Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>C(#N)C>[CH2:20]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1)[CH3:21]
Reactant: CCI
Reactant: OCCCCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(CCCCO)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g).
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:27])[NH:22][CH2:23][CH2:24][O:25][CH3:26])[CH:18]=[C:17]([Cl:28])[C:16]=1[C:29](Cl)=[O:30]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:29]([C:16]3[C:17]([Cl:28])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:27])=[CH:20][C:15]=3[Cl:14])=[O:30])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-(2-methoxyethyl)benzamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 17).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C(O)(=O)C.[ClH:41].O>O1CCOCC1>[ClH:41].[NH2:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:34]([OH:36])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)C

Procedure:
The title compound was prepared using the previously described process using the following reagants: 0.85 grams (1.7 mmoles) t-butyloxycarbonyl-Valyl-valyl-tryptophan, 6 ml glacial acetic acid and 3 ml 5.68 N HCl in dioxane Total yield was 0.75 grams (100 percent). Anaylsis calculated for C21H30N4O4.HCl.1/3 H2O: C, 56.69; H, 7.17; N, 12.59. Found: C, 57.06; H, 7.3; N, 12.17.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[CH3:19][O-:20].[Na+].Cl>CO>[CH3:19][O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OCCCCCCBr)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
A solution of methyl 4-(6-bromo-n-hexyloxy)benzoate (186 g) in methanol (1 L) was treated with 28% sodium methoxide in methanol (340 ml) and the solution refluxed for 2 hours. After cooling, the stirred solution was adjusted to pH 2 with 1M-hydrochloric acid then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated to give a crude oil. This oil was purified on a silica gel column (2 kg, 9:1 hexane-ethyl acetate elution) to give methyl 4-(6-methoxy-n-hexyloxy)benzoate (127 g) as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].O=C1CCC(=O)N1[O:40][C:41](=O)[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH3:44])[CH3:43].O>C1COCC1>[C:49]([O:48][C:46](=[O:47])[NH:45][C:42]([C:41](=[O:40])[NH:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6]1)=[O:4])([CH3:44])[CH3:43])([CH3:52])([CH3:50])[CH3:51]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccc(F)cc3)C2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 7-[(R)-2-Amino-3-(4-fluoro-benzyloxy)-propionyl]-2-methyl-4-phenyl-2,7-diaza-spiro[4.5]decan-1-one (130 mg, 0.3 mmol) (step 2) and 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (synthesis described in EP1486498A1 page 20) (89 mg, 0.3 mmol) in THF (4 ml)/water (1 ml) was treated with TEA (0.12 ml, 0.89 mmol). The resulting mixture was stirred at 50° C. for 6 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (25 ml) and 5% citric acid aqueous solution (10 ml). The organic phase was separated, washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:17])[NH2:16])[CH:10]=[C:9]2[NH:18][C:19]([N:21]1[C@H:26]([C:27](=[O:38])[NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:25][C@@H:24]2[C@H:22]1[CH2:23]2)=[O:20].[OH-].[Na+]>C1COCC1.O>[C:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:14][CH:13]=2)[C:9]([NH:18][C:19]([N:21]2[C@H:26]([C:27](=[O:38])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[F:37])[CH2:25][C@@H:24]3[C@H:22]2[CH2:23]3)=[O:20])=[CH:10]1)(=[O:17])[NH2:16]
Reactant: COC(=O)COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (1-carbamoyl-3-{[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-5-yloxy)-acetic acid methyl ester Example 133 (85 mg, 0.145 mmol) in THF (1.2 mL) and H2O (120 μL) was added NaOH 1N (290 μL, 0.29 mmol) and the reaction mixture was stirred at RT for 20 min. The crude was directly purified using trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g from Varian) pre-washed with CH3CN (10 mL) and the compound was released with 10 mL of HCl 0.1N in CH3CN. The resulting solution was concentrated and purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give the desired material after lyophilization of the purified fractions. MS (UPLC-MS): 544.3/546.3 [M+H]+, 566.4/568.3 [M+Na]+, 542.3/544.4 [M−H]−; tR (HPLC conditions f): 1.72 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][CH2:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: BrCCCc1ccccc1CBr
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCCc1ccccc1C2
Reaction time: 2 h
Yield: 21.6 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1.2 g, 5.71 mmol) and 1-(bromomethyl)-2-(3-bromopropyl)benzene (1.66 g, 5.71 mmol) in THF (40 mL) was added NaH (457 mg, 60%, 11.42 mmol) at room temperature. The mixture was refluxes for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give the residue, which was purified by column chromatography to give 6′-bromo-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-inden]-1′(3′H)-one (420 mg, 22%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:8][C:7]1[C:2]([N:10]([CH3:9])[CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CNCCOc1ccccc1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Product: CN(CCOc1ccccc1)c1nccnc1Cl
Yield: 71 %

Procedure:
A mixture of 2,3-dichloropyrazine (6.64 g, 44.6 mmol) and N-methyl-N-(2-phenoxyethyl)amine* (4.5 g, 29.8 mmol) in DMF (5 mL) was placed in a sealed Pyrex tube and heated in a microwave oven (Labwell MW10) for 1×2 min followed by 2×1 min at 75 W. The mixture was concentrated and the resulting oil was purified by column chromatography on silica using hexane/EtOAc (95:5 followed by 93:7) to give 5.56 g (71%) of the title product as a colorless oil. HRMS m/z calcd for C13H14CIN3O (M)+263.0825, found 263.0824.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[CH2:26]([N:33]1[CH2:38][CH2:37][CH2:36][C:35](=[O:39])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:26]([N:33]1[CH2:38][CH2:37][CH2:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:39])[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2(O)CCCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 20.0 g. (51.4 mmols) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 75 ml. of tetrahydrofuran is slowly added to 2.5 g. (103 mmols) of 70-80 mesh magnesium metal. The resulting mixture is refluxed for 20 minutes and is then cooled to -10° C. A solution of 9.71 g. (51.4 mmols) of N-benzyl-3-piperidone in 25 ml. of tetrahydrofuran is then added at such a rate that the reaction temperature is maintained below 0° C. The reaction mixture is stirred for 30 minutes following completion of addition and is then added to 500 ml. of saturated ammonium chloride and 500 ml. of ether. The ether extract is washed with two 250 ml. portions of sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 700 g. of silica gel eluted with 50% ether-cyclohexane to yield 17.1 g. (67%) of the title compound as an oil:
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][C:14]1([C:24]([OH:26])=O)[S:21](=[O:23])(=[O:22])[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH2:15]1.ClC(Cl)C>>[CH3:13][C:14]1([C:24]([NH2:3])=[O:26])[S:21](=[O:23])(=[O:22])[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH2:15]1
Reactant: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(Cl)Cl
Product: CC1(C(N)=O)Cc2ccsc2S1(=O)=O
Yield: 52.9 %

Procedure:
Carbonyldiimidazole (13.3 g, 82.0 mmol) was added to a solution of 2,3-dihydro-2-methylthieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (12.7 g, 54.7 mmol) in dry, degassed DMF (200 mL). The reaction was stirred under N2 until an aliquot quenched with methanol showed no more starting material by tlc (about 1 h). An excess of a saturated solution of NH3 (g) in CHCl3 was added and the reaction stirred 1.5 h. The reaction was diluted with water and extracted with ethyl acetate 3X. The combined organic extracts were washed with brine and dried over MgSO4, filtered, and the solvent removed in vacuo to give a semi-solid. This semi-solid was treated with dichloroethane, cooled in the freezer, and filtered to give the title compound (6.69 g, 53%). 1H NMR (300 MHz,DMSO-d6) 1.70(s,3H), 3.00(d, 1H), 3.85(d,1H), 7.10(d,1H), 7.63(bs,1H exch.), 7.69(bs,1 H, exch.), 8.05(d,1H).
Reaction SMILES: [Br-:1].C(O[C:7]([N:9]([CH2:11][C:12]([O:14][C:15]1[C:53]([CH3:54])=[CH:52][C:18]([CH2:19][N+:20]2[CH:21]=[N:22][N:23]([CH2:25][C@:26]([OH:51])([C:42]3[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=3[F:50])[C@H:27]([C:29]3[S:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[N:33]=3)[CH3:28])[CH:24]=2)=[CH:17][C:16]=1[CH3:55])=[O:13])C)=O)(C)(C)C.[ClH:56]>C(OCC)(=O)C>[ClH:56].[Br-:1].[C:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([C@H:27]([CH3:28])[C@@:26]([OH:51])([C:42]3[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=3[F:50])[CH2:25][N:23]3[CH:24]=[N+:20]([CH2:19][C:18]4[CH:17]=[C:16]([CH3:55])[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:9][CH3:7])=[C:53]([CH3:54])[CH:52]=4)[CH:21]=[N:22]3)[S:30][CH:31]=2)=[CH:39][CH:38]=1)#[N:41]
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3cc(F)c(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CNCC(=O)Oc1c(C)cc(C[n+]2cnn(C[C@](O)(c3cc(F)c(F)cc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of 167 mg of (2R,3R)-4-[4-(N-tert-butoxycarbonyl-N-methylaminoacetoxy)-3,5-dimethylbenzyl]-1-[3-[4-(4-cyanophenyl)thiazol-2-yl]-2-hydroxy-2-(2,4,5-trifluorophenyl)butyl]-1H-[1,2,4]triazol-4-ium bromide and 2 ml of 4N-HCl in ethyl acetate in 4 ml of ethyl acetate was stirred for 4 h at room temperature and filtered. The white solid was washed with ether and dried in vacuo to obtain 141 mg(92%) of 1-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-hydroxy-2-(2,4,5-trifluorophenyl)butyl]-4-(3,5-dimethyl-4-methylaminoacetoxybenzyl)-1H-[1,2,4]triazol-4-ium bromide hydrochloride.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([CH2:19][O:20]C(=O)C)[CH:15]=2)[O:7][C@H:6]1[N:24]1[CH:32]=[N:31][C:30]2[C:25]1=[N:26][CH:27]=[N:28][C:29]=2Cl)(=O)C.C(N(CC)C(C)C)(C)C.Cl.[OH:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[NH2:50].C(N)(C)(C)C>C(O)(C)C.CO>[OH:44][C@H:45]1[CH2:49][CH2:48][CH2:47][C@@H:46]1[NH:50][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[C:30]=1[N:31]=[CH:32][N:24]2[C@H:6]1[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=2)[O:7]1
Reactant: CC(=O)OCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Reactant: NC1CCCC1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)N
Solvent: CO
Product: OCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H]5CCC[C@@H]5O)ncnc43)[C@H](O)[C@@H]2O)on1
Temperature: 50 °C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a solution of (2R,3R,4R,5S)-4-(acetyloxy)-5-{3-[(acetyloxy)methyl]isoxazol-5-yl}-2-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3-yl acetate (20 mg) in isopropyl alcohol (2 ml) was added N,N-diisopropylethylamine (0.043 ml) and 2-hydroxycyclopentylamine hydrochloride (11.4 mg). The mixture was stirred at 50° C., under nitrogen for 18 h, cooled and evaporated to dryness in vacuo. The resulting residue was purified by automated preparative HPLC (gradient profile 5%-90% (ii) over 20 min) to give the intermediate triacetoxy protected product. To this residue was added methanol (1 ml) and t-butylamine (0.013 ml) and the mixture was stirred at 0° C. for 3 hours. The solvent evaporated in vacuo to yield title compound as a white solid (5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].I[CH3:16].Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CI
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC)c1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (28.0 g) in DMF (300 mL) was added 60% sodium hydride (4.70 g) at 0° C., and the mixture was stirred for 30 min. Iodomethane (23.7 g) was added dropwise, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.1 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](Cl)=[S:26].O.[NH2:29][NH2:30].O>O1CCCC1>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:26])[NH:29][NH2:30]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)Cl)OCO3
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reaction time: 1 h
Yield: 90.2 %

Procedure:
1.0 g (2.47 mmol) of carbothioyl chloride XI was added to a stirred solution of 0.37 g (7.42 mmol) of hydrazine hydrate in 15 ml of tetrahydrofuran at 5-10° C. over a period of about 0.5 h, then after 1 h stirring, the mixture was poured into water and the precipitated product was filtered off to yield 0.89 g (90%) of the crude product. After drying, it was used in the further reaction steps. The melting point of the product after recrystallization from ethanol was 196° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:16]([NH:24][C:25](=[S:26])[NH:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=S)NC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.1 %

Procedure:
To an ice cold solution of (S)-methyl 3-amino-2-((tert-butoxycarbonyl)amino)propanoate (see US2007/93414A1, 10.3 g, 47.2 mmol) in anhydrous dichloromethane (170 mL) is slowly added benzoyl isothiocyanate (6.35 mL, 47.2 mmol). The reaction is stirred for 2.5 h while slowly warming to room temp. The solvent is removed in vacuo and the residue is purified by BIOTAGE® Silica gel chromatography on a 300 g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% EtOAc over 10 column volumes to give 4.7 g (26.1%) of the title compound as a pale yellow solid. LC/MS (Condition A): ret. T=3.48 min, (M+Na) 404.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[O:12])=[CH:3][CH:2]=1.[BH4-].[Na+].O.C(O)(=O)C>C(O)C>[OH:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: OCc1ccnc2ccccc12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 10 g of 4-quinolinecarboxaldehyde in 400 ml of absolute ethanol at room temperature is added 2.4 g of sodium borohydride. After 45 minutes, 20 ml of water is added and the reaction mixture is stirred for an additional 20 minutes. Acetic acid (20 ml) is added slowly. The reaction mixture is evaporated to a small volume and partitioned between water and methylene chloride. The organic layer is washed with saturated potassium carbonate, saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (1:10) as eluent to yield 4-hydroxymethylquinoline; Rf =0.59.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([CH2:31][C:32]([O-])=[O:33])[CH2:30][CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C:27]5([OH:26])[CH2:30][CH2:29][CH2:28]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C([O-])CC1(O)CCC1
Agent: Cl
Product: O=C(CC1(O)CCC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (20.5 mg, 68.2%), MS (ISP) m/z=443.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0744 mmol) and 2-(1-hydroxycyclobutyl)acetate acid prepared previously by saponification of the corresponding ethyl 2-(1-hydroxycyclobutyl)acetate using lithium hydroxide or another base in the presence of a solvent mixture such as tetrahydrofuran, water and methanol.