Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:23][CH2:22][CH2:21][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH2:48])[OH:44])[CH3:40]>C(#N)C>[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH:48][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6](=[O:7])[C@@H:5]1[CH2:21][CH2:22][CH2:23][N:4]1[C:1](=[O:3])[CH3:2])[OH:44])[CH3:40]
Reactant: CCOC(=O)C(O)(CC(=O)N(C)N)C(=O)C(C)O
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)C(O)(CC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O)C(=O)C(C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.00185 moles of acetylprolylalanylproline and 0.20 ml of N-methylmorpholine in 20 ml of acetonitrile is cooled to -20° by means of a Dry Ice acetone bath. To this is added 0.28 ml of isobutyl chloroformate. After stirring for 10 minutes at -20° there is added 0.00185 moles of 2-azaalanyllactyllactic acid ethyl ester in 5 ml of acetonitrile. The reaction mixture is allowed to warm to room temperature after which it is stirred for 2 hours and then concentrated in vacuo. The residue is extracted between 50 ml of methylene chloride and 20 ml of cold 0.25 N hydrochloric acid. The acid layer is backwashed 2 times with 25 ml of methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to give a glass. This residue is chromatographed on 75 gm of silica gel. Elution with methanol/methylene chloride (1-4%) gives pure acetylprolylalanylprolyl-2-azaalanyllactyllactic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>C(Cl)Cl.N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of tetrahydro-3-furanmethanol (Aldrich, 1.0 mL, 10.4 mmol) in 5 mL CH2Cl2 and 5 mL pyridine was added para-toluenesulfonyl chloride (3.0 g, 15.6 mmol) portion-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours then 5 mL H2O was added. The layers were separated and the aqueous layer was extracted 2×5 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound (2.62 g, 10.2 mmol, 98% yield). 1H NMR (300 Mhz, CDCl3) δ ppm 1.49-1.63 (m, 1H) 1.94-2.08 (m, 1H) 2.46 (s, 3H) 2.52-2.68 (m, 1H) 3.49 (dd, J=9.16, 5.09 Hz, 1H) 3.64-3.84 (m, 3H) 3.88-4.03 (m, 2H) 7.36 (d, J=8.14 Hz, 2H) 7.76-7.82 (m, 2H); MS (DCI/NH3) m/z 257 (M+H)+.
Reaction SMILES: [N:1]1([CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+]>C(O)C>[N:1]1([CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)C(C(=O)OCC)n1ccc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(C(=O)O)n1ccc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of diethyl (1H-indol-1-yl)malonate (0.02 mole) in 25 ml of absolute ethanol is added 25 ml (0.02 mole) of 0.8N ethanolic potassium hydroxide. This solution is stirred overnight. The solvent is flash evaporated and the residue is dissolved in 25 ml of water and washed twice with 50 ml of ether. The aqueous phase is separated, acidified to pH of 2.5, saturated with sodium chloride and extracted twice with 80 ml of ether. The ether extracts are combined, dried and evaporated to give the monoethyl ester of (1H-indol-1-yl)malonic acid.
