Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[C:28]([Br:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[Br:30][C:28]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([C@@:13]2([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[C@H:14]([CH2:22][OH:23])[CH2:15][C@H:16]([CH:19]3[CH2:20][CH2:21]3)[O:17][CH2:18]2)[CH:29]=1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Benzoyl isothiocyanate (120 mg, 0.74 mmol) was added drop-wise to a solution of [(2R,4R,5S)-5-amino-5-(5-bromo-2-fluorophenyl)-2-cyclopropyltetrahydro-2H-pyran-4-yl]methanol (C56) (from the previous step, 225 mg, ≦0.78 mmol) in dichloromethane (25 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1.5 hours, then was warmed to room temperature and stirred overnight before concentrating in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 127 mg, 26% over 2 steps LCMS m/z 454.3 [M+H+].
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]2)=[CH:17][CH:16]=1.F[C:29](F)(F)C(O)=O>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24]3=[N:25][CH:29]=[C:10]4[CH2:9][CH2:8][CH2:7][C:6]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:11]4=[C:23]3[CH:22]=[N:21]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CCCCc2ccccc21
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCCc2ccccc2-4)cc1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
To a mixture of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (8.5 g, 39.5 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (8.2 g, 44.47 mmol) was added trifluoroacetic acid (4.25 mL, 54.3 mmol). The reaction mixture was heated at 100° C. for 24 hours. On completion of the reaction, the solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (SiO2, gradient from 5% EtOAc in hexanes to 30% EtOAc in hexanes) to give the desired product (4.2 g, 30%) as an off-colored solid. 1H NMR (CDCl3, 400 MHz) δ: 7.97 (s, 1H), 7.85 (s, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.46-7.44 (m, 1H), 7.38 (d, J=7.6 Hz, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 6.84 (d, J=7.6 Hz, 2H), 5.69 (s, 2H), 3.76 (s, 3H), 2.59 (q, J=6.0 Hz, 4H), 2.21 (quintet, J=7.2 Hz, 2H); LCMS [M+H]: 356.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:15]>CN(C)C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:15])=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClOCl
Reactant: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 60 °C
Yield: 59 %

Procedure:
A suspension of 0.45 g 7-bromo-2-methyl-3H-quinazolin-4-one in 0.48 ml N,N-dimethylaniline is treated with 1.41 ml phosphourous oxychloride and heated at 60° C. for 2 h. The reaction mixture is evaporated in vacuo and the residue is taken up with 20 ml water, neutralized with 10 ml saturated aqueous sodium bicarbonate and extracted with 25 ml dichloromethane twice. The organic layer is washed with 25 ml water, 25 ml brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel with Heptane/ethylacetate 2:1. 0.288 g (59%) of 7-bromo-4-chloro-2-methyl-quinazoline are obtained as an orange solid. Mp. >82° C. (dec). MS (EI): peaks at m/e: 258(M+, 37%), 221 (100%), 179(9%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]1([CH3:14])[NH:13][CH2:12][CH2:11][O:10]1.[C:15](=[S:17])=[S:16]>CCOCC>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]1([CH3:14])[N:13]([C:15]([S-:17])=[S:16])[CH2:12][CH2:11][O:10]1
Reactant: S=C=S
Reactant: CC1(C)NCCO1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)OCCN1C(=S)[S-]
Product: CC[NH+](CC)CC

Procedure:
To a cold (-10°) solution of 202 g (2.0 moles) of triethylamine and 360 g (1.27 moles) of 2,2-dimethyloxazolidine[(prepared by the method of E. Bergman, J.A.C.S. 75, 358 (1953)] in 1 liter of ether was added 152g (2.0 moles) of carbon disulfide over a period of 15 minutes. Solids formed during the additional one hour of stirring at -10° to 6°. The mixture was then filtered; the solids were washed with 2 × 250 ml of ether and were air-dried for 20 minutes to obtain 347g of the pale yellow, solid triethylammonium bis(2,2-dimethyl-3-oxazolidinecarbodithioate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[O:20][C:10]2[CH:11]=[CH:12][C:13]3[C:14]([C:17]([OH:19])=O)=[CH:15][C:16]=3[C:9]=2[O:8]1.[H-]>C(OCC)C>[OH:19][CH2:17][CH:14]1[C:9]23[O:8][CH2:7][O:20][C:10]2=[CH:11][CH:12]=[CH:13][CH:16]3[CH2:15]1
Reactant: O=C(O)C1=Cc2c1ccc1c2OCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CC2C=CC=C3OCOC321
Yield: 87 %

