Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1.[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[O:16])[S:10][C:11]=2[CH2:12][CH3:13])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: CCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (130 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (278 mg, 0.43 mmol, 82% yield) as a yellow oil: LCMS (ES) m/e 581 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].N1C=CC=CC=1.[S:37](Cl)([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 76.2 %

Procedure:
To a suspension of 210 mg of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 10 ml of methylene chloride were added 0.03 ml of pyridine, 115 mg of tosyl chloride and a catalytic amount of 4-dimethylaminopyridine and the mixture was stirred at room temperature for one hour. The reaction solution was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was chromatographed over a silica gel column to afford 219 mg of the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH3:12])[N:10]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)/[C:9](=[N:19]/C(=O)C(F)(F)F)/[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([C:7]1[N:11]([CH3:12])[N:10]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:9](=[NH:19])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(C)(C)C)cc(=N)n1CC1CCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of sodium hydroxide (1.7 g, 41.5 mmol) in water (2 mL) was added to a solution of Example 127D (2.75 g, 8.3 mmol) in MeOH (10 mL) and the mixture stirred at 50° C. for 3 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic extracts were concentrated and the residue crystallized from MeOH and EtOAc to afford the title compound (1.9 g, 8.1 mmol, 97% yield). 1H NMR (300 MHz, Methanol-d4) δ ppm 1.23-1.37 (m, 2H), 1.41 (s, 9H), 1.53-1.64 (m, 2H), 1.64-1.78 (m, 4H), 2.17-2.44 (m, 1H), 3.34 (s, 1H), 3.80 (s, 3H), 4.12 (d, J=7.5 Hz, 2H), 5.75 (s, 1H); MS (ESI+) m/z 236 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O)#[N:21].N1C=CC=CC=1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccccc1O
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3C#N)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-cyanophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evaporated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (40%); mp: 181-183° C.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC3C=NC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]([O-])(=O)/[CH:35]=[CH:36]/[C:37]([O-])=O>>[C:28]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:34][CH2:35][C:36]3[CH:37]=[N:12][CH:11]=[CH:10][CH:9]=3)[CH2:11][CH2:10]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCc2cccnc2)CC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCc2cccnc2)CC1

Procedure:
3-[7-[4-(2,2-diphenylethenyl)-1-piperidinyl]heptyl]pyridine (1:1)-(E)-2-butenedioate salt hemihydrate;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([CH2:14][C:15]#[N:16])[CH2:6]2.CO.N.[H][H]>CO.[Ni]>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([CH2:14][CH2:15][NH2:16])[CH2:8]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(CC#N)C2
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc2c(cc1OC)CC(CCN)C2

Procedure:
5 g (2.3 mmoles) of (5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl)acetonitrile are dissolved in 50 ml of methanol. 50 mL of a (7N) MeOH—NH3 solution and 0.5 g of Raney nickel are then added. Hydrogen is carried out for 4 days under a pressure of 5 bar, at 25° C. Filtration over Celite and evaporation of the filtrate to dryness are carried out. The residue is taken up in 50 mL of HCl (1N) and washed with ethyl acetate; the aqueous phase is then brought to pH=10 by adding NaOH (20%). Extraction with Et2O, washing with water, drying over MgSO4, filtration and evaporation to dryness are carried out. The expected product is obtained in the form an oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH:20](I)([CH3:22])[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 18 mg of 60% sodium hydride was added at 0° C. to 2 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.05 ml of isopropyl iodide was added at 0° C., and the mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 17 mg of the above compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(C)c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (150.3 mg, 0.3998 mmol) in dichloromethane (15 mL) were added acetyl acetate (81.5 mg, 0.798 mmol) and N,N-diethylethanamine (81.3 mg, 0.803 mmol). The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow solid (120.0 mg, 71.82%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([OH:22])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@H:36]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>C(#N)C>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][C@H:36]([NH:35][C:20](=[O:22])[C@@H:4]2[CH2:3][CH:2]([OH:1])[CH2:6][N:5]2[C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:37]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC(O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of 4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.79 g) in anhydrous acetonitrile (30 ml), N,N,-carbonyldiimidazole (981 mg) was added at room temperature, followed by stirring at room temperature for one hour. To the reaction mixture, a solution of (3S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (1.02 g) in anhydrous acetonitrile (20 ml) was added under ice cooling. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was purified in a similar manner to that described in Referential Example 1-(1), whereby 1.22 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolylamino]pyrrolidine were obtained as an amorphous substance.
Reaction SMILES: [NH2:1]C1C=C(SC(F)(F)F)C=CC=1O.CCN=C=NCCCN(C)C.[C:25]([OH:33])(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[C:25]([NH2:1])(=[O:33])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1ccncc1
Temperature: 80 °C

