Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH:5]=[CH:4]1.C(OC(=O)C)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.CCCCCC>[Br:1][C:5]1[C:6]2[C:7]([C:12]#[N:13])=[CH:8][CH:9]=[CH:10][C:11]=2[NH:3][CH:4]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: N#Cc1cccc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.41 %

Procedure:
Bromine in DMF (0.796 g, 4.975 mmol) was added to a stirred solution of 1H-indole-4-carbonitrile (700 mg, 4.9295 mmol) in DMF (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was poured into ice water containing 0.5% ammonia and 0.5% sodium metabisulphite. The precipitate was collected, washed with cold water and dried to afford 850 mg of 3-Bromo-1H-indole-4-carbonitrile (78.41% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([F:11])[CH:3]=1.COC(OC)[N:15]([CH3:17])C.O.[NH2:21]N>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:15][CH:17]=[N:21][N:8]=2)=[C:4]([F:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cc1F
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)ccc1-c1nnc[nH]1
Temperature: 85 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
4-Bromo-2-fluorobenzamide (9.53 g, 43.7 mmol) and N,N-dimethylformamide dimethylacetal (75.0 mL) were combined in a 500 mL round bottom flask and purged with nitrogen. The reaction was heated to reflux at 85° C. for 2 h. The resulting mixture was concentrated under reduced pressure and dried under vacuum to afford a yellow oil. The oil was suspended in concentrated acetic acid (75.0 mL) and cooled to 0° C. Hydrazine hydrate (21.88 g, 437 mmol) was added dropwise and the mixture was allowed to stir at rt for 5 h. The reaction was poured warm onto cold ice and extracted with dichloromethane (3×200 mL). Organic volatiles were removed under reduced pressure to afford 3-(4-bromo-2-fluorophenyl)-4H-1,2,4-triazole (7.20 g, 29.7 mmol, 68.1% yield) as a white solid. MS (ESI) m/z 241.9 [M]+, 243.9 [M+2]+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:28][C@@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1.CN1CCCC1=[O:41]>>[CH:15]([O-:14])=[O:41].[CH2:24]([N:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][C@H:29]([CH3:28])[CH2:34]2)=[N:10][C:9]2[C:4]1=[N:5][C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)=[N:7][C:8]=2[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@@H]1CNCCN1
Reactant: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Product: O=C[O-]
Temperature: 120 °C
Reaction time: 4 h

Procedure:
N-Methylpyrrolidone (2 ml) was added to 5-(8-chloro-9-isobutyl-6-morpholin-4-yl-9H-purin-2-yl)pyrimidin-2-amine (200 mg, 0.51 mmol) and (2R)-2-methylpiperazine (412 mg, 4.1 mmol) and the resulting mixture was stirred at 120° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give a formate of the title compound (204 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:20]([C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[F:17])=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NNc1ccc(Cl)nn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Fc1ccccc1-c1nnc2ccc(Cl)nn12
Reaction time: 0.67 h

Procedure:
6-Chloro-3-hydrazinopyridazine (6.9 mmol) was suspended in dioxane (45 mL) with triethylamine (1.1 equiv), and the acyl chloride of 2-fluorobenzoic acid (1.1 equiv) in dioxane (10 ml) was added dropwise over 5-10 min at room temperature. The reaction mixture was stirred at the same temperature for 30-50 min (monitored by TLC), and then the dioxane was removed by rotary evaporation. The residue was refluxed in phosphorus oxychloride (40 ml) for 3-4 hours, and then the solvent was evaporated. 6-Chloro-3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine was obtained by washing the residue several times with ethyl acetate followed by filtration then adding ice-cold water (50 ml) to the residue. The aqueous layer was neutralized to pH 7 with saturated aqueous sodium hydrogen carbonate, and the resulting solid was collected by filtration, washed twice with water and then with hexane, and dried under vacuum at 50° C. 1H NMR (400 MHz, Me2SO-d6): 8.57 (d, 1H, pyridazine, J=9.3 Hz), 7.85-7.89 (td, 1H, Ph, J=1.6 Hz and 7.4 Hz), 7.68-7.72 (m, 1H, Ph), 7.58 (d, 1H, pyridazine, J=9.4 Hz), 7.45-7.53 (m, 2H, Ph). FABMS (M+H) calculated for C11H6ClFN4.H was 249.0337. found 249.0339.