Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2].C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCc1ncc(-c2ccc(N)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncc(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 4-(2-ethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 73286-36-9) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as a light yellow solid (270 mg, 44%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ=9.80 (s, 1H, NH), 7.61 (d, 2H), 7.52 (d, 2H), 7.46 (s, 1H), 3.80 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:1][N:2]2[CH2:7][CH2:6][CH:5]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCC(Sc2ccccc2)CC1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 63.4 %

Procedure:
1-Amino-4-phenylthiopiperidine (1.10 g, 6.7 mmol) was reacted with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.5 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenylthio-1-piperidinyl)adenosine (1.25 g, 65%) as a foam, 1H NMR (DMSO-d6) δ 3.51-3.60 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.08 (1H, t, 5'-0H), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.24-7.45 (5H, 2m, Ar--H), 8.41 (1H, s, H-8), 9.44 (1H, s, N--H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]([C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:17]3[N:21]([CH3:22])[N:20]=[C:19]([CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[N:18]=3)[N:6]=2)=[N:12][N:11]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
tert-Butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (36.81 g, 76.12 mmol) was added to a solution of 2,2,2-trifluoroacetic acid (100 mL, 1305.87 mmol) in DCM (100 mL). The mixture was stirred for 3 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (1.5 L) and added to vigorously stirred concentrated ammonia (150 mL) in water (400 mL). The aqueous was washed with DCM (400 mL) and the combined organic solutions were dried with magnesium sulfate, filtered and concentrated to dryness to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (30.0 g, 103%) as a yellow solid:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].C([N-]C(C)C)(C)C.[Li+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:15]1([N+:21]([O-:23])=[O:22])[CH:16]=[CH:17][C:18]([F:20])=[CH:19][CH2:14]1
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C1(OCCCl)C=CC(F)=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 2-chloro-ethanol (1) (8.3 ml, 120 mmoles) in THF, under nitrogen, was cooled to 0° C., treated dropwise with lithium diisopropylamide (LDA) (60 ml, 120 mmoles, while maintaining the temperature constant at 0° C. The mixture was stirred at 0° C. for 15 minutes, treated with 2,4-difluoro-1-nitro-benzene (1) (11 ml, 100 mmoles), stirred at room temperature overnight, diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (20.0 g, 91 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [OH-].[Na+].C(O)C.[NH2:6][C:7]1[C:8](=[O:28])[N:9]([CH2:23][C:24]([O:26]C)=[O:25])[C:10]([CH3:22])=[CH:11][C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]>ClCCl>[NH2:6][C:7]1[C:8](=[O:28])[N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:10]([CH3:22])=[CH:11][C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: COC(=O)Cn1c(C)cc(S(=O)(=O)c2ccccc2)c(N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)c2ccccc2)c(N)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.7 ml of a 1 N aqueous sodium hydroxide solution and 5.7 ml of ethanol are added to 1.6 g (4.76 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylsulphonyl)-1,2-dihydropyridine-1-acetate. 1.5 ml of dichloromethane are then introduced and the mixture is kept stirred for 2 hours at room temperature. The reaction medium is concentrated under vacuum and 8 ml of water and 5.8 ml of a 1 N aqueous hydrochloric acid solution are added. The precipitate is filtered, it is rinsed with water and it is dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(NC(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCC(N)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of tert-butyl (1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate (0.33 g, 0.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue partitioned between 3 M ammonium hydroxide solution and dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-15% methanol/dichloromethane elute) afforded 0.19 g (62%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.36-7.26 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.01 (dd, J=8.8, 2.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.78-6.67 (m, 3H), 5.21 (s, 2H), 5.01 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.60-3.52 (m, 2H), 2.85-2.72 (m, 3H), 1.98-1.90 (m, 2H), 1.80 (b, 2H), 1.62-1.50 (m, 2H) ppm; (M+1)=474.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)=[CH2:12]>C(Cl)(Cl)Cl>[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:3][CH2:2][CH2:1][NH:4][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1)=[CH2:12]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(CNCCNCc2ccc(C=C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
