Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[OH-].[Na+].[CH3:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][N:11]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([CH2:20][CH2:21][CH2:22][C:23]([NH2:24])=[O:1])[CH2:10][C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:26][CH:25]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(CN(CCCC#N)Cc2ccc(C)cc2)cc1
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CN(CCCC(N)=O)Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrogen peroxide (30% w/v; 5.67 ml), tetra-n-butylammonium hydrogensulphate (1.70 g) and 5N aqueous sodium hydroxide (4 ml) were added successively to a stirred solution of 4-(N,N-bis-(4-methylbenzyl)amino]butyronitrile (2.93 g) in dichloromethane (10 ml), with water cooling. The mixture was stirred vigorously at room temperature for 16 hours then dichloromethane (100 ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (1×10 ml), dried (Na2SO4) and concentrated in vacuo to give a viscous oil (4.61 g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene→ethyl acetate and triturated with cyclohexane to give the title compound (1.77 g), m.p. 85°-86° C.
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[CH:4]=[CH2:5].C1OCCOCCOCCOCCOCCOC1.[OH:25][CH:26]1[CH2:43][CH2:42][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:3]([O:25][CH:26]1[CH2:27][CH2:28][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)[CH2:42][CH2:43]1)[CH:4]=[CH2:5]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Yield: 92 %

Procedure:
KOH (257.46 mmol, 21.0 eq.), allyl bromide (36.8 mmol, 3.0 eq.) and 18-crown-6 (4.9 mmol, 0.4 eq.) were added to a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (12.26 mmol, 1.0 eq.) in toluene (65 ml) at 0° C. and then reaction mixture was heated at reflux for 1 h. Then the reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (150 ml) and brine (150 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the crude product which was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as a yellow oil. Yield: 92%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.CC([O-])=O.[Na+].[NH2:21][OH:22].Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([C:8](=[N:21][OH:22])[CH3:9])[CH:7]=1
Reactant: NO
Reactant: CC(=O)c1cc(Br)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1cc(Br)cc(C(C)(C)C)c1O

Procedure:
A mixture of 1-(5-bromo-3-(tert-butyl)-2-hydroxyphenyl)ethanone (0.5 g, 1.8 mmol), NaOAc (246 mg, 3.0 mmol) and NH2OH.HCl (187 mg, 2.7 mmol) in EtOH (10 mL) was heated at reflux for 3 h, concentrated and the obtained solid was washed with water to give compound P8a (0.5 g, 97%) as solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:18][C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:11][N:12]=[CH:13]1
Reactant: Nc1nc(CCl)cs1
Reactant: Cn1cncc1C(=NO)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1csc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 17.9 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-phenylmethanimine (3.90 g, 19.4 mmol) and 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (3.95 g, 21.3 mmol) in acetonitrile (50 mL) were added cesium carbonate (13.3 g, 40.7 mmol) and potassium iodide (322 mg, 1.93 mmol). After stirring at room temperature for 29 h, N-N-dimethylformamide (5 mL) was added and the mixture was further at room temperature for 72 h. The reaction mixture was filtered, the insolubles washed with acetone, and the filtrate concentrated in vacuo. Purification on silica gel afforded 4-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine [1.09 g, yield 16%; HPLC/MS: m/z=314 (M+H); log P(HCOOH)=0.69].
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:20](=[O:21])[C:15]2=[C:14]([CH3:28])[NH:13]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[N:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[S:55](Cl)(=[O:57])=[O:56])[CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:55]([C:53]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:54]=2[N:45]=[CH:46][CH:47]=[CH:48]3)(=[O:56])=[O:57])=[CH:6][C:5]=1[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:20](=[O:21])[C:15]2=[C:14]([CH3:28])[NH:13]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: Cc1[nH]n(Cc2cc(N)ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1[nH]n(Cc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc2Cl)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.5 %