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-5-methyl-2-hexanone (298.7 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-5-methylhexane (295.6 mg; yield: 98.5%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 4.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:20])[CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl.O>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:20][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=1)[CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:32]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCS(=O)(=O)c1ccc(C(N)CN2CCCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)c1ccc(C(CN2CCCC2)NC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of {1-[4-(propylsulphonyl)phenyl]-2-pyrrolidin-1-ylethyl}amine (100 mg, 0.337 mmol) in dichloromethane (5 mL) under nitrogen was added triethylamine (47 □L, 0.337 mmol) followed by 2,4-dichlorobenzoyl chloride (47 □L, 0.336 mmol). The mixture was stirred at ambient temperature for 2 h, then diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The product was purified by chromatography on silica eluting with 3% MeOH in dichloromethane to give the product as an off-white solid (123 mg, 78%). 1H NMR δ (400 MHz, CDCl3) δ 1.00 (3H, t, J=7.4 Hz), 1.69-1.81 (6H, m), 2.46-2.49 (2H, m), 2.58-2.62 (2H, m), 2.73 (1H, dd, J=12.5, 5.1 Hz), 2.91 (1H, dd, J=12.52, 9.5 Hz), 3.03-3.07 (2H, m), 5.01-5.09 (1H, m), 7.33 (1H, dd, J=8.3, 1.9 Hz), 7.46 (1H, d, J=1.9 Hz), 7.56 (2H, d, J=8.3 Hz), 7.64 (1H, d, J=8.3 Hz), 7.72 (1H, br d, J=3.9 Hz), 7.87 (2H, d, J=8.32 Hz); m/z (ES+) 471 (M+H), 469 (M+H), 400 (M-pyrrolidine), 398 (M-pyrrolidine).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[OH-:15].[Na+:16].[S:17]([O-:20])([OH:19])=[O:18].[Na+]>[Cu]Cl>[C:7]([C:6]1[S:5][C:4]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:3]=2[C:2]=1[S:17]([O-:20])(=[O:19])=[O:18])([OH:15])=[O:8].[Na+:16]
Reactant: [OH-]
Reactant: O=C(Cl)c1sc2cc(Cl)ccc2c1Cl
Reactant: O=S([O-])O
Agent: Cl[Cu]
Agent: [Na+]
Product: O=C(O)c1sc2cc(Cl)ccc2c1S(=O)(=O)[O-]

Procedure:
Prepared analogous to Example 1(a) from 3,6-dichlorobenzo[b]-thiophene-2-carboxylic acid chloride (m.p. 132°-133° C.) by hydrolysis with aqueous sodium hydroxide solution and subsequent reaction with sodium hydrogen sulfite in the presence of copper(I)-chloride as a catalyst.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[CH2:35]([N:37]=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[Cu]C#N>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:28](=[O:30])[CH2:27][C:24]5[CH:25]=[CH:26][C:21]([C:35]#[N:37])=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:23]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Agent: N#C[Cu]
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(CC(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from Example 54F (100 mg, 0.300 mmol), 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid (127 mg, 0.450 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (115 mg, 0.600 mmol), hydroxybenzotriazole hydrate (92 mg, 0.600 mmol), and diisopropylethylamine (0.262 mL, 1.500 mmol) in dichloromethane (3.0 mL) was stirred at room temperature for 3 hours. The mixture was partitioned between water and ethyl acetate, and the organic extract was dried over Na2SO4. The mixture was filtered, concentrated and dried in vacuo, and the residue was dissolved in anhydrous N,N-dimethylformamide (2 mL). Copper(I) cyanide (0.11 g, 1.228 mmol) was added, and the resulting mixture was stirred at 130° C. under N2 for 2 days. The mixture was allowed to cool to room temperature and was partitioned between water (10 mL) and ethyl acetate (4×10 mL). The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (45 mg, 32%). 1H NMR (300 MHz, CDCl3) δ ppm 0.84-1.05 (m, 4 H), 1.80-2.07 (m, 3 H), 2.13-2.53 (m, 3.5 H), 2.73-3.10 (m, 2 H), 3.22-3.35 (m, 0.5 H), 3.63-3.99 (m, 4 H), 4.53-4.80 (m, J=38.32, 12.55 Hz, 1 H), 5.31-5.42 (m, 1 H), 7.56 (d, J=7.80 Hz, 1 H), 7.67 (s, 1 H), 7.80 (d, J=8.14 Hz, 1 H), 7.92-7.95 (m, 1 H), 8.00-8.05 (m, J=1.36 Hz, 1 H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1([C:17]#[N:18])[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].C([N-]C(C)C)(C)C.[Li+].Cl>O1CCCC1>[OH2:13].[C:1]([CH:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:17]1=[NH:18])#[N:2].[CH2:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:17](=[NH:18])[CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)N1CCC(C#N)(CCCC#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CCC(C#N)C2=N)CC1