Reaction SMILES: [CH:1]#[C:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>O1CCCC1>[CH:1]#[C:2][C:3]([NH:6][Si:15]([CH3:18])([CH3:17])[CH3:14])([CH3:5])[CH3:4]
Reactant: C#CC(C)(C)N
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)(C)N[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
In a 5000 ml flask were combined 250 g of commercial HC≡CCMe2NH2, 581.8 g of triethylamine, and 1637.5 g of tetrahydrofuran solvent. The flask and contents were cooled at 17° and addition of 625.5 g of trimethylchlorosilane begun with rapid stirring under nitrogen. The addition was completed in 90 min, followed by stirring for 85 min. Analysis by gas chromatography (GC) showed a small amount of HC≡CCMe2NH2, which was converted to product by an additional 53.4 g of trimethylchlorosilane. Reaction mixture was pressure-filtered and the solids triturated with fresh tetrahydrofuran and refiltered. The organic solutions were combined and distilled, providing the desired product, HC≡CCMe2NHSiMe3, as a liquid boiling at 135° at atmospheric pressure. Its structure was confirmed by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.[I:13]N1C(=O)CCC1=O>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([I:13])[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ncc2c(Cl)ccn2n1
Solvent: ClCCCl
Product: CSc1ncc2c(Cl)cc(I)n2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
5-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.27 mmol) was dissolved in 1,2-Dichloroethane (2.0 mL and then N-Iodosuccinimide (75 mg, 0.33 mmol) was added in one portion and the reaction was stirred in a vial at 60° C. overnight. The heterogenous mixture was powdered onto silica gel (0.75 g) and purified on ISCO (12 g, 0-5% EtOAc:Hex) to afford 5-Chloro-7-iodo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (49 mg; Yield=56%) as a yellow solid. m.p. 216-220° C.; LCMS (Bruker, Fragile): 4.0 min, m/z=326; 1H-NMR (CDCl3): 8.55 (s, 1H), 6.90 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([Cl:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[ClH:37].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: CS(=O)(=O)Nc1cc(N2CCCNCC2)ccc1NS(=O)(=O)c1ccc(F)cc1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-fluorobenzenesulfonylchloride (89 mg, 0.455 mmol) to give before Boc-deprotection 170 mg of a purple solid. M+ 1 443.1 Calcd 443.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]=[C:11]([C:29]([F:32])([F:31])[F:30])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][CH2:17][C:16]1[CH:15]=[C:14]([N:13]2[C:9]([C:7]([NH:6][CH2:5][C:4]3[CH:33]=[CH:34][CH:35]=[CH:36][C:3]=3[O:2][CH3:1])=[O:8])=[CH:10][C:11]([C:29]([F:31])([F:32])[F:30])=[N:12]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Temperature: 21 °C
Reaction time: 2 h
Yield: 128.2 %

Procedure:
To a stirred solution of 57 (900 mg, 1.784 mmol) in CH2Cl2 (3.4 mL) was added TFA (2.8 mL, 35.7 mmol). The mixture was allowed to stir at 21° C. for 2 h. A saturated NaHCO3 aqueous solution was added and followed by extractions with CH2Cl2. It was then dried over Na2SO4 and evaporated. The crude was used without any further purification. The title product 58 (925 mg, 100% yield) was isolated as a beige powder. LRMS (ESI): calc. 404.4; found 405.6 (MH)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[O:12][CH2:11]1)[CH:2]1[O:4][CH2:3]1.[K].[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:22][CH2:11][CH:10]([OH:12])[CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]([CH2:3][O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: CCCCCCCCO
Agent: [K]
Product: CCCCCCCCOCC(O)COCCOCC(O)COCCCCCCCC
Yield: 49 %

Procedure:
One part of ethylene glycol diglycidyl ether and 15 parts of octyl alcohol were reacted at 60° C. for 20 hours in the presence of 0.05 parts of potassium. Purification by distillation provided 1,8-bis(octyloxymethyl)-3,6-dioxaoctane-1,8-diol (boiling point 150° C./0.03 Torr) of the following formula: ##STR8## in a yield of 49%. This compound was then added to a greatly excess amount of a mixture of chlorosulfonic acid and acetic acid and reacted at room temperature for 3 hours. The resulting product was neutralized with sodium carbonate and extracted with n-butyl alcohol, obtaining a compound of the following formula: ##STR9## in a yield of 90%. This was a viscous liquid having a purity of 80% as measured by the modified Epton method which is a method for the quantitative measurement of anionic active agents.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:25][C:26]3[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)c1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
A mixture of 0.226 g (0.58 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.42 mmol) of 3-aminobenzoic acid, ethyl ester was fused in a 170° C. oil bath to give a clear melt. After 6 minutes, the melt was cooled to ca. 100° C. Glacial acetic acid (1 mL) was added to dissolve the melt. Water (5 mL) was added to precipitate a solid. The solid was filtered, washed well with water, and triturated with 2 mL of methanol. The mixture was filtered, and the cake was washed with 1 mL of methanol and then ether; wt 0.194 g. Recrystallization from ethyl acetate gave pure product; wt 0.075 g; mp 238°-240° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:17](=[O:18])[N:16]([CH3:19])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([CH3:14])=[CH:13][C:5]=2[CH2:4]1.[C:20](=O)(ON1C(=O)CCC1=O)[O:21]N1C(=O)CCC1=O.C(N(CC)CC)C.Cl.[NH:46]1[CH2:51][CH2:50][CH:49]([N:52]2[CH2:61][C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[NH:54][C:53]2=[O:62])[CH2:48][CH2:47]1>ClCCl>[CH3:14][C:12]1[C:11]2[NH:10][N:9]=[CH:8][C:7]=2[C:6]2[CH2:15][N:16]([CH3:19])[C:17](=[O:18])[CH:3]([NH:2][C:20]([N:46]3[CH2:47][CH2:48][CH:49]([N:52]4[CH2:61][C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[NH:54][C:53]4=[O:62])[CH2:50][CH2:51]3)=[O:21])[CH2:4][C:5]=2[CH:13]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: Cc1cc2c(c3cn[nH]c13)CN(C)C(=O)C(N)C2
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(c3cn[nH]c13)CN(C)C(=O)C(NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Reaction time: 2 h

Procedure:
To a solution of (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester (50 mg, 0.132 mmol) in methanol and chloroform (0.5 mL) was added 10% palladium on carbon (20 mg) under nitrogen atmosphere. The reaction mixture was brought to hydrogen atmosphere (1 atm) and stirred for 3 h. The catalyst was filtered and the solvent was evaporated to give 7-amino-4,9-dimethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one, hydrochloride in almost quantitative yield. To the amine salt in dichloromethane was added disuccinimidyl carbonate (37 mg, 0.145 mmol) and triethylamine (0.11 mL, 0.8 mmol) at room temperature. After 120 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, hydrochloride (39 mg, 0.145 mmol) was added and stirring continued for 12 h. The solvent was evaporated and the crude product was purified by Prep HPLC to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide in 59% overall yield. MS (ESI) 502 (M+H); Rf=1.31.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH2:17][C:18]([OH:20])=[O:19])[CH:11]=2)[CH:9]=1)([CH3:3])[CH3:2]>CCCCCCC.CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@@H:16]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH2:17][C:18]([OH:20])=[O:19])[CH:11]=2)[CH:9]=1)([CH3:3])[CH3:2].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH3:28])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C@H:16]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH2:17][C:18]([OH:20])=[O:19])[CH:11]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Solvent: CO
Solvent: CCCCCCC
Product: COc1ccc(C(C)C)cc1-c1cccc([C@@H](CC(=O)O)c2nnc(C)o2)c1
Product: COc1ccc(C(C)C)cc1-c1cccc([C@H](CC(=O)O)c2nnc(C)o2)c1

Procedure:
The racemic 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is subjected to chromatography on a chiral column using a heptane-methanol gradient to isolate the pure enantiomers (S)-3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid and (R)-3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid. The configuration on the chiral carbon atom is arbitrarily assigned (S) to the enantiomer with the shortest retention time on the applied chiral column and (R) to the enantiomer with the longest retention time on the applied chiral column.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:21]([CH3:30])[N:22]=CC1C=CC=CC=1)[NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[O:20]CCO2)[CH:11]=1)#[N:2].[ClH:31].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:31].[CH3:30][N:21]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][OH:20])[CH:13]=[CH:14][CH:15]=2)=[N:3][C:1]([NH2:2])=[N:22]1
Reactant: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(N)nc1NCCCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-Cyano-N-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidamide (18.2 g) in tetrahydrofuran (150 ml) was treated with 5N hydrochloric acid (30 ml) at 30° C. for 30 mins. Triethylamine (20 ml) was added followed by sodium borohydride (8.0 g). The resulting mixture was stirred at room temperature for 14 hrs, diluted with ethyl acetate (150 ml) and evaporated to a red oil which was dissolved in ethyl acetate, washed with sodium bicarbonate solution and evaporated to leave an oil. This oil was treated with etheral hydrogen chloride to give the title compound as a white solid (8 g). m.p. 148°-9°. TLC silica, ethyl acetate, water, isopropanol 0.88 ammonia (25:8:15:2) Rf 0.56.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][CH:14]2[CH:13](CO)[O:12]1.[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48]([OH:51])[CH:47]=1)=[O:45].CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:42][O:43][C:44]([C:46]1[O:50][N:49]=[C:48]([O:51][CH2:23][C:14]23[CH2:13][O:12][CH:11]([N:6]4[CH:5]=[N:4][C:3]5[C:7]4=[N:8][CH:9]=[N:10][C:2]=5[Cl:1])[CH:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[CH:47]=1)=[O:45]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(O)no1