Procedure:
A solution of 1-(2-chloro-5-aminophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one dihydrochloride salt (0.55 g, 1.4 mmol), pyridine (10 ml) and triethylamine (0.18 ml, 1.36 mmol) was stirred at 0° C. under argon for 20 minutes and dimethylaminopyridine (0.016 g, 0.14 mmol) and 8-quinoline sulfonyl chloride (0.37 g, 1.6 mmol) were added. The mixture was stirred at 0° C. for 2.5 hours and poured into ice-water with stirring. The product was collected by filtration to afford 0.66 g (88%) of 1-[2-chloro-5-((8-quinolinylsulfonyl)amino)phenylmethyl]-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a tan powder, m.p. 325° C. (dec.) when dried at 100° C. for 24 hours in high vacuum.
Reaction SMILES: CCOCC.[CH3:6][C:7]1([CH3:21])[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2[CH:12]=[C:11]([CH:19]=[O:20])[CH:10]=[CH:9][C:8]1=2.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(=O)C.O1CCCC1.O.S(=O)(=O)(O)O.[Zn].O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Zn].[Cu].[O-2].[Cr+6].[O-2].[O-2]>[O:20]=[C:19]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH3:21])([CH3:6])[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]=2[CH:12]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: CCOC(=O)CBr
Agent: [Cr+6]
Agent: [Cu+2]
Agent: [Cu]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1.25 h
Yield: 29.8 %

Procedure:
15 g (0.23 mole) of zinc powder and 1.5 g (8.3 millimoles) of copper(II) acetate monohydrate in 50 ml of glacial acetic acid were stirred for 30 minutes while cooling with ice. The mixture was then stirred with 50 ml of dry ether, and the solid was filtered off under suction and washed twice with dry ether and once with dry tetrahydrofuran. The solution of 21.6 g (0.1 mole) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthaldehyde and 21.0 g (0.125 mole) of ethyl bromoacetate in 500 ml of dry tetrahydrofuran was added dropwise to a suspension of a zinc/copper product pair prepared in this manner, the reaction reaching the reflux temperature. The refluxing mixture was stirred for a further 75 minutes, cooled, acidified with 5N sulfuric acid and filtered. The filtrate was extracted with ether and the organic phase was washed with water, dried over sodium sulfate and evaporated down. The residue (27.8 g) was dissolved in 100 ml of acetone, and a solution of 12.0 g (0.12 mole) of chromium(VI) oxide in 36.8 ml of water and 12.9 ml of concentrated sulfuric acid was added dropwise at 10° C. Stirring was continued for 30 minutes at 10° C., after which the mixture was poured onto ice/water and was extracted with ether. The organic phase was washed twice with water, dried over sodium sulfate and evaporated down. Distillation of the residue gave 9.0 g of ethyl 3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-propionate of boiling point 150°-152° C./0.4 mbar.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[F:28][C:29]1([F:39])[CH2:32][N:31]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:36]3[CH2:35][CH2:34][CH:33]([N:31]4[CH2:32][C:29]([F:28])([F:39])[CH2:30]4)[CH2:38][CH2:37]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: FC1(F)CN(C2CCNCC2)C1
Product: FC1(F)CN(C2CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 4-(3,3-difluoroazetidin-1-yl)-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (115 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.OS([O-])(=O)=O.[K+].[CH2:17]([OH:19])[CH3:18]>>[C:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CCO
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
p-Hydroxyacetophenone was converted to 1-(p-acetoxyphenl) ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al. (J. Org. Chem., 1958, 23, 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0.5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralized with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anhydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[CH:5][C:3]1=[O:4].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[C:5]([N+:15]([O-:17])=[O:16])[C:3]1=[O:4]
Reactant: Cc1ccc2c(c1)c(O)cc(=O)n2C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c(O)c([N+](=O)[O-])c(=O)n2C
Temperature: 100 °C