Procedure:
Under a nitrogen atmosphere, 7.4 g of lithium aluminium hydride are added to 100 ml of diethyl ether and then 15 g of the compound prepared in Stage F, dissolved in 300 ml of diethyl ether, are added dropwise thereto. When the addition is complete, the mixture is refluxed for 3 hours. The excess hydride is hydrolysed, the mixture is filtered, the residue is washed several times with diethyl ether and the filtrate and washings are concentrated. The alcohol is obtained in the form of an oil.
Reaction SMILES: ClCCl.[C:4]([Si:8]([CH3:11])([CH3:10])Cl)([CH3:7])([CH3:6])[CH3:5].[N:12]([C@@H:15]1[CH2:20][C@H:19]([OH:21])[C@@H:18]([CH2:22][OH:23])[O:17][CH2:16]1)=[N+:13]=[N-:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:12]([C@@H:15]1[CH2:20][C@H:19]([OH:21])[C@@H:18]([CH2:22][O:23][Si:8]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:11])[CH3:10])[O:17][CH2:16]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=N[C@H]1CO[C@H](CO)[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])C[C@@H]1O
Temperature: 25 °C
Reaction time: 50 h
Yield: 89 %

Procedure:
A dichloromethane (4 ml) solution of tert-butyldimethylchlorosilane (381 mg, 2.54 mmol) was added to a dichloromethane (10 ml) solution of 1,5-anhydro-2-azido-2,3-dideoxy-D-ribo-hexitol (440 mg, 2.54 mmol) and triethylamine (0.46 ml, 3.30 mmol) under ice cooling. After stirring at room temperature for 50 hours, the reaction mixture was diluted with chloroform and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=10:1→4:1 (v/v)] to give 650 mg (89%) of the title compound as a colorless oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[N:36]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:39]2[CH2:40][CH2:41][N:36]([CH2:42][CH2:43][OH:44])[CH2:37][CH2:38]2)=[O:18])[N:8]([C:6]([C:30]2[CH:29]=[CH:28][C:27]([C:21]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:32][CH:31]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: OCCN1CCNCC1
Product: CON=C1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4carboxylic acid, and 2-(1-piperazinyl)ethanol, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=479.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(C)(C)O
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC(C)(C)O)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (120 mg, 0.257 mmol), N,N-diisopropylethylamine (0.5 mL, 2.87 mmol), and 3-hydroxy-3-methylbutyne (90 mg, 1.07 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.0157 mmol) and copper(I) iodide (5.5 mg, 0.0288 mmol). The mixture was stirred at 25° C. for 18 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (25 mL) and a 0.2M aqueous hydrochloric acid solution (20 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), and each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with increasing concentrations of ethyl acetate/hexanes) afforded the 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 77%) as a yellow foam: (ES)+-HRMS m/e calcd for C25H31N3O4S (M+H)+ 470.2108, found 470.2113.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:3])=[CH:15][CH:16]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 29 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with methane sulfonamide as described in the preparation of compound 1 to yield 100 mg solid (29% yield), mp=137° C. (decomposition). HRMS (M−H) cacld for C13H14FN2O6S: 345.056. Found: 345.0570. Anal calcd for C13H15FN2O6S: C, 45.08; H, 4.36; N, 8.08. Found: C, 45.20; H, 4.29; N, 7.92. 1H NMR (500 MHz, CDCl3) δ: 3.36 (s, 3), 3.71 (s, 3), 4.81 (s, 2), 6.56 (s, 1), 7.04 (m, 2), 7.32 (m, 2), 8.97 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 41.60, 48.27, 63.16, 92.57, 115.65, 115.81, 130.19, 130.24, 130.97, 158.99, 160.05, 161.65, 163.61, 170.79.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+]([O-])=O)[CH:23]=2)[C:18]1=[O:30])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[CH:10]=3)[CH:23]=2)[C:18]1=[O:30])[CH3:13]
Reactant: Cc1nc2ccc(O)cc2s1
Reactant: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CN1C(=O)c2ccc(Oc3ccc4nc(C)sc4c3)cc2C1=O
Temperature: 105 °C
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-benzothiazol-6-ol (2.30 g, 13.92 mmol), 5-nitro-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester (4.26 g, 15.31 mmol), potassium carbonate (2.3 g, 16.64 mmol) and dimethylacetamide (30 mL) was stirred at 105° C. for twenty hours before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow solid (2.35 g): MS: (+) m/z 397.19 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OC(=O)CC(C)=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:8])[C@@H:4]([CH3:7])[CH2:5][O:6][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](C)CO
Solvent: ClCCl
Solvent: CCOC(=O)CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)COS(C)(=O)=O
Reaction time: 1 h
Yield: 100 %