In a 500 mL, 3-necked round-bottomed flask were taken 5.31 grams of 1,2-ethylenediamine and 32.48 g of anhydrous potassium carbonate, and 300 mL of chloroform. To this suspension was added 30 g of 4-vinylbenzyl chloride. The resulting reaction mixture was stirred at 25° C. for 18 hr. Subsequently the reaction mixture was filtered. The solvent was moved under reduced pressure. To the residue was added 300 mL of deionized water followed by 37% aqueous HCl until the pH of the solution was 2.0. The resulting aqueous solution was extracted with tert-butyl methyl ether (2×250 mL). The aqueous layer was collected and was treated with 40% (w/w) NaOH until the pH of the solution was 11.4. The resulting aqueous solution was extracted with tert-butyl methyl ether (2×250 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure yielding 3 g of the product as a light yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)[N:5]=1)([CH3:3])[CH3:2].IC.[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]([C:4]1[C:8]([C:9]([O:11][CH3:35])=[O:10])=[CH:7][N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(C(C)C)n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
A mixture of 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylic acid (10.09 g), iodomethane (2 ml), potassium carbonate (4.83 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carboxylate (9.80 g, yield: 94%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 90–91° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38](B(O)O)[CH:39]=1)([CH3:33])[CH3:32]>COCCOC>[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:39]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(C(C)C)cc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 30.2 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 5-isopropyl-2-methoxy-phenylboronic acid (37 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (18 mg, 31%). LC-MS m/e 459.35 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([O:27][CH:28]([CH3:33])[CH2:29][C:30](Cl)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:30](=[O:31])[CH2:29][CH:28]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:33])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CC(CC(=O)Cl)OCc1ccccc1
Product: CC(CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12)OCc1ccccc1

Procedure:
The titled compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and 3-benzyloxybutyryl chloride (Eberlein, T. H. et al., J. Org. Chem. 1992, 57, 3479).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15]>COCCO>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[NH:10][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1
Reactant: Nc1cccc(CO)c1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Solvent: COCCO
Product: O=c1cc(Nc2cccc(CO)c2)[nH]c(=O)[nH]1
Yield: 86 %

Procedure:
6-chlorouracil (1 mmol) and meta-aminobenzyl alcohol (2.0 mmol) were dissolved in 10 ml 2-methoxyethanol to form a reaction mixture. The mixture was then stirred at reflux for 10 hours to form 6-(meta-hydroxymethyl anilino)uracil with a yield of 86%. The hydroxy group was displaced by a bromo group by reacting the hydroxymethyl anilino-uracil (0.5 mmol) with 30% HBr in acetic acid (10 ml), thus forming 6-(meta-bromomethyl anilino)uracil with a yield of 90%. The bromo group was further replaced by a thiocyanate group by reacting 0.4 mmol 6-(meta-bromomethyl anilino)uracil with 2 mmol KSCN to form 6-(meta-mercaptocyanomethyl anilino)uracil (MMCMAU) with a yield of 80%. mMCMAU was then hydrolyzed to 6-(meta-thiomethyl anilino)uracil in 5 mL of 2N NaOH. The final product, 6-(meta-disulfidemethyl anilino)uracil, was formed quantitatively by reacting 6-(meta-thiomethyl anilino)uracil with methyl methane thiosulfonate in 2 molar excess.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (800 mg.; 2.45 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.68 mL; 4.9 mmol) and cyclohexanecarbonyl chloride (0.33 mL; 2.45 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour. The mixture was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to afford the free base of the title compound as a white gummy foam (610 mg; 57%). Treatment with an equimolar amount of maleic acid in ethanol yielded the maleate salt as an off-white amorphous solid, m.p. 145–147° C.; MS (+) FAB [M+H]+ @ m/z 437, [M+Na]+ @ m/z 459; 1H NMR, 400 MHz, DMSO-d6. Analysis for C26H36N4O2.C4H4O4.0.5H2O Calculated: C, 64.15; H, 7.36; N, 9.97 Found: C, 64.23; H, 7.37; N, 9.88
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([OH:13])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17].[C:18]([O:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([OH:21])(=[O:20])[CH3:19].[NH2:1][C:2]1[C:3]([Cl:17])=[CH:4][C:5]([CH:6]([OH:13])[CH2:7][N:8]([C:9]([CH3:12])([CH3:10])[CH3:11])[C:22](=[O:24])[CH3:23])=[CH:14][C:15]=1[Cl:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: c1ccncc1
