Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH:12]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1CCC=O
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(Cl)cc1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 5-amino-4-chloro-2-(3-oxopropyl)benzonitrile (50 mg, 0.240 mmol, Example 566A) in THF (0.5 mL) at room temperature was added morpholine (37.6 mg, 0.431 mmol), sodium cyanoborohydride (30.1 mg, 0.479 mmol), and a drop of acetic acid. The reaction was stirred at room temperature for 1 h at which point LCMS indicated full conversion. The reaction was quenched with aq. Na2CO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (0-10% MeOH/DCM) to give 5-amino-4-chloro-2-(3-morpholinopropyl)benzonitrile (54 mg) as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1>CN(C)C=O>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1ccc(O)cc1NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1NC(=O)OC(C)(C)C
Yield: 70 %

Procedure:
In the same manner as in Reference Example 33 and using tert-butyl (5-hydroxy-2-methylphenyl)carbamate (18.9 g, 85.0 mmol), cesium carbonate (41.8 g, 0.128 mol), N,N-dimethylformamide (100 mL) and 5-bromo-2-nitropyridine (16.4 g, 80.7 mmol) as starting materials, the title compound (19.5 g, 53%) was obtained as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][C:10]1=[O:19].[F:28][C@@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]2([N:32]1[CH2:33][C@@H:29]([F:28])[CH2:30][C@H:31]1[C:34]([O:36][CH3:37])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Reaction time: 13 h
Yield: 109.9 %

Procedure:
2.79 g of triethylamine was added under ice cooling and a nitrogen atmosphere to a 50 mL chloroform solution of 1.70 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 1.03 g of the compound obtained in step 4-1, after which the reaction mixture was raised to room temperature and stirred for 13 hours at the same temperature. The reaction solution was stirred while a 50 mL saturated sodium hydrogencarbonate aqueous solution was added, and the reaction mixture was stirred for 15 minutes. After liquid separation, the aqueous layer thus obtained was extracted with chloroform. The combined organic layer was washed with saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 2.54 g of residue (yellow, amorphous). The residue thus obtained purified by column chromatography (silica gel 60, mobile phase: ethyl acetate), and stirred and washed in diisopropyl ether to obtain 1.98 g of a diastereoisomer mixture of the titled compound (pale green, amorphous).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([F:13])[CH:5]=1)=[O:3].[C:14](=O)([O:17]C)[O:15][CH3:16].FSI>>[CH3:16][O:15][C:14](=[O:17])[CH2:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([F:13])[C:7]([O:11][CH3:12])=[C:8]([F:10])[CH:9]=1
Reactant: COc1c(F)cc(C(C)=O)cc1F
Reactant: COC(=O)OC
Agent: FSI
Product: COC(=O)CC(=O)c1cc(F)c(OC)c(F)c1
Yield: 97 %

