Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(=O)C)C>[C:24]([CH2:23][CH2:22][CH2:21][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:25]
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
The mixture of 4.6 g of 7,7-diphenyl-hexahydro-1,4-oxazepine, 1.88 g of 4-chlorobutyronitrile, 1.88 g of anhydrous sodium carbonate, 0.3 g of sodium iodide and 60 ml of 2-methyl-4-pentanone is stirred at reflux for 23 hours and evaporated. The residue is partitioned between diethyl ether and water, the ethereal solution separated, washed with saturated aqueous sodium chloride, dried and evaporated, to give the 4-(3-cyanopropyl)-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 89°-90°. (Analogously the 4-(4-cyanobutyl and 6-cyanohexyl)-7,7-diphenyl-hexahydro-1,4-oxazepines are prepared, melting at 67°-69° and showing an I.R. band at 2252cm-1 respectively).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:25](#N)C.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC#N
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1Cl
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 92) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 3.96 (3H, s), 5.18 (2H, s), 5.74 (1H, d, J=1.6 Hz), 7.21-7.26 (2H, m), 7.45 (1H, s), 7.58 (1H, d, J=2.0 Hz), 7.77-7.78 (1H, m), 8.33 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.628 min. [M+H] Calc'd for C18H16ClN3O3, 358; Found, 358.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:26][C:27](=[O:44])[C@@H:28]([NH:36]C(=O)OC(C)(C)C)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH:19]=2)=[CH:14][CH:13]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:36][C@@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([NH:26][C@H:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH:19]=2)=[CH:14][CH:13]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
Tert-butyl [(1S)-2-({1-(1H-benzimidazol-2-yl)-2-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}amino)-1-benzyl-2-oxoethyl]carbamate (10 mg, 0.016 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and methylene chloride (1 mL) and stirred for 45 minutes. The solvent was removed in vacuo. The diastereomers alpha to the benzimidazole were resolved through preparative LCMS purification to yield 5.5 mg (95%) of (2S)-2-amino-N-{(1R)-1-(1H-benzimidazol-2-yl)-2-[4-({1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}-3-phenylpropanamide (Peak A) and 5.5 mg (95%) of (2S)-2-amino-N-{(1S)-1-(1H-benzimidazol-2-yl)-2-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}-3-phenylpropanamide (Peak B). Peak A: 1H NMR (500 MHz, CD3OD): δ 7.84 (d, J=8.4 Hz, 2H), 7.76–7.79 (m, 2H), 7.56–7.59 (m, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.28–7.31 (m, 3H), 7.10–7.13 (m, 2H), 6.93 (s, 1H), 5.59–5.63 (m, 1H), 4.19–4.22 (m, 1H), 3.50–3.55 (m, 1H), 3.32–3.41 (m, 1H), 3.08–3.13 (m, 1H), 2.86–2.91 (m, 1H); LCMS found for C27H25N5O4S (M+H)+: m/z=516.0 Peak B: 1H NMR (500 MHz, CD3OD): δ 7.77–7.82 (m, 4H), 7.62–7.64 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 6.88–7.01 (m, 6H), 5.61–5.65 (m, 1H), 4.14–4.18 (m, 1H), 3.48–3.53 (m, 2H), 2.97–3.25 (m, 2H); LCMS found for C27H26N5O4S (M+H)+: m/z=516.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(N2CCN(CCO)CC2)c(Br)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Methyl 3-bromo-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate (100 mg, 0.291 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.9 mL). Under ice-cold conditions, sodium hydride (15.2 mg, 0.350 mmol) and benzyl bromide (38 μL, 0.320 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added water under ice-cold conditions, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (43 mg (yield 34.3%)) was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cccc(F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.20 ml 2-(3-fluoro-phenyl)-ethyl-amine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 2:1) to give 478 mg colorless viscous oil (100%). MS (ISP) 286.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18]CC3C=CC=CC=3)[CH:11]=2)=[CH:4][N:3]=1.[ClH:26].[H][H]>CO.[Pd]>[ClH:26].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=2)=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1O

Procedure:
