10 M), 3 eq of NMM, 1.5 eq of Py-BOP and 1.1 eq of 4-aminophenol were added and the mixture was stirred at RT for 20 min. DMF was concentrated in vacuo and the residue diluted with EtOAc and aqueous HCl (1N). The resultant precipitate was filtered off and dried in vacuo to afford the title compound (73%); MS (ES+) m/z 292 (M+H)+, m/z 294 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22](O)=[O:23].B.O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][OH:23]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene)inden-3-ylacetic acid (1.70 g, 5 mmol) in THF (25 mL) at 0° C. and under nitrogen atmosphere, there was added a solution of borane (1M) in THF (5.5 mL, 5.5 mmol) and the mixture stirred in the cold for 30 minutes, then at room temperature for 2 hours. More borane was added (2.5 mL) and stirring was continued for 1 hour. Water was added slowly (20 mL), the THF was evaporated and the residue partitioned between water and ethyl acetate. The crude product from the organic phase was purified by chromatography on silica gel using a 1:2 mixture of ethyl acetate-hexane as eluent to afford the desired product (1.25 g) as a yellow oil which solidified on standing. This was triturated with hexane and filtered to yield the title compound as a yellow solid, mp 101-103° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1oc(COc2ccc(C=O)cc2)nc1-c1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)o2)cc1

Procedure:
According to the method described for Reference Example 22, 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.109°-110° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:26]([OH:37])=[CH:25]2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:17]([NH:16][C:5]1[C:4]([CH2:3][C:25]2[C:24]3[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=3)[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:26]=2[OH:37])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 (305 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (250 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 94:6) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 61 mg of 4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 53 as a yellow solid (68 mg, 12% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][C@@H:15]([O:32]C(=O)C2C=CC=CC=2)[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=[CH:20][CH:19]=2)[CH:8]=1.C(=O)([O-])O.[Na+]>CO.O>[C:30]([C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C@H:15]([OH:32])[CH2:14][CH2:13][C:9]3[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: N#Cc1cccc(-c2ccc(OC[C@@H](CCc3cccnc3)OC(=O)c3ccccc3)cc2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Potassium carbonate (0.21 g) was added to a solution of (2R)-4-(3-pyridyl)-2-benzoyloxy-1-(3'-cyanobiphenyl-4-yloxy)butane (0.34 g) in methanol (15 ml) and water (5 ml) and the reaction stirred for 2 hours. The mixture was then poured into saturated aqueous sodium hydrogencarbonate solution and the mixture extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as an oil (0.21 g).