Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][Br:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CO)COC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25.8 g. (0.176 mole) of (R)-(+)-3-tert. butoxy-2-methyl-1-propanol and 50.5 g. (0.193 mole) of triphenylphosphine in 105 ml. of CH2Cl2 was stirred while 32.8 g. (0.184 mole) of N-bromosuccinimide was added in portions, keeping the temperature below 30° C. with occasional ice bath cooling. The resulting solution was stirred at room temperature for one hour then most of the solvent was distilled under a water aspirator pressure using a Vigreaux column. The product was distilled from the residue using a short distilling head giving 0.7 g. of forerun b.p. 58-62° C. (23 mm Hg) and then the main fraction (31.1 g.) b.p. 62-69° C. (14-18 mm Hg). The total distillate (31.8 g.) was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume and 9:1 parts by volume hexane-ether yielded the pure (S)-(+)-3-tert. butoxy-2-methyl1-bromopropane which was distilled giving 26 g. (70.6%) of colorless liquid, b.p. 71° C. (16 mm Hg); [α] 25D+ 23.32° (c 4.23, C6H6).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](O)[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].C(Cl)[Cl:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([Cl:20])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
Via chloride: A solution of 374 g (1.48 mol) (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3–5° C. and treated in 10 min with 1.241 (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4l of n-heptane, the reaction was evaporated to 2.91, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1.[NH4+].[Cl-].CCOCC>C(#N)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([Cl:35])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1c(Cl)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 100 mg (0.26 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of acetonitrile were added 25 mg (0.185 mmol) of NCS. After stirring at RT for 2 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/CH2Cl2 1:3 yielded 70 mg (65%) of 2-(1-benzyl-3-chloro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, white solid, MS: 420 ((M−H−), 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]=O.[ClH:13].[CH3:14][NH:15][CH3:16].Cl>CC(O)C>[ClH:13].[CH3:14][N:15]([CH3:11])[CH2:16][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCC(=O)c1ccc(F)cc1
Yield: 94.2 %

Procedure:
To a solution of 4′-fluoroacetophenone (5 g, 36.2 mmol) in propan-2-ol (90 ml) was added paraformaldehyde (4.35 g, 0.145 mol), dimethylamine hydrochloride (54.2 mmol) and concentrated HCl (0.8 ml). The reaction was heated at reflux for 18 h and on cooling the solvent was removed in vacuo. The residue was treated with acetone giving a white precipitate which was collected by filtration and dried in vacuo to give the title compound as a white solid (7.9 g). MS (ES): MH+ 196.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:18]=[C:19]=[O:20])[CH2:15][CH2:16][CH3:17]>C1(C)C(C)=CC=CC=1.P([O-])(OCCCC)(OCCCC)=O>[CH2:14]([NH:18][C:19]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:20])[CH2:15][CH2:16][CH3:17]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCN=C=O
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1C
Product: CCCCNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 60 %

Procedure:
0.5 mole of diphenylamine was taken together with 0.53 mole of n-butyl isocyanate and 1 g of di-n-butyl phosphate in 150 ml of xylene. The mixture was heated at 120° C. for 24 hours, with stirring, and then cooled to room temperature. After the product had been filtered off, washed with 100 ml of cold xylene and dried, 0.3 mole of N-n-butyl-N',N'-diphenylurea was obtained. Melting point: 92° C./yield: 60% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)=[O:5])[CH3:2].[C:19](P(=O)(OCC)OCC)#[N:20].[C-]#N.[Li+].O>C1COCC1.CN(C=O)C>[C:19]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][C:8]=1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:20]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCOC(=O)CCC1CCc2ccccc2C1=O
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC1=C(C#N)c2ccccc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
2-(2-Ethoxycarbonylethyl)-3,4-dihydro-1(2H)-naphthalenone (19.7 g, 80 mmol), from Step 1, was dissolved in 200 mL of dry THF and diethyl cyanophosphonate (23.6 mL, 160 mmol), commercially available from Aldrich Chemical Company, was added, followed by 160 mL of a 0.5M solution of lithium cyanide in DMF. The reaction mixture was stirred at ambient temperature overnight and then poured into water. The aqueous mixture was extracted with three portions of diethyl ether. The ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of toluene and 20 g of p-toluenesulfonic acid was added. The reaction mixture was heated at reflux for 3 h and allowed to cool to ambient temperature. The toluene solution was washed with 5% aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexane to give 13.1 g (64.2% yield) of the title compound; MS DCl--NH3 M/Z: 273 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C.