Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1.C(Cl)CCl.[NH2:33][O:34]C1CCCCO1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:33][OH:34])=[O:28])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (133 mg, crude compound from STEP B) was dissolved in DCM (4 ml) and TEA (0.098 ml, 0.704 mmol). EDC (101 mg, 0.53 mmol) HOBT (71 mg, 0.53 mmol) and NH2OTHP (49 mg, 0.42 mmol) were added, the mixture was stirred at RT overnight and then partitioned between water and DCM. The organic phase was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.2) and the resulting (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with HCl/Et2O for 4 h. The precipitate was filtered and washed with DCM to give (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide as its di-hydrochloride (66 mg, white powder).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])[CH2:5][CH3:6]>C1COCC1.[OH-].[Na+].CO>[CH3:30][C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9])([CH2:5][CH3:6])[C:3]([OH:31])=[O:2]
Reactant: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccccc1)C(=O)O

Procedure:
419 mg 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid methyl ester in 25 ml THF, 1.5 ml of 2 M sodium hydroxide and 8 ml methanol were heated under reflux for 3 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated. After recrystallization from toluene 240 mg of 2-methyl-2-{[1-(2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-butyric acid were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCOc1ccc(NC(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-ethoxy-4-isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 467.2 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[C@@H:31]([CH:32]=[O:33])[CH2:30][O:29][C@@H:28]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:40][C:41]1[CH:46]=[C:45]([CH2:47][CH2:48][N+:49]([O-:51])=[O:50])[CH:44]=[C:43]([F:52])[CH:42]=1>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C@@H:31]([C@@H:32]([OH:33])[C@@H:48]([N+:49]([O-:51])=[O:50])[CH2:47][C:45]2[CH:46]=[C:41]([F:40])[CH:42]=[C:43]([F:52])[CH:44]=2)[CH2:30][O:29][C@@H:28]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])CCc1cc(F)cc(F)c1
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
Add tetrabutylammonium fluoride (18.32 mL, 18.32 mmol, 1.0 M in tetrahydrofuran) to (2R,5R)-2-(2,2-dimethylpropoxy)-5-formylmorpholine-4-carboxylic acid tert-butyl ester (5.02 g, 16.66 mmol) and 1,3-difluoro-5-(2-nitroethyl)-benzene (3.43 g, 18.32 mmol) in tetrahydrofuran (28 mL) at −10° C. and stir 20 minutes. Pour into ice cold saturated aqueous sodium chloride and extract with ethyl acetate. Wash with 0.1 N aqueous citric acid and saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30%:70 diethyl ether:hexanes) to give a mixture of 2 diastereomers (3.66 g, 75:25 mixture) which are separated using chiral chromatography to give the desired compound (˜2.45 g, 34.0%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][CH:15]([CH3:19])[CH2:16][CH2:17][NH:18][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(O)c2ccccc12
Product: CC(C)CCNCc1ccc(O)c2ccccc12

Procedure:
Using the procedure outlined in Preparation 83, 4-hydroxynaphthaldehyde and 3-methylbutylamine were converted to the title compound: RT=2.38 min; m/z (ES+)=144.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:31]1COC[CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH2:31][CH3:32])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (650 mg, 2.07 mmol) in THF (2 mL) at −78° C. was added lithium hexamethyldisilazide (LiHMDS) in THF (3.1 mL, 1.0 M in THF, 3.1 mmol) dropwise over 15 min. The resulting mixture was allowed to stir at −78° C. for 30 min before the addition of Etl (650 mg, 8.75 mmol). The reaction mixture was stirred at −78° C. for 2.5 h before it was allowed to warm up to room temperature for 15 min. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and EtOAc (25 mL, 1:1, v/v). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to give 9-(4-chloro-benzenesulfonyl)-2-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. Retention time (min)=2.295, Method [1], MS (ESI) 342 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[CH:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11].CNC.CN(C=[O:33])C>O=O.[Cu](Cl)Cl>[CH3:1][CH2:2][C@@:3]1([OH:33])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]
Reactant: CCC1C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CN(C)C=O
Agent: Cl[Cu]Cl
Agent: CNC
Agent: O=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Yield: 91 %

