Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[CH:13]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN(C)C(=O)C>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:31]([C:30]5[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=5)=[O:32])[CH:3]=[CH:4][C:5]=4[CH3:24])=[CH:13][N:12]3[N:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2ccc(C)c(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 91.2 %

Procedure:
In the same manner as in Example 24 and using N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (265 mg, 0.820 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (260 mg, 1.64 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (333 mg, 91%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(F)(F)F.CCOCC.[CH2:26]([SH:29])[CH2:27][SH:28]>C(Cl)Cl>[CH2:12]([C:11]1([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)[S:29][CH2:26][CH2:27][S:28]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=O)c1cc(OC)cc(OC)c1
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a stirred solution of Compound 5 (3.52 g, 15.9 mmol) in anhydrous CH2Cl2 (58 ml); was added BF3-Et2O (0.58 ml, 4.8 mmol) and ethane-1,2-dithiol (2.71 g, 28.8 mmol) and stirred at room temperature for 16 h. The organic phase was then extracted with 10% NaOH (20 ml) followed by water and brine. The organic phase was dried, concentrated and the residue resolved over silica gel eluting with EtOAc/hexanes (5:10) to yield 4.50 g (95.2%) of Compound 9 as a colorless oil. Rf=0.51 (hexane:ethyl acetate 9:1); IR (neat) 2955, 1205, 1067 694 cm−1; 1H NMR δ 6.89 (d, J=2.22 Hz, 2H), 6.34 (t, J=2.21 Hz, 1H), 3.81 (s, 6H). 3.40–3.20 (m, 4H), 2.33 (t, J=7.53 2H), 1.31–1.20 (m, 4H), 0.85 (t, J=6.78 Hz, 3H). 13C NMR δ 160.56, 148.04, 106.01, 98.74, 74.58, 55.60, 45.92, 39.33, 30.23, 23.03, 14.13; MS: (ESI, Pos.) m/z 299 (M+).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[OH-].[Na+]>CCOCC.O>[O:12]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCN
Reactant: O=C1CCC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butylamine (9.05 g, 0.1225 mole) was dissolved in Et2O (30 ml). Succinic anhydride (5 g, finely powdered) was added portionwise. After addition was complete, the heterogeneous mixture was stirred 1 hour at room temperature. The reaction mixture was then poured into 10% NaOH in H2O (10 ml) and Et2O (30 ml). The layers were separated and the ether layer was extracted with additional 10% NaOH (10 ml). The combined aqueous layers were washed with ether (30 ml) and acidified with concentrated HCl to give a layer of oil above the water layer. This was extracted with Et2O (50 ml×2). The ether extracts were washed with saturated NaCl solution (3×30 ml) and dried (MgSO4). The solvent was removed in vacuo to give a white solid (7.5 g) which was recrystallized from benzene to give title acid as needle shaped crystals (4.83 g, 56%), m.p. 93.5°-94.5° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C@H:10]([C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:12])=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:26][C:25](=[O:27])[C@H:14]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH:13][C:11](=[O:12])[C@H:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:41]
Reactant: CCI
Reactant: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of Nα-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan (300 mg) in N,N-dimethylformamide (10 ml) were added potassium carbonate (69 mg) and ethyl iodide (155 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2), saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml) successively and the organic layer was dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give N [(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan ethyl ester as an amorphous powder (260 mg).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2)=[O:16].[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=CC=C[CH:28]=1.C(O)(C)C>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([O:26][CH:27]([CH3:32])[CH3:28])[CH:22]=[CH:21][CH:20]=2)=[O:16]
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1cc2c(OC(C)C)cccc2[nH]1
Reaction time: 0.33 h

Procedure:
DEAD (0.227 ml, 1.47 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (200 mg, 1.05 mmol), triphenylphosphine (384 mg, 1.47 mmol) and isopropanol (0.108 ml, 1.43 mmol) in 2 ml of THF. Stirring is continued for 20 minutes and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using cyclohexane/EtOAc (9/1).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31]([NH:30][CH2:29][C:28]3[CH:33]=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[O:32])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: COc1ccc(CNC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Yield: 40 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxybenzyl isocyanate in a yield of 40%, according to the procedure for the synthesis of example 42.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7]C)=[O:6].B(Br)(Br)Br>C(Cl)Cl.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([OH:12])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCc1c(O)cc(O)c(C)c1C(=O)OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(O)cc(O)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4.61 g of methyl 3,5-dihydroxy-2-methyl-6-propylbenzoate in 20 ml of methylene chloride were added at 0° C. within 30 minutes 50 ml of a 1M solution of boron tribromide in methylene chloride. The mixture was stirred for 5 hours at room temperature and then diluted with 100 ml of ethyl acetate. The mixture was washed with water and with brine, and the organic layer was dried over sodium sulfate and evaporated in vacuo to yield crude 3,5-dihydroxy-2-methyl-6-propylbenzoic acid.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([SH:15])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C>Cl>[ClH:14].[Cl:14][C:8]1[C:7]([SH:15])=[C:6]2[C:11]([CH2:12][CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1CCc2ccc(Cl)c(S)c2C1
Agent: Cl
Product: Sc1c(Cl)ccc2c1CNCC2

