Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)#[C-:2].[Si:13]([O:20][NH2:21])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[Si:13]([O:20][N:21]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([N+:1]#[C-:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: [C-]#[N+]c1ccc2c(c1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: [C-]#[N+]c1ccc2c(c1)CCC2=NO[Si](C)(C)C(C)(C)C
Yield: 74.9 %

Procedure:
5-isocyano-2,3-dihydroinden-1-one (6) (3.00 g, 19.1 mmol) was combined with 1.4 eq. of O-(tert-butyldimethylsilyl)hydroxylamine (3.94 g, 26.7 mmol) and TsOH-H2O (0.363 g, 1.91 mmol) in 100 mL CHCl3 and heated to reflux overnight. TLC showed a small amount of remaining starting material and two non-polar spots corresponding to the oxime isomers. The reaction mixture was filtered and concentrated to a brown semi-solid, then purified immediately by loading onto a silica column with DCM and eluting with 1% MeOH/DCM to give 4.1 g (75%) of 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime (7).
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3]1.[OH-].[NH4+:10].CCO>O1CCCC1>[NH2:10][CH2:4][CH2:3][CH:2]([S:6]([OH:5])(=[O:8])=[O:7])[CH3:1]
Reactant: [NH4+]
Reactant: CC1CCOS1(=O)=O
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CCN)S(=O)(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of 2,4-butanesultone (1.0 g, 7 mmol) in tetrahydrofuran (THF, 4.0 mL) was added via syringe pump over a 4 h period to ammonium hydroxide (28-30% NH3, 43 mL, 350 mmol) at 5° C. The solution was stirred at 5° C. for an additional 30 minutes. The solvent was coevaporated with EtOH (3×25 mL). The solid was dried in vacuo. Yield: 94%. 1H NMR (D2O, 500 MHz) δ ppm 3.05 (m, 2H), 2.90 (m, 1H), 2.05 (m, 1H), 2.06 (m, 1H), 1.77 (m, 1H), 1.18 (d, 3H, J=6.8 Hz), 1.14 (t, 3H, J=7.3 Hz). 13C (DMSO, 125 MHz) δ ppm 52.75, 38.20, 30.87, 17.27. ES-MS 154 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]3[CH:11]=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1cc(Cl)cc(-n2ncc3c(I)ccnc32)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1cc(F)cc(Cl)c1
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 75A (558.6 mg, 1.46 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569.2 mg, 2.24 mmol), potassium acetate (584.3 mg, 5.95 mmol), and anhydrous DMSO (11 mL). The reaction mixture was flushed with argon and treated with PdCl2(dppf).CH2Cl2 (59.1 mg, 0.081 mmol). The reaction mixture was heated to 85° C. for 1 h and then at 105° C. for 1.5 h to give conversion to the desired product. LC/MS (Condition B): ret. T=4.29 min, (M+H)+ 291.99, 292.99.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])[CH:18]=[CH:19][CH:20]=1.[C:31]([O:35][CH2:36]C)(=[O:34])[CH:32]=C>>[CH3:36][O:35][C:31](=[O:34])[CH2:32][C:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22]#[N:23])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1cccc(C(C#N)Cc2ccccc2)c1
Reactant: C=CC(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Temperature: 25 °C

Procedure:
Benzyl trimethylammonium hydroxide (40% in MeOH, 100 μl, 0.22 mmol) was added to a stirred mixture of 2-(3-methoxyphenyl)-3-phenylpropanenitrile (1 g, 4.2 mmol) and ethyl acrylate (0.51 g, 5.1 mmol). After the initial exothermic reaction had subsided the mixture was refluxed for 4 h, cooled to room temperature and extracted three times with DCM. The combined organic layers were washed with water, dried, filtered and evaporated to obtain a pale yellow oil m(CR)=1.06 g that was purified by flash chromatography on 12 g SiO2 using 20% EtOAc in cyclohexane affording 594 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH:41]=O>ClC(Cl)C>[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH2:41][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1ccc(N)c(C(=O)c2cccc(F)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-methoxyphenyl)(3-fluorophenyl)methanone (0.984 g, 4.01 mmol) in 15 mL of dichloroethane was added 4 Å powdered molecular sieves (1 g), followed by sodium triacetoxyborohydride (2.55 g, 12.0 mmol) and acetic acid (0.69 mL, 12.0 mmol). 2,4-Dimethoxybenzaldehyde was added (0.667 g, 4.01 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a red oil (1.66 g) which was used in the next step without further purification. ESI+ MS: 396.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13]CC)=[O:12])[C:2]=1[C:16]([O:18]CC)=[O:17].[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[C:2]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc2ccccc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2ccccc2nc1C(=O)O

