Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][CH:12]=[N:11][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:19]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([I:19])=[N:11][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ncsc1NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(I)sc1NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a solution of ethyl 5-[(tert-butoxycarbonyl)amino]-1,3-thiazole-4-carboxylate (10 g, 36.7 mmol) in DMF (122 ml) was added N-iodosuccinimide (20 g, 88.9 mmol). The mixture was stirred for 36 hrs at 60° C. One additional equivalent of N-iodosuccinimide (1.2 g) was added and the mixture was stirred at 60° C. for 18 hrs. The reaction was then cooled to room temperature and concentrated to one-third its volume in vacuo. The resulting mixture was partitioned between water and ethyl acetate. The aqueous layer was further extracted once with dichloromethane. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo, and purified via flash chromatography (silica, 0-20% ethyl acetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C11H16IN2O4S) [M+H]+, 399.0; found 398.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][C@H:9]1[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCCCC2C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a stirred solution of [1-tert-butoxycarbonyl-(2S)-octahydroindolyl]carboxylic acid (1.0 g, 3.7 mmol) in THF (10.0 ml) was added BH3.THF (1.0 M in THF, 8.0 ml) at 0° C. After stirred at room temperature for 1.0 h, the reaction mixture was heated under reflux for 1.5 hr. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0° C., and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give [1-tert-butoxycarbonyl-(2S)-octahydroindolyl]methanol (947 mg, quant) as a a colorless oil.
Reaction SMILES: [C:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:29]=1[CH2:38][N:39]1[CH2:43][C@@H:42]([CH3:44])[C@@:41]([CH2:54][C:55]([OH:57])=[O:56])([C:45](=[O:53])[NH:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:40]1>O1CCCC1.CO.O>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[C:29]=1[CH2:38][N:39]1[CH2:43][C@@H:42]([CH3:44])[C@@:41]([CH2:54][C:55]([OH:57])=[O:56])([C:45](=[O:53])[NH:46][CH:47]2[CH2:48][CH2:49][N:50]([CH2:7][C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)[CH2:51][CH2:52]2)[CH2:40]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCNCC1
Reactant: O=CC1=CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCN(CC2=CCCCC2)CC1
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Cyclohex-1-ene-1-carbaldehyde (25.9 μl, 0.227 mmol), acetic acid (30 μl) and sodium triacetoxyborohydride (68.8 mg, 0.325 mmol) were added to a solution of 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-3-[(piperidin-4-yl)carbamoyl]pyrrolidin-3-yl]acetic acid obtained by the method of Example 5d (15 mg, 0.0325 mmol) in tetrahydrofuran (dehydrated) (2 mL), followed by stirring overnight. Water and methanol were added to the reaction liquid, which was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (elution solvent: water/methanol) to give the title compound (12.8 mg, yield: 70.8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(#N)C.CCOCC>[NH2:12][C:10]([C@@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: O=C(Cl)CCCCl
Reactant: CC[C@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC[C@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 78.7 %

Procedure:
345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propy]-4-chlorobutanamide.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:8]1([SiH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][Si:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CCOCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
0.5 ml of a 0.1 N solution of chloroplatinic acid as the catalyst in 2-propanol was added to an excess amount [18.3 g (187 mmol)] of diallyl ether (F). 16 g (62.3 mmol) of triphenylsilane (A) was added thereto and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction according to the disappearance of an absorption due to SiH at 2100 cm-1 in the I.R. absorption spectrum, excess (F) was distilled off under reduced pressure. The residue was purified according to column chromatography to obtain 16.5 g (50.0 mmol) of 3-allyloxypropyltriphenylsilane (G-4) (yield: 80.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1c(C)cccc1NC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(C)c1C(=O)OC
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Add a solution of 2-isopropoxycarbonylamino-6-methyl-benzoic acid methyl ester (3.77 g, 15.0 mmol) in DMF (60 mL) to a suspension of sodium hydride 60% dispersion mineral oil (600 mg, 15.0 mmol) in DMF (60 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (3.2 mL, 22 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (4.60 mg, 84%): 1H NMR (CDCl3, 300 MHz) δ 1.05-1.30 (m, 9H), 1.90 (m, 2H), 2.32 (m, 2H), 2.36 (s, 3H), 3.85 (s, 3H), 4.11 (q, J=7.3 Hz, 2H), 4.88 (m, 1H), 7.02 (m, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H). MS (ES+): 366 (M+H).
Reaction SMILES: Br[C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C(=O)C2NC=NC=2NC1=O>>[CH2:21]([NH:28][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: CCCCn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(CCCC)c1=O