Procedure:
A suspension of N-acetyl-7-chloro-8-mercapto-1,2,3,4-tetrahydroisoquinoline (1 g., 0.004 m.) in dilute hydrochloric acid was refluxed for three hours under an argon atmosphere. The reaction mixture was evaporated under reduced pressure and the residue was dried by evaporation from methanol-toluene. Recrystallization from methanol-ethyl acetate gave 7-chloro-8-mercapto-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 205°-207° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CS(N)(=O)=[O:29].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[OH:29][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH:4]=[CH:3][S:2](=[O:1])(=[O:26])[CH2:7][CH2:6]1
Reactant: CS(N)(=O)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(O)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
A solution of (S)-N-[[3-[4-(3,6-dihydro-1,1-dioxido-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.415 g, 1.08 mmol; prepared as described in U.S. Pat. No. 5,968,962) in 1:1 t-butanol-water (4 mL) is added to a solution of the standard reagent AD mix-β (1.51 g; available from Aldrich Co.) and methanesulfonamide (0.103 g, 1.08 mmol) in 1:1 t-butanol-water (10 mL) cooled at 0° C. The reaction mixture is stirred 5 days at 4° C. and then treated with sodium sulfite (1.5 g) and stirred 30 minutes. The solution is then extracted with four 10 mL portions of ethyl acetate and the combined organic phases dried (MgSO4), filtered and concentrated. Purification by column chromatography (0-5% MeOH-DCM) provided the title compound as a mixture of diastereomers. Yield 0.29 g (64%). 1H NMR.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[Br:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][OH:34])=N)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]2[N:2]=[C:1]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]([CH:23]4[CH2:25][CH2:24]4)[C:10](=[O:22])[C:11]4[CH:12]=[CH:13][C:14]([C:17]5[O:21][CH:20]=[N:19][CH:18]=5)=[CH:15][CH:16]=4)[CH2:7][CH2:8]3)[O:34][N:33]=2)=[CH:29][CH:28]=1
Reactant: N=C(NO)c1ccc(Br)cc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(Br)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4-bromo-N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=2.08 min; Mass spectrum (ESI+): m/z=534/536 (Br) [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(O)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a mixture of 4-hydroxy-4-methylcyclohexanone (4.1 g, 32.0 mmol) and benzyl amine (6.8 g, 64.0 mmol) in 1,2-dichloroethane (120 mL) was added acetic acid (3.84 g, 64.0 mmol). After the resulting mixture was stirred at RT for 2 hours, the mixture was added NaBH(OAc)3 (13.6 g, 64.0 mmol). The resulting mixture was then stirred at RT overnight. After the reaction was completed, the mixture was basified to pH 11 by addition of 2 N NaOH. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (MeOH:DCM=3:100 to 1:10) to afford 4-(benzylamino)-1-methylcyclohexanol as a white solid (5.7 g, yield: 80.0%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)Cn1c(C(C)(C)O)nc2c(Cl)nc3ccccc3c21
Reactant: N
Product: CC(C)Cn1c(C(C)(C)O)nc2c(N)nc3ccccc3c21