Procedure:
3 g (25.3 mmol) of (S)-3-hydroxy-2-methyl-propionic acid methyl ester was dissolved in dichloromethane 50 mL, then 5.3 mL (37.9 mmol) of triethylamine was dropwise added thereto. Thereafter, 2.16 mL (27.9 mmol) of methanesulfonyl chloride was added to the solution at 0° C. After 1 hour, 200 mL of ethylacetoacetate was added to the solution and then the reaction solution was washed with water and then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 4.97 g (25.3 mmol) of the title compound in a yield of 100%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=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>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:39]2[CH:40]=[CH:41][C:36]([C:26]3[C:27]4[O:28][C:29]5[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=5[C:31]=4[CH:23]=[CH:24][CH:25]=3)=[CH:37][CH:38]=2)=[CH:9][CH:8]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)C(CSc1ccc(Br)cc1)NC(=O)OC(C)(C)C
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: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-3-(4-bromophenylsulfanyl)-propanoic acid methyl ester (0.55 g, 1.41 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.44 g, 1.52 mmol) and Pd(PPh3)4 (0.073 g, 5 mol %) in toluene (15 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (2.2 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave the desired product (552 mg, 72%) as a white solid. 1H NMR (CDCl3), δ 8.01 (d, J=6 Hz, 2H), 7.96 (dd, J=4 Hz, 8 Hz, 2H), 7.74 (d, J=9 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 5.41 (d, J=7 Hz, 1H), 4.62 (m, 1H), 3.73 (s, 3H), 3.45 (d, J=4 Hz, 2H), 1.57 (s, 9H). LCMS 454 (M+−100).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][N:4]([CH3:28])[C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1O.[CH3:29][OH:30]>>[CH3:3][N:4]([CH3:28])[C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:1][C:29](=[O:30])[C:7]([CH3:12])([CH3:8])[CH3:6]
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)c1ccc(Cn2nnc(-c3ccc(O)c(N(C)C)c3)n2)cc1
Agent: [Na+]
Product: CN(C)c1cc(-c2nnn(Cc3ccc(C(=O)O)cc3)n2)ccc1OC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of aqueous 10% sodium hydroxide (0.67 ml) in methanol (5 ml) was added methyl 4-[5-(3-dimethylamino-4-hydroxyphenyl)tetrazol-2-ylmethyl]benzoate (296 mg) obtained in reference example 6. The mixture was heated at 50° C. for 1 h, and the solvent was evaporated. To the residue were added acetone (10 ml) and H2O (10 ml), and pivaloyl chloride (150 mg) was added dropwise to it under ice cooling. The mixture was stirred at the same temperature for 1 h, acidified with aqueous citric acid, and extracted with ethyl acetate. The extract was dried and evaporated to dryness. The residue was purified by column chromatography on silica gel with chloroform-methanol (100/4-5) as an eluate to give 46 mg (12%) of the title compound.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])(CC1C=CC=CC=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44].[H][H]>CO.O.[C].[Pd]>[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[CH2:1]([P:8](=[N:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@H](N=[P+]([O-])Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 103.6 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (1 g, 1.84 mmole) and L-arginine (0.64 g, 3.67 mmol) were dissolved in a mixture (20 ml) of methanol and water (1:1, v/v) and 5% palladium carbon (0.1 g) was added thereto. Hydrogen gas (41.2 ml, 1.84 mmol) was adsorbed by the solution while stirring. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Water was added thereto and the water solution was freeze-dried to obtain monobenzylphosphoryl-L-alanyl-L-prolyl-L-proline di-L-arginine salt (1.46 g, quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33]CC4C=CC=CC=4)[C@@H:21]([O:22]CC4C=CC=CC=4)[C@@H:12]3[O:13]CC3C=CC=CC=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([NH2:41])[N:3]=1.COC(O)C.[H][H]>[Pd].C(O)(=O)C>[C@@H:11]1([N:8]2[C:7]3[C:2]([NH2:1])=[N:3][C:4]([NH2:41])=[CH:5][C:6]=3[N:10]=[CH:9]2)[O:31][C@H:30]([CH2:32][OH:33])[C@@H:21]([OH:22])[C@@H:12]1[OH:13]
Reactant: Nc1cc2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2c(N)n1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Product: Nc1cc2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3O)c2c(N)n1
Yield: 78.4 %

