Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].C[N:26]([C:28]1[CH:33]=[CH:32]C=CN=1)C.C(S(N)(=O)=O)CC.CO.ClCCl>ClCCl.CN(C1C=CN=CC=1)C>[CH2:28]([NH:26][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:19])[CH2:33][CH3:32]
Reactant: CN(C)c1ccccn1
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Agent: CCCS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCCC)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(N-[5-Bromo-2-propoxvbenzyl]-N-ethylamino)pyridazine-3-carboxylic acid (example 18) (500 mg, 1.27 mmol) was dissolved in dichloromethane (50 ml), (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDAC),(365 mg, 2.07 mmol), dimethylaminopyridine, (DMAP) (465 mg, 3.81 mmol) and propanesulfonamide (190 mg, 1.54 mmol) was added. The mixture was stirred at ambient temperature under argon overnight, after which TLC (5% methanol/dichloromethane) suggested the reaction was complete. The reaction mixture was loaded directly onto a MPLC column (silica) and the title compound obtained by elution 5% methanol/dichloromethane as a foam (380 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20](O)=[O:21])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:21])[NH:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1ccccn1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with pyridin-2-ylmethylamine; ESI-MS [M+H]+: 551.5
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH2:8][CH2:7]1.Cl.Cl.N[CH:31]1[CH2:36]CN(CC2CCCCCC2)C[CH2:32]1>>[CH:4]1([CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)([OH:20])[C:15]3[S:19][CH:18]=[N:17][CH:16]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2][CH2:1][CH2:36][CH2:31][CH2:32]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2cncs2)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1cncs1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-hydroxy-2-(5-thiazolyl)acetic acid obtained in Example 57 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:12]=[C:13]([CH3:16])[CH:14]=[CH2:15].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:13](=[O:12])[CH3:16])[CH2:15][O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(C(C)=O)=C2

Procedure:
1.52 g (10 mmol) of 2-hydroxy-4-methoxybenzaldehyde, 0.66 g (10 mmol) of 3-oxo-1-butene and 0.79 g (10 mmol) of pyridine are added at room temperature and with mechanical stirring to a suspension of 0.14 g (1 mmol) of potassium carbonate in 100 ml of dimethylformamide. The mixture is brought to reflux while magnetic stirring is maintained for 6 hours. The reaction medium is then poured into 200 ml of 0.5 N aqueous sodium hydroxide solution and thereafter extracted three times with 100 ml of diethyl ether. The organic phases are combined, washed twice with 100 ml of saturated aqueous sodium chloride solution and dried. The solvents are evaporated off and the product is purified by chromatography (see Table Al)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1ccc(N)nc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-picoline (98.1 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide (197 mg, 77%) as a white foam: [α]23589=−47.8° (c=0.046, chloroform); EI-HRMS m/e calcd for C21H25ClN2O3S (M+) 420.1274, found 420.1273.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24]C(=O)OC(C)(C)C)[N:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:9]1[N:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:12]2[C:13](=[O:16])[NH:14][CH2:15][C:11]=2[CH:10]=1
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (94 mg, 0.22 mmol) and TFA (1 mL, 12.98 mmol) in DCM (1 mL) was stirred at RT for 2 h. The mixture was subsequently concentrated. The residue was purified by preparative HPLC (01-25; 5.45 min) and basified to give the title compound as a yellow solid (10 mg, 14%). 1H NMR (500 MHz, DMSO-d6) δ ppm 122-1.61 (m, 8 H), 3.63 (s, 3 H), 4.19 (s, 2 H), 6.46 (br s, 1 H), 7.98 (s, 1 H), 8.29 (s, 1 H), 8.85 (s, 1 H). [M+H] calc'd for C17H22N6O, 327; found, 327.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]3)=[N:14][CH2:15][N:16]2N2CCNCC2)=[N:11][C:10]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([SH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([NH:8][C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])[CH2:27][CH2:26]3)=[N:14][C:15]([N:11]3[CH2:12][CH2:17][NH:18][CH2:9][CH2:10]3)=[N:16]2)=[N:11][C:10]=1[S:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: SCc1ccccc1
Reactant: O=S1CCN(C2=NCN(N3CCNCC3)c3nc(NCc4ccccc4)c(Cl)nc32)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3nc(NCc4ccccc4)c(SCc4ccccc4)nc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 7-benzylamino-6-chloro-4-(1-oxido-thiomorpholino)-1-piperazino-pteridine and benzylmercaptan.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([Cl:20])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C2=CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1

Procedure:
A solution of 17 g of α-[para-(1-cyclohexenyl)-phenyl]-propionic acid in 100 ml of absolute benzene is treated with 8 ml of thionyl chloride and then heated at 80°-90°C for one hour. The solution is evaporated under reduced pressure, the residue dissolved in 3 × 50 ml of absolute benzene, followed each time by evaporation under reduced pressure. There is thus obtained as residue α-[para-(1-cyclohexenyl)-phenyl]-propionic acid chloride which can be used as it is for the manufacture of the afore-described ester.
