Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[C:23][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:16])([F:18])[F:17])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trimethylsilylethynylpyrazole (0.4657 g) in dichloromethane (5 ml) cooled in an ice-water bath was slowly added tetra-n-butylammonium fluoride (1.07 ml of a 1M solution in tetrahydrofuran). After five minutes the ice-water bath was removed. Stirring was continued for ten minutes then the reaction mixture was washed with water. The aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide the title compound as an oily solid which upon drying in an oven crystallised to a white solid m.p. 175.7-176.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.O[C@@H]1[CH2:33][N:32](C(OC(C)(C)C)=O)[C@:31](C)(C2C=CC=CC=2)C1.FC(F)(F)C(O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:32]([CH3:33])[CH3:31])=[O:15])[C@:11]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)c1ccccc1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(C)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl(2S)-4-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (21-3, prepared from tert-butyl(2S,4S)-4-hydroxy-2-methyl-2-phenylpyrrolidine-1-carboxylate (21-2) by the procedures of Scheme 20, 24 mg, 0.065 mmol, 1 equiv) in a 1:1 mixture of trifluoroacetic acid and dichloromethane (10 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (2×10 mL), then dissolved in dichloromethane (10 mL). Triethylamine (0.090 mL, 0.65 mmol, 10 equiv) and dimethylcarbamoyl chloride (0.030 mL, 0.33 mmol, 5.0 equiv) were added, and the resulting mixture was stirred at 40° C. for 6 hours, then 23° C. for 2 days. The reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution (30 mL) and ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to provide (2S)-4-(2,5-difluorophenyl)-N,N,2-trimethyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (21-4) as an off-white solid. 1H NMR (500 MD, CDCl3) δ 7.40 (br d, 2H, J=7.7 Hz), 7.32 (br t, 2H, J=7.8 Hz), 7.22 (t, 1H, J=7.5 Hz), 7.08-6.91 (m, 3H), 6.24 (m, 1H), 4.82 (dd, 1H, J=13.9, 1.5 Hz), 4.77 (dd, 1H, J=13.9, 1.5 Hz), 2.77 (s, 6H), 2.02 (s, 3H). LRMS m/z (M+H) 343.0 found, 343.2 required.
Reaction SMILES: O=[C:2]([CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].S(O)(O)(=O)=O.[CH3:20][S:21][C:22](=[NH:24])[NH2:23].[O-]CC.[Na+].[OH-].[Na+]>C(O)C>[CH3:20][S:21][C:22]1[N:24]=[C:2]([C:3]([OH:5])=[O:4])[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]=1
Reactant: CSC(=N)N
Reactant: O=C(O)C(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1nc(C(=O)O)cc(-c2ccccc2)n1
Yield: 89.3 %

Procedure:
A mixture of 2,4-dioxo-4-phenylbutanoic acid (19.2 g, 100 mmol), 2-methylisothiourea sulfate (27.8 g, 100 mmol) and sodium ethoxide (37 mL, 21% wt. solution, 100 mmol) in ethanol (200 mL) was heated to reflux overnight. After removal of volatiles, water was added (200 mL) to give a suspension, which was adjusted to pH>9 with 10% NaOH. The mixture was extracted with diethyl ether (2×100 mL). The aqueous layer was taken to pH=2 with conc. HCI and extracted with diethyl ether (4×100 mL). The combined ethereal extracts were evaporated, and the residue was dried in vacuo overnight to afford 22.0 g of 2-methylsulfanyl-6-phenylpyrimidine-4-carboxylic acid as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (dd, J=7.8, 1.8 Hz, 2H), 8.12 (s, 1H), 7.58 (m, 3H), 2.64 (s, 3H). 13C NMR (DMSO-d6, 75 MHz) δ 172.8, 165.7, 165.6, 157.9, 135.8, 132.5, 129.8, 128.0, 14.6. HPLC ret. time 1.95 min, 10-100% CH3CN, 5 min run. ESI-MS m/z 247.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-])=O.O.NN>CO.[Pd]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccccc1CO
Yield: 90.6 %

