Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][O:22][CH3:23])[C:4]([NH:6][C@@H:7]([CH2:18][O:19][CH3:20])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].[C:24](=[O:27])([O-:26])[O-:25].[K+].[K+]>CN(C=O)C.O>[CH3:20][O:19][CH2:18][C@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([NH:2][CH2:11][C:12]1[O:27][C:24](=[O:26])[O:25][C:13]=1[CH3:14])[CH2:21][O:22][CH3:23])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC[C@H](NC(=O)[C@@H](N)COC)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](NCc1oc(=O)oc1C)C(=O)N[C@@H](COC)C(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
Referring to FIG. 38, 4-(bromomethyl)-5-methyl-1,3-dioxo-2-one (278 mg. 1.44 mmol) was added to (S)-benzyl 2-((S)-2-amino-3-methoxypropanamido)-3-methoxypropanoate hydrochloride salt (1.0 g, 2.88 mmol) and potassium carbonate (400 mg, 2.88 mmol) in DMF (15 mL) at 0° C. The reaction was stirred at 0° for 2.5 hours and then diluted with water and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a yellow oil. MS for C20H26N2O8 m/z: 423 (M+H)+.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[C:10](=[O:12])=[O:11]>C1COCC1>[CH:3]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[C:10]([OH:12])=[O:11])=[CH2:4]
Reactant: C=CC1(Br)C=CC=CC1
Reactant: O=C=O
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)C=CC=CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
Preparation of ##STR89## Mg turnings (1.75g, 0.072 g atom) were placed in an oven dried 250 ml 3 neck flask with condenser and addition funnel (all assembled hot). The entire apparatus was evacuated and filled with argon. The flask was charged with 10 ml of anhydrous THF and the addition funnel was charged with 8.0 gm (43.7 mmol) of 1-bromostyrene in 50 ml of anhydrous THF. Five (5) ml of the 1-bromostyrene solution was added to the Mg turnings and the mixture was heated to 65°-70° C. and the remainder of the solution was added over 1 hour. The mixture was heated an additional 30 min., then cooled to room temperature over 1 hour, then poured over crushed dry ice and the dry ice was allowed to evaporate. The mixture was made strongly acidic with 150 ml of 10% HCl solution. The organic phase was separated and the aqueous phase was extracted three times with ether. The combined organic phase was poured into 150 ml of 20% KOH solution, the solution was separated and the basic phase was filtered to remove polymer. The basic phase was then acidified with 10% HCl solution and extracted three times with 100 ml portions of ether. The extracts were combined, washed with 100 ml of brine and dried over Na2SO4. The solution was filtered and concentrated to a white solid which was recrystallized from chloroform/hexane solution to yield 6.44 g (66%) of 1-vinylbenzoic acid in two crops. ##STR90## Iodine (4.12 g, 16.22 mmol) was added in a single portion to a degassed solution of 1.20 gm (8.11 mmol) of compound 17a in 12 ml of acetonitrile. The solution was stirred for 1 hour, then poured into 50 ml of saturated sodium thiosulfate solution. The solution was extracted three times with 50 ml portions of ethyl acetate. The combined organic phases were washed sequentially with 40 ml portions H2O, saturated NaHCO3 solution and saturated sodium thiosulfate solution then dried over MgSO4. The solution was filtered and concentrated to a yellow solid (1.87 g, 84% yield) which was recrystallized from ethanol. ##STR91##
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N5O3Cl2 [(M+H)+] 692.3129, observed 692.3125.
Reaction SMILES: [O:1]([CH2:8][CH2:9]CCBr)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=O>CC(O)C>[O:1]([CH2:8][CH2:9][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN1CCNCC1
Reactant: BrCCCCOc1ccccc1
Solvent: CC(C)O
Product: c1ccc(OCCN2CCNCC2)cc1