A solution of 55 g (0.15 mole) of 2,4-diamino-5-(3-benzyloxy-4-methoxybenzyl)pyrimidine from the preceding step in 2500 ml of methanol and 20 ml of concentrated hydrochloric acid is hydrogenated at about 2.5 to 3.0 atm. in the presence of 4 g of 10% Palladium-on-charcoal catalyst. After the uptake of hydrogen has stopped (3.5 hr.) the catalyst is filtered and the filtrate concentrated in vacuo to 250 ml. The crystalline product weighs 41.5 g (90%), m.p. 230°-32°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ICCCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccco2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixture of 1.16 g of 1-tert-butoxycarbonylpiperazine, 1.47 g of 2-(3-iodopropyl)furan and 20 ml of N,N-dimethylformamide was added 0.86 g of anhydrous potassium carbonate, and the mixture was stirred overnight at room temperature. To the reaction solution was added 300 ml of ethyl acetate, the solution was washed successively with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with ethyl acetate to give 1.5 g of oily 1-tert-butoxycarbonyl-4-[3-(2-furyl)propyl]piperazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:49])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH2:39][CH3:40])C(=O)OCC3C=CC=CC=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1>CO.[OH-].[Pd+2].[OH-].[C]>[CH3:49][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[C:6]([C:19]3[N:20]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([NH:28][CH2:39][CH3:40])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CCN(C(=O)OCc1ccccc1)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNc1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
Under a nitrogen atmosphere, benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylcarbamate was obtained in the same manner as in Example 1, Step 6, from benzyl (2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate obtained in Example 1, Step 5. To a solution of the obtained benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylcarbamate (979 mg, 1.4 mmol) in methanol (8 ml) was added 20% palladium hydroxide-carbon (400 mg). Then, the mixture was stirred under a hydrogen atmosphere at normal pressure for 1.5 hr. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (802 mg, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15](Cl)=[O:16]>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[NH:1][C:15](=[O:16])[C:14]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:13]=1[O:12][CH3:11])#[N:5]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: COc1cccc(C)c1C(=O)Cl
Solvent: c1ccncc1
Product: COc1cccc(C)c1C(=O)Nc1cc(C)ccc1C#N
Temperature: 0 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
2-Amino-4-methyl-benzonitrile (15.4 g, 0.117 mol) was dissolved in 100 mL pyridine and cooled to 0° C. To this mixture was added dropwise 2-methoxy-6-methylbenzoyl chloride (24 g, 0.13 mol, 1.1 equiv). During the addition the temperature did not exceed 2° C. The reaction was stirred at room temperature for 48 hours. The mixture was poured into 400 mL ice water, and the precipitate was collected by filtration and washed with water. The crude product was dissolved in 600 mL CH2Cl2, and the solution was washed twice with 500 mL of a 1 N HCl solution and once with 400 mL of a saturated aq. NaCl solution. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated to dryness to yield 25.44 g (0.09 mol, 77.6%) of N-(2-cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide.
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine (495 mg, 1.5 mmol) was dissolved in toluene (30 mL) and catalytic sodium hydride (10 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture was removed by distillation. The mixture was cooled to 25° C. and water (20 mL) and ethyl acetate (40 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:3) as eluant to afford 5-ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil (250 mg, 61%). LRMS (EI) m/e 217 (M+ +H --isobutylene), 216 (M+ --isobutylene); 1H NMR (CDCl3, 300 MHz): δ 8.59 (b-s, 1H), 8.42 (d, J=1.5 Hz, 1H), 7.59 (b-s, 1H), 4.94 (b-m, 0.5H), 4.77 (b-m, 0.5H), 3.64 (b-m, 2H), 3.21 (s, 1H), 2.39 (m, 1H), 1.75-2.0 (b-m, 3H), 1.46 (s, 3H), 1.21 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])=[C:22]([Br:31])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:37][C:36]([F:39])([F:38])[S:33]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][C:22]=1[Br:31])(=[O:34])=[O:32]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCOS(=O)(=O)C(F)(F)F)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of the product of Example 1A (300 mg, 0.598 mmol) dissolved in anhydrous CH2Cl2 (6.0 mL) was added Tf2O (203 mg, 0.718 mmol), DMAP (87.7 mg, 0.718 mmol) and Et3N (0.125 mL, 0.897 mmol). The reaction mixture was stirred at room temperature for 1.5 h then concentrated to yield an oil. The crude material was directly purified using silica gel chromatography (4:1 to 1:1 hexanes:EtOAc) to yield a colorless oil (312 mg, 82% yield). 1H NMR (CDCl3, 300 MHz): δ 9.39 (brs, 2H), 7.54 (d, J=3.0 Hz, 1H), 7.26 (m, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.08 (brs, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.27 (m, 2H), 1.50 (s, 9H), 1.39 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 160.7, 154.9, 154.3, 133.2, 132.8, 128.1, 113.2, 112.0, 84.7, 79.3, 65.8, 46.7, 40.7, 32.4, 28.5, 28.2; 19F NMR (CDCl3, 282 MHz): δ-75.5 (s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