Procedure:
To a stirred suspension of 1,6-dimethyl-4-hydroxy carbostyril (1.70g; 0.009 mole) in glacial acetic acid (10 ml) was added concentrated nitric acid (2.5 ml; d, 1.42) with swirling. The solid dissolved on warming to 100°C to give a red solution which precipitated the 3-nitro compound as yellow crystals on cooling. m.p. 185°C. (Found: C, 56.05; H, 4.33; N, 11.86%, C11H10N2O4 requires; C, 56.41; H, 4.30; N, 11.96%).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([Cl:16])=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[CH3:18][C:19]1([CH3:30])[CH2:28][C:27]2[CH:26]=[C:25]([OH:29])[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:15]1[C:3]([CH2:2][O:29][C:25]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]([CH3:30])([CH3:18])[CH2:28][C:27]=3[CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC1(C)CCc2ccc(O)cc2C1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)cc2C1
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (200 mg, 0.62 mmol), 7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-ol (109 mg, 0.62 mmol) and potassium carbonate (257 mg, 1.86 mmol) in acetone (20 mL) was stirred at 50° C. for 4 hrs. The reaction mixture was filtered, the filtrate was concentrated and purified by SGC (eluting with petroleum ether/ethyl acetate from 100/1 to 25/1) to get the desired compound (220 mg, 85%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([CH3:9])=[C:6]([Cl:8])[CH:7]=1.[Li]CCCC.[CH3:16][S:17]SC.O>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([S:17][CH3:16])[C:3]([NH2:10])=[N:4][C:5]=1[CH3:9]
Reactant: CSSC
Reactant: Cc1nc(N)c(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(Cl)c(C)nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
3-Bromo-5-chloro-6-methylpyridin-2-amine (300 mg, 1.35 mmol, Eq: 1.00) was dissolved in tetrahydrofuran (5 ml). 1.6M n-BuLi in hexanes (3.39 ml, 5.42 mmol, Eq: 4) was added at −78° C. The mixture was stirred for 10 min. 1,2-Dimethyldisulfane (510 mg, 481 μl, 5.42 mmol, Eq: 4) was added and mixture allowed to warm to room temperature. The mixture was stirred for 30 min. Water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (158 mg, 61.8%) was obtained as a light yellow solid by chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=230.1 (M+acetonitrile+H+)
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10].CCN(C(C)C)C(C)C.C1C(=O)N([O:27][C:28]([C:30]2[C:35]([C:36]3[C:46]4[CH:47]=[CH:48][C:49]([OH:51])=[CH:50][C:45]=4[O:44][C:43]4[C:37]=3[CH:38]=[CH:39][C:40]([CH:42]=4)=[O:41])=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[CH:33]1[CH:32]=[CH:31][C:30]([C:28]([OH:29])=[O:27])=[C:35]([C:36]2[C:37]3[CH:38]=[CH:39][C:40]([OH:41])=[CH:42][C:43]=3[O:44][C:45]3[C:46]=2[CH:47]=[CH:48][C:49]([CH:50]=3)=[O:51])[CH:34]=1.[NH2:3][CH2:4][CH2:5][S:6][S:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C(ON1C(=O)CCC1=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: Cl
Agent: NCCSSCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cystamine dihydrochloride (68 mg, 0.301 mmol) and DIEA (110 μL, 2.1 eq.) were dissolved in DMF (10 mL), followed by addition of NHS-fluorescein, a mixture of 5- and 6-carboxyfluorescein (300 mg, 0.634 mmol) and the resulting reaction mixture was stirred overnight at room temperature. Then it was diluted with ethyl acetate and washed three times with water and one time with brine. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, redissolved in small amount of methanol and ethyl acetate, and then triturated with diethyl ether to obtain 140 mg of fluorescein-cystamine adduct as a bright orange solid.
Reaction SMILES: [OH:1][CH:2]1[C:6](=O)[N:5]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].B.O.C(O)C>O1CCCC1.C(N(CC)CC)C>[OH:1][CH:2]1[CH2:6][N:5]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Agent: B
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C[C@H](c1ccccc1)N1CC(O)[C@](C)(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.1 %