Product: O
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of ethyl 4-(3-cyanopropyl)-4-cyano-1-piperidinecarboxylate (5g) in tetrahydrofuran (75 ml) was added lithium diisopropylamide (2.5 g) at -70° C., under nitrogen, with stirring. The reaction mixture was warmed to ambient temperature over 10 min and heated at reflux for 90 min. The reaction mixture was cooled to ambient temperature, neutralized with 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was recrystallized from chloroform/petroleum ether to afford 1.8 g (36%) of product, mp 215°-216° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:25]=[CH:26][CH:27]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=349.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:9])([F:8])[F:10])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH3:1])[CH2:6][N:25]1[C:33]2[CH2:32][CH2:31][CH2:30][C:29](=[O:34])[C:28]=2[CH:27]=[CH:26]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(S(C)(=O)=O)cc2c1OCC2
Temperature: 85 °C
Yield: 48.5 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (101 mg, 0.33 mmol) and 1,5,6,7-tetrahydroindol-4-one (74.9 mg, 0.56 mmol) in 0.75 mL of anhydrous ethanol was added sodium ethoxide (21 wt. % solution in ethanol, 103 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50% to 60% ethyl acetate-hexanes) to give 80.0 mg (58% yield) of the title compound as a white solid, m.p. 207° C.-208° C.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>CC#N.O.CC#N>[C:4]([O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:5])[NH:2][NH2:3]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NN
Solvent: O
Solvent: CC#N
Product: NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a well-stirred solution of hydrazine hydrate (19 g, 386 mmol) in 150 mL of CH3CN/H2O (1/1, v/v), a solution of FmocCl (10 g, 38.65 mmol) in 600 mL CH3CN was added dropwise at 0° C. over 2 h. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 12 hours, concentrated in vacuo to 150 mL and filtered to yield the title compound as a white solid, which was washed with water and hexane and dried to a constant weight in vacuo (9.74 g, 99%): mp 172-173° C.; 1H NMR (DMSO) δ 4.08 (brs, 2H), 4.21 (t, J=7.2 Hz, 1H), 4.28 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.69 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.4 Hz, 2H), 8.36 (brs, 1H); 13C NMR (DMSO) δ 47.7, 66.7, 121.1 (2C), 126.3 (2C), 128.1 (2C), 128.7 (2C), 141.7 (2C), 144.9 (2C), 159.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23]I)([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1.C1OCCOCCOCCOCCOCCOC1.[C-:43]#[N:44].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][C:43]#[N:44])([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: [C-]#N
Reactant: Fc1cc(OC2CCCCO2)cc(C23CCC(CI)(CC2)CO3)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 40 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
A mixture of 1-(3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-(iodomethyl)-2-oxabicyclo[2.2.2]octane (732 mg, 1.640 mmol), 18-crown-6 (43 mg, 0.164 mmol), and NaCN (88 mg, 1.80 mmol) in DMF (1 mL) was stirred at 40° C. under N2 for 18 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo. The residue was taken up in DCM (50 mL) and filtered. The residual solid was washed with DCM (10 mL×2). The combined organic filtrates were concentrated in vacuo. The crude oil was purified by flash chromatography (SiO2) using a 0% to 30% EtOAc/hexane gradient (15 min) to give the title compound (560 mg, 1.62 mmol, 99% yield) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[CH2:13][NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[CH2:23]=O>>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]2[O:19][CH2:23][N:14]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:13]2)[CH:20]=[CH:21][CH:22]=1