(1S,4R)-4-(2-Amino-6-chloro-9-H-purin-9-yl)-2-cyclopentene-1-methanol (U.S. Pat. No. 5,206,435) or the hydrochloride salt thereof (Example 8) was refluxed in ethanol with 10 molar equivalents of cyclopropylamine for 2 hours. The resulting solution was cooled to ambient temperature and 1 N sodium hydroxide (1 or 2 molar equivalents, depending on whether the starting material was VIIa or the hydrochloride salt of VIIa) was added. The volatiles were evaporated in vacuo. (1S,4R)-4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (IXa) was washed from a silica gel pad eluted with 5% methanol-chloroform or 10% methanol-ethyl acetate and isolated as a white solid foam (80%); spectra identical to those of the product of Example 9.
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH3:31])=[CH:25][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccc(NC)cc1

Procedure:
100 ml 2N hydrochloric acid is added to a solution of which 60.6 g (0.15 mol) N, N-octadecylmethyl-p-nitroaniline is dissolved into 500 ml ethyl alcohol. 52.5 g (0.13 mol) N, N-octadecylmethyl-p-phenylenediamine is obtained after adding 48.8 g (0.75 mol) zinc dust to the solution and heat and reflux it for one hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1)[C:6](O)=[O:7].[CH2:30]([NH2:33])[CH:31]=[CH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH2:30]([NH:33][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:12]2[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]3[CH2:20][C:21]([CH3:27])([CH3:28])[NH:22][C:23]([CH3:26])([CH3:25])[CH2:24]3)=[CH:16][CH:17]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:31]=[CH2:32]
Reactant: COc1cc(C(=O)O)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Reactant: C=CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCNC(=O)c1ccc(-c2ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a solution of crude 3-methoxy-4-(6-(methyl(2,2,6,6 tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzoic acid (0.354 mmol) in DMF (4 mL) and CH2Cl2 (4 mL) was added TEA (0.40 mL, 2.83 mmol), allyl amine (0.053 mL, 0.71 mmol), and HATU (202 mg, 0.53 mmol). The crude reaction was allowed to stir at RT overnight. The crude mixture was quenched with sat aq NaHCO3 and diluted with CH2Cl2. The organic layer is washed with water (6×), brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via HPLC to give N-allyl-3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzamide (8.2 mg). LCMS Rt=1.08 min (condition B); MS (M+1)=438.1
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Trifluoromethanesulphonic anhydride (2.67 mL, 16.29 mmol) was added dropwise to a stirred solution of methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (85% by LCMS) (2 g, 10.86 mmol) in DCM (47.1 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (4.54 mL, 32.58 mmol) was added dropwise over 5 minutes (keeping internal temperature between 5-10° C.) and the resulting solution stirred at room temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (2.250 g, 65.5%) as a straw yellow oil.
Reaction SMILES: Cl.[NH2:2][C@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:5][C@@H:4]1[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[NH2:2][C@:3]1([C:13]([O:15][CH3:16])=[O:14])[CH2:5][C@@H:4]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccc(Br)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@]1(N)C[C@@H]1c1ccccc1
Yield: 24 %

Procedure:
A mixture of (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate hydrochloride (120 mg) and palladium on carbon (10%) (47.3 mg) in methanol (20 mL) was stirred at 5 bar of hydrogen for 48 h. The catalyst was removed by filtration and the filtrate evaporated to dryness. The residue was purified by preparative HPLC on a Phenomenex Gemini column using a 95-5% gradient of aqueous 0.1% ammonia in acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (1R,2R)-methyl 1-amino-2-phenylcyclopropanecarboxylate (18 mg) as a colourless oil.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in ahydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structurewas confirmed by nmr and mass spectra.