Procedure:
To a solution of 18 (47.8 mg, 0.144 mmol), copper(II) chloride (80 mg) and dimethylamine (100 μl) in DMF (16 mL) was bubbled in oxygen for 7 h. The reaction mixture was concentrated in vacuum to about 5 mL, and was then diluted with water. A solution of saturated ammonium chloride was used to adjusted the pH of the above mixture to about 6, and the resulting mixture was extracted with chloroform (10 mL×10). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 2% methanol in chloroform to give dl-camptothecin (45.5 mg, 91%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1ccc(Cn2nccc2CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nccc2Cn2nc(I)c3c([N+](=O)[O-])cccc32)cc1
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (1.55 g, 5.37 mmol) in DMF (20 mL) was added 5-(bromomethyl)-1-(4-methoxybenzyl)-1H-pyrazole (1.51 g, 5.37 mmol) and K2CO3 (1.11 g, 8.06 mmol). The reaction mixture was stirred overnight, diluted with EtOAc (100 mL), washed with H2O and brine (10 mL), and then concentrated under reduced pressure. Silica gel chromatography (Hexanes/EtOAc 5:1) provided the desired product (2.35 g).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2F)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 61b (2 g, 3.9 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-4-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)C1
Reactant: OB(O)c1ccoc1
Product: OC1CCCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate R) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]CS([O-])(=O)=O)[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:23]([CH2:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[CH2:12][CH2:13]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CCS(=O)(=O)[O-])CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
In 50 ml of dry dimethylformamide was suspended 2.0 g of trans-4-(1-t-butyldimethylsilyloxyethyl)cyclohexylmethylmethanesulfonate and 1.85 g of sodium azide, and the resulting mixture was stirred at 110° C. for 45 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.7 g of the desired compound as a pale yellow oil. This oil was used for the subsequentareaction without purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)(=O)C.C[Si](C)(C)[C:15]#[CH:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[C:15]([C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][CH:9]=1)#[CH:16]
Reactant: CC(=O)OCc1cccc(Br)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C#Cc1cccc(CO)n1
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a round-bottom flask was added 2.3 g of 6-bromopyridin-2-ylmethyl acetate, 1.18 g of trimethyl silylacetylene, 210 mg of bis(triphenylphosphine)-palladium(II) chloride, 114 mg of copper(I) iodide and 12 mL of triethylamine, and then the mixture was heated to reflux under argon atmosphere for 5 hours. After allowing to cool, the mixture was concentrated to dryness under reduced pressure, thereto water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, 7 mL of methanol and 30 mL of 1N aqueous potassium hydroxide were added to the residue, and the mixture was stirred for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and concentrated under reduced pressure. The concentrated solution was basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed off under reduced pressure. The product was purified by chromatography on silica gel (hexane-ethyl acetate=4:1) to give 212 mg of (6-ethynylpyridin-2-yl)methanol as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-1-oxo-2-(quinolin-3-yl)-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (42 mg, 0.1 mmol) obtained in Step 2 in CH2Cl2 was added trifluoroacetic acid (20 eq, 1.0 mmol). After being stirred for 1 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.[NH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH:45]1[CH2:44][NH:43][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:26][CH2:27]2)[NH:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:42])[F:41])=[CH:8][CH:7]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCCN1)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (300. mg, 0.487 mmol, Example 16(e)), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (209 mg, 0.974 mmol, Astatech), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (323 mg, 0.731 mmol, Aldrich), and DIEA (0.25 mL, 0.98 mmol, Aldrich) in DCM (3 mL) reacted under the condition of Example 16(f) to give the title compound as a light purple solid. MS (ESI, positive ion) m/z: 812 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S-:32].[Na+]>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([S:32][CH3:31])[CH:25]=2)=[O:23])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(Cl)c2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccn1
Temperature: 70 °C

Procedure:
4-tert-Butyl-N-[4-chloro-2-(2-chloro-pyridine-4-carbonyl)-phenyl]-benzenesulfonamide (475 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with solid sodium thiomethoxide (355 mg, 5 mmol) and the mixture heated at 70° C. for 16 h. The solvent was concentrated to about 2 mL and added to 5 mL cold 1M HCl. The light yellow solid precipitate was collected by filtration and product was purified by HPLC. 1H-NMR (400 MHz, CDCl3): δ 1.26 (s, 9H), 2.61 (s, 3H), 6.86 (d, 1H, J=5.2 Hz), 7.18 (s, 1H), 7.28 (d, 1H, J=2.4 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.51 (dd,1H, J=8.8 Hz, 2.4 Hz), 7.67 (m, 2H), 7.76 (d, 1H, J=8.8 Hz), 8.56 (d, 1H, J=5.2 Hz), 10.13 (s, 1H). MS: m/z476.1 (M++1).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH3:15])[CH2:3]1.[N:16]1[NH:17][N:18]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][C:24]=2[F:34])[CH:20]=1>>[F:34][C:24]1[CH:25]=[C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:19]1[CH:20]=[N:16][N:17]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH3:15])[CH2:3]2)[N:18]=1
Reactant: Fc1cc(-n2cnnn2)ccc1OCc1cn[nH]n1
Reactant: CC1CC(O)CCN1C(=O)OC(C)(C)C
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate and 1-(4-((2H-1,2,3-triazol-4-yl)methoxy)-3-fluorophenyl)-1H-tetrazole (Intermediate 16) in a manner similar to that described in Example 48, Step 4. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>CCCCCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:29]([NH:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])=[O:30])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: CCCCCC
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(C)cc2C)cc1

Procedure:
Many of the novel ureas and thioureas of this invention are prepared by reacting arylisocyanates and arylisothiocyanates with secondary amines. These reactions may be performed in aprotic solvents such as hexane, diethyl ether, toluene, tetrahydrofuran, and the like at temperatures from room temperature or below up to the boiling point of the solvent used. The ureas and thioureas are isolated by filtration or by evaporation of the solvent, and they may be purified by recrystallization, absorption chromatography, or distillation under reduced pressure. Examples of this process are the reaction of 2,4-dimethylphenylisocyanate with N-benzyl-N-(n-butyl)amine to yield 1-benzyl-1-(n-butyl)-3-(2,4-dimethylphenyl)urea and the reaction of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol with 2,4-dimethylphenyl isocyanate in hexane at room temperature to yield 1-[(4-butylphenyl)methyl]-3-(2,4-dimethylphenyl)-1-(6-hydroxyhexyl)urea.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH2:15](Br)[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[O:20]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:15][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC3CCCO3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), tetrahydrofurfuryl bromide (51 mg, 0.31 mmol, Alfa Aesar, Cat. No. A15192), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate. The organic solution was washed with water and brine, and dried over Na2SO4. After filtration the filtrate was concentrated to yield 51 mg of the product.