Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O:4][C@H:5]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[C@@H:6]([O:35][C:36](=[O:38])[CH3:37])[C@H:7]([O:31][C:32](=[O:34])[CH3:33])[C@@H:8]([O:27][C:28](=[O:30])[CH3:29])[C:9]([P:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])=[O:10])(O)O.OO>C1COCC1.CCOCC>[CH2:13]([P:11]([C:9]([C@@H:8]([C@H:7]([C@@H:6]([C@@H:5]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[OH:4])[O:35][C:36](=[O:38])[CH3:37])[O:31][C:32](=[O:34])[CH3:33])[O:27][C:28](=[O:30])[CH3:29])=[O:10])([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC[C@@H](OP(O)O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)P(=O)(Cc1ccccc1)Cc1ccccc1
Agent: OO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)P(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Compound 78 (1.2 g, 2.2 mmol) in THF (50 mL) cooled to −78° C. with a dry ice-acetone bath was added dropwise 30 percent H2O2 (10 mL), and the mixture was allowed to warm up to room temperature, and stirred for 1.5 hours at room temperature. The mixture was diluted with ether and successively washed with ice-cold saturated Na2S2O3, saturated NaHCO3, saturated NaCl, and water. The organic phase was dried over anhydrous Na2SO4 and concentrated to give a α:β (1:4) mixture of Compound 85 (1.36 g, 98 percent) as judged by 1H-NMR (CDCl3). This product was used for the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C(O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
A mixture of 2.13 g (4.68 mmol) 2-[(2,4-Dichloro-benzoyl)-(4-chloro-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The mixture was subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 0.955 g (48%) of the title compound. MS (m/e): 429.1 (MH+, 100%)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCCC1
Temperature: 0 °C

Procedure:
30 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 150 ml piperidine. The temperature of the reaction was allowed to rise during the addition. After the addition was complete, the reaction was heated at reflux temperature for two hours. The hot reaction mixture was poured into ice water, made acid by the addition of concentrated HCl until precipitation of the product was complete and filtered. The filter cake was recrystallized from ethanol to give 30.4 grams 5-nitro-2-piperidinobenzoic acid. m.p. = 201°-203° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-piperidinobenzoic acid. m.p. = 232°-235° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:26])=[C:4]([CH:22]=[C:23]([Br:25])[CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19])=[O:6].[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([O:26][C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:34])=[C:4]([CH:22]=[C:23]([Br:25])[CH:24]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[CH:10][C:9]=1[C:18]([F:19])([F:20])[F:21])=[O:6]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)cc(Br)c1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)cc(Br)c1OC(=O)N1CCOCC1
Yield: 70.6 %