Reaction SMILES: [N:1]1([CH:7](O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].COC1C=CC(O)=CC=1.[C:22]([O:27]C)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C(O)(=O)C>[C:22]([O:27][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)OC
Reactant: CC(O)N1CCCCC1
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C(C)C(=O)OCCN1CCCCC1
Reaction time: 2 h

Procedure:
A 1 liter resin kettle was fitted with an air bubbler, temperature probe and still head. To the kettle was added, in order: 233 grams piperidinoethanol, 5.0 grams sodium methoxide, 0.5 grams p-methoxy phenol (to inhibit polymerization), and 750 milliliters methyl methacrylate. With a slow stream of air bubbling through the reaction mixture, the mixture was stirred vigorously and heated to 80 degrees with a constant temperature water bath. 5.0 grams sodium methoxide were added 30 and 60 minutes after the start of the reaction. After 120 minutes, the reaction mixture was cooled and neutralized with 17.0 grams acetic acid. The reaction mixture was transferred to a separatory funnel. The product was extracted from the reaction mixture into one liter of aqueous solution containing 95 grams concentrated sulfuric acid. The reaction mixture was treated with 500 milliliters of aqueous solution containing 15 grams concentrated sulfuric acid to extract remaining product. The two aqueous portions were combined and extracted with petroleum ether (boiling point 30-60 degrees) to remove residual methyl methacrylate, then rendered basic with 500 milliliters of aqueous solution containing 150 grams potassium hydroxide. The product was extracted from the aqueous solution with petroleum ether. The petroleum ether solution was dried over anhydrous magnesium sulfate. The petroleum ether was removed from the product with a rotary film evaporator under reduced pressure.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C.[CH2:27]([O:34][C:35]1[CH:62]=[CH:61][C:60](I)=[CH:59][C:36]=1[C:37]([NH:39][C:40]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:49][C:41]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]Cl.C(OCC)(=O)C.CN1CCCC1=O>[CH2:27]([O:34][C:35]1[CH:62]=[CH:61][C:60]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:59][C:36]=1[C:37]([NH:39][C:40]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:49][C:41]=1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(I)ccc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Phenol (0.029 mL), cesium carbonate (0.11 g), 2,2,6,6-tetramethylheptane-3,5-dione (3.4 μL), and copper(I) chloride (8.2 mg) were added to a 1-methyl-2-pyrrolidone (0.60 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-iodobenzamido)-4-phenylbenzoate (0.10 g), followed by stirring under a nitrogen atmosphere at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then 2,2,6,6-tetramethylheptane-3,5-dione (3.4 μL) and copper(I) chloride (8.2 mg) were added thereto, followed by stirring under a nitrogen atmosphere at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-95% hexane/ethyl acetate] to obtain 0.049 g of tert-butyl 2-(2-(benzyloxy)-5-phenoxybenzamido)-4-phenylbenzoate (0.049 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N+:13]([O-])=O)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].Cl[Sn]Cl>C(O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12])[NH2:13]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 261 mg (1.00 mmol) of 3,4-bis(trifluoromethyl)nitrobenzene and 989 mg (5.23 mmol) of SnCl2 in 6 mL of ethanol was heated at 70° C. for 2 h. It was evaporated to dryness and the residue was treated with 1N NaOH to pH=13. White precipitate was observed. The mixture was extracted by CHCl3 (4×8 mL). The extract was dried (MgSO4) and evaporated to leave 228 mg (99%) of oil. 1H NMR (CDCl3), 4.167 (sb, 2), 6.803 (d, 1, J=7.41), 7.026 (s, 1), 7.579 (d, 1, J=8.58). 19F NMR (CDCl3), 55.014 (q, 3), 56.919 (q, 3).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O>C(O)C>[SH:4][C:1]1[S:3][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:2]=1
