Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([F:31])[C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#[CH:33]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N:1]3[CH:33]=[C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[N:3]=[N:2]3)[C:29]([CH3:30])=[C:28]([F:31])[CH:27]=2)[CH:15]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1c(NC(=O)c2cc(F)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cccnc1
Product: COc1c(NC(=O)c2cc(F)c(C)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 21 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-5-fluoro-4-methyl-benzamide and 3-ethynyl-pyridine in the same manner as Example 15. ESI MS m/z 553 [C27H29FN6O4S+H]+.
Reaction SMILES: C(O)(=O)C.[NH2:5]/[C:6](/[C:24]1[CH:29]=[N:28][C:27]([NH2:30])=[C:26]([C:31]2[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=2)[N:25]=1)=[N:7]\[NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=O>O1CCOCC1>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:6]2[NH:7][N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:5]=2)=[N:25][C:26]=1[C:31]1[O:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n2)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
Acetic acid (200 mL) was added to dioxane (500 mL) in a 3 L fixed double jacketed vessel and the solution was heated to 70° C. under nitrogen. (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)-piperidine-1-carboxylate (74.5 g, 152.80 mmol) was added portionwise to the warm mixture. After 10 minutes the temperature was increased to 100° C. (slight reflux). The reaction mixture was stirred at 100° C. for 1.5 hours (suspension) then held at 80° C. overnight (solution formed after overnight hold). The resulting solution was concentrated under reduced pressure, then diluted with toluene, evaporated to dryness, taken up with toluene and concentrated again. The residual oil was mixed with some ethyl acetate and concentrated to dryness. A solid crystallised from solution which was triturated with MTBE (200 mL) and isolated by filtration. The filter cake was washed with water and MTBE to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (50 g, 70%) as a grey solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9]([C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH:2]1([CH2:1][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@@H:9]([OH:10])[C@H:11]([CH:13]2[CH2:14][CH2:15]2)[OH:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2.83 g (8.77 mmol) of tert.-butyl [(1S,2R)-1-benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate are dissolved in methylene chloride (130 ml), acetic acid (3 ml) is added thereto and the mixture is then treated portionwise at 0°-10° with 332 mg (8.78 mmol) of sodium borohydride. The reaction solution is stirred at 5° for a further 2 hours and then partitioned between 2N sodium bicarbonate solution and methylene chloride. After the usual working-up of the organic phase the residue is crystallized from ether/hexane, whereby there are obtained 2.1 g (74%) of tert-butyl [(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamate, melting point 83°-85°.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[CH3:24])=[CH:13][C:8]=2[C:7](=[O:25])[N:6]([CH3:26])[C:5]2[CH:27]=[CH:28][CH:29]=[N:30][C:4]1=2)[CH3:2].Br[C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1.C(O[Na])(C)(C)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:32]4[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=4)=[CH:19][C:18]=3[CH3:24])=[CH:13][C:8]=2[C:7](=[O:25])[N:6]([CH3:26])[C:5]2[CH:27]=[CH:28][CH:29]=[N:30][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CCN1c2ncc(CCOc3ccc(N)cc3C)cc2C(=O)N(C)c2cccnc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)c(C)c2)cc1
Temperature: 105 °C
Yield: 39.9 %

Procedure:
A degassed mixture of 11-ethyl-5,11-dihydro-8-[2-(4-amino-2-methylphenoxy)ethyl]-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (100 mg, 0.25 mmol), ethyl 4-bromobenzoate (61.0 μL, 0.37 mmol), t-BuONa (36.0 mg, 0.37 mmol), Pd2(dba)3 (2.5 mg, 2.7 μmol) and (+/−)-BINAP (5.0 mg, 8.0 1mol) in toluene (8 mL) was heated to 105° C. under nitrogen for 48 h. The cooled reaction mixture was diluted with EtOAc, filtered through a short pad of diatomaceous earth and was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 1:1) to give the title compound (55 mg, 40% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 2-bromo-5-methylbenzoic acid (215 mg, 1.0 mmol) in DCM (4 mL) and DMF (1 drop) at 0° C. was slowly added oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred at rt for 1 h and to it was added additional oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred for 1 h, added with MeOH (2 mL) and stirred for 6 h. The mixture was treated with Na2CO3 to pH of 9 and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (15:1) to give methyl 2-bromo-5-methylbenzoate (210 mg; yield 92%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J=1.6 Hz, 1 H), 7.53 (d, J=8.8 Hz, 1 H), 7.15 (q, J=3.2 Hz, 1 H), 3.92 (s, 3 H), 2.33 (s, 3 H) ppm.