[Cl:56][C:57]1[C:58]([F:100])=[C:59]([C@@H:63]2[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:82])([CH3:81])[CH3:80])[NH:65][C@H:64]2[C:83]([NH:85][C:86]2[CH:97]=[CH:96][C:89]([C:90]([O:92][CH2:93][CH2:94]O)=[O:91])=[CH:88][C:87]=2[O:98][CH3:99])=[O:84])[CH:60]=[CH:61][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([O:12][CH2:94][CH2:93][O:92][C:90](=[O:91])[C:89]1[CH:96]=[CH:97][C:86]([NH:85][C:83]([C@H:64]2[C@H:63]([C:59]3[CH:60]=[CH:61][CH:62]=[C:57]([Cl:56])[C:58]=3[F:100])[C@:67]([C:70]3[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][C:71]=3[F:77])([C:68]#[N:69])[C@H:66]([CH2:78][C:79]([CH3:80])([CH3:81])[CH3:82])[NH:65]2)=[O:84])=[C:87]([O:98][CH3:99])[CH:88]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of (S)-L-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 13.6 mg, 0.072 mmol), HATU (Bachem, 27.3 mg, 0.072 mmol), N,N-diisopropylethylamine (18.6 mg, 0.025 mL, 0.144 mmol) and dimethylaminopyridine (Aldrich, 2.2 mg, 0.018 mmol) in dimethyl formamide (8 mL) was stirred for 10 min before 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 19 mg, 0.028 mmol) in dimethyl formamide (1 mL) was added. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed successively with aqueous sodium bicarbonate solution, water (3×15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (hexane/ethyl acetate, 95/5 to 65/35) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((S)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (17 mg, 71% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:11][C:10]([NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:9][C:10](=[O:13])[CH2:11][N:23]2[CH2:22][CH2:21][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)[CH2:25][CH2:24]2)=[O:13])[CH2:24][CH2:25]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(C)c(NC(=O)CCl)c1
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1NC(=O)CN1CCN(c2ccccn2)CC1
Yield: 74 %

Procedure:
The procedure described in Example 181 was followed, substituting 2-chloro-N-[2-(2-chloroacetylamino)phenyl]acetamide (Aldrich) for N-(2,5-dimethylphenyl)-2-chloroacetamide and using 2.4 equivalents of 1-pyridin-2-yl-piperazine to provide the title compound (74% yield) as a light tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.59 (m, 8H), 3.18 (s, 4H), 3.52 (m, 8H), 6.63 (dd, 2H, J=5.1, 5.1 Hz), 6.78 (d, 2H, J=8.5 Hz), 7.20 (dd, 2H, J=5.8, 3.4 Hz), 7.51 (dd, 2H, J=8.5, 8.5 Hz), 7.60 (dd, 2H, J=5.8, 3.7 Hz), 8.10 (d, 2H, J=3.7 Hz), 9.64 (br s, 2H); MS (DCI/NH3) m/e 515 (M+H)+; Anal. calcd for C28H34N8O2.0.4 C4H8O2.0.1 H2O: C, 64.44; H, 6.83; N, 20.31. Found: C, 64.42; H, 6.67; N, 20.12.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH2:18](N(CC)CC)C.CN(C)[C:27]1[CH:32]=[CH:31]C=CC=1>C(C(C)=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:18]=[C:32]([CH3:31])[CH3:27])=[C:3]([N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]3=[N:10]2)[CH:4]=1.[CH2:18]([N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[NH:13][N:9]1[C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[OH:1])[C:32](=[CH2:31])[CH3:27]
Reactant: CCN(CC)CC
Reactant: CN(C)c1ccccc1
Agent: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: CCC(C)=O
Product: C=C(C)CN1c2ccccc2NN1c1cc(C)ccc1O
Product: CC(C)=COc1ccc(C)cc1-n1nc2ccccc2n1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
10 g of 2-(2-hydroxy-5-methylphenyl) benzotriazole (0.044 moles), 4.5 g of the triethylamine (0.044 moles) and 16.1 g of N,N-dimethylaniline (0.13 moles) were introduced into a reacting chamber and stirred for 5 minutes to make a solution. 0.09 moles of 3-chloro-2-alkyl propylene were dissolved in the methyl ethyl ketone and then were added to the solution within 10 minutes into the reacting chamber where air inside the chamber was nitrogen gas. The solution was heated to 80° C. for 5 hours, further heated to 180° C. and held on for 3 hours to allow Claisen rearrangement before removing heat and allowing to cool to 80° C. Then, the solution was filtered using activated carbon A filtrate was recrystallized using 40 ml of isopropanol. Then, filter paper was used to filter a yellow recrystallized filtrate. The yellow recrystallized filtrate was isolated by column chromatography to obtain 3.1 g of 2-(2-hydroxyl-5-methylphenyl) benzotriazole, 0.2 g of 2-(5-methyl-2-(2-methyl-propenyloxy)-phenyl)-2H-benzotriazole, 4.9 g of 1-methallyl-2-(2′-hydroxyl-5′-methylphenyl) benzotriazole (yield: 40%) and 0.1 g of by-products including 2-benzotriazol-2-4 methyl-6-(2-methyl-propenyl)-phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][Cl:17])[C:7](OC)=[O:8].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:28].[CH3:29]O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:8])[NH:28][CH:29]=[N:18]2)=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][Cl:17]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Reactant: CO
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