Procedure:
To a solution of 2-nitrobenzyl alcohol (500 g, 3.2 mol) in MeOH (2.5 L) was added Pd/C (40 g) under N2 and refluxed for 30 min. Hydrazine hydrate (500 mL) was added slowly with stirring. The resulting mixture was stirred under reflux for another 2 h. The solid formed was filtered, concentrated and the crude residue was extracted with ethyl acetate (2×500 mL). The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvents, 2-aminobenzyl alcohol (357 g, 89% yield) was isolated as pale yellow solid.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C([O:12][C:13]([C:15]1[N:16]=[N:17][C:18]([O:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])=[CH:19][CH:20]=1)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:13]([C:15]2[N:16]=[N:17][C:18]([O:21][CH2:22][C:23]3[C:24]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[N:25][O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC2CC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 587 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of aminomethylcyclopropane (85 mg, 101 μL, 1.2 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) in dioxane (4 mL) was added. The resulting mixture was heated at 85-95° C. for 3 h, cooled to room temperature, poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (78 mg, 73%) which was obtained as a light yellow solid. MS: m/e=366.3 [M+H]−.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1C1C=CC=CC=1B(O)O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[C:9]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1-c1ccc(F)cc1F
Reactant: O=Cc1ccc(OCCOc2cccc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(OCCOc2cccc(-c3ccc(F)cc3F)n2)cc1
Yield: 73.1 %