Procedure:
Using 3,5-dibromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](N3C=C(C4C=CC=CC=4O)N=C3CC(C)C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S([O-])(=O)(=O)C>CN(C=O)C.O>[C:7]1([O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:30][CH:29]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)Cc1nc(-c2ccccc2O)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol (2 mmol) was added to a solution of Cs2CO3 (10 eq., 20 mmol) in anhydrous DMF (5 ml). This was followed by addition of the mesylate obtained above and the reaction mixture was heated to 90° C. for 2-3 h. The reaction mixture was then cooled to rt, diluted with cold water and the product was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give desired phenyl ether.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1.Cl.[CH3:17][NH:18][CH3:19].[OH-].[K+]>CO>[OH:1][CH:2]([CH2:15][N:18]([CH3:19])[CH3:17])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: CNC
Reactant: O=Cc1cn(CC2CO2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC(O)Cn1cc(C=O)c2ccccc21
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of 1-(2,3-epoxypropyl)indole-3-carboxaldehyde (0.5 g, 2.5 mmol), N,N-dimethylamine hydrochloride (4 g, 49 mmol) and anhydrous potassium hydroxide (2.75 g, 49 mmol) was stirred in dry methanol (50 ml) at −30° C. for 8 h., then allowed to slowly warm to room temperature. The mixture was concentrated under reduced pressure to half the original volume, then water was added and the mixture was extracted with dichloromethane. After drying with anhydrous sodium sulfate the solvent was removed under reduced pressure, and the oily residue was chromatographed on a silica gel column (eluent dichloromethane:methanol from (9:1) to (8:2)) to yield the entitled product as a yellow oil 0.49 g (80%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[CH:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([NH:6][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:2]1
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccsc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccsc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thiophen-3-amine (see Galvez, C., et al, J. Heterocycl. Chem. (1984), 21:393-5) (5.70 g, 57.0 mmol) and triethylamine (5.82 g, 58.0 mmol) in dichloromethane (100 mL) was added pentanoyl chloride (6.93 g, 57.0 mmol) dropwise at 0° C. The reaction mixture was stirred at ambient temperature overnight and quenched with water (50.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound: MS (ES+) m/z 184.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([CH:26]=[O:27])[CH:23]=[N:24][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]([C:22]1[CH:21]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:25]=[N:24][CH:23]=1)=[O:27]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: COc1cc(C#N)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1-c1cncc(C=O)c1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
A mixture of 4-bromo-3-methoxy-benzonitrile (400 mg, 1.88 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (440 mg, 1.88 mmol), PdCl2(PPh3)2 (108 mg, 0.15 mmol) and Na2CO3 (2M in water, 1.88 mL, 3.77 mmol) in 1,4-dioxane (8 mL) was heated at 100° C. for 1.5 h. After concentration in vacuo, the resulting residue was purified by flash column to give the title compound (449 mg, 100%) as white solid; ESI-MS m/z: 239 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:9]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:20]4[CH:24]=[N:23][N:22]=[CH:21]4)[CH:18]=3)[NH:13][CH:12]=2)[CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.[OH-].[Na+]>Cl>[CH3:1][N:2]1[CH:9]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N:20]4[CH:24]=[N:23][N:22]=[CH:21]4)[CH:18]=3)[NH:13][CH:12]=2)[CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CC(Cc3c[nH]c4ccc(-n5cnnc5)cc34)N(C)C2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1C(Cc2c[nH]c3ccc(-n4cnnc4)cc23)CC2CNCC21
Yield: 83.9 %

Procedure:
A solution of (1RS,3RS,5RS)-2-methyl-3-[{5-(1,2,4-triazol-4-yl)-1H-indol-3-yl}methyl]-2,7-diazabicyclo[3.3.0]octane-7-carboxylic acid, ethyl ester (0.3452 g, 0.875 mmol) in concentrated hydrochloric acid (10 mL) was heated at reflux for 40 h, whilst stirring magnetically. After cooling, the reaction mixture was basified with 50% NaOH solution (8 mL) and extracted with CH2Cl2 (4×75 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (alumina, CH2Cl2 --MeOH--NH3 (aq); 90:10:1) to give 0.2367 g (84%) of the title compound as a yellow gum. δH (360 MHz, CDCl3) 1.42 (1H, m), 1.87 (1H, m), 2.43-2.59 (2H, m), 2.54 (3H, s), 2.66 (1H, d, J=11.1 Hz), 2.77 (1H, m), 2.81-2.86 (1H, m), 2.99 (1H, m), 3.13 (1H, dd, J=3.7 and 14.2 Hz), 3.29 (1H, m), 3.46 (1H, m), 7.14-7.17 (2H, m), 7.49 (1H, d, J=8.4 Hz), 7.52 (1H, d, J=2.0 Hz), 8.47 (2H, s), 8.58 (1H, br s). m/e (ES+) 323 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:25]=[C:19]2[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]2[C:17](=[O:26])[N:16]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:15]2[CH:25]=[C:19]3[N:20]([CH3:24])[CH2:21][CH2:22][CH2:23][N:18]3[C:17](=[O:26])[N:16]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(F)c(C(F)(F)F)c1
Product: CN1CCCn2c1cc(OCc1ccc(F)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-fluoro-3-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: C[O:2][C:3]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[C:18]([O:25]C)=[C:17]([CH3:27])[C:4]=1[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>C(#N)C.O>[CH3:24][O:23][C:19]1[C:18](=[O:25])[C:17]([CH3:27])=[C:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[C:3](=[O:2])[C:20]=1[O:21][CH3:22]
Reactant: COc1c(C)c(Cc2ccc(CCC(=O)O)cc2)c(OC)c(OC)c1OC
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
The compound (1.00 g, 2.67 mmol) obtained in Step 6 was dissolved in a mixture of acetonitrile (30 ml) and water (10 ml), to which was added CAN (ceric ammonium nitrate) (2.34 g, 4.27 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, the solvent was distilled off. The residue was purified by a silica gel column chromatography (5% methanol-methylene chloride) and then was crystallized in ethanol/hexane to yield the title compound (662 mg, 1.92 mmol, yield 72%).
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=2
Reactant: COCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 65 °C