Reactant: C=O
Reactant: CC(C)(C)NCC(O)c1cccc(OCc2ccccc2)c1
Product: CC(C)(C)N1COC(c2cccc(O)c2)C1

Procedure:
In the manner described in Example 28, m-(benzyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol is reacted with formaldehyde to afford the oxazolidine derivative, which is debenzylated by the procedure of Example 26 to give the title compound.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:14])([O-:3])=[O:2]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC(=O)OCCCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.22 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Octyl acrylate (10.2 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid octyl 4,4-dinitropentanoate (5.0 g, yield: 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:21])=O>CN(C)C=O>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:21])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 6-(4-nitrophenoxy)-hexanoic acid (20 g), thionyl chloride (40 ml) and dimethylformamide (0.5 ml) was refluxed for 5 hours. Excess thionyl chloride was distilled off under reduced pressure. Dry toluene (20 ml) added and solvent was removed under reduced pressure to obtain 6-(4-nitrophenoxy)-hexanoyl chloride (20 grams) as light yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:36])[CH:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)C1C=CC=CC=1.[OH-].[K+].C1COCC1>CO.O>[CH2:21]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:11][C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:9]([OH:36])=[O:8])=[CH:13]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)O
Reaction time: 2 h

Procedure:
To 3-(1-benzyl-1H-indol-3-yl)-2-tert-butoxycarbonylamino-propionic acid benzyl ester (2.1 g. 4.3 mmol) in MeOH (10 mL) was added KOH (0.740 g, 12.9 mmol) in water (5 mL). THF (5 mL) was added until the solution became homogenous. The solution was stirred until completion (about 2 h). Volatile solvents were removed and the residue taken up into CH2Cl2 and water. The aqueous layer was carefully acidified with dilute aqueous HCl and extracted with Et2O. The Et2O was washed with water and brine and then dried with MgSO4. The solution was filtered and the solvent removed to afford the required material without further purification (1.555 g, 91%). ESMS 395 (M+H+), mp 163.8-165.4° C. (EtOAc/petroleum ether). 1H NMR (DMSO-d6) δ 7.56 (1H, d, J=7.83 Hz), 7.39-6.99 (10H, m), 6.65 (1H, d), 4.18 (1H, m), 5.36 (2H, s), 3.15 (1H, dd, J=4.67, 14.56 Hz), 2.99 (1H, dd, J=9.18, 14.56 Hz), 1.32 (9H, s). 13C NMR (DMSO-d6) δ 174.0, 155.2, 137.6, 136.4, 128.7, 127.5, 127.2, 126.7, 126.6, 121.7, 119.3, 119.2, 109.7, 109.6, 79.4, 54.1, 49.9, 28.3, 27.7. ISMS: 395 (M+H),
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([OH:16])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[C:4]([F:19])[CH:3]=1.[F:20][CH2:21][CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH2:22][CH2:21][F:20])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2F)c1O
Reactant: OCCF
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(OCc2ccc(Cl)cc2F)c1OCCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-Chloro-2-fluoro-benzyloxy)-2-hydroxy-benzaldehyde (659, 140 mg, 0.5 mmol, prepared by protocol of Example 43, Steps 1 and 2 of Scheme 71, using 4-chloro-2-fluoro-benzyl bromide in place of 4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (8 mL) was added dropwise a mixture of 2-fluoro-ethanol (64 mg, 1.0 mmol), triphenylphosphine (180 mg, 0.7 mmol), and diisopropyl azodicarboxylate (120 mg, 0.6 mol) in tetrahydrofuran (5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and then at 40° C. for 3 days. The reaction mixture was dissolved in water and ethyl acetate. The organic layers were collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the compound as a white solid (660, 88 mg, 54%). MS (ESI) [M+H+]+=327.12.