Procedure:
Heat together a mixture of one equivalent of 8-bromo-1,3-di-n-butyl-xanthine with three to four equivalents of benzylamine at 160°-180° C. until thin layer chromatography analysis shows that no starting xanthine remains. Cool. Triturate with ethanol and water to yield 8-benzylamino-1,3-di-n-butyl-xanthine.
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)=[O:15])[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (1.23 g, 5.25 mmol, Intermediate 15, step b) in THF (12 mL) at 4° C. was added 0.5 M (3-chlorophenyl)magnesium bromide in THF (12.7 mL, 6.35 mmol). The mixture was stirred at 4° C. to room temperature overnight, and quenched with NH4Cl (aqueous). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (40 g silica gel column, 0-70% EtOAc in heptanes) to give the title compound as an oil, which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][Cl:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nn1
Solvent: ClCCl
Product: ClCc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0° C., 200 mg (1.38 mmol) of the compound from example 10A and 198 mg (1.66 mmol) of thionyl chloride are initially charged in 1.5 ml of dichloromethane and, after warming to RT, stirred at this temperature for 24 h. The solvent is removed on a rotary evaporator and the product that remains is directly reacted further.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)CCBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 37.9 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 1-bromo-3-methylbutane (1.9 ml; 15.4 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 24 h. After aqueous work-up and flash chromatography the pure material (0.62 g; 1.86 mmol) is de-acetylated under reflux in 2-propanol (2 ml) and hydrochloric acid (6 N; 7 ml). Pure 5-amino-3,3-dimethyl-1-(3-methyl-butyl)-6-nitro-1,3-dihydro-indol-2-one (419 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (50:1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][N:5]([C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9])[C:4](=[O:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li].[H-]>O1CCCC1>[CH3:14][C:7]([N:5]1[CH2:6][C:2]([CH3:1])=[C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]1=[O:15])([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(C)N1CC(C)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)CO)C1
Temperature: -30 °C
Yield: 83.4 %

Procedure:
52.4 g (200 mmol) of ethyl 2-(4-methyl-2-oxo-3-phenyl-3-pyrrolin-1-yl)isobutyrate was dissolved in 300 ml of tetrahydrofuran, and the solution was cooled to -30° C. In a dropping funnel, 7.6 g (200 mmol) of lithium alminum hydride was suspended in 100 ml of tetrahydrofuran, and the suspension was dropwise added at -30° C. After completion of the dropwise addition, the cooling medium was removed, and a suitable amount of water was added, and excess of lithium aluminum hydride was quenched. Insoluble material was removed by filtration, and the filtrate was concentrated and the solid thus obtained was washed with isoproyl ether to obtain 40.9 g (yield: 83%) of the desired product having a melting point of from 77° to 78° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].I[CH2:15]Cl.C([Zn]CC)C>ClC(Cl)C>[CH:2]1([CH2:1][C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:15][CH2:3]1
Reactant: ClCI
Reactant: C=CCc1cccc(C(=O)OC)c1
Agent: CC[Zn]CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-allylbenzoate (8.39 g, 47.6 mmol) in dichloroethane (100 mL) was added iodochloromethane (26.9 mL, 152 mmol). The solution was cooled to 0° C. and diethyl zinc (1.0 M in heptanes, 76.2 mL, 76.2 mmol) was added. The cooling bath was removed and the reaction was stirred at rt for 30 min. The reaction mixture was quenched with 1N HCl, extracted with methylene chloride (three times), dried with MgSO4 and concentrate under vacuum to afford the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])=[CH:16][CH:15]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:31])=O>CN(C)C=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[CH:11]=[CH:10][C:6]([C:7]([Cl:31])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl

Procedure:
The product from Example 162a (2.0 g, 42.9 mmol) in thionyl chloride (10 mL) containing 1 drop of dimethylformamide and was heated to reflux for 3 hours. Cooled and concentrated under vacuum and dried under high vacuum overnight. The title compound was used without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:21][N:22](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:22]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)(C)CCn1ncc2c(Br)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)CCn1ncc2c(C#N)cccc21
Temperature: 100 °C
Yield: 36 %

Procedure:
To a solution of ethyl 4-(4-bromo-1H-indazol-1-yl)-2,2-dimethylbutanoate (D112) (600 mg, 1.77 mmol) and Zn(CN)2 (207 mg, 1.77 mmol) in DMF (5 ml) at room temperature was added Pd(PPh3)4 (204 mg, 0.18 mmol) and the resulting mixture was stirred at 100° C. over the weekend, heated for a further 5 hours and then cooled to room temperature and diluted with AcOEt. The organic phase was filtered through celite and washed with water then brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [10-20% EtOAc/cyclohexane] gave the title compound (200 mg, 36%) as a colourless oil. MS (ES) C16H19N3O2 requires 285, found 286 [M+H]+.
Reaction SMILES: [C:1]1([O:7][C:8]([P:10]([O:16]OCC)([O:12]OCC)=[O:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C(#N)C.C[Si](C)(C)Br>[C:1]1([O:7][C:8]([P:10]([OH:16])([OH:12])=[O:11])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOOP(=O)(OOCC)C(=O)Oc1ccccc1
Agent: C[Si](C)(C)Br
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(Oc1ccccc1)P(=O)(O)O
Reaction time: 2 h

Procedure:
25.8 parts by weight of diethoxyphosphonoformic acid phenyl ester are dissolved in 80 parts by volume of acetonitrile, and 36.7 parts by weight of trimethylbromosilane are added at 20° C. The mixture is stirred at 40°-45° C. for 2 hours and the solution is then evaporated in vacuo. The evaporation residue is taken up in 60 parts by volume of water and, after separating off the hexamethyldisiloxane formed, the resulting solution is neutralised with dilute lithium hydroxide solution and then evaporated in vacuo.
Reaction SMILES: N1C2C=CC=CC=2NC=1.[NH2:10][C:11]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].[CH:21]([C:23]1[CH:42]=[CH:41][CH:40]=[CH:39][C:24]=1[O:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=O>>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([O:25][C:24]2[CH:39]=[CH:40][CH:41]=[CH:42][C:23]=2[C:21]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=3[N:10]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)CC1
Reactant: Nc1cccc(C(=O)O)c1N
Agent: c1ccc2[nH]cnc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2nc3c(C(=O)O)cccc3[nH]2)CC1

Procedure:
The same general procedure outlined above for the preparation of benzimidazole derivatives was used, employing 2,3-diaminobenzoic acid 1 and tert-butyl 4-(2-formylphenoxy)piperidine-1-carboxylate 26 to produce 2-(2-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 27. MS (ESI) calcd for C24H27N3O5: 437.20; found: 438 [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[S:9].[C:10](#[N:12])[CH3:11]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8](=[S:9])[N:7]2[CH:2]=[CH:3][CH:4]=[CH:11][C:10]2=[N:12][C:8]1=[S:9]
Reactant: S=C=Nc1ccccn1
Reactant: CC#N
Product: S=c1nc2ccccn2c(=S)n1-c1ccccn1

Procedure:
10 G. of freshly distilled 2-pyridylisothiocyanate is dissolved in 100 ml. of acetonitrile and the reaction mixture stirred at room temperature for 2 days. The solid precipitate is filtered and washed with fresh acetonitrile affording 3-(2-pyridyl) pyrido (1,2-a) 1,3,5-triazine-2,4-dithione m.p. 107°-109° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C@@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:22]([CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[C@H:21]2[C@H:12]1[C@:13]1([CH3:36])[C@@H:18]([CH2:19][CH2:20]2)[CH2:17][C@H:16]([OH:32])[C@@H:15]([O:33][CH2:34][CH3:35])[CH2:14]1>N1C=CC=CC=1.O>[CH2:34]([O:33][C@H:15]1[CH2:14][C@@:13]2([CH3:36])[C@@H:18]([CH2:19][CH2:20][C@@H:21]3[C@@H:12]2[C@H:11]([NH:10][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:30][C@@:29]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C@@H:25]2[C:26](=[O:28])[CH3:27])[CH2:17][C@@H:16]1[O:32][C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH3:35]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Solvent: c1ccncc1
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1OC(=O)OCC(Cl)(Cl)Cl