Procedure:
8-Bromo-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.4489 g) was suspended in dry methanol (11.5 mL) and then treated with 25% (w/v) sodium methoxide in methanol (2.5 mL). The reaction mixture was heated to reflux (65° C., externally) were upon a solution was obtained. After 4 hours the reaction mixture was concentrated under reduced pressure and saturated aqueous ammonium chloride (100 mL) was added. This was then extracted with ethyl acetate (100 mL, twice). The organic layers was separated, combined and washed with brine (100 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. This was then evaporated under reduced pressure to give the title compound as a white solid (1.2032 g) after placing under high vacuo, overnight.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>C(O)(=O)C>[C:11]([O:14][CH2:9][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:14][C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc(CCl)cc1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc(COC(C)=O)cc1
Yield: 63 %

Procedure:
438 gms (2.5 moles) of p-xylylene dichloride were added slowly to a refluxing solution of 539 gms (5.5 moles) of anhydrous potassium acetate in 2000 mls of glacial acetic acid. The resultant mixture was refluxed for a further 2 hours and then cooled. The solution was extracted several times with hot benzene, and the benzene extracts were washed with water until neutral. After distilling off the benzene, the residue was recrystallised from petroleum ether to yield 350 gms of p-xylylene diacetate.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH3:31])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:30])([CH3:29])[C:25]([F:27])([F:28])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH3:31])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reaction time: 18 h
Yield: 22.7 %

Procedure:
In a 50-mL round bottomed flask, a mixture of 2-(2-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (108 mg, 0.224 mmol), ammonium formate (30.1 mg, 0.478 mmol, Sigma-Aldrich, St. Louis, Mo.), and 10% Pd/C (25.4 mg, 0.024 mmol) in EtOH (10 mL) was stirred under an atmosphere of H2 (1 atm) for 18 h. Afterwards, the mixture was filtered through a plug of Celite and the filtrate was concentrated to give the crude product. The crude product was dissolved in CH2Cl2 and filtered through a plug of silica gel. The filtrate was concentrated to give 2-(2-((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (23 mg) as a mixture of two isomers.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[CH3:16][S:17]([O:12][CH2:11][CH:10]([O:9][C:8]1[CH:14]=[CH:15][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:13])(=[O:19])=[O:18]
Reactant: CC(CO)Oc1ccc(C(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(C(C)(C)C)cc1

Procedure:
As in Example 56, 5.1 g of 2-(p-tert-butylphenoxy)-1-propanol is reacted with 2.3 ml of methanesulfonyl chloride in 150 ml of dichloromethane in the presence of 8 ml of triethylamine. The product (7.4 g) is obtained as an amber-colored liquid.
Reaction SMILES: [N:1]1C=C2C(N=CN2)=NC=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[N:17]=[C:18]([CH2:29][N:30]3[C:34]4[N:35]=[CH:36][N:37]=[C:38]([NH2:39])[C:33]=4[N:32]=C3)[N:19]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:21])[C:12]=12>>[NH2:39][C:38]1[C:33]2[N:32]=[N:1][N:30]([CH2:29][C:18]3[N:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH3:28])[C:20](=[O:21])[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][C:11]=4[CH3:10])[N:17]=3)[C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(C)c2c1=O
Reactant: c1ncc2[nH]cnc2n1
Product: Cc1ccccc1-n1c(Cn2nnc3c(N)ncnc32)nc2cccc(C)c2c1=O

Procedure:
1H NMR (300 MHz, d6-DMSO) δ: 8.43 (br s, 1H), 8.19 (s, 1H), 8.10 (br s, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.49-7.28 (m, 5H), 7.22 (d, J=8.1 Hz, 1H), 5.49 (d, J=17.0 Hz, 1H), 5.19 (d, J=17.0 Hz, 1H), 2.73 (s, 3H), 2.11 (s, 3H). Alkylation at purine N7 determined by similarity to nmr spectrum of D-030. LRMS (ES pos.) m/z=399 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccccc1Br
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccccc1Oc1ncccn1
Temperature: 120 °C