Procedure:
The procedure of Example 2 was repeated in entirety substituting 57.0 g (0.27 moles) of 2-bromoethyl phenyl ether for 4-phenoxybutyl bromide, using 61.6 g (0.54 moles) of 1-formylpiperazine in 300 ml of 2-propanol and refluxing the mixture for 8 hours. Evaporation of the final dried chloroform extracts gave 35 g of 1-[2-phenoxyethyl]piperazine as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>N1C=CC=CC=1.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[CH:17][N:16]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1ccc(Cc2cnc(NCCCN)[nH]c2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCNc3ccc(C#N)cn3)[nH]c2=O)cn1

Procedure:
2-Chloro-5-cyanopyridine (0.61 g), 2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.09) and potassium carbonate (0.61 g) were heated together under reflux in pyridine (10 ml) for 2.5 hr. The mixture was stripped, the residue taken up in water and the pH adjusted to 3 with hydrochloric acid. After extracting with chloroform the aqueous solution was filtered and the pH raised to 6.5 with sodium hydroxide. The precipitate thus obtained was chromatographed (silica gel, chloroform/methanol, graded 1:0 to 20:1) and the required component recrystallised twice from ethanol to give 2-[3-(5-cyanopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 0.2H2O, (0.38 g; 25%) m.p. 175°-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2cccc(Br)c2)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2cccc(Br)c2)CC1
Temperature: 60 °C

Procedure:
To a solution 1-(3-bromophenyl)cyclopropanecarboxylic acid (530 mg, 2.2 mmol) in methanol (5 mL) was added HCl (2.0 M in Et2O, 0.5 mL). The mixture was heated at 60° C. overnight. The solvent was evaporated and water (10 mL) was added to the residue. The mixture was neutralized with saturated NaHCO3 solution until pH 7-8. The mixture was extracted with CH2Cl2 (10 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford methyl 1-(3-bromophenyl)cyclopropanecarboxylate (530 mg), which was used without further purification. ESI-MS m/z 255/257 (M+1)+. Retention time 1.68 minutes.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Si:9]([O:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1>[Si:9]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22](=[O:23])[CH2:2][C:1]#[N:3])=[CH:25][CH:26]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cl)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a chilled (−78° C.) solution of acetonitrile (MeCN) (1.13 mL, 4 equiv) in THF (54 mL) was added butyllithium (BuLi) (1.62 mL, 10 M in hexanes, 3 equiv) dropwise, keeping the temperature under −60° C. The mixture was stirred for 15 minutes at −78° C. A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzoyl chloride (1.44 g) in THF (5 mL) was slowly added, and the reaction mixture was stirred at −78° C. for 45 minutes. The reaction was then quenched with aqueous ammonium chloride and diluted with EtOAc. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated onto silica gel. Purification by silica chromatography (9:1 hexanes:EtOAc to EtOAc) provided the title compound (370 mg, 24% yield) and the de-silylated product (330 mg).
Reaction SMILES: O[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:3].[C:21](C1NC=CN=1)([C:23]1[NH:24][CH:25]=[CH:26]N=1)=O.C(NCC)C>CN(C=O)C>[CH3:21][CH2:23][N:24]([C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]=42)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:3])[CH2:25][CH3:26]
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
A mixture of 4.0 g (0.015 mol) of D-lysergic acid and 200 mL of dry DMF, under argon, was treated with 3.6 g (0.022 mol) of carbonyl diimidazole and stirred at room temperature for 1 hour. The reaction was treated with 15.2 mL (0.15 mol) of diethylamine and stirred at room temperature overnight. The reaction was concentrated at reduced pressure. The residue was taken up in 250 mL of CH2Cl2 and washed with 250 mL of H2O. Insoluble material was removed by filtration and the layers were separated. The organic portion was washed with 250 mL of saturated brine solution, dried over anhydrous Na2SO4 and concentrated at reduced pressure. The residue was chromatographed on 500 g of silica gel using 3% CH3OH in CH2Cl2 as eluent to yield 3.65 g (75.7%) of D-LSD [α]D=+50.4° (c=1%; CHCl3) as a light brown amorphous solid. The 8 α-epimer (also known as iso-LSD) has [α]D=+226° (c=1%; CHCl3).
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19]>>[CH2:6]1[C:1]2=[C:7]3[CH:8]([CH:19]=[C:18]([C:17]([O:21][CH3:22])=[O:20])[CH:2]2[CH2:3][CH2:4][CH2:5]1)[O:9][C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:12]3
Reactant: C#CC(=O)OC
Reactant: C1=C(C2=COc3ccccc3O2)CCCC1
Product: COC(=O)C1=CC2Oc3ccccc3OC2=C2CCCCC12