Procedure:
4-Chloro-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol (Example 22) was aminated in a Parr bomb at 150° C. using 15% methanolic ammonia. The product was purified by silica gel column chromatography (5% methanol in ethyl acetate as eluent). The product was then recrystallized from ethyl acetate/hexane to give a solid, m.p. 214-217° C. Analysis: Calculated: C, 68.4; H, 7.4; N, 18.8. Found: C, 68.2; H, 7.4; N, 18.7.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(#N)C>[NH:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1
Reactant: CS(=O)(=O)Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(OCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(1-trityl-1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide (0.63 g, from above) and 1N HCl (10 mL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solvent was removed and the residue was brought to basic pH with saturated potassium carbonate solution. The mixture was extracted with dichloromethane, washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with methanol (containing 2% NH4OH)/dichloromethane (7:93) to give N-(3-(1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide. This was converted to N-[3-(1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide oxalate salt, mp 178-180° C. by treating with 1M oxalic acid in ether.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C1COC(=O)C1
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stirring solution of 650 mg (6.5 mmol) of tetronic acid in 20 mL of dimethylformamide is added 1.0 mL (7.17 mmol) of triethylamine and 230 mg (1.88 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.50 g (7.81 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.81 mmol) of palmitic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is recrystallized from pentane to give 2.0 g (91%) of 4-hydroxy-3-[1-oxohexadecyl]-2(5H)-furanone, mp 81°-83° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH:10]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)([CH3:12])[CH3:11]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:10]([CH3:12])[CH3:11])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CC(C)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)c1nccn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole-4-sulfonylchloride and 150 ml of THF. This solution was treated with 11.10 g of 2-isopropylimidazole in one portion and the solution stirred 24 hours at room temperature. The solution was concentrated to a clear oil and partitioned between ethylacetate and water. The organic layer was washed with water and the water washes back extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to a foam. The foam was dissolved in acetone and chromatographed on activity III alumina to separate 1-(4-imidazolylsulfonyl)-2-isopropylimidazole, mp 118°-120°.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:20])=[O:7])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[N:10]([CH3:19])[C:9]=1[CH3:20])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(C(=O)NCC(C)C)c(C)n(C)c2c1
Agent: BrB(Br)Br
Product: Cc1c(C(=O)NCC(C)C)c2ccc(O)cc2n1C

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indol-3-carboxylic acid isobutyl-amide 67a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ7.52 (1H, d, J=8.5 Hz, 6.74 (1H, d, J=2.3 Hz), 6.68 (1H, dd, J=2.3, 8.5 Hz), 3.61 (3H, s), 3.22 (2H, m), 2.58 (3H, s), 1.95 (1H, m), 1.02 (3H, s), 1.00 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 261, found 261.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CCC(C)=O
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 64.9 %

Procedure:
A mixture of 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester (1000 g, 3.27 mol), ethyl 4-bromobutyrate (639 g, 3.45 mol) in 2-butanone (5.6 L) was heated at reflux for 24 hours. After the reaction was completed, the mixture was poured into ice-water, and the resultant precipitates were collected by filtration. The filtrates were washed with ethyl acetate to give 2-[(3-Ethoxycarbonyl-propyl)-(toluene-4-sulfonyl)-amino]-benzoic acid methyl ester (890 g, 65%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=O)[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.NN.[OH-].[K+]>C(O)COCCO.C(O)CCC>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][CH2:18]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CCCCO
Product: C[C@@]12CCC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Temperature: 50 °C
Yield: 97.5 %

Procedure:
Into a stirring suspension of estrone (8.1 g, 30 mmols) in 60 mL diethylene glycol, 20 mL 1-butanol and 2 mL hydrazine anhydrous (60 mmols) were added. The reaction mixture was heated under reflux for 1 hour to get clear solution. After cooling reaction mixture to 50 ° C., 5.04 g KOH pellets (90 mmols) were added and butanol was distilled. The reaction mixture was heated at 50° C. for 2 hours and then cooled to RT. On pouring in to ice (50 g), 20 mL 6N HCl was added and the reaction mixture stirred to give white solid product. The product was separated by filtration, washed with cold water and dried under vac. to give 7.5 g (90%) product. The product was purified on silica gel column eluted with CHCl3/MeOH 99:1. 1H NMR in CDCl3 confirmed the product as estra-1,3,5(10)-triene-3-ol.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:20][C:19]=2[CH2:28][CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:20][C:19]=2[CH2:28][CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C(CC)CC)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(C(CC)CC)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 38.8 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[2-ethyl-5-(1-ethylpropyl)thiophen-3-yl]methoxy}benzoic acid (212 mg) synthesized in Example 73 (5) and ethyl 3-(methylamino)propanoate (80.4 mg) to give the title compound (99.2 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]=[C:28]=[O:29]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:28]([NH:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)=[O:29])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc2ccccc2c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc3ccccc3c2)cc1-c1c(Br)cnn1C
Yield: 75 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 2-naphthyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 14 (0.040 g, 0.09 mmol, 70%) as a white solid. LCMS m/z (%)=451 (M+H79Br, 95), 453 (M+H79Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.30 (s, 1H), 8.20 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 7.56-7.84 (m, 3H), 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.8 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH:12]([SH:14])[CH3:13]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:14][CH:12]([CH3:13])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)S
Reactant: N#Cc1ccc(F)cc1Cl
Product: CC(C)Sc1ccc(C#N)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 2-chloro-4-(isopropylthio)benzonitrile. 1.6 g of 2-chloro-4-(isopropythio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(isopropylthio)benzoic acid. 1 g of 2-chloro-4-(isopropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 449.1 (M)+.