Procedure:
To a toluene (80 mL) solution containing 4-{2-[(6-bromo-2-pyridinyl)oxy]ethoxy}benzaldehyde (1 g) and tetrakis(triphenylphosphine)palladium (0.18 g), a 2M aqueous solution (4 mL) of sodium carbonate and a solution of 2,4-difluorophenylbenzeneboronic acid (0.64 g) in ethanol (4 mL) were added. The resultant mixture was refluxed for four hours. After completion of reaction, the reaction mixture was poured into saturated saline, and the thus-obtained toluene layer of the resultant mixture was separated. The separated layer was dried over magnesium sulfate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was purified by means of a silica gel column, to thereby yield 0.71 g of the title compound as colorless crystals (yield 64.5%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[NH:22]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:23]([C:32](O)=[O:33])[CH2:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:22][C@H:23]([C:32]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:19][CH2:20][CH3:21])[CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)=[O:33])[CH2:24][C:25]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:31])=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-2) 12.9 g (45 mmol) and Fmoc-Asp(tBu)-OH 24.2 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 19.6 g, (yield 64%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C@H:8]([NH:16]C(=O)OC(C)(C)C)[C:9](=[O:15])[N:10]2[CH2:14][CH2:13][S:12][CH2:11]2)[CH2:4][CH2:3]1.[CH:24]1[C:29]([S:30](Cl)(=[O:32])=[O:31])=[CH:28][CH:27]=[C:26]([I:34])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[NH2:16][C@@H:8]([CH:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:30]([C:29]2[CH:24]=[CH:25][C:26]([I:34])=[CH:27][CH:28]=2)(=[O:32])=[O:31])[CH2:7][CH2:6]1)[C:9](=[O:15])[N:10]1[CH2:14][CH2:13][S:12][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCSC1)[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N[C@H](C(=O)N1CCSC1)C1CCC(NS(=O)(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 50 mg (0.139 mmol) of tert-butyl trans-(1S)-1-(4-aminocyclohexyl)-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl-carbamate in 1 mL of methylene chloride was added 53 mg (0.175 mmol) of pipsyl chloride, and 0.022 mL (0.27 mmol) of pyridine, and the reaction was stirred at ambient temperature for 16 h. The solvent was removed in vacuo and the product purified by preparative thin layer chromatography (TLC) (silica gel, 5:95 methanol:methylene chloride) afforded 51 mg of the title compound as is Boc carbamate. Deprotection was effected by treatment with 2 mL of a 1:1 mixture of trifluoroacetic acid:methylene chloride at ambient temperature for 2 h, followed by concentration in vacuo and removal of the excess trifluoroacetic acid by azeotropic distillation with methylene chloride. Purification by preparative TLC (silica gel, 9:1:90 methanol:concentrated ammonium hydroxide:methylene chloride) afforded 37 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.94 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz), 4.64–4.62 (m, 0.45H), 4.58–4.52 (m, 1H), 4.47–4.43 (m, 0.55H), 3.91–3.64 (m, 2H), 3.41 (d, 0.45H, J=7 Hz), 3.37 (d, 0.55H, J=7 Hz), 3.07 (t, 1.1H, J=6 Hz), 3.02 (t, 0.9H, J=6 Hz), 3.00–2.92 (m, 1H), 1.84–1.72 (m, 3H), 1.59–1.52 (m, 1H), 1.48–1.38 (m, 1H), 1.23–1.10 (m, 3H), 1.09–0.97 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][OH:7])=[O:4].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:9]([NH:8][C@@H:5]([CH2:6][O:7][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([O:2][CH3:1])=[O:4])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](COc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.8 g of trt-Ser-OMe (Bachem), 0.75 of phenol, and 2.25 g of triphenylphosphine were dissolved together in 60 ml of THF, absolute, and treated dropwise with 1.49 g of diethyl azodicarboxylate at 0° C. in the course of 30 min. The reaction mixture was stirred at 0° C. for 30 min and warmed to RT (about 1 h). For working-up, the solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel (heptane/ethyl acetate=1.5/1). The methyl (S)-2-tritylamino-3-phenoxypropionate thus obtained crystallized slowly in long needles, and was heated under reflux for 1 h in 5 M HCl to remove the protective groups. The reaction solution was evaporated to dryness under reduced pressure by coevaporating a number of times with toluene and the residue was recrystallized from a little tert-butanol.
Reaction SMILES: CN(C[N:5]=[CH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.[ClH:31]>CCOCC.C(N(CC)CC)C>[ClH:13].[ClH:31].[NH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:11][CH2:12]1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: CN(C)CN=CC1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NCC1CCN(CCOc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(dimethylaminomethyliminomethyl)piperidine (7.2 g, prepared as in Example 1), 2-bromoethyl 4-chlorophenyl ether (10.0 g), toluene (100 ml) and triethylamine (5.9 ml) was heated on a steam bath for 6 hours. The mixture was evaporated to dryness and the residue was dissolved in a 1:1 mixture of methanol/concentrated aqueous ammonia solution (S.G. 0.880, 80 ml). The mixture was stirred at ambient temperature for 16 hours and then evaporated to dryness. Water (50 ml) was added to the residue and the mixture was extracted with dichloromethane to give an oil. The oil was dissolved in ether and acidified with ethereal hydrogen chloride to give 4-aminomethyl-1-[2-(4-chlorophenoxy)ethyl]piperidine dihydrochloride m.p. 250°-252° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)C(C)C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]>CN(C)C=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylamino)ethanol (10.7 g, 11.5 ml, 144 mmol, 1.5 equivalents, commercially available e.g. from Aldrich) in dry N,N-dimethylformamide (300 ml) was added N,N-diisopropylethylamine (25 ml, 18.5 g, 144 mmol, 1.5 equivalents). To this mixture was added 1,1-dimethylethyl 4-[(8-bromooctanoyl)amino]benzoate (38.1 g, 96 mmol, 1 equivalent) in dry N,N-dimethylformamide (250 ml) over 12 minutes. The mixture was then heated to and at about 60° C. for 4.25 hours. The mixture was then cooled and the solvent was removed by evaporation using high vacuum to give a golden oil. An attempt to partition this oil between water and ethyl acetate gave a cloudy organic phase and phase separation was poor; an oil separated out as a third layer, some of which was collected and evaporated to give crude product (16.69 g). The remaining emulsion was allowed to stand overnight, giving a clear organic layer which was decanted off, dried (MgSO4) and evaporated to give further crude product as a golden oil (28.11 g). Attempts to further extract the aqueous phase with ethyl acetate or dichloromethane gave an emulsion again, from which further crude product (about 10 g) was finally isolated. The combined crude product was purified by chromatography on silica gel (about 1400 ml of 7734 silica), eluting with 5% methanol in dichloromethane, then 8% methanol in dichloromethane, then 10% methanol in dichloromethane, and finally 20% and 30% methanol in dichloromethane, to afford the title compound as a white foam (28.4 g). LCMS showed MH+=393; TRET=2.52 min.
Reaction SMILES: Cl[C:2]1[CH:7]=C[C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[N:53]1C=CC=CC=1C1[C@@H]2CNC[C@@H]2ON=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([C:5]5[CH:4]=[CH:3][CH:2]=[CH:7][N:53]=5)=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: c1ccc(C2=NO[C@H]3CNC[C@@H]23)nc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccccn5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4e. Acid 104 was isolated as a tan solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].C1(CC(=O)C(OCC)=O)C=CC=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCOC(=O)C(=O)Cc1ccccc1
Agent: [Br-]
Product: CCOC(=O)/C(=C/c1ccccc1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 37 %