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[OH:10])[CH2:4]1.[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[C@@H:30]1[CH2:32][O:31]1>>[OH:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([NH:2][CH2:32][C@H:30]([OH:31])[C:21]2[C:20]([CH3:19])=[C:28]3[C:24](=[CH:23][CH:22]=2)[C:25](=[O:29])[O:26][CH2:27]3)[CH2:4]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C(O)CN2CC[C@@H](N)C2)nc1
Agent: Cl
Product: Cc1c([C@@H](O)CN[C@@H]2CCN(CC(O)c3ccc(C#N)cn3)C2)ccc2c1COC2=O

Procedure:
6-(1-Hydroxy-2-((R)-3-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethylamino)pyrrolidin-1-yl)ethyl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 6-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-hydroxyethyl}pyridine-3-carbonitrile hydrochloride [INTERMEDIATE 11] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].
Reaction SMILES: Br[CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3].[CH3:26][OH:27]>FC(F)(F)S([O-])(=O)=O.[Ag+].ClCCCl>[CH3:26][O:27][CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3]
Reactant: CO
Reactant: CC(Br)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCCl
Product: COC(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 3-[3-(1-bromoethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.720 g, 0.00166 mol), methanol and 1,2-dichloroethane is added silver trifluoromethane sulfonate (0.510 g, 0.00199 mol). The resultant mixture is stirred 23 hours at room temperature and filtered through diatomaceous earth with ethyl acetate. Saturated sodium bicarbonate is added to the filtrate and the resultant mixture is stirred vigorously for one hour. The organic layer is saved while the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo to a syrup, which is chromatographed on silica gel with hexanes:ethyl acetate to give the title compound as a white solid (0.660 g, 100%, mp 133-135° C.) which is identified by NMR spectral analysis.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C1COCC1>ClCCl>[CH3:5][O:6][C:7]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:8]=1[CH:9]=[O:10]
Reactant: COc1cc(C#N)ccc1C(=O)O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Thionyl chloride (50 ml) was added to 2-methoxy-4-cyano benzoic acid (Tetrahedron Letters, 1986, 27(49), 5997–6000) (8 g, 45.2 mmol) in dichloromethane (70 ml) and the solution was refluxed for 5 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude benzoyl chloride was dissolved in diglime (120 ml), cooled at −78° C. and 1M lithium tritertbutoxyaluminium hydride in THF (46 ml, 46 mmol) was added dropwise in 3 h. Stirring was continued for 30 min at −78° C. then the reaction was allowed to reach 0° C. and quenched with water (15 ml) and 2N NaOH (15 ml). The reaction mixture was stirred for 1 h, filtered and the organic phase was removed under reduced pressure. The crude residue was purified by column chromatography eluting with n-hexane/ethyl acetate 80:20 to give 4 g of the title compound (yield 55%) as a yellow powder, mp=112–114° C.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1>>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[C:15](=[O:16])[C:14]1[C:9]([Cl:8])=[CH:10][CH:11]=[N:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cnccc1Cl
Product: CC(C)N(C(=O)c1cnccc1Cl)C(C)C

Procedure:
substituting diisopropylamine and 4-chloronicotinic acid gave N,N-diisopropyl-4-chloronicotinamide; and
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[NH2:21][CH2:22][CH2:23][CH2:24]O.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:21]3[CH2:22][CH2:23][CH2:24][O:8][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN2CCCOC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.75 g. (50 mmole) of 3-aminopropanol, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The reaction mixture was then evaporated to a residue which was washed with water, dissolved in methylene chloride and chromatographed over a column of Florisil. The first fraction yielded the recovery of 2.7 g. of starting material. Elution with acetone, ethanol, methanol and finally with ammonial methanol gave a compound of very low Rf on fluorescent silica eluted with ethanol. Crystallization from acetone and recrystallizations from ether-petroleum ether gave the above-titled product as colorless prisms, m.p. 142°-144°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7](/[CH:10]=[C:11](\[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[C:12]([O:14][CH2:31][C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)OCC(=O)N(CC)CC)n1Cc1ccccc1Cl
