Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([OH:16])=[O:15].CO>C1COCC1.O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CBr
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a flask containing NaH (1 g, 25 mmol) in dry THF (25 mL) at 0° C., was added a solution of 4-bromobenzyl alcohol (2.11 g, 11.3 mmol) in dry THF (10 mL). The solution was stirred at 0° C. for 1 h, then a solution of bromoacetic acid (1 g, 7.14 mmol) in dry THF (10 mL) was added. The solution was refluxed for 3 h, then cooled. A solution of MeOH (1 mL) in water (100 mL) was added, and mixture was extracted with EtOAc (2×20 mL). The water layer was acidified by 1N HCl to pH=2, then extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated to give 67A. (1.66 g, 95%). MS (ESI) m/z 169.0 (M-OCH2CO2 H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[OH:19])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:11]2[C:12]([O:19][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[C:13]([F:18])[C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(F)c(F)c1O
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Oc1c(C(=O)Cc2ccc(Cl)cc2)ccc(F)c1F
Reaction time: 5 h

Procedure:
A solution of 2-(4-chlorophenyl)-1-(3,4-difluoro-2-hydroxy-phenyl)-ethanone (4.5 g, 87% pure, 13.85 mmol) and triethylamine (1.7 g, 2.35 ml, 16.8 mmol, 1.2 eq.) in methylene chloride (100 ml) is treated dropwise at ambient temperature with isobutyryl chloride (1.79 g, 1.76 ml, 16.8 mmol, 1.2 eq.). After stirring for 5 h, the solution is washed successively with 2M HCl solution and saturated sodium hydrogen carbonate solution. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness in vacuo to afford a black residue. This is triturated with methanol at room temperature overnight to afford a brown solid, which is filtered and washed with methanol. The solid is purified twice by flash chromatography (ethyl acetate/cyclohexane=1:9) to furnish the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9](O)[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH3:11].S(Cl)(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]/[CH:9]=[C:10](\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[CH3:11]
Reactant: CC(c1ccncc1)C(O)Cc1ccccc1F
Solvent: O=S(Cl)Cl
Product: C/C(=C/Cc1ccccc1F)c1ccncc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
To the said solid, that is, 1.59 g (6.49 mmol) of 1-(2-fluorophenyl)-3-(4-pyridyl)-2-butanol, 2.5 ml of thionyl chloride was added and stirred for one hour at 40° C. After distilling away excessive thionyl chloride under reduced pressure, water was added and the residue was alkalized with sodium carbonate and was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, ethyl acetate was distilled away under reduced pressure to obtain a brown oily substance. The resulting oily substance was purified by silica gel column chromatography to obtain 0.54 g of the desired compound (yield: 31.6%).
Reaction SMILES: Cl.[CH2:2]([NH2:8])[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1.[S-:9][C:10]#[N:11].[NH4+].O.C(OCC)(=O)C>BrC1C=CC=CC=1>[CH2:2]([NH:8][C:10]([NH2:11])=[S:9])[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCc1ccco1
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Brc1ccccc1
Product: NC(=S)NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
Furfurylamine hydrochloride (33.46 grams, 0.250 moles) and ammonium thiocyanate (38.14 grams, 0.501 moles) in 71 ml bromobenzene were heated under nitrogen at reflux temperature for 20 minutes and then cooled to room temperature. The reaction mixture was mixed with a solution of 125 ml water and 100 ml ethyl acetate and left at room temperature overnight. The mixture was then diluted to give 500 ml ethyl acetate and 350 ml water and the aqueous layer separated. The organic layer was washed with water and dried over sodium sulfate. After filtration, the organic layer was evaporated to dryness and bromobenzene removed under vacuum. The resulting solids were ground in a mortar and pestle and the fine particles stirred in diethyl ether to remove residual bromobenzene. The solids were then filtered, washed with diethyl ether and vacuum dried over phosphorus pentoxide, yielding 12.06 grams (30%) of N-furfurylthiourea, m.p. 80°-91° C. Recrystallization from benzene gave yellow needles, m.p. 98°-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:14][NH2:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1cnc2ccc(Br)cc2n1
Solvent: CCO
Solvent: O
Product: NNc1cnc2ccc(Br)cc2n1
Temperature: 78 °C
Yield: 87 %