Procedure:
The title compound was prepared as described for C4 using (ethyl 3-(phenyl)-2-oxopropanoate B6 (100 mg, 0.520 mmol), sodium hydride (13.73 mg, 0.572 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (214 mg, 0.520 mmol). The resulting compound was isolated in the form of white solid in 37% yield.
Reaction SMILES: N1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2C=CC=N1.[H-].[Na+].[Br:14][CH2:15][C:16]([CH2:18]Br)=[O:17]>>[CH:6]1([CH2:18][C:16]([CH2:15][Br:14])=[O:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(CBr)CBr
Reactant: C1=Cc2ccccc2NN=C1
Agent: [H-]
Agent: [Na+]
Product: O=C(CBr)CC1CCCCC1
Yield: 231.9 %

Procedure:
This was prepared following the method of Example 1B, using the Bock benzodiazepine (250 mg, 0.62 mmol), sodium hydride (26 mg of an 80% dispersion in oil, 0.87 mmol) and the bromomethylketone of Example 32A (219 mg, 1 mmol). The crude product was purified by flash chromatography on silica gel eluant (EtOAc:hexane fr 35:65 v/v) to afford the title compound as a colourless crystalline solid (315 mg, 97%).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](COCC[Si](C)(C)C)[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]#[C:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH:26]=3)=[N:8][C:7]=2[N:6](COCC[Si](C)(C)C)[C:5]1=[O:45])[CH2:2][CH3:3].Cl>C(O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]#[C:29][C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[CH:26]=3)=[N:8][C:7]=2[NH:6][C:5]1=[O:45])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4ccc(C)cc4)c3)n2COCC[Si](C)(C)C)n(COCC[Si](C)(C)C)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)[nH]c2nc(-c3cnn(CC#Cc4ccc(C)cc4)c3)[nH]c2c1=O
Temperature: 85 °C
Yield: 43.7 %

Procedure:
A mixture of 1-propyl-8-[1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazol-4-yl]-3,7-bis-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione obtained in step 1 (0.035 g, 0.053 mmol;), 2 N HCl (1.5 ml), ethanol (3 ml) were heated at 85° C. for 6 hours. The mixture was cooled to 10-15° C. The solid obtained was filtered and washed with water (1 ml), ethanol (1 ml) to afford 1-propyl-8-[1-(3-p-tolyl-prop-2-ynyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (0.009 g, 47%) as a brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:29])[CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:30].[NH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:29]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCN)ccc21
Yield: 74.1 %

Procedure:
A solution of the compound obtained in Step 1 (1.0 g, 2.53 mmol) and 4M hydrogen chloride/ethyl acetate (4 mL, 16.00 mmol) in ethyl acetate (10 mL) was stirred at room temperature for 14 hr. The precipitate was collected by filtration, and washed with ethyl acetate to give 4-amino-N-(9-ethyl-9H-carbazol-3-yl)butanamide hydrochloride (0.622 g, 1.875 mmol, 74.2%) as a white powder.