Procedure:
A mixture of 5.0 g of 4,6-diamino-3-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-3H-imidazo[4,5-c]pyridine, 1.5 g of 20% palladium on carbon, 1.6 ml of acetic acid and 150 ml of methoxyethanol is hydrogenated at 50° C. and ca. 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, dissolved in water, and treated with 50 ml of wet IR-45 ion exchange resin. The filtrate is concentrated to dryness and recrystallized from ethanol-water to provide 2.0 g of 3-β-D-arabinofuranosyl-4,6-diamino-3H-imidazo-[4,5-c]pyridine.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:17]=[CH:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)=[O:15])=[CH:10]1.[CH2:40]1COCC1>CCOC(C)=O>[O:8]1[CH2:7][CH2:6][CH2:40][O:5][CH:4]1[CH2:3][CH2:2][C:14]([C:16]1[N:17]=[CH:18][N:19]([C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:20]=1)([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)[OH:15]
Reactant: BrCCC1OCCO1
Reactant: O=C(c1ccsc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(CCC1OCCCO1)(c1ccsc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 30 °C

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (2.9 mL, 25 mmol) was added to Mg (0.7 g, 29 mmol) and THF (50 mL) and heated to 30° C. for 1.5 h under nitrogen atmosphere. A solution of thiophen-3-yl-(1-tritylimidazol-4-yl)methanone (4.69 g, 11.2 mmol) in THF (15 mL) was added slowly and the reaction was heated for 18 h at 30° C. The reaction was diluted with EtOAc, washed with NH4Cl (sat'd), water, and brine. The organic layer was dried with MgSO4, filtered and the solvent was evaporated in vacuo to yield 3-(1,3-dioxan-2-yl)-1-(1-tritylimidazol-4-yl)-1-(thiophen-3-yl)-propan-1-ol as ton crystals (6.01 g, 90%). mp 120-123° C. A solution of this material (1 g, 1.86 mmol) in dichloroethane (10 mL) was added to trimethylsilyl trifluoromethanesulfonate (0.36 mL, 18.6 mmol) and dichloroethane (50 mL) at 0° C. After stirring for 3 h at 25° C. the reaction mixture was cooled to 0° C. and treated with Na2CO3 (sat'd). The organic layer was dried with MgSO4, filtered and solvent was evaporated in vacuo. Purification by chromatography using EtOAc/MeOH/NH4OH, 98:1.9:0.1 as eluant afforded 4-(thionaphth-4-yl)imidazole (0.146 g, 40%). 1H NMR (CD3OD) δ7.31 (t, 1H), 7.40 (s, 1H), 7.60 (d, 1H), 7.61 (d, 1H), 7.77 (d, 1H), 7.80 (s, 1H), 7.83 (d, 1H). This material (0.146 g, 0.73 mmol) was dissolved in hot isopropyl alcohol (4 mL) and treated with maleic acid (0.847 g, 0.73 mmol) to yield Cp-1 (0.23 g, 100%) mp 173-174° C. 1H NMR (DMSO) δ6.12 (s, 2H), 7.45 (t, 1H), 7.68 (d, 1H), 7.88 (d, 1H), 7.90 (d, 1H), 7.92 (s, 1H), 8.05 (d, 1H), 8.62 (s, 1H). MS m/e 201 (M+H), 100.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][NH:15][C:16]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH2:12][N:11]([C:26]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:37]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([CH2:14][N:15]([CH3:37])[C:16]3[N:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][N:21]=3)[CH2:12][N:11]([C:26]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=3)=[O:27])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: Cc1cc(C(=O)N2C[C@H](CNc3ncc(C(F)(F)F)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2C[C@H](CN(C)c3ncc(C(F)(F)F)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Yield: 57.1 %

Procedure:
{(3S,4S)-3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl)-(6-methyl-pyridazin-4-yl)-methanone (50.0 mg, 0.1 mmol) were dissolved in DMF (1 mL) and treated with NaH (55% dispersion in oil) (5 mg, 0.11 mmol) at ambient temperature. After 5 min methyl iodide (7.3 μL, 0.12 mmol) were added and the reaction mixture was stirred over night. After quenching with water and extraction with ethyl acetate (3×10 mL) the combined organic phases were dried on sodium sulfate and filtered. After evaporation of the solvent the crude product was subjected to column chromatography (silica gel, dichloro methane, dichloro methane/methanol 4:1) to yield the title product (30 mg, 58%) as a brown foam. ES-MS m/e: 525.2 (M+H+).