In a 10 mL volume stainless pressure-resistant vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of methyl 4-methoxy-5-(3-chloropropoxy)-anthranilate, 0.93 g (8.8 mmol) of methyl orthoformate, 0.67 g (8.8 mmol) of ammonium acetate, and 5 mL of methanol. The vessel was closed, and the reaction was carried out at 90-95° C. for 8 hours. After the reaction was complete, 50 mL of water was added to the reaction mixture. The aqueous reaction mixture was stirred at 25° C. for one hour, to precipitate a crystalline product. The crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 0.89 g (isolated yield: 91%) of 7-methoxy-6-(3-chloropropoxy)quinazolin-4-one as a white crystalline product.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15](Br)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=3)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: N#CCc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: N#CCc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (83) (135 mg, 0.44 mmol) was coupled to 3-fluoro-phenylboronic acid (68 mg, 0.49 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][C:23]3[C:32]4[O:31][C:30]([C:33]([O:35]CC)=[O:34])=[CH:29][C:28](=[O:38])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][C:23]3[C:32]4[O:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][C:28](=[O:38])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CCC(COCc3ccccc3)O4)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc2c(=O)cc(C(=O)O)oc12)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 96.9 %

Procedure:
A suspension of ethyl 8-[2-(benzyloxymethyl)chromane-6-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylate (0.240 g, 0.47 mmol) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added with 0.510 ml of a 1M NaOH solution, stirring at room temperature for 1.30 h. After that the mixture was evaporated to dryness and the resulting residue was suspended in water adding 0.2M hydrochloric acid to slightly acid pH (pH=4-5). The solid was recovered by filtration, washed with methanol and dried on phosphorous pentoxyde under vacuum, thereby obtaining 0.221 g of the title compound as a white solid which decomposes above 283° C. (97% yield).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[CH:23]([CH2:26]O)[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:52]I>C(Cl)Cl>[I:52][CH2:26][CH:23]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[C:25](=[C:14]([O:13][CH:10]4[CH2:11][CH2:12][CH:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH2:8][CH2:9]4)[N:15]=[CH:16][N:17]=3)[C:24]1=2
Reactant: OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with a solution of (12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl)methanol (260 mg, 0.67 mmol, 1.00 equiv) in DCM (20 mL). Imidazole (91 mg, 1.34 mmol, 2.00 equiv) and PPh3 (264 mg, 1.01 mmol, 1.50 equiv) were added successively, followed by the addition of I2 (255 mg, 1.00 mmol, 1.50 equiv) at room temperature. The resulting solution was stirred overnight at ambient temperature and diluted with DCM and washed with Na2SO3 (sat.) and brine. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by a silica gel column with EtOAc/petroleum ether (1:1-3:1) to provide the desired 3-(iodomethyl)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (287 mg, 86%) as a light yellow solid. MS (ES): m/z 500 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C@@H:24]([NH:26][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:15][CH:14]=2)[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: COc1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc([C@H](C)NC(=O)c2ccc(-c3ccncc3)cc2)c1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 4-(pyridin-4-yl)benzoic acid (0.970 g, 4.87 mmol), (S)-1-(3-methoxyphenyl)ethanamine (0.884 g, 5.84 mmol), DIEA (1.7 ml, 9.8 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.87 g, 5.82 mmol) in DMF (10 ml) was stirred overnight, diluted with EtOAc, washed with 1N NaOH, sat NaHCO3, and brine, dried (Na2SO4), and chromatographed (20-85% EtOAc/dichloromethane) and triturated (Et2O) to give the title compound (1.075 g, 3.23 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[CH2:33]([NH:40][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][O:14][CH:15]([F:17])[F:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(difluoromethoxy)propanoic acid (510 mg, 2.0 mmol) and triethylamine (607.1 mg, 6 mmol) in THF (10 mL) at −78° C., isobutyl chloroformate (348 mg, 2.55 mmol) was added dropwise. After 30 minutes, benzylamine (321.5 mg, 3.0 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture then was diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated, and triturated with ether-hexanes (1:3) to give tert-butyl {(1R)-2-(benzylamino)-1-[(difluoromethoxy)methyl]-2-oxoethyl}carbamate (345 mg, 50%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.40-7.80 (m, 5H), 6.60 (t, 1H), 6.22 (wt, 1H), 5.25 (w, 1H), 4.32-4.55 (m, 4H), 4.05 (dd, 1H) and 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:25])[CH3:26])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[S:29][CH2:30][C:31]([OH:33])([CH3:34])[CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CS
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(C)(C)O)cc(C(C)(C)C)n1C
Yield: 25.7 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 1-mercapto-2-methylpropan-2-ol (213 mg, 2 mmol) and potassium tert-butoxide (225 mg, 2 mmol) in dimethylacetamide (10 mL) was heated at 100° C. for 12 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, eluant: EtOAc-MeOH 9:1) afforded 125 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 6H), 1.31-1.42 (m, 11H), 1.58-1.81 (m, 2H), 2.95 (s, 2H), 3.87 (s, 3H), 4.30-4.43 (m, 2H), 4.70 (s, 1H), 6.84 (s, 1H), 7.40-7.65 (m, 2H), 8.21 (d, J=2.0 Hz, 1H). MS (ESI+) m/z 486 (M+H)+. Anal. calculated for C24H34F3N3O2S: C, 59.36; H, 7.06; N, 8.65. Found: C, 59.27; H, 6.74; N, 8.40.