Procedure:
In a sealed tube, 500 mg of 2-(1-cyclohexenyl)-1,4-benzodioxin and 1.4 ml of methyl propiolate are stirred for 22 hours 30 minutes at 70° C. The regioisomers are separated by chromatography on silica gel (eluent: petroleum ether/ethyl acetate, 98:2).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[OH:24][CH2:23][C@H:22]1[CH2:26][C@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 900 ml of THF was added 21.75g (574.9 mmol) of sodium borohydride and the mixture was cooled to 10° C. before 97.92 ml (776.2 mmol) of borontrifluoride etherate was added dropwise over a period of 1 hour. Then 82 g (287.4 mmol) of N-(4-toluenesulfonyl)-4-hydroxy-D-proline was added carefully in 330 ml of THF at 0° C. and the mixture was warmed to room temperature and allowed to stir for 16 hours. The reaction was cooled to 0° C. and quenched with methanol: 10% aqueous HC1 solution was then added and the mixture was gently heated to 60° C. for 1 hour. The pH of the reaction was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 78 g of the product as a white solid in 100% yield. M.P.=131°-132° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][NH:21][CH2:20][CH2:19]2>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:20][CH2:19]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: N#Cc1ccc(F)c2ccccc12
Product: COc1ccc2c(c1)CCN(c1ccc(C#N)c3ccccc13)C2
Yield: 19 %

Procedure:
The title compound (7 mg, 19% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 6-methoxy-3,4-dihydro-1H-isoquinoline (76 mg, 0.468 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[Cl:14])(=[O:3])[CH3:2].[C:15]([O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27](=[O:41])[CH:28]([NH:30]C(=O)C1C=CC(N)=C(Cl)C=1)[CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27](=[O:41])[CH:28]([NH:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([Cl:14])[CH:7]=1)[CH3:29])=[O:21])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1Cl
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1Cl
Yield: 77 %

Procedure:
Prepared from 95 and 4-acetylamino-3-chlorobenzoic acid according to the method used for 96a to afford the title compound as a white solid (9.18 g, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.30-1.62 (m, 12H), 1.85-2.16 (m, 3H), 2.16-2.44 (m, 1H), 2.27 (s, 3H), 3.47-3.83 (m, 2H), 4.34-4.54 (m, 1H), 4.89 (m, 1H), 7.27-7.39 (m, 1H), 7.59-7.71 (m, 2H), 7.83-7.97 (m, 1H), 8.47 (d, 1H). Analytical HPLC 9.43 min.
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[CH2:10]([Li])CCC.[C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Br)C#C.C1(C)C=CC=CC=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:23][C:22](=[O:24])[CH:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:1]#[CH:2]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: [Li]CCCC
Agent: C#CCBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCC(C(=O)OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 15 %

