Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23]C)=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:25])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1c(C)cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Agent: BrB(Br)Br
Product: Cc1cc(-c2nc3c(CC(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc(C)c1O
Yield: 83.9 %

Procedure:
Analogously to example 1 (e), the reaction of 850 mg of 5-(4-chlorobenzyl)-7-isobutyl-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine with boron tribromide gave 690 mg (84%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([O:31][Si](C(C)(C)C)(C)C)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]2[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([OH:21])[C:19]=3[CH2:20][C@H:11]2[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[C:42]([O:45][CH2:46]C)(=[O:44])[CH3:43]>BrCC(OC)=O>[Si:1]([O:8][C@H:9]1[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C@H:12]2[CH2:13][C:14]3[C:19]([CH2:20][C@H:11]2[CH2:10]1)=[C:18]([O:21][CH2:43][C:42]([O:45][CH3:46])=[O:44])[CH:17]=[CH:16][CH:15]=3)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: COC(=O)CBr
Agent: Cl
Agent: [Na+]
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2Cc3cccc(OCC(=O)OC)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol (0.5 g, 0.89 mmol) in methyl bromoacetate (3 ml) was treated with 50% NaOH (1 g). The mixture was stirred at room temperature for 60 min. The reaction mixture was cooled to 10° C. and 3N HCl was added slowly until pH=7, and then the reaction was exacted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 0.2 g of Methyl 2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetate was obtained. The product was then dissolved in THF (1.3 ml), acetic acid (3.9 ml) and distilled water (1.3 ml) for overnight at room temperature. The reaction mixture was poured to saturated sodium bicarbonate aqueous (1.0 ml) and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 20 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The titled compound was obtained in a crystalline form. (Yield: 58%)
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([OH:3])=[O:2].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])([O:3][CH2:15][CH3:16])=[O:2]
Reactant: O=C(O)CCCCC1CCCC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCC1CCCC1=O

Procedure:
A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109° C. (0.23 mm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of ethyl(2RS,3RS)-3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (3.8 g, 9.06 mmol, (2RS,3RS) form: (2RS,3SR) form=9:1) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (9.1 ml), 18.2 mmol), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave (2RS,3RS)-3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionic acid (2.14 g, 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:31][C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[N:14]=2)=[N:10][CH:11]=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:31][C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[N:14]=2)=[N:10][CH:11]=1
Reactant: COCCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)c(Oc2cccnc2C)c1
Solvent: O=C(O)C(F)(F)F
Product: COCCSc1cnc(Nc2nc(C3CCNCC3)ns2)c(Oc2cccnc2C)c1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A flask was charged with tert-butyl 4-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (376 mg, 0.673 mmol) in TFA (5 mL), and the reaction was stirred for 15 minutes. The reaction mixture was concentrated and redissolved in 10% methanol in dichloromethane. Saturated sodium bicarbonate was added. The mixture was filtered, and the organic layer was separated, dried, filtered to provide N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (298 mg, 0.650 mmol, 96.6% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Solvent: C1COCCO1
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1cccs1
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To a stirred suspension of 150 mg (0.57 mmol) 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile in 3 ml dioxane was added 0.16 ml (1.42 mmol) benzylamine and the mixture heated at 100° C. for 30 minutes. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/3) followed by trituration in ether/hexane afforded 118 mg (68%) 2-amino-4-benzylamino-6-thiophen-2-yl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.I[C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: Oc1cccc(I)c1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccc(O)c2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.12 g were added 3-iodophenol 0.17 g, cesium carbonate 0.25 g, tetrabutylammonium bromide 37 mg and polymer-carried bis(acetato)triphenylphosphine palladium (II) 58 mg at room temperature, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-hydroxyphenyl)vinyl)benzoate.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1(=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]21[CH2:23][CH2:22][CH2:21][CH2:20]2>S(=O)(=O)(O)O>[N+:6]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C:11]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]2=[O:24])=[CH:15][CH:16]=1)([O-:9])=[O:7]
Reactant: O=C1c2ccccc2CCC12CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2CCC12CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
41.1.14 ml of a sulphuric acid/nitric acid 65% 1:1 mixture was slowly added dropwise to a solution of 20 g of 3'4'-dihydro-spiro[cyclopentane-1,2'(1'H)-naphthalen]-1'-one in 60 ml of sulphuric acid. After stirring for 2 hrs. at RT the mixture was poured on to 200 g of ice, extracted with ether, washed with a saturated aqueous NaHCO3 solution and with water, dried on Na2SO4, filtered, concentrated and chromatographed over silica gel with cyclohexane/ethyl acetate 9:1. Yield: 12.7 g (52%). A sample was recrystallized from hot isopropyl ether and gave 7'-nitro-3'4'-dihydro-spiro[cyclopentane-1,2'(1'H)-naphthalen]-1'-one as white crystals; m.p. 69°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][OH:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].ClN1C(=O)CCC1=O.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:26]=[C:27]([Cl:29])[CH:28]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2([C:32]([F:35])([F:33])[F:34])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)[CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(C=NO)ccc1Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
In dimethylformamide (30 mL), 2-chloro-5-hydroxyiminomethylnitrobenzene (2.92 g) and N-chlorosuccinimide (1.94 g) were dissolved, and the mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature, and thereto was added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (3.50 g), followed by triethylamine (1.46 g), and then the mixture was stirred for 6 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-chloronitrobenzene (4.42 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([CH2:29][NH2:30])[OH:28]>C(#N)C.C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][NH:30][CH2:29][CH2:27][OH:28])[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: NCCO
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](CNCCO)CC1
Temperature: 50 °C