Procedure:
To a 48 mL pressure tube containing a stirbar were added 2-chloropyrimidine (1.69 g, 14.7 mmol), 2-bromophenol (1.63 mL, 14.0 mmol), Cs2CO3 (5.49 g, 16.8 mmol) and DMSO (30 mL). The vial was sealed and heated at 120° Celsius for 15 hours. The reaction was then diluted with 100 mL of ethyl acetate and extracted with brine (2×50 mL). The organic layer was isolated, dried and concentrated to dryness to provide the crude product which was subsequently purified FCC to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.56 (s, 1H), 7.72-7.60 (dd, J=8.0, 1.6, 1H), 7.45-7.34 (m, 1H), 7.32-7.23 (m, 1H), 7.23-7.11 (m, 1H), 7.10-7.01 (t, J=4.8, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[S:5][C:4]=1[CH:16]=O)[CH3:2].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)(=[O:20])[CH3:19]>>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:11][C:6]=2[S:5][C:4]=1[CH:16]=[CH:19][C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=[O:20])[CH3:2]
Reactant: CCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Product: CCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from 3-ethyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde [WO 2005077926] (185 mg, 0.716 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (156 mg, 0.715 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (186 mg, yield 57%).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4].P(Br)(Br)[Br:16]>>[Br:16][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC(C)(O)CCC=C(C)CCCC
Reactant: BrP(Br)Br
Product: CCCCC(C)=CCCC(C)=CCBr

Procedure:
By the procedure described in Example 13, from 6-methyl-5-decen-2-one and vinyl-magnesium bromide there is obtained 3,7-dimethyl-1,6-undecadien-3-ol; nD26 = 1.4618, boiling point 116° C./9 mm Hg. This alcohol is reacted with phosphorus tribromide by the procedure of Example 13 to give 1-bromo-3,7-dimethyl-2,6-undecadiene.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4](C(=O)C)[CH2:3]1.Cl>CCO>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: 70 °C

Procedure:
1-(3,3-Dimethyl-6-nitro-2,3-dihydro-indol-1-yl)ethanone (1.8 g, Step C) was dissolved in EtOH (50 mL), 12N HCl (50 mL) was added and the resulting mixture was heated at 70° C. overnight. After the mixture was concentrated in vacuo, it was partitioned between saturated NaHCO3 solution and EtOAc, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. MS: 193 (M+1). Calc'd. for C10H12N2O2—192.21.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18]Cl)[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].O>C1COCC1>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:18][C:17]([CH3:21])([CH3:20])[C:16]3=[O:22])[C:11]2=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(CCl)C(=O)NC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(C2CCN(c3cccc(OC(F)(F)F)c3)C2=O)C1=O
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
A stirred solution of 1-(3-trifluoromethoxyphenyl)-3-(3-chloro-2,2-dimethylpropanoyl)amino-2-pyrrolidinone (0.31 g) in THF (5 ml) was treated with a 60% dispersion of sodium hydroxide in oil (0.036 g). Once the effervescence had ceased, the yellow mixture was stirred for 5 min then poured into water. The mixture was extracted with dichloromethane (x2), the combined extracts were washed with brine and dried (MgSO4). Evaporation of the solvent under reduced pressure left an oil, which was purified by chromatography on silica-gel, eluting with ethyl acetate/hexane mixtures, to give the title compound as a pale tan crystalline solid (0.20 g).
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+].Cl>CO.CCOCC>[CH2:3]([O:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]34[CH2:8][CH2:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])([CH2:11][CH2:10]3)[CH2:13][CH2:12]4)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)/[CH:2]=[CH:1]/[CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC12CCC(c3ccc(C4CCC(=O)CC4)cc3)(CC1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCC/C=C/CO[C@H]1CC[C@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(4-pentylbicyclo[2.2.2]octyl)penyl]cyclohexanone (1.5 g, 4.3 mmol) and a mixture of 9:1 methanol/ether (25 cm3) is added dropwise to a freshly prepared mixture of sodium borohydride (1.2 g, 8.5 mmol) and a mixture of 9:1 methanol/ether (25 cm3) at 0° C. When the addition is complete, the reaction mixture is stirred overnight at room temperature. A 25 per cent hydrochloric acid solution is added carefully to the reaction mixture, which was extracted into ethyl acetate (3×50 cm3). The combined organic extracts are washed with water (2×500 ml) and dilute sodium carbonate solution (2×500 ml), dried (MgSO4), filtered and then evaporated down. The residue is purