Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42](OC)=[O:43].[OH2:46].[NH2:47][NH2:48]>>[OH:46][C:13]([C:9]1[CH:10]=[CH:11][C:12]2[C:3]3[CH2:2][NH:47][NH:48][C:42](=[O:43])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:8]=1)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: NN
Reactant: O
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)NNC3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.62 g) and hydrazine monohydrate (0.35 ml), 8-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2,3-dihydrobenzo[f]phthalazin-4(1H)-one (0.05 g) was obtained as a colorless amorphous solid and 8-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]benzo[f]phthalazin-4(3H)-one (0.07 g) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].O>C(Cl)Cl>[CH2:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:22](=[O:23])[CH2:21][O:20][CH3:19])[C:3]=1[C:4]#[N:5])[CH3:12]
Reactant: CCNc1cccc(N)c1C#N
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCNc1cccc(NC(=O)COC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (3.4 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise methoxyacetyl chloride (2.8 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (3.2 g) having the following physical properties.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:62][CH2:61]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Brc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL), was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.0001686 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0393 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0375 g (58%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 482.11 (M+1)+, 91.09%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.38 (m, 4H), 7.16 (t, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 6.5 (t, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 67.8 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (4.90 g, 14.0 mmol) and thiourea (1.07 g, 14.1 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 100 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (3.10 g) as yellow solids in 68% yield: 1H NMR (500 MHz, CDCl3) δ 6.98 (m, 2H), 6.88 (m, 2H), 6.64 (s, 2H), 6.27 (s, 1H), 5.40 (bs, 2H), 3.81 (s, 3H), 2.13 (s, 6H).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[C:16]([C@H:18]1[CH2:26][CH:25]=[CH:24][CH2:23][C@H:19]1[C:20]([OH:22])=O)=O)[CH3:11].[ClH:33].Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][NH2:42])[CH2:37][CH2:36]1>CC(O)C>[ClH:33].[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([C:16]2[C@@H:18]3[C@@H:19]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:20](=[O:22])[N:41]([CH:38]3[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]3)[N:42]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH3:11]
Reactant: NNC1CCNCC1
Reactant: CCOc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OCC
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from the salt of (S)-(−)-α-methylbenzylamine, (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (compound P) and piperidin-4-yl-hydrazine dihydrochloride in 2-propanol as described for compound 5d. M. p. 248-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[NH2:31][CH:28]1[CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:9][CH:10]4[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]4)[CH2:15]2)[CH2:17]3)=[O:5])[CH2:26][CH2:27]1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: C1COCCO1
Product: NC1CCN(CCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.5 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 4-piperidinyl-carbamic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.065 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:4][CH2:3][CH2:2][CH2:14][CH3:13])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[CH:3]=1
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCCCCCCCCCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCCCCCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (4.28, 10 mmol) in dry THF (70 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (2 ml of a 0.1M solution in THF, 2 mol %). A solution of dodecylmagnesium bromide (22 ml of a 1.0M solution in diethyl ether, 0.022 mol) was added dropwise over 15 min. The reaction was stirred for 3 h at 0-5° C. before quenching with 5% NaOH (100 ml). The reaction was stirred for 10 min and then filtered through celite. The organic layer was separated and the aqueous layer further washed with ethyl acetate (100 ml). The combined organics were washed with brine (100 ml), dried (sodium sulfate), and concentrated under reduced pressure. The crude oil was further purified by filtration through a plug of silica (5 cm×5 cm) covered with a layer of basic alumina (1 cm×5 cm), eluting with petrol. After concentration the residue was recrystallized from isohexane to afford 4.2 of the product as white crystals (62%). Purity (HPLC>98%). 1H and 13C NMR spectra as expected.
Reaction SMILES: [I-].[N+:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[CH2:8][N+:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:19])([CH3:18])[C:10]=1[CH3:20])([O-:4])=[O:3].O[C:28]1[C:29](=[O:34])[C:30](=O)[C:31]=1[OH:32].[I-].[C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N+:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:54])([CH3:53])[C:45]=1[CH3:55])([OH:38])=[O:37].C(OC(=O)C)(=O)C>C(O)(=O)C.N1C=CC=CC=1>[C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH3:53])([CH3:54])[C:45]1=[CH:55][C+:28]1[C:31]([O-:32])=[C:30]([CH:20]=[C:10]2[C:11]([CH3:19])([CH3:18])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]2[CH2:8][C:7]2[CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=2)[C+:29]1[O-:34])([OH:38])=[O:37]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccccc2C1(C)C
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccccc2C1(C)C
Agent: [I-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)C(=C[c+]2c([O-])c(C=C3N(Cc4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)c4ccccc4C3(C)C)[c+]2[O-])N(CCCCCC(=O)O)c2ccccc21

Procedure:
To 1-(3,5-dinitrobenzyl)-2,3,3-trimethyl-3H-indolium iodide (467 mg) was added 3,4-dihydroxy-3-cyclobuten-1,2-dione (110 mg), 1-(5-carboxypentyl)-2,3,3-trimethyl-3H-indolium iodide (354 mg), pyridine (4.5 ml), acetic acid (4.5 ml) and acetic anhydride (1 ml). The mixture was heated to reflux for 3 hours and the solvent then stripped using rotary evaporation. This crude material was subjected to silica flash column chromatography (eluted with MeOH/DCM). Fractions containing product were combined and stripped of solvent. The resulting material was further purified by reverse phase HPLC (CH3CN/H2O/TFA).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:16]3[N:20](C)[N:19]=[N:18][N:17]=3)[CH:9]=2)=[CH:4][CH:3]=1.COC(C1SC(C2C=CC(F)=CC=2)=CC=1C1N(C)N=NN=1)=O.[OH-].[Li+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnnc1-c1cc(-c2ccc(F)cc2)sc1C(=O)O
Agent: COC(=O)c1sc(-c2ccc(F)cc2)cc1-c1nnnn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(-c2ccc(F)cc2)cc1-c1nnn[nH]1
Yield: 90 %

Procedure:
5-(4-Fluoro-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-thiophene-2-carboxylic acid (DNM-143) A solution of 5-(4-fluoro-phenyl)-3-(1-methyl-1H-tetrazol-5-yl)-thiophene-2-carboxylic acid methyl ester (28 mg, 0.088 mmol) and lithium hydroxide (10.5 mg, 0.44 mmol) in 3 mL of methanol, 4.5 mL of THF and 2 mL of H2O was stirred overnight at room temperature. The solvent was removed, and the residue was redissolved in 5 mL of H2O. After being acidified with 1N HCl, the precipitate formed was collected by suction filtration, washed with H2O, and dried under vacuum overnight. 24 mg (90%) of product was obtained as a white solid, mp: 270.0-272.0° C. (decomposed); 1H NMR (DMSO, 500 MHz) δ 7.89 (m, 2H), 7.77 (s, 1H), 7.36 (m, 2H); 13C NMR (DMSO, 125 MHz) δ 163.76, 161.79, 161.46, 150.48, 147.83, 132.96, 128.94, 128.49, 128.45, 128.39, 127.03, 116.56, 116.39, 34.12.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:15][C:16]([F:25])([F:24])[C@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1>>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([O:14][C@H:20]2[CH2:21][CH2:22][C@H:17]([C:16]([F:25])([F:24])[F:15])[CH2:18][CH2:19]2)=[O:13])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Product: CCCCC[C@H]1CC[C@H](C(=O)O[C@H]2CC[C@H](C(F)(F)F)CC2)CC1

Procedure:
0.005 mol of trans-4-pentylcyclohexanecarboxylic acid are esterified analogously to Example 4 using 0.005 mol of trans-4-trifluoromethylcyclohexanol (prepared as in Example 2). The product is obtained as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@@H:25]([O:29][Si](C(C)(C)C)(C)C)[C@H:24]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:23]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@@H:25]([OH:29])[C@H:24]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:23]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of tert-butyl tert-butoxycarbonyl(4-((3R,4R,5S)-3-((tert-butoxycarbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)-5-methylpiperidin-1-yl)pyridin-3-yl)carbamate (1.0 equiv.) in THF (0.20 M) at RT was added TBAF (1.0 equiv.). The resulting mixture was stirred at rt for 4 hrs. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with Brine, dried over MgSO4, concentrated and purified by flash column chromatography to yield tert-butyl tert-butoxycarbonyl(4-((3R,4R,5S)-3-((tert-butoxycarbonyl)amino)-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)carbamate in 87% yield. LC/MS (m/z)=523.4 (MH+), Rt=0.72 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.03 (d, J=6.65 Hz, 3 H), 1.34-1.51 (m, 54 H), 1.72-1.87 (m, 1 H), 2.05 (s, 1 H), 2.46-2.57 (m, 1 H), 2.69 (t, J=11.35 Hz, 1H), 2.78-2.94 (m, 1 H), 3.00-3.14 (m, 1 H), 3.45 (d, J=12.52 Hz, 1 H), 3.53-3.76 (m, 1H), 4.63 (d, J=6.26 Hz, 1 H), 6.88 (d, J=5.48 Hz, 3 H), 8.13 (s, 3 H), 8.26-8.36 (m, 3 H).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[C:25]([SH:31])[CH:24]=1>ClCCl.O>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[C:25]([S:31][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[N+:17]([O-:19])=[O:18])[CH:24]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S)c1
Reactant: O=[N+]([O-])c1c(Cl)cccc1CBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.16 mL, 8.61 mmol) was added to a stirred solution of compound of Example 37a (2.87 g, 11.78 mmol) and compound of Example 1f (1.5 g, 5.74 mmol) in dry dichloromethane (75 mL). The reaction mixture was stirred at 0° C. for 20 min, was poured in water (100 mL) and extracted with chloroform (2×50 mL). The combined extract was washed with water (50 mL), brine (50 mL) and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (silica gel, 5% ethyl acetate in pet ether 60-80° C.) to obtain the title compound. Yield: 1.93 g, (77.82%); 1H NMR (DMSO-d6, 300 MHz): δ 2.55 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.25 (s, 2H, CH2), 7.45 (s, 1H, Ar), 7.50-7.60 (m, 2H, Ar), 7.75 (s, 1H, Ar), 7.85 (s, 1H, Ar); MS: m/e (ES−) 431 (M−1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][C:2]([F:13])([F:14])[F:1])[C:8]([OH:10])=[O:9])([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-trifluoromethoxybenzoic acid (2.96 g) in concentrated sulphuric acid (19 ml) at room temperature was added a mixture of concentrated nitric acid (8.5 ml) and concentrated sulphuric acid (8.5 ml) drop-wise. After 15 min a white precipitate had formed. The reaction was slowly poured onto ice (approx. 100 ml). Once the ice had melted the resulting suspension was filtered, and the residue washed with water (3×10 ml) and then dried in vacuo to give the title compound as a white solid (3.41 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[C:9](Cl)([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.C([O-])(=O)C.[Na+]>CN(C=O)C>[C:9]([S:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[NH2:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10% sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1c (205 g, 89%) was obtained as a white powder. 1c: m.p. 192° C. (decomp); 1H NMR (300 MHz, DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])=[O:3].[CH3:17][NH:18][CH3:19]>C(OCC)C>[CH3:17][N:18]([CH3:19])[C:2](=[O:3])[O:4][CH:5]([CH3:16])[CH2:6][C:7]([CH3:15])([O:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8]
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Reactant: CNC
Solvent: CCOCC
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)N(C)C
Reaction time: 2 h

Procedure:
To a solution of (97%) 1,3-dimethyl-3(t-butylperoxy)butyl chloroformate 5.2 g. (0.02 mole) diethyl ether, cooled to 0°±1° C. was added a solution of dimethylamine, 1.8 g. (0.04 mole) in diethyl ether over a period of 10 minutes. After the addition was complete the mixture was allowed to stir for two hours while the reaction temperature was allowed to rise to 20°±1° C. The reaction mixture was then filtered to remove the amine hydrochloride and the organic phase washed with 10% aqueous Tartaric acid solution and water to neutrality.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][NH2:7].[Br:10][C:11]1[CH:12]=[N:13][C:14](I)=[N:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[N:13][C:14]([NH:7][CH2:6][CH2:5][C:4]([F:9])([F:8])[F:3])=[N:15][CH:16]=1
Reactant: NCCC(F)(F)F
Reactant: Brc1cnc(I)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCNc1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Sodium hydride (560 mg, 14.0 mmol) was added in portions to a solution of 3,3,3-trifluoro-propylamine (1.59 g, 14.0 mmol) in dry tetrahydrofuran at ambient temperature. The reaction mixture was stirred for 30 min and a solution of 5-bromo-2-iodopyrimidine (2.0 g, 7.0 mmol) in tetrahydrofuran was added. The reaction mixture was stirred for 30 min and then quenched with water (10 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography using a gradient of ethyl acetate in hexane to yield 950 mg (48%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (s, 2 H), 5.42 (br. s, 1 H), 3.64 (m, 2 H), 2.41 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Reactant: CC(=O)N1CCOCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Temperature: 50 °C

Procedure:
4-Chloro-3',4'-dimethoxy benzophenone (6.29 g, 25 mmol), sodium tert.-amylate (5.50 g, 50 mmol), acetyl morpholine (23.90 g, 185 mmol), and anhydrous toluene (50 ml) were stirred under reflux for 8 hours. After cooling, the solution was washed twice with water, dried, and the toluene distilled off on a rotary evaporator. The viscous residue was stirred at 50° C. with diisopropyl ether (40 ml), whereupon the substance solidified. After it had cooled to room temperature, the crude product was crushed, filtered by suction, washed with diisopropyl ether (2×5 ml) and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[S:8])[NH:6][CH:7]=1.[C:9]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:21]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:20][C@H:19]1Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:9]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:21]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:20][C@H:19]1[S:8][C:5]1[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: S=c1ncc(Cl)c[nH]1
Reactant: O=C(OC[C@H]1O[C@@H](Cl)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC[C@H]1O[C@@H](Sc2ncc(Cl)cn2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A mixture of 5-chloropyrimidine-2-thione (4.3 mmol), 2,3,5-tri-O-benzoyl-β-D-ribofuranosyl chloride (4.3 mmol) and triethylamine (4.3 mmol) in dichloromethane (25 ml) was stirred together at room temperature for 4 h, the mixture evaporated and the residue triturated with water; the residue was the title compound; yield 28% 1H NMR (CDCl3): δ4.75 (CH2), 6.0-6.5 (4 H), 7.2-8.2 (3 Ph), 8.50 (H-4, H-6).