Reactant: O=C1CCCCC1Br
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Product: Sc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of ammonium dithiocarbamate (1.4 g, 12.4 mmol) in 25 mL of ethanol was added 2-bromocyclohexanone (2.2 g, 12.4 mmol). The reaction was stirred at rt overnight. The next morning the reaction was heated at 70° C. for 1 h. The solvent was removed under reduced pressure. The product was subjected to flash chromatography (3:1 hexane/ethyl acetate) to recover a yellow solid. Recrystallization from ethyl acetate afforded 0.54 g of 2-mercapto-4,5,6,7-tetrahydrobenzothiazole.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([C:14](Cl)=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[CH3:17][C:18]1[C:19]([CH2:30][S:31]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)=[O:32])=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:14]([N:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:31]([CH2:30][C:19]1[C:18]([CH3:17])=[C:23]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:22]=[CH:21][N:20]=1)=[O:32])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN(C(=O)Cl)c1ccccc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCN(C(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 67.8 %

Procedure:
To a solution (10 mL) of 2-[(chlorocarbonyl)(phenyl)amino]ethyl acetate (0.58 g) prepared in the same manner as in Synthetic Example 25 in tetrahydrofuran were added 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.739 g), triethylamine (0.558 mL) and 4-dimethylaminopyridine (0.024 g), and the mixture was stirred at 60° C. for 15 hrs. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:4, then 3:2). Crystallization from diethyl ether gave the title compound (0.779 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:34])[NH:15][NH:16][C:17](=O)[C:18]3[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:20][C:19]=3[O:29][CH2:30][O:31][CH3:32])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>>[Br:24][C:22]1[C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:20][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:18]([C:17]2[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[C:14](=[S:34])[NH:15][N:16]=2)[CH:23]=1
Reactant: COCOc1cc(OCOC)c(C(=O)NNC(=S)Nc2ccc(N3CCOCC3)cc2)cc1Br
Agent: [Na+]
Agent: [OH-]
Product: COCOc1cc(OCOC)c(-c2n[nH]c(=S)n2-c2ccc(N3CCOCC3)cc2)cc1Br
Yield: 35.6 %

Procedure:
The crude crystals of 4-[4-(morpholin-4-yl)-phenyl]-1-(5-bromo-2,4-bis methoxymethoxy-benzoyl)thiosemicarbazide (IM5-S-d01) and 5% aqueous sodium hydroxide (1 mL) were added in a test tube and refluxed for 2 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the combined organic layer was dried over anhydrous sodium sulfate. Filtration and evaporation gave crude crystals of 5-(5-bromo-2,4-bis-methoxymethoxy-phenyl)-4-[4-(morpholin-4-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (IM6-S-d01) (2 steps, 35.6%). These crude crystals were subjected to the next reaction without purification in particular.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]#[N:22])=[CH:16][C:15]=1[O:30][CH3:31].[CH3:32][CH2:33][O:34][C:35](C)=[O:36]>C1COCC1>[CH2:33]([O:34][C:35](=[O:36])[C:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:21]#[N:22])[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([O:30][CH3:31])[CH:16]=1)[CH3:32]
Reactant: CCOC(C)=O