Procedure:
This compound was prepared from 3,5-difluoro-4-methoxyacetophenone and dimethyl carbonate according to method A. Yellow solid; Yield: 97%; mp 64-67° C.; 1H-NMR (300 MHz, CDCl3) δ 3.77 (s, 3H), 3.93 (s, 2H), 4.13 (t, J=1.7 Hz, 3H), 7.52 (m, 2H). Minor tautomer: 3.81 (s, 3H), 4.06 (m, 3H), 5.58 (s, 1H), 7.34 (m, 2H), 12.47 (s, 1H); MS (FSI) m/z 243 ([M−H]−), 245 ([M+H]+); Anal. Calcd for C11H10F2O4: C, 54.10; H, 4.13. Found: C, 54.37; H, 4.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:30])=[C:11]([CH:15]([C:23]2[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=2)[NH:16][C:17]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(F)=C(C(N)C2C(Cl)=NC=C[N:47]=2)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C1(C(Cl)=O)CCC1>C(Cl)Cl>[NH2:47][C:28]1[C:23]2[N:24]([C:17]([CH:19]3[CH2:22][CH2:21][CH2:20]3)=[N:16][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[F:30])[CH:25]=[CH:26][N:27]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl)C1CCC1
Reactant: NC(c1cccc(OCc2ccccc2)c1F)c1nccnc1Cl
Agent: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccccc4)c3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
N-[(3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl)methyl]cyclobutylcarboxamide: To a solution of C-(3-benzyloxy-2-fluoro-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine (1.1 g, 3.2 mmole) in methylene chloride (10 mL) was added diisopropylethylamine (1.1 mL, 6.4 mmole) under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and cyclobutanecarboxylic acid chloride (0.55 mL, 4.8 mmole) was added in one portion. The reaction mixture was stirred overnight at room temperature then quenched with water (10 mL). The organic layer separated and washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography using hexane:ethyl acetate (60:40) as an eluant to give the title compound (911 mg, 67%). FAB-MS: m/z 426.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>COCCOC>[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:34])=[CH:31][CH:30]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice-and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield the product as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate was made by the general procedure of U.S. Pat. No. 2,714,120 by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of α-methylstyrene in the presence of 25.7 grams (0.135 moles) of p-toluenesulfonic acid monohydrate catalyst. This mixture was heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture was cooled to 110° C. and 1125 ml of toluene was added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride, the organic phase was washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product was obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melted at 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[O:6]/[C:5]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:37][N:36]=[C:5]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]2)=[O:21])[CH:14]=1
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4ccc(Cl)cc43)ccc2F)CC1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Cl)cc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
(Z)-5-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1 (3H)-one (66) (53 mg, 0.13 mmol) was suspended in water (1.5 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (35 μl, 0.72 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (13 mg, 24% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.38 (1H, m), 1.40-1.50 (1H, m), 1.49-1.76 (1H, m), 1.83-1.91 (1H, m), 3.01-3.09 (1H, m), 3.25 (3H, s), 3.26-3.37 (2H, m), 3.40-3.46 (1H, m), 3.88-3.96 (1H, m), 4.34 (2H, s), 7.22 (1H, t), 7.35-7.42 (2H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.26 (1H, d), 12.68 (1H, s); m/z (LC-MS, ESI+), RT=2.24 (M+H 430.6).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:25])[CH2:21][NH:22][CH2:23][CH3:24])=[C:4]([F:26])[CH:3]=1.[CH3:27][OH:28].C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]2[C:20](=[O:25])[CH2:21][N:22]([CH2:23][CH3:24])[C:27]2=[O:28])=[C:4]([F:26])[CH:3]=1
Reactant: CO
Reactant: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CC(=O)N(c2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)C1=O

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide (0.82 g) and 1,11 -carbonyldiimidazole (0.43 g) in toluene (20 ml) was heated at reflux for 2 hours, cooled and processed. Column chromatography on silica gel eluting with 2.5% methanol-methylene chloride gave a buff colored solid (0.8 g), mp 162-3° C. 1H NMR (CDCl3, TMS): 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([N:72]([C:13](=[O:15])[CH2:12][O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:42])[CH3:41]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of (2-t-butoxycarbonylamino-2-methylpropoxy) acetic acid (504 mg, 2.0 mmol) in dichloromethane (10 ml) were added 1-hydroxy-7-azabenzotriazole (278 mg, 2.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429 mg, 2.3 mmol) and the mixture was stirred for 30 min. 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-propyl acetate (500 mg, 1.0 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.23 ml, 1.32 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (60 g) with ethyl acetate/heptane 4:1 to give 623 mg of 3-((2R)-2-(N-((2R)-2-(N-((2-(tert-butoxycarbonylamino)-2-methylpropoxy) acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate as an oil. The obtained product was taken up in 50% trifluoroacetic acid in dichloromethane (3 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and the mixture was liophilized to give 434 mg of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([S:41]([NH:1][C@@H:2]([C:20]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10])(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](N)C(=O)NCC(=O)OCc2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.42 h
Yield: 97 %