Procedure:
To a solution of tert-butyl(3R)-4-hydroxy-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (9.35 g, 29.3 mmol) in tetrahydrofuran (150 mL), a solution of borane in tetrahydrofuran (82.6 mL, 96.6 mmol, 1.17M solution in tetrahydrofuran) was added in an ice bath, and the mixture was stirred room temperature for 14 hours. Water (20 mL), ethanol (80 mL), and triethylamine (20 mL) were added to the reaction mixture in an ice bath, and the mixture was heated under reflux in an oil bath at 88° C. for 2 hours. After concentrating the reaction mixture under reduced pressure, water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:2) to obtain 4.75 g (53.1%) of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:34]=[C:35](O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[C:37]([CH:36]=[CH:35][CH:34]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: SMS m/e: 533.1 (M+H)+.
Reaction SMILES: [S-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccc3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of sodium thiophenoxide and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C. for 0.40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-phenylthioimidazo [1,2-a] pyridine m.p. 108°-109° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][N:10]([CH2:19][C@H:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([Cl:33])[CH:24]=1)[CH3:21])[C:11](=[O:18])[CH2:12][CH:13](OC)OC)(C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C.O>[Cl:33][C:25]1[CH:24]=[C:23]([N:22]2[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:5])=[O:34])[CH2:19][C@H:20]2[CH3:21])[CH:28]=[CH:27][C:26]=1[C:29]([F:32])([F:30])[F:31]
Reactant: COC(CC(=O)N(CCCC(=O)OC(C)(C)C)C[C@@H](C)Nc1ccc(C(F)(F)F)c(Cl)c1)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C[C@@H]1CN(CCCC(=O)O)C(=O)C=CN1c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A cooled solution (0° C.) of 1.00 g (2.00 mmol) of 4-[[(R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propyl]-(3,3-dimethoxy-propionyl)-amino]-butyric acid tert-butyl ester (22% ee) in 18 ml CH2Cl2 was treated with 2.25 ml (29.40 mmol) of trifluoroacetic acid and after 2 h at RT with 1.55 ml (9.80 mmol) of triethylsilane. The reaction was stirred at RT for 16 h, cooled (0° C.) and neutralized with 4.09 ml (29.40 mmol) of triethylamine. The residue was dissolved in diethyl ether and cold water. The reaction was extracted with 10% aq. KHSO4 solution/EtOAc (3×). The organic phases were washed with 10% aq. KHSO4 solution, dried over Na2SO4 and evaporated. Flash silica gel column (CH2Cl2/MeOH 99:2 to 9:1) afforded 0.57 g (74%) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as brown oil. MS: 389.09 (M−H−, Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:19][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN(C)CCN
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NCCN(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (5.0 g, 25.4 mmol) and N1,N1-dimethylethane-1,2-diamine (2.7 g, 30.5 mmol) in dichloromethane (200 mL) were added 1-hydroxybenzotriazole hydrate (7.8 g, 50.8 mmol), 1-ethyl-(3-dimethyl aminopropyl)carbodiimide hydrochloride (9.7 g, 50.8 mmol) and N,N-diisopropyl ethylamine (13.1 g, 101.6 mmol) and the mixture was stirred at ambient temperature for 16 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 20/1 dichloromethane/methanol to give the title compound. MS: 268 (M+H+).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1.Cl>>[N:24]1([CH2:23][N:12]2[C:13](=[O:16])[C:14]3[CH:15]=[C:7]4[CH2:6][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:19][CH2:20][CH3:21])[CH2:18][C:8]4=[CH:9][C:10]=3[C:11]2=[O:17])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Reactant: ClCn1nnc2ccccc21
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cn1nnc2ccccc21)C3=O

Procedure:
Using procedure 48, 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.14 g, 0.5 mmol) was treated with 1-(chloromethyl)-1H-benzotriazole (0.08 g, 0.5 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 98 as a white solid (m.p. 254-256° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=[O:19].Cl[C:22]([S:24]Cl)=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[O:19][C:22](=[O:23])[S:24][N:20]=1
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: O=C(Cl)SCl
Solvent: C1CCOC1
Product: O=c1oc(-c2cn(CC3CCOCC3)c3c(Cl)cccc23)ns1
Yield: 55.6 %

Procedure:
To a suspension of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (8.0 g, 27.0 mmol) in tetrahydrofuran (100 ml) was added chlorocarbonylsulfenyl chloride (4.7 ml, 55.0 mmol) and the reaction mixture was heated at reflux for 3 h and allowed to cool. The precipitate was filtered off and dried to give 7-chloro-3-([1,3,4]-oxathiazol-2-on-5-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole (5.3 g, 15.0 mmol) as a white solid. The filtrate was concentrated in vacuo, and the resulting solid was washed with 5% ethyl acetate in n-heptane then dried to afford a further batch of 7-chloro-3-([1,3,4]-oxathiazol-2-on-5-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole (2.6 g, 7.0 mmol) as a pink solid.