Procedure:
To a solution of diethyl 2,3-quinolinedicarboxylate (0.162 mol) in ethanol (150 mL) is added a solution of sodium hydroxide (0.50 mol) in water (400 mL). The mixture is heated at reflux for five hours, and the ethanol then removed by distillation at atmospheric pressure. The solution is cooled in an ice bath, diluted with water (100 mL), and acidified with concentrated hydrochloric acid, added in small increments. The precipitate is filtered, washed with water, and air dried to afford the desired 2,3-quinolinedicarboxylic acid as the trihydrate; mp 271°-277° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1

Procedure:
The title compound was prepared in analogy to example 108, step 3 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with methanesulfonic acid 4-amino-phenyl ester (synthesis: S. Kobayashi, et al.; Synlett. 2000, p 883) as a mixture of cis and trans diastereomers. MS (m/e): 340.121 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[OH:28].[OH-].[K+].Cl>O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:28])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
2-[4-(4-Chlorophenyl)cyclohexyl-3-chloro-1,4-naphthoquinone (20 gm) was added to methanol (400 ml) at 25-30° C., the contents were heated to reflux and then potassium hydroxide solution (20 gm) in water (200 ml) was slowly added for 30 minutes at reflux. The reaction mass was stirred for 6 hours at reflux, to the resulting mass added hydrochloric acid (72 ml) slowly for 15 to 20 minutes at reflux and then cooled to 25-30° C. The resulting mass was further cooled to 0° C. and then stirred for 1 hour at 0-5° C. The solid was filtered, washed with water and then dried at 50-60° C. to give 18.1 gm of atovaquone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH:7]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)CNC(c1ccccc1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N(CC(=O)OCC)C(c1ccccc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
(RS)-{[(4-Chloro-phenyl)-phenyl-methyl]-amino}-acetic acid ethyl ester (18 g, 59 mmol) was dissolved under nitrogen in DCM (1500 mL), N-ethyldiisopropylamine (12.2 mL, 71 mmol) was added, cooled in ice and treated with a solution of allyl chloroformate (6.4 mL, 71 mmol) in DCM (50 mL). Stirring at 20° C. was continued for 16 h. The solution was extracted with 1 M citric acid (200 mL) and 50% NaCl solution. The crude product was purified by chromatography on silica gel in heptane with a gradient of ethyl acetate from 0-50% in 60 min. One obtained 18.1 g (78%) of colorless oil. MS: m/z=388 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:17]([NH2:19])[CH3:18]>>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:19][O:17][CH3:18])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Reaction of 4-formyl-benzoic acid tert-butyl ester with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate, 96:4) (79% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.60 (9H, s, t-Bu), 4.00 (3H, s, OCH3), 7.62 (2H, d, J=8.0 Hz, aromatics), 7.97 (2H, d, J=8.0 Hz, aromatics), 8.08 (1H, s, CH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[S:21][C:22]2[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=2[N:24]=1>O.COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:20]3[S:21][C:22]4[C:28]([N+:29]([O-:31])=[O:30])=[C:27]([O:32][CH3:33])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2nc(-c3ccc4c(c3)OCO4)sc2c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
0.697 g (4.2 mmol; 1.1 equivalent) of 1,3-benzodioxol-5-yl boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.1 g (3.82 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 133 mg (0.115 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 90° C. for 4 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a solution of water saturated with sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 0.960 g (yield of 76%) of 2-(1,3-benzodioxol-5-yl)-6-methoxy-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.P(Cl)(Cl)(Cl)=O.[CH3:18][S:19](C)=O>Cl(O)(=O)(=O)=O>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[C:8]([S:19][CH3:18])[CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1
Reactant: CS(C)=O
Reactant: CC1(C)Cc2cccc(O)c2O1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1cc(O)c2c(c1)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a mixture of 2,3-dihydro-2,2-dimethyl-7-benzofuranol (16.4 g), 20 ml of 70% perchloric acid and 16 ml of phosphorus oxychloride, dimethyl sulfoxide (7.8 g, 0.1 mol) was gradually added at a temperature of not higher than 5° C. The reaction solution was stirred at room temperature for further one hour, then poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated and then heated and refluxed, together with 200 ml of pyridine, for 4 hours. Pyridine was concentrated under reduced pressure, and the residue was washed with ether. The ether layer was washed with 1N hydrocloric acid and water successibly, then dried over anhydrous sodium sulfate and concentrated. The solid substance thereby obtained was recrystallized from ether-hexane, whereby 9.7 g of 2,3-dihydro-2,2-dimethyl-5-methylthio-7-benzofuranol was obtained. The melting of this product was 57°-59° C. The structure was confirmed by 1H-NMR spectrum and IR spectrum. Then, this phenol derivative was reacted with O-ethyl-ethylthionophosphonic acid chloride in the same manner as in Example 1, whereby the compound (No. 49) identified in Table 1 was obtained.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]3)[C:21]=12.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:17]1[CH:18]=[CH:19][N:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH:31][C:12]([C:9]4[N:10]=[CH:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:8]=4)=[O:14])[CH2:27]3)[C:21]=12
Reactant: N[C@@H]1CCN(c2nccn3ccnc23)C1
Reactant: O=C(O)c1ncn(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCN(c2nccn3ccnc23)C1)c1ncn(-c2ccccc2)n1
Reaction time: 0.05 h
Yield: 39.7 %