Procedure:
To a solution of D-Arg(Tos)-Gly-OBn (5.2 mmol; Boc previously removed by treatment with 40% TFA/DCM (0.1M) for 15 min. and then concentrated in vacuo; RP-HPLC: 13.8 min.; C18, 0-100% CH3CN over 25 min., 1.5 mL/min) in 21 mL of DCM is neutralized with DIEA before cooling to −78° C. where 1.19 g (6.24 mmol) of BnSO2Cl is added as a solid followed by 900 uL (10.4 mmol). The solution is allowed to warm to 23° C. and stirr for 18 h. The eaction mixture was extracted twice with 10% citric acid, twice with 5% NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to give 3.2 g (97%) of BnSO2-D-Arg(Tos)Gly-OBn as a white solid. RP-HPLC: 18.0 min.;C18, 0-100% CH3CN over 25 min., 1.5 mL/min.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([OH:3])=[O:2].C[C:18](C)([O-:20])C.[K+].C(OCC)=O>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH:18]=[O:20])[C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [K+]
Solvent: CCOC=O
Solvent: CN(C)C=O
Product: O=CC1c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Carboxyfluorene (2.8 g, 0.014 mole) was dissolved in anhydrous dimethylformamide (DMF, 133 mL). Potassium t-butoxide (12.5 g, 0.11 mole) and ethyl formate (400 mL) were added to the reaction solution. The temperature of the solution was increased to 60° C. for 5-10 minutes. The reaction solution was cooled to room temperature. Total reaction time was three hours. Ethyl formate was distilled off and 1M hydrochloric acid (150 mL) was added to the reaction mixture. The solid was filtered and washed with distilled water. The precipitate was dried overnight under reduced pressure with phosphorous pentoxide present. NMR confirmed the structure by the appearance of one new proton at δ11.47 ppm (aldehyde hydrogen).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 90 °C
Yield: 92.2 %

Procedure:
A solution of 2.14 g(31.4 mmol) of imidazole and 10.9 g(62.8 mmol) of dibasic potassium phosphate in 190 mL DMSO was treated with 5.25 g(3.7 mL, 50.9 mmol) of 3,4-difluoronitrobenzene followed by warming at 90° C. for 18 h. The solution was diluted with ethyl acetate and was extracted with water. The water layer was back-extracted with ethyl acetate and the combined organic layers were then extracted with water (2×). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford a brown solid. This material was chromatographed over 250 g of 230-400 mesh silica gel, eluting with dichloromethane, and then with 1%(v/v) methanol in dichloromethane, and finally with 2%(v/v) methanol in dichloromethane. These procedures afforded 6.0 g(92%) of the title compound as a bronze colored solid. 1H NMR (CDCl3): δ8.17, 7.96, 7.63, 7.35, 7.26.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:28][CH2:27][CH2:26]3)[O:8][C:7]=12.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[Sn](CCCC)(CCCC)CCCC>C1COCC1.O.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>[CH3:32][C:30]([CH3:31])([CH3:33])[CH2:29][C:4]1[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:28][CH2:27][CH2:26]3)[O:8][C:7]2=[C:2]([C:36]2[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2-c1nccn1C
Temperature: 160 °C

Procedure:
A solution of N-((1S)-1-((1R)-2-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-hydroxyethyl)-3-buten-1-yl)-2-methoxyacetamide (225 mg, 469 μmol) and tetrakis(triphenylphosphine)palladium (108 mg, 93.7 μmol) in THF (3.0 mL) is added to a vial with 1-methyl-2-(tributylstannyl)-1H-imidazole (217 mg, 586 μmol). The reaction was heated in the microwave at 160° C. for 20 min. The residue was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 ml). The organic layers were dried (MgSO4), concentrated and purified by reverse phase HPLC to give the title compound as a white amorphous solid. MS m/z=526.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[I-].[K+].Br[CH2:16][CH2:17][CH2:18][OH:19]>C(O)C.O>[OH:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCCO)cc1
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (25.0 g, 0.18 mol), potassium hydroxide (27.6 g, 0.49 mol), and potassium iodide (3.0 g, 0.018 mol) in ethanol (75 mL) and water (5 mL) was added dropwise 3-bromopropanol (25.6 g, 0.19 mol). The reaction was allowed to continue for 24 h under reflux. The solid residue was filtered off, and the filtrate was evaporated to dryness. The resultant solid was dissolved in water (200 mL) and then acidified with a 10% HCl solution. The precipitate was filtered for recrystallization from ethanol: water (1:1) to yield 1(26.7 g, 75%). 1H NMR (200 MHz, DMSO-d6): δ 1.85 (quintet, 2H, —CH2—), δ 3.55 (t, 2H, —CH2OAr), δ 4.10 (t, 2H, HOCH2—), δ 6.95 (d, 2H, aromatic ring), δ 7.85 (d, 2H, aromatic ring).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([C:53](O)=[O:54])[N:52]=1)([CH3:47])[CH3:46].C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:53]([C:51]2[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=2)=[O:54])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1

Procedure:
HATU (1.184 g) was added to a solution of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.41 g) and triethylamine (1 mL) in DMF (12 mL) at 20° C. and the resultant mixture stirred for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.78 g.