Procedure:
Diisopropyl ethyl amine (5.9 mL, 42 mmol) was dissolved in tetrahydrofuran (30 mL). Butyllithium, 2.5 M in hexanes, (16.8 mL, 42 mmol) was added slowly at A solution of phenyl acetic acid (2.72 g, 20 mmol) in tetrahydrofuran (20 mL) was added slowly via a dropping funnel over 20 minutes. The reaction was stirred for 25 minutes. Propargyl bromide was added as an 80% weight solution in toluene (2.3 mL, 21.0 mmol). The reaction was stirred for 1.5 hours and 4N hydrochloric acid (15 mL) was added. The mixture was diluted with ethyl acetate (50 mL). The organic portion was concentrated in vacuo. The residue was dissolved in diethyl ether and extracted with water (3×) and 1 N hydrochloric acid (3×). The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow solid (1.7 g) was dissolved in methanol (50 mL) and cooled to 0° C. Acetylchloride (2 mL) was added and the reaction was allowed to warm to room temperature. After the reaction stirred for 18 hours, the solvent was removed in vacuo. The residue was dissolved in diethyl ether. The solution was extracted with saturated sodium bicarbonate, water, and brine. The organic portion was dried over magnesium sulfate and the solvent removed in vacuo. The residue was chromatographed on silica gel with 10% ethyl acetate in hexanes to give the title compound as an oil (0.58 g, 15%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([N:8]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(O)cc2)c2cccc(Cl)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
300 mg of N2-(3-chloro-2-methylphenyl)-N-(4-hydroxybenzyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 2.00 mL of DMF, and 110 mg of potassium carbonate and 133 mg of ethyl bromoacetate were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 30:70) to obtain 370 mg of ethyl 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]phenoxyacetate.
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1)C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:10]=1
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)propenoate (7.33 g), 5% palladium-carbon (7.11 g) and tetrahydrofuran (50 ml) was stirred overnight under a hydrogen atmosphere at room temperature. Palladium-carbon was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (4.85 g, yield 89%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 150–151° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[C:8]([C:23]#[N:24])[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].O.CP(C)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[CH:7]=[C:8]([C:23]#[N:24])[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(N)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3-fluorophenyl)quinoline-5-carbonitrile (0.020 g, 0.063 mmol) in tetrahydrofuran (0.2 mL) and water (0.0455 mL, 2.52 mmol) was added 1.0 M trimethylphosphine in tetrahydrofuran (0.076 mL, 0.076 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The LCMS of the crude, showed two peaks with the same desired mass, and was used directly in the next step (18 mg, 98%). LCMS calculated for C18H15FN3 (M+H)+: m/z =292.1; Found: 292.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH:29]12[O:34][CH:33]1[CH2:32][O:31][CH2:30]2>CCOC(C)=O>[OH:34][CH:29]1[CH2:30][O:31][CH2:32][CH:33]1[O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: C1OCC2OC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC2COCC2O)cc(-c2ccc(C)cc2)c1
Temperature: 110 °C

Procedure:
A stirred mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (370 mg, 1.4 mmol), potassium carbonate (421 mg, 3.05 mmol), DMSO (8 mL), and 3,6-dioxabicyclo[3.1.0]hexane (260 mg, 3.0 mmol) was heated at 110° C. overnight. After cooling, the reaction mixture was diluted with EtOAc. The organic phase was washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 90 %

Procedure:
A flame-dried round bottom flask was charged with 80 (4.37 g, 9.48 mmol) and glacial acetic acid (61 mL). The flask was sealed with a septum and flushed with nitrogen. Zinc-copper couple (6.07 g, Aldrich) was added and the reaction stirred at room temperature for a period of 21 h. The reaction was then heated to 80° C. for 1 h. The reaction mixture was cooled to room temperature, filtered thru a pad of Celite®, washed with EtOAc (200 mL) and concentrated under vacuum. The resulting white solid (residue) was diluted with CH2Cl2 (250 mL) and washed with 0.5 M NaOH (500 mL). The aqueous layer was extracted with CH2Cl2 (2×150 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated. Purification by flash chromatography (SiO2, 5% Acetone-CH2Cl2) afforded 78 (3.64 g, 90%) as a white powder identical in all respects to material isolated in Example 38, step 2.