Temperature: 70 °C
Yield: 78.1 %

Procedure:
A solution of (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(benzyl)-2-propenoic acid (Example 2) (2.05 g, 5 mmol) in dry dimethylformamide (10 mL) was treated with 2-chloro-N,N-diethylacetamide (0.825 g, 5.51 mmol) followed by powdered potassium carbonate. This mixture was heated at 70° C. for 7 hours, diluted with water and extracted with ethyl acetate. The water-washed, dried, concentrated product solidified and after trituration with ether/hexane afforded 2.04 g (78%) of the title ester; mp 76°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH:16]([O:19]C=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)[C:22]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(OC=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: N
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
To a solution of formic acid 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-2-(pyrazin-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (375 mg, 0.83 mmol) in methanol (50 mL) at 0° C. was bubbled ammonia gas for 15 min. The resulting reaction solution was stirred at 0° C. for 15 min. The solvent was removed in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 1-5% methanol/methylene chloride) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (260 mg, 62.5%) as an off-white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([OH:37])(=[S:36])[CH3:35].[CH3:38][C@:39]12[CH2:56][CH2:55][C@H:54]3[C@@H:44]([CH2:45][C@H:46]([OH:58])[CH:47]4[C@:52]3([CH3:53])[CH2:51][CH2:50][C@H:49](O)[CH2:48]4)[C@@H:43]1[CH2:42][CH2:41][C@@H:40]2[OH:59]>C1COCC1.CCOC(C)=O>[C:34]([S:36][C@@H:49]1[CH2:50][CH2:51][C@@:52]2([CH3:53])[CH:47]([C@@H:46]([OH:58])[CH2:45][C@@H:44]3[C@@H:54]2[CH2:55][CH2:56][C@@:39]2([CH3:38])[C@H:43]3[CH2:42][CH2:41][C@@H:40]2[OH:59])[CH2:48]1)(=[O:37])[CH3:35]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@H](O)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)S[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of triphenylphosphine (2.38 g) in THF (140 mL) cooled at 0° C., diisopropyl azodicarboxylate (1.79 mL) was added dropwise. After stirring for 30 minutes, thioacetic acid (0.65 mL) and androstane-3β,6α,17β-triol (2.00 g) were added. After 2 hrs at 0° C. and overnight at room temperature EtOAc was added. The mixture was washed with water and the organic layer evaporated to dryness. The crude product was purified by flash chromatography (SiO2, cyclohexane:EtOAc 55:45) to give 3α-acetylthioandrostane-6α,17β-diol (1.60 g, 66%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.42 (1H, bb), 4.28 (1H, bb), 3.91 (1H, bb), 3.42 (1H, m), 3.11 (1H, m), 2.28 (3H, s), 2.00-0.80 (20H, m), 0.74 (3H, s), 0.60 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:23][C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccco1
Yield: 38 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 2-Furaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine (100 mg) was suspended in 5 mL MeOH and sodium borohydride (10 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D96 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 40 mg (38% yield) of final product was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].IC1C=C(C(Cl)=O)C=CC=1C(Cl)=O.ClC1C=CC=C(C(Cl)=O)C=1C(Cl)=O>>[C:4]([Cl:6])(=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([Cl:13])=[O:12])=[CH:10][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)c(Br)c1
Agent: O=C(Cl)c1ccc(C(=O)Cl)c(I)c1
Agent: O=C(Cl)c1cccc(Cl)c1C(=O)Cl
Product: O=C(Cl)c1ccc(C(=O)Cl)cc1
Yield: 100 %

Procedure:
Fibers were made in a similar manner from the same diaminedithiol intermediate and 100% bromoterephthaloyl chloride; from 100% iodoterephthaloyl chloride; from 50% iodoterephthaloyl chloride/50% terephthaloyl chloride; from 50% chlorophthaloyl chloride/50% terephthaloyl chloride; and from 100% terephthaloyl chloride to give the control polybisbenzothiazole.
Reaction SMILES: [CH2:1]([OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:1]([O:27][S:42]([C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Yield: 21.9 %

Procedure:
A solution of hexacosanol (250 mgs, 0.654 mmol), triethylamine (125 1, 0.900 mmol) and 4-chlorobenzenesulphonyl chloride (150 mgs, 0.711 mmol) in methylene chloride (30 ml) is stirred at room temperature for 120 h. The reaction mixture is then diluted with methylene chloride (20 ml) and washed with water (2×50 ml). The organic phase is dried over magnesium sulphate, filtered and concentrated to give a crude product. Flash column chromatography on silica gel (10:1 hexane:ethyl acetate) followed by recrystallization from methanol gives n-hexacosanyl-4-chlorobenzenesulphonate (80 mgs, 22%).
Reaction SMILES: C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C.[N+:19]([C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=O)([O-:21])=[O:20].C(=O)(OC(=O)C1C=CC=CC=1[N+]([O-])=O)OCC.[C:48]1([CH2:58][NH2:59])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[C:48]1([CH2:58][NH:59][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[N+:19]([O-:21])=[O:20])[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: NCc1cccc2ccccc12
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: CCOC(=O)OC(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(NCc1cccc2ccccc12)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
1-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (7.5 g), was added in portions to a solution of 2-nitrobenzoic acid (5.01 g) in methylene chloride (300 ml) cooled to 0° C. The mixture (containing ethyl 2-nitrobenzoyl carbonate) was stirred for 15 minutes and then 1-naphthylmethylamine (4.7 g) was added dropwise at 0-5° C. The mixture was then stirred for 1 hour at ambient temperature and then washed successively with M hydrochloric acid, M sodium hydroxide and then with water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with methylene chloride/ether (80/20 v/v) to give N-(1-naphthylmethyl)-2-nitrobenzamide as a white solid (7.9 g), of satisfactory purity.
Reaction SMILES: N1C=CN=C1.[I:6]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:27][C@H:28]([CH2:38]O)[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[F:27][C@H:28]([CH2:38][I:6])[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC[C@H](F)CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](F)CI
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Imidazole (19.8 g, 0.29 mol) was dissolved in methylene chloride (900 mL) at room temperature. Iodine (73.9 g, 0.29 mol) was added and the reaction mixture was stirred for 10 min at room temperature and then cooled to 0° C. Triphenylphosphine (76.3 g, 0.29 mol) was added portionwise over 10 min such that the internal temperature remained below 10° C. A solution of tert-butyl (2S)-2-fluoro-3-hydroxypropylcarbamate (45.0 g, 0.23 mol) in methylene chloride (300 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 12 h. The reaction mixture was filtered through a pad of Celite® and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with methylene chloride. This procedure afforded tert-butyl (2S)-2-fluoro-3-iodopropylcarbamate as a colorless oil (42.5 g, 62%). 1H NMR (300 MHz, CDCl3) δ4.80-5.10 (br s, 1H), 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0.5H), 3.48-3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H).