Procedure:
1-Phenyl-1,2,4-triazole-3-carboxylic acid (1.2 g, 6.3 mmol), (3R)-1-imidazo[1,2-a]pyrazin-8-ylpyrrolidin-3-amine dihydrochloride (2.0 g, 7.4 mmol), and diisopropylethylamine (13 mL, 75 mmol) were combined together in 50 mL DMF. To this mixture was added HATU (2.5 g, 6.6 mmol). After stirring 3 minutes, LCMS of an aliquot indicated the reaction was complete. DIPEA and most of the DMF were removed under reduced pressure. The residue was diluted in 400 mL EtOAc and washed with 50 mL saturated NaH2PO4. It was determined that a large amount of the desired product was present in the organic phase, therefore it was extracted with 400 mL 10 vol % i-PrOH/CHCl3. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (SiO2, 2-5% MeOH/dichloromethane) to provide 936 mg of the desired product (39% yield). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1 H), 7.74 (td, J=1.1, 7.5 Hz, 2 H), 7.56-7.48 (m, 4 H), 7.47-7.40 (m, 2 H), 7.37 (d, J=8.2 Hz, 1 H), 7.33 (d, J=4.3 Hz, 1 H), 5.00-4.80 (m, 1H), 4.50-4.35 (br, 1 H), 4.30-4.15 (br, 3 H), 3.45-3.30 (m, 1H), 2.90-2.75 (m, 1 H), 2.50-2.38 (m, 1 H), 2.25-2.15 (m, 1 H). MS: (ES) 375.2 (M+H+).
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3][CH2:2]1.[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C)C=O>[C:9]([Si:13]([CH3:16])([CH3:15])[O:7][C@@H:4]1[CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2][CH2:3]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](O)CC1

Procedure:
In a manner similar to the method described in example 94a, cis-1,4-cyclohexanediol (3.8 g, 33 mmol) was reacted with tert-butyldimethylchlorosilane (5 g, 34 mmol) and imidazole in N,N-dimethylformamide to give cis-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol as a colorless oil (2.4 g, 31%).
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([OH:27])=[O:26])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:25]([O:27][CH3:3])=[O:26])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodomethane (2.0 mL), K2CO3 (5.60 g), (S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (1) (NovaBiochem, A29340), and anhydrous DMF (20 mL) were combined and stirred at ambient temperature for 2 hours. The reaction mixture was subjected to an aqueous work-up, affording (S)-methyl 6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (TU3000-090) as clear oil. MS (ESI+): calcd. 417.20. found 417.20 (MNa+), calcd. 295.16. found 295.209((M-Boc)H+). H-NMR (400 MHz, CDCl3):1.372 (2H, m), 1.425 (9H, s), 1.515 (2H, m), 1.623 (1H, m), 1.785 (1H, br.s), 3.175(2H, m), 3.723 (3H, s), 4.284 (1H, m), 4.848 (1H, br.s), 5.084 (3H, overlapping br.s and s), 7.344 (5H, m). C-NMR (100 MHz, CDCl3): 22.340, 28.268, 29.307, 32.313, 40.569, 52.272, 53.099, 66.597, 79.897, 128.061, 128.100, 128.471, 136.519, 155.435, 156.426, 173.230.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:10]3[C:11]4[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=4[S:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:9])=[CH:6][CH:7]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 81 %

Procedure:
The title compound was prepared using 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-hydroxyphenyl ketone and 1-(2-chloroethyl)piperidine hydrochloride in 81% yield by essentially following the same procedures detailed in Example 24, Part B.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[ClH:8].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.[BH4-]>CO>[ClH:8].[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ncc[nH]2)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole-2-carboxaldehyde (2.45 g, 25.5 mmol) is added to a solution of 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride (11.1 g, 24.9 mmol) and triethylamine (5.05 mL, 50.0 mmol) in methanol (500 mL). The mixture is stirred at room temperature for 16 hours. Polymer supported borohydride (Aldrich, borohydride on Ambelite IR-400, 2.5 mmol/g, 10.0 g, 25.0 mmol) is added, the mixture stirred for 2 hours, filtered and concentrated under reduced pressure. The residue is taken up in ethanol (100 mL) and a saturated solution of hydrochloric acid gas in diethyl ether (10 mL) is added. The white precipitate is collected to yield 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-imidazolylmethylamino)-indan-5-yl] amide hydrochloride m.p. 240-242° C. Free base has m.p. 169-170° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=3)[CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(Br)c2)nc1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane→ethyl acetate:heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.80 min.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1F>CS(C)=O.C(OCC)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][C:16]=1[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OC2CCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.