Procedure:
To the solution of 7-bromo-2-chloroquinoxaline (2 g, 8.2 mmol) in ethanol (20 mL) was added hydrazine hydrate (85%, 4.5 mL, 32.8 mmol). The mixture was heated to 78° C. for 2 h. After cooling to r.t., the precipitate was collected by filtration to afford 7-bromo-2-hydrazinylquinoxaline as white solid in 87% yield (1.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.N1CCCCC1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)[C:8]2=[O:13]
Reactant: COc1cccc2c1CCCC2=O
Reactant: O=Cc1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cccc2c1CCC(=Cc1ccncc1)C2=O
Temperature: 130 °C
Yield: 49.8 %

Procedure:
A mixture of 5-methoxy-1-tetralone (0.1 g; 0.56 mmol), pyridine-4-carboxaldehyde (91 μl ; 0.85 mmol), piperidine (16.8 μl; 0.17 mmol) and acetic acid (9.7μl ; 0.17 mmol) was heated at 130° C. for one hour. The mixture was taken up in CH2Cl2 and washed in water and in a saturated aqueous solution of NaCl. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with CH2Cl2 /CH3CN (7/3) to give 5-methoxy-2-(4-pyridylmethylene)-1-tetralone (74 mg; 52%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][CH2:67]O>O1CCCC1>[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][CH2:67][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCc1ccccn1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OCCc5ccccn5)cc4)CC3)C2)c2ccccc21
Yield: 33 %

Procedure:
(1R)-1′-{[1-(4-Hydroxyphenyl)-cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.043 mmol), diisopropyl azodicarboxylate (20 ul, 0.10 mmol), and triphenylphosphine (24 ul, 0.10 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 5 minutes. To the mixture, with stirring, was added 2-(2-pyridyl)ethanol (13 mg, 0.10 mmol). The resulting mixture then was stirred at room temperature overnight. Then the desired product was obtained from the mixture by prep-HPLC (6.4 mg, yield: 33%). LCMS: m/z 455.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=[O:15].C[Si]([C:26]#[N:27])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-].O.C(#N)C>[NH2:27][CH2:26][C:8]1([OH:15])[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7]1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2(O)CN
Yield: 73.4 %

Procedure:
5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (14.6 g, 51.7 mmol), from Example 1, 24 mL of acetonitrile, 10.3 g (104 mmol) of trimethylsilylcyanide, commercially available from Aldrich Chemical Company, and 100 mg of aluminum chloride were mixed together and heated at reflux temperature for 2.5 h. The reaction mixture was cooled and concentrated. The residue was added dropwise to a solution of 4.3 g (113 mmol) of lithium aluminum hydride in 101 mL of diethyl ether. After the reaction mixture was heated at reflux temperature for 2.5 h, 4.3 mL of water was added dropwise, followed by 4.3 mL of 15% aqueous sodium hydroxide solution, followed by a second 4.3 mL of water. The reaction mixture was stirred until a granular precipitate formed. The solid was filtered and washed with 30×80 mL of methylene chloride. The filtrate was concentrated and the resultant solid was triturated with ethyl acetate/hexane to give 11.9 g (73% yield) of the title compound, m.p. 175°-176° C.; 1H NMR (d6 -DMSO) δ: 2.03 (t, 1H), 2.28 (dt, 1H), 2.65 (dd, 1H), 2.83 (dd, 1H), 2.95-3.1 (m, 2H), 3.28 (dd, 1H), 3.75 (s, 3H), 3.86 (s, 3H), 6.87 (d, 1H), 7.2-7.4 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[C:5]2[CH2:6][CH:7]=[CH:8][CH:9]([CH3:14])[C:10]=2[C:11](=[O:13])[CH:12]=1.[K+].[Br-]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[C:4](=[O:15])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[C:9]([CH3:14])[CH:8]=[CH:7][CH:6]=2
Reactant: COC1=CC(=O)C2=C(CC=CC2C)C1=O
Agent: O=[Mn]=O
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC1=CC(=O)c2c(C)cccc2C1=O
Temperature: 25 °C
Yield: 1695.6 %