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(Cl)ncnc43)C2O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Product: COC(=O)c1cc(OCC23COC(n4cnc5c(Cl)ncnc54)C2OC(C)(C)O3)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of [6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (0.570 g, 1.74 mmol) in 16 mL of dry dichloromethane was added polymer-bound triphenylphosphine (PS-TPP; Argonaut Tech., 2.14 mmol/g, 0.91 g, 1.2 eq), followed by methyl-3-hydroxy-5-isoxazolecarboxylate (0.248 g, 1 eq). The mixture was sonicated for 15 minutes then stirred at room temperature for 1 h under argon. The reaction mixture was cooled to 0° C. and under argon flow diethylazodicarboxylate (0.33 g, 1.1 eq), dissolved in 1 ml of dichloromethane, was added dropwise via syringe. The mixture was protected from light and stirred at 0° C. for 30 min. then at room temperature for 20 h. The resin was washed liberally with dichloromethane and methanol. The organic solution obtained from the washes was concentrated to give, after flash chromatography purification, 0.740 g of the product as a white solid (95% yield). 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (s, 1H), 6.42 (s, 1H), 6.23 (d, J=2.1 Hz, 1H), 5.43 (dd, J=2.1 Hz, 1H), 5.14 (dd, J=3.6 Hz, 1H), 4.7 (m, 1H), 4.61 (dd, J=3.9 Hz, 1H), 4.49 (dd, J=5.7 Hz, 1H), 3.93 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H). MW calculated for C18Hl8ClN5O7 (MH+) 452, found 452 by LCMS.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:38])([C:14]2[S:15][CH:16]=[C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxy-4-[4-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 86, 5.29 g, 11.3 mmol) in CH2Cl2 (100 mL) at 0° C. was added DAST (1.8 mL, 1.2 eq.). The reaction mixture was stirred for 30 minutes before it was quenched by addition of saturated NaHCO3 solution (20 mL). The organic phase was separated and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=2:3) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05˜2.32 (4H, m), 1.46 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH:16][C:11]([NH:10][C:8](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[S:12]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 52%).
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+].[CH3:6][CH2:7][CH2:8][CH2:9][CH:10]=O.[NH3:12]>O>[NH2:12][CH:10]([S:1]([OH:3])(=[O:2])=[O:4])[CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCC=O
Reactant: N
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCC(N)S(=O)(=O)O
Temperature: 25 °C

Procedure:
52 g (500 mmoles) of sodium bisulfite are dissolved in 250 ml of warm water, 53.6 ml (510 mmoles) of n-valeraldehyde are added, and the resulting orange-red mixture is stirred on a steam bath until it turns colorless. The solution is cooled to room temperature, 400 ml of concentrated aqueous ammonia are added, the mixture is stirred at room temperature for one hour, and then allowed to stand in a refrigerator overnight. The reaction mixture is washed with 100 ml of diethyl ether, decolourized with carbon, filtered, and the pH of the filtrate is adjusted to 3 with concentrated aqueous hydrochloric acid under cooling. The separated crystalline substance is filtered off, washed with water and diethyl ether, and dried in a vacuum desiccator. 47.6 g (56.8%) of DL-α-aminopentanesulfonic acid are obtained; m.p.: 142° C., Rf9 =0.3-0.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)C1(c2ccccn2)CCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1(c2ccccn2)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyridin-2-yl-cyclopentanecarboxylic acid (431) (5 g, 26.178 mmol) in tetrahydrofuran was added BH3.tetrahydrofuran (1M) (52.36 mL) at 0° C. and stirring was continued for 1 h, then this reaction mixture was allowed to stir at room temperature for 5 h while silica thin layer chromatography was performed (50% ethyl acetate in Hexane; Rf=0.5).
Reaction SMILES: [C:1]1([CH:11]=[CH:12][C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCCC1.B.O.Cl>CO.O1CCCC1.[C].[Pd]>[C:1]1([CH2:11][CH2:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1cccc2ccccc12
Agent: [Pd]
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
3-(1-Naphthyl) acrylic acid (5.00 g) was dissolved in methanol (30 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (2.40 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 13 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a white solid (5.00 g. The white solid was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 27.4 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 18 hr. To the reaction mixture was added water, and 1M aqueous hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the object product (4.70 g) as a colorless oil.