Reactant: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1ccc(F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. cooled solution of diisopropylamine (5.11 ml, 35.8 mmol) in THF was added n-butyllithium (22.40 ml, 35.8 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up <−40° C. 2-(4-Fluoro-3-methoxyphenyl)-3-phenylpropanenitrile (6.1 g, 23.89 mmol) dissolved in THF was added followed by ethyl chloroformiate (3.42 ml, 35.8 mmol). The reaction mixture was stirred over night and was allowed to heat up to room temperature. Evaporated solvents and redissolved in EtOAc, washed with 10% citric acid, water and brine and the combined organic layers were dried over MgSO4, filtered and evaporated to obtain 7.2 g of a yellow oil, that was purified by flash chromatography on 330 g SiO2 using 20% EtOAc in cyclohexene to obtain 18.26 g of the desired product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:17]1[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][C@H:19]([CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:18]1=[O:37])[C:10]([N:12]1[CH2:15][CH:14](O)[CH2:13]1)=[O:11].C(N(S(F)(F)[F:44])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:17]1[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][C@H:19]([CH:28]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[C:18]1=[O:37])[C:10]([N:12]1[CH2:13][CH:14]([F:44])[CH2:15]1)=[O:11]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CC(O)C1)c1ccc(F)cc1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CC(F)C1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
The azetidinol (Example 15) (57 mg) in anhydrous dichloromethane (2 mL) was stirred at −5° C. and diethylaminosulfur trifluoride (50 μL, excess) was added in one portion. The mixture was left at room temperature overnight and saturated aqueous sodium hydrogen carbonate (3 mL) was added. The mixture was diluted with dichloromethane (10 mL) and the organic phase was separated using a hydrophobic frit and blown down with nitrogen. The crude reaction mixture was purified using the mass-directed autoprep system to give (3R,6R)-1-[(1R)-1-(2,4-difluorophenyl)-2-(3-fluoroazetidin-1-yl)-2-oxoethyl]-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutylpiiierazine-2,5-dione (26 mg) as a white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:39])[C@H:17]1[C@H:21]2[CH2:22][CH2:23][C@@H:18]1[C@H:19]([O:24][C:25](=[O:38])[C:26]([OH:37])([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[CH2:20]2)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:39])[C@H:17]1[C@H:21]2[CH2:22][CH2:23][C@@H:18]1[C@H:19]([O:24][C:25](=[O:38])[C:26]([OH:37])([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[CH2:20]2
Reactant: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCCCCCCCO)[C@H]1[C@H]2CC[C@@H]1[C@H](OC(=O)C(O)(c1cccs1)c1cccs1)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-{[9-(tert-butyl-dimethyl-silanyloxy)-nonyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester (0.51 g, 0.82 mmol) in THF (7 mL) was treated with 1 M HCl (3.5 mL) and stirred at RT for 45 min. The reaction mixture was neutralised with satd NaHCO3 (aq) and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dryness to afford a light brown oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[C:4](Cl)[N:3]=1.C(O)=[O:20]>>[OH:17][CH2:16][CH2:15][CH:12]([CH2:13][OH:14])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O=CO
Reactant: Nc1nc(Cl)c2ncn(CC(CO)CCO)c2n1
Product: Nc1nc2c(ncn2CC(CO)CCO)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A solution of (-)-2-(2-amino-6-chlorpurin-9-ylmethyl)-1,4-butanediol (11.5 mg, 0.0423 mmol) in 50% aqueous formic acid (0.75 ml) was kept at 100° C./2 h and then evaporated to dryness, dissolved in 2 ml of water and lyophilized. The product was dissolved in 1 ml of water, 2 drops of conc. aqueous ammonia was added and the solution kept at 100° C. for 10 min, flushed with nitrogen to remove ammonia, and lyophilized. The residue was dissolved by warming with 1.2 ml of 20% aqueous methanol and the solution filtered and kept in open air to allow for slow partial evaporization of solvent. Crystalline needles were formed. Filtration, washing with 3 drops of water and drying yielded 6.4 mg (60%) of (-)-9-(4-hydroxy-2-hydroxymethylbutyl)guanine.