Procedure:
To a solution of 5,8-dihydro-2-methoxy-5-methylnaphthalene-1,4-dione (100 mg, 490 μmol) in CHCl3 (5 mL), there was added MnO2 (213 mg, 2.45 mmol, Fluka). The stirred suspension was heated at reflux for 45 min (progress of the reaction may best be monitored by 1H NMR since TLC gives ambiguous results). The reaction was allowed to cool to rt and was filtered through a pad of Celite (the pad was washed with CHCl3 (3×3 mL)). Solvent removal yielded a yellow powder (99 mg, 100%, pure by TLC and 1H NMR); mp 138.5°-140° C.; 1H NMR δ (CDCl3) 2.76 (s, 3H), 3.88 (s, 3H), 6.11 (s, 1H), 7.54 (m, 2H), 8.07 (dd, J=1.8, 6.6 Hz, 1H); IR (KBr) 2984 (w), 2949 (w), 2927 (w), 2849 (w), 1677 (s), 1646 (s), 1619 (s), 1231 (s), 1078 (m), 1060 (m), 861 (m), 776 (m). Crystallization from MeOH yielded orange needles (mp 140°-141° C.). A 1.8 g run performed in an analogous manner yielded 1.68 g (94%) of product (>95% pure by 1H NMR with the impurity being unreacted starting material).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of methyl 5-(difluoromethoxy)picolinate from step K2 (730 mg, 3.59 mmol) in THF (8 mL), was added a solution of lithium hydroxide (430 mg, 18.0 mmol) in water (5 mL). The mixture was stirred at rt for 3 h, then concentrated in vacuo. After the addition of 10 mL of 1 N HCl, 150 mL of EtOAc was added. The resulting mixture was washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(difluoromethoxy)picolinic acid (610 mg, 3.23 mmol, 90% yield). LCMS (M+H)+=190.1. 1H NMR (500 HMz, chloroform-d) δ 8.52 (d, J=2.0 Hz, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 2.6 Hz, 1H), 6.84-6.53 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[N:23][OH:24])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a stirred solution of 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 55 mmole) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.68 gm, 165 mmole) and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated under vacuum, and the contents were poured into 1N HCl (250 ml). The aqueous phase was extracted with methylene chloride (2×300 ml) and dried (anhyd. magnesium sulfate). The methylene chloride was removed under vacuum to afford 2-oxo-5-oximino-6-benzhydrylpiperidine (10.62 gms, 65%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:19][C:9]2[N:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:23]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+ 402.0, 404.0 for C19H14C12FN5.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cccnc1-c1cccc(N)c1
Yield: 145.3 %

Procedure:
A suspension of 3-(3-cyanopyridin-2-yl)nitrobenzene (0.27 g) in ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 80 mg) under a hydrogen atmosphere for 5 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-cyanopyridin-2-yl)aniline (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:17][OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[CH:29][CH:28]=1.ClC1C=CC(S(N(CC2C=CC(C#N)=CC=2)[C@@H]2CCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:17][OH:18])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[O:34][CH:35]=[CH:36][N:37]=3)=[CH:31][CH:32]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCC[C@@H]1CO)c1ccc(Cl)cc1
Reactant: BrCc1ccc(-c2ncco2)cc1
Agent: N#Cc1ccc(CN([C@@H]2CCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1)[C@@H]1CCC[C@@H]1CO
Yield: 52.4 %