Procedure:
A mixture of 0.70 g of 2-amino-4-(trifluoromethylthio)phenol, 0.83 g of WSC, 0.41 g of isonicotinic acid and 7 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was poured into the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.42 g of N-[2-hydroxy-5-trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 40.6 %

Procedure:
Using cyclohexyl[1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.33 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.31 g, 41%) was obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:35]=[CH:34][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:33])[C:15]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:36](Cl)([CH3:39])(=[O:38])=[O:37].N1C=CC=CC=1>CC(C)=O>[CH3:32][C:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][C:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:34]=[CH:35][C:3]([NH:2][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:33]
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 74.7 %

Procedure:
A solution of Example 37B (0.374 g, 0.722 mmol), mesyl chloride (0.224 mL, 2.89 mmol), and pyridine (0.467 mL, 5.78 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.302 g, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[CH3:8].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCNc1ccc(Oc2ccc(CC(=O)OCC)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A slurry of 3.45 g of anhydrous potassium carbonate in 50 ml of hexamethylphosphoramide (HMPA) containing 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate is heated to 50° C. A solution of 6 g of n-octyliodide in 10 ml of HMPA is added over 2 hours. The heating is continued for 24 hours. The mixture is diluted with 100 ml of H2O and extracted with two 100 ml portions of ether. The combined extracts are washed with two 100 ml portions of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid, which yields, after silica gel chromatography (benzene, then CHCl3) and bulb-to-bulb distillation of the CHCl3 elutate, a pale yellow oil, b.p. 194° at 0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]3[CH:16]=[CH:17][CH:18]=[C:14]3[C:8]3([CH2:13][CH2:12][N:11]([C:23]([C:22]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=4[F:20])=[O:24])[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:19]=1
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: Clc1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)c1
Reaction time: 6 h

Procedure:
7-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (62 mg, 0.20 mmol), 2-fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 μL, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with 1N HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(2-fluoro-5-methoxyphenyl)methanone. ESI-MS m/z calc. 426.1. found 427.5 (M+1)+. Retention time: 2.12 minutes (3 min run). NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 1H), 7.13-7.07 (m, 2H), 7.05-6.96 (m, 2H), 6.94-6.85 (m, 2H), 6.33 (t, J=3.2 Hz, 1H), 6.08-5.98 (m, 1H), 4.69 (d, J=13.1 Hz, 1H), 3.80 (s, 3H), 3.63-3.44 (m, 2H), 3.33 (t, J=12.8 Hz, 1H), 2.19 (d, J=13.8 Hz, 1H), 2.09-1.96 (m, 2H), 1.60 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1[CH:8]=[C:9]2[C:26](=CC=1)[O:25][C:12]1([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:29]>[C-]#N.[C-]#N.[Zn+2].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.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]2[C:26](=[CH:9][CH:8]=1)[O:25][C:12]1([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]1)[CH2:11][C:10]2=[O:29])#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C1CCNC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1ncccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncccc1C(F)(F)F
Yield: 2 %

Procedure:
As described for example 320a, 2-hydroxy-3-(trifluoromethyl)-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 40:60) afforded 2 compounds. The title compound was eluted first and was obtained as a colorless liquid (yield: 2%). MS: m/e=250.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:13]2[C:14]3[C:6](=[C:7]([C:27]4[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=4)[CH2:30][O:31]C(=O)C)[NH:8][C:9]=3[CH:10]=[C:11]([NH:15][C:16]([C@@H:18]3[CH2:20][C@H:19]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:17])[CH:12]=2)[CH:5]=[N:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].O1CCCC1>CO>[OH:31][CH2:30][C:29]1[CH:28]=[C:27]([C:7]2[NH:8][C:9]3[CH:10]=[C:11]([NH:15][C:16]([C@@H:18]4[CH2:20][C@H:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:17])[CH:12]=[C:13]4[C:2](=[O:1])[NH:3][N:4]=[CH:5][C:6]=2[C:14]=34)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)OCc1cccc(-c2[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc4c3c2C=NNC4=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NN=Cc2c(-c3cccc(CO)c3)[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Yield: 99.5 %

Procedure:
The title compound of Example 85 (0.288 g, 0.58 mmol) and K2CO3 (0.161 g, 1.17 mmol) were stirred in methanol (0.2 M, 1.7 mL) and tetrahydrofuran (0.2 M, 1.7 mL) for 1.5 hours at 22° C. After the solution was filtered and acidified with two drops of glacial acetic acid, the volatiles were removed in vacuo. Silica gel chromatography (40:60 to 0:100 hexane/ethyl acetate) afforded the title compound (0.26 g) as a yellow powder in 95% yield.