Product: CC(=O)N(CC(O)c1cc(Cl)c(N)c(Cl)c1)C(C)(C)C
Product: CC(=O)O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture containing 2.5 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride is stirred for three hours and evaporated to dryness in vacuo with heating up to 70° C. The residue is treated with ice, 100 ml of CH2Cl2 and 50 ml of 10% NaOH solution. The CH2Cl2 phase is separated, and the aqueous portion is further extracted with CH2CL2 (2×50 ml). The combined CH2CL2 solutions are dried (Na2SO4) and evaporated to dryness to afford a solid after scratching. The solid is washed with hexane and collected to afford 2.61 g of the title compound, mp 126°-136° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[C:30]([O:32][CH3:33])=[O:31].[CH3:34][C:35]([CH3:37])=[O:36]>C1COCC1>[OH:36][C:35]([C:22]1([C:30]([O:32][CH3:33])=[O:31])[CH2:21][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)([CH3:37])[CH3:34]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)(C)O)Cc2ccccc2C1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a dried THF solution of lithiumdiisopropylamide prepared from 107.3 ml (0.149 mole) of n-butyllithium and 15.81 g (0.156 mole) of diisopropylamine, was added dropwise at -50° C. a solution of 25.0 g (0.142 mole) of methyl indane-2-carboxylate in 50 ml of dried THF over a period of 10 minutes. To the resulting mixture, which had been stirred for 30 minutes at -50° C., was added dropwise over a period of 10 minutes a solution of 9.88 g (0.17 mole) of dried acetone in 10 ml of dried THF. After the addition, stirring was continued for further 10 minutes. The reaction mixture was poured into ice water and extracted with ether. The aqueous layer was extracted twice with ether. The ether layers were combined, washed successively with 3% aqueous hydrochloric acid solution, saturated aqueous hydrogen-carbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the intended product as a oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc2ccccc2n1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.84 g, 35.0 mmol) in dimethylformamide (120.0 mL), is added ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate (3.19 g, 11.67 mmol) and 2- (chloromethyl)quinoline (2.62 g, 12.26 mmol), and the reaction is stirred for three days at room temperature. Then, additional Nail (0.46 g, 11.67 mmol) is added, and the reaction is heated to 50° C. for 5 hours. The reaction is cooled to 0° C., quenched with water, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is removed to give ethyl 2-[[4-methoxybenzenesulfonyl]-(2-quinolinylmethyl)amino]acetate.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:34]([F:37])([F:36])[F:35])[N:18]=[CH:17]4)[C:10](=[O:12])[N:11]=2)[C@@H:4]([CH2:38][OH:39])[CH2:3]1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[F:35][C:34]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[C:20]2[C:16](=[CH:15][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:5]4[C@@H:4]([CH2:38][OH:39])[CH2:3][C@@H:2]([NH:1][C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[CH2:6]4)=[N:11][C:10]3=[O:12])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: O=C(Cl)C1CC1
Reactant: N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Product: O=C1N=C(N2C[C@H](NC(=O)C3CC3)C[C@@H]2CO)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
N-{(3R,5R)-1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}cyclopropanecarboxamide was prepared from 2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one (example 258) and Cyclopropylcarbonyl chloride.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#[N:2].[CH2:14]([OH:16])[CH3:15].[ClH:17]>C(OCC)C>[ClH:17].[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH:4]1[CH2:3][C:1](=[NH:2])[O:16][CH2:14][CH3:15]
Reactant: N#CCC1COc2ccccc2O1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC1COc2ccccc2O1
Reaction time: 96 h
Yield: 59 %

Procedure:
17.5 g (0.10 mole) 2-cyanomethyl-1,4-benzodioxane, prepared as described by Augstein, et al., J. Med. Chem. 8: 446 (1965), was dissolved in a mixture containing 7 g ethanol and 50 ml diethyl ether. 4.5 g (0.15 moles) of dry HCl was bubbled though the mixture, which was then capped. The mixture was allowed to stand at 5° C. for 4 days, followed by 3 days at room temperature. The crude product imidate hydrochloride (IV) precipitated out and was harvested by filtration, and washed with 100 ml ether, followed by 3×100 ml portions of methylene chloride. The solid was then purified by thin layer chromatography using 10% methanol in chloroform as a developing solvent. The product has an Rf value of 0.7-0.8; starting material moves farther in this solvent system, and none was present in the crude product. The yield of product was 15.3 g, as the hydrochloride, or 59% yield.