Procedure:
The title compound was synthesized from 4-chloro-N-(cis-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide 145 mg, 0.50 mmol), cesium carbonate (326 mg, 1.0 mmol), and 2-(4-(bromomethyl)phenyl)oxazole (143 mg, 0.60 mmol) according to the procedure described for 4-chloro-N-(4-cyanobenzyl)-N-(trans-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (Example 2) to give 4-chloro-N-(cis-2-(hydroxymethyl)cyclopentyl)-N-(4-(oxazol-2-yl)benzyl)benzenesulfonamide (117 mg, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (2H, d, J=8.31 Hz), 7.63-7.69 (3H, m), 7.33-7.44 (4H, m), 7.19 (1H, s), 4.62 (1H, d, J=16.62 Hz), 4.34 (1H, d, J=16.87 Hz), 4.19 (1H, q, J=7.47 Hz), 3.52 (1H, dd, J=11.21, 6.92 Hz), 3.33 (1H, dd, J=11.33, 5.54 Hz), 2.37-2.63 (1H, m), 2.09-2.25 (1H, m), 1.38-1.74 (5H, m), 1.15-1.30 (1H, m). LC/MS R.T.=2.76 min; [M+H]+=447.20. HRMS [M+H]+ calc'd 447.1145, found 447.1137.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:27])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:21]1([CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
In a four necked round bottom flask, Et3N (1.4 ml, 10.1 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(3-phenylpropoxy)carbonyl]amino}butanoic acid (0.95 g, 3.38 mmol) in dry CH2Cl2 (40 mL) under argon. After cooling at 0° C., HBTU (1.92 g, 5.07 mmol, 1.5 eq) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.280 g) was further triturated with cyclohexane to afford the pure title compound (0.240 g, 31%), as white solid. MS (ESI) m/z: 262.27 [M−H]−. Rf=0.29 (Cy/EtOAc 8:2; detection: phosphomolybdic acid). FTIR (cm−1): 3328, 3064, 3030, 2972, 2929, 2859, 1851, 1691, 1542, 1333, 1270, 1130, 1083, 1024, 843, 822, 697. 1H NMR (CDCl3): δ 1.46 (d, 3H); 1.93-2.00 (m, 2H); 2.67-2.71 (m, 2H); 4.09-4.18 (m, 2H); 4.84-4.90 (m, 1H); 5.38-5.48 (m, 2H); 7.11-7.31 (m, 5H).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1(/[CH:7]=[N:15]/[S@:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/C1CCCCC1
Temperature: 37 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
Cyclohexanecarbaldehyde, 26-a, (13.6 g, 0.121 mol) in dichloromethane (250 mL) were added (S)-2-methylpropane-2-sulfinamide (17.6 g, 0.145 mol), PPTS (3.03 g, 0.0121 mmol) and anhydrous CuSO4 (58 g, 0.363 mol) and the resulting mixture was stirred at 37° C. overnight. The mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=100/1) to provide the product, 27-a, (14 g, 31.1%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[N+]([O-])([O-])=[O:17].[Na+]>O>[OH:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc2c(c1)C(=O)CC21CCCC1
Agent: [Na+]
Solvent: O
Product: O=C1CC2(CCCC2)c2ccc(O)cc21
Temperature: 0 °C
Yield: 98.9 %

Procedure:
A mixture of 5'-amino-spiro(cyclopentane-1,1'-indan)-3'-one (20.1 g; 0.1 mole) 2 N sulphoric acid (150 ml) and ice (30 g) is diazotised at about +5° C. with a solution of sodium nitrate (11 g) in water (25 ml). The solution is filtrated and poured in boiling mixture of 100 ml of water and 10 ml of conc. sulphuric acid. The boiling is continued until the development of nitrogen gas ceases, after which the mixture is chilled and the solid, dark brown substance is filtered off. After drying there are obtained 20 g of a crude product, which is recrystallized from trichloroethylene. Yield 12 g of a light powder of mp. 145° C. 4 g of the substance can be recovered from the mother liquid by means of extraction with 2 N sodium hydroxide and subsequent precipitation with 2 N hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NCc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.7 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of benzyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH3:37][NH:38][CH3:39]>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:38]([CH3:39])[CH3:37])[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Reactant: CNC
Product: CN(C)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=543.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C:13](=[O:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](CC2=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a solution of tert-butyl (1R,3S,4S)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 22-1 (80 mg) in methanol (8 mL), was added sodium borohydride (1 mg). The mixture was stirred at 0° C. for 1 hr. To the reaction mixture, was added citric acid solution. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with ether to give the target compound (82 mg) as a solid.