Procedure:
2,2,2-Trichloroethyl chloroformate (1 ml) was added to a stirred solution of 11α-amino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one (2 g) in pyridine (20 ml). After 16 hours complete reaction was not obtained. A further quantity of 2,2,2-trichloroethyl chloroformate (1 ml) was added and after 30 minutes the mixture was diluted with water (30 ml). The mixture was extracted with ether (x 2) and the extracts were washed with 2 M-HCl (x 4) and water (x 2) and dried. Evaporation of the solution left a yellow froth which was purified by column chromatography on silica eluted with ethyl acetate:petrol (1:3) to give a solid (2.5 g). A portion was crystallised from ether/petrol to give the title compound m.p. 147°-149° C., [α]D +48°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][N:17]([CH3:18])[CH2:19][CH3:20])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(C)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: Cl
Product: CCN(C)CC1(c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-N-ethyl-N-methylcyclohexanecarboxamide (130 mg, 0.414 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH3CN (3 mL) to give pure N-((1-(3,4-dichlorophenyl)cyclohexyl)methyl)-N-methylethanamine as white crystals. HPLC Rt=9.00 min; 1H NMR (400 mHz, MeOH-d4) 7.65 (d, J=2.2 Hz, 1H), 7.56 (d, J=8.43 Hz, 1H), 7.42 (dd, J=2.2, 8.43 Hz, 1H), 3.43-3.40 (m, 1H), 2.96-2.94 (m, 2H), 2.48 (s, 3H), 2.24 (m, 2H), 1.66-1.53 (m, 5H), 1.41-1.31 (m, 3H), 1.14 (t, 3H); LC-MS 10.07 min, (M+1)+ 300@10.3 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH3:23])[CH:14]=1)[C:5]([O:7]C)=[O:6].O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:9]=[C:10]([Cl:24])[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:22])=[C:15]([CH3:23])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(Oc2cc(C)c(O)c(C(C)C)c2)c(Cl)c1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2c(Cl)cc(C(=O)O)c(C)c2Cl)cc(C(C)C)c1O
Yield: 93.6 %

Procedure:
A solution of methyl 3,5-dichloro-2-methyl-4-(3-methyl-4-hydroxy-5-isopropylphenoxy)benzoate (125 mg, 0.33 mmol) and LiOH H2O (68 mg, 1.63 mmol) in a 5:1 THF/H2O (6 mL) was stirred overnight at 20° C. under N2. The solution was concentrated under vacuum and acidified to pH 1 with 1N HCl. The resulting tan solid was collected by filtration, washed with H2O and air dried to yield 114 mg of 3,5-dichloro-2-methyl-4-(3-methyl-4-hydroxy-5-isopropylphenoxy)benzoic acid.
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:20][CH2:19][C:16]([CH3:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)(C1C=CC(C)=CC=1)(=O)=O.[C-:22]#[N:23].[Na+].CS(C)=O>C(Cl)Cl>[CH3:21][C:16]12[CH2:15][CH2:14][C:13]([CH2:12][C:22]#[N:23])([CH2:18][CH2:17]1)[CH2:20][CH2:19]2
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(C)(CC2)CC3)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC12CCC(CC#N)(CC1)CC2

Procedure:
The mixture containing 0.065 mole of 4-methylbicyclo[2.2.2]oct-1-yl methanol tosylate, 0.1 mole of sodium cyanide, and 100 ml. of dimethyl sulfoxide is stirred at 70° C for 4 hours and then poured into 500 ml. of methylene chloride. The organic phase is then washed four times with water, separated and dried with anhydrous magnesium sulfate and filtered. The filtrate is then evaporated under vacuum affording an oil which is then chromatographed on silica gel eluting with 10% ethyl acetate-90%, vol., hexane affording 4-methylbicyclo[2.2.2]oct-1-yl acetonitrile.