Procedure:
To a solution of toluene-4-sulfonic acid trans-4-(tert-butyldimethylsilanyloxy)-cyclohexylmethyl ester (600 mg, 1.50 mmol) in acetonitrile (15 mL) was added ethanolamine (2.0 mL, 25 eq). The solution was heated to 50° C. overnight. The reaction was diluted with DCM (200 mL), washed with saturated aqueous sodium bicarbonate and brine, and dried over potassium carbonate. Solvent was removed to give crude title intermediate (0.44 g) as a yellow oil. (m/z): [M+H]+ calcd for C15H33NSiO2, 288.3; found 288.2.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:27]([OH:26])([CH3:33])[CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (18.7 mg, 62%), MS (ISP) m/z=431.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 3-hydroxy-3-methylbutanoic acid
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCOC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCOC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(n-hexyloxycarbonylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH3:11])=[C:9](Cl)[N:8]=[C:7]([NH2:13])[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:13][C:7]1[N:8]=[C:9]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([CH3:11])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=1
Reactant: CCCCCN
Reactant: CCCCc1nc(N)nc(Cl)c1C
Product: CCCCCNc1nc(N)nc(CCCC)c1C
Yield: 42.7 %

Procedure:
A mixture of 4-butyl-6-chloro-5-methylpyrimidine-2-ylamine (93.5 mg, 0.47 mmol) and amylamine (1.5 ml) was refluxed for 8 hours. After reaction, the procedure according to pro-treatment of Example 7 was carried out to give the object compound (50 mg, 42.7%).
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11].O>CO>[CH:10]([N:13]=[N:14][C:15]1([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(Oc2ccccc2)CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5.95 grams (.09 moles) of 85% potassium hydroxide in 50 mls of methanol in a 125 ml erlenmeyer flask was added 8.46 grams (.09 moles) of phenol and the solution stirred for 15 minutes. The solution was cooled to 20° C and 15.0 grams (.08 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 5 minutes and the reaction mixture stirred an additional hour at 20°-25° C. The reaction mixture was poured into 300 mls water and the product extracted with 200 mls of pentane. The pentane solution was separated and washed successively with 100 ml portions of 10% sodium hydroxide, water, 10% HCl (twice), 15% HCl, water, 15% sodium bisulfite solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and it weighed 15.7 grams (76.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-phenoxycyclohexane. Gas chromatography indicated there was also a small amount of 1-isopropylazo-1-methoxycyclohexane from a competing reaction of the methanol with the 1-isopropylazo-1-chlorocyclohexane.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]([O:10][C:11](=O)[O:12]C(C)(C)C)([CH3:9])([CH3:8])[CH3:7]>>[CH3:7][C:6]([O:10][C:11](=[O:12])[NH:1][CH2:2][CH2:3][CH2:4][NH2:5])([CH3:9])[CH3:8]
Reactant: NCCCN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCCN

Procedure:
In Step 1, 1,3-diaminopropane (II) is reacted with a di-t-butylcarbonate (III) to give 3- aminopropyl carbamic acid 1,1-dimethylethyl ester (IV).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O.NN>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][NH2:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1ccccc1
Agent: NN
Solvent: O
Product: NCc1ccccc1-c1ccccc1
Temperature: 0 °C
Yield: 78.9 %

Procedure:
N-(2-Phenyl-phenylmethyl)-phthalimide (6.5 g) in 25 cc of hydrazine hydrate were stirred at room temperature overnight. Ice water was added and the solid separated by filtration. The filtrate was salted out with brine and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate, filtered and concentrated to dryness to afford 3 g of subtitled product as an oil.
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=1[C:27]([O:29][CH2:4][C:5](=[O:23])[C@@H:6]([NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)CBr
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)COC(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium fluoride (0.326 g, 5.61 mmol) was added to a mixture of the tert-butyl (S)-3-bromo-2-oxo-1-phenethylpropylcarbamate (1.00 g, 2.81 mmol) and 2,5-dichlorobenzoic acid (1.07 g, 5.61 mmol) in DMF (10 mL). The mixture was stirred for 2 hours at room temperature and then ethyl acetate (75 mL) was added. The solution was washed with 1M hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (MgSO4), filtered, and evaporated to dryness to provide crude (S)-3-tert-butoxycarbonylamino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([SH:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:13])[CH2:11][S:24][CH2:18][C:19]1[O:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Reactant: SCc1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.4 %

Procedure:
To a solution of (s)-3-tert-butoxycarbonylamino-1-chloro-2-heptanone (6.54 g) and furfurylmercaptan (3.11 g) in tetrahydrofuran (200 ml) was added 2N sodium hydroxide (13 ml), and the mixture was stirred at room temperature for 17 hours. Then, aqueous sodium hydrogencarbonate was added to the mixture, which was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and chromatographed on a silica gel column, eluting with hexane containing 10 % ethyl acetate to give the titled product (7.82 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[N:18]=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:12])[N:18]=2)(=[O:21])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1cccc(S(=O)(=O)Cl)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2cccc3cccnc23)n1
Yield: 22.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (250 mg, 1.73 mmol), 6-methyl-pyridine-2-sulfonyl chloride 441 (530 mg, 2.77 mmol), DMAP (cat.), pyridine (3 ml) and DCM (2 ml) gave the title compound (115 mg, 22%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C2C(=CC=CC=2)CC1CCO.C[N+]1([O-])CCOCC1>C1COCC1.C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][CH:11]=[O:12]
Reactant: O=C(O)CC1Cc2ccccc2C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: O=CCC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Use of indan-2-yl-acetic acid (commercially available from Lancaster) (Intermediate SEVENTEEN-1) (1.58 g, 8.88 mmol) in THF (15 mL) was added dropwise to a solution of LiAlH4 (9 mL, 1M in Et2O) in THF (10 mL) at 0° C. The mixture was reacted for 2 h at rt and quenched with Rochelle's salt solution and extracted with Et2O (3×). The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The alcohol (1.35 g, 94%) was used in the next step without further purification. A solution of 2-indan-2-yl-ethanol (1.35 g, 8.32 mmol) in 18 mL of CH2Cl2 and CH3CN (2 mL) was treated with 4 Å molecular sieves (4.2 g) N-methylmorpholine-N-oxide (1.5 g, 13.5 mmol) and TPAP: tetra-n-propylammonium perruthenate (VII) (commercially available from Aldrich) (0.3 g, 0.85 mmol). The mixture was stirred for 16 h at rt. The mixture was poured directly onto a column of silica gel and eluted with 10% EtOAc:hexane. To give indan-2-yl-acetaldehyde (Intermediate SEVENTEEN-2), 1.25 g (˜90%). Indan-2-yl-acetaldehyde (Intermediate SEVENTEEN-2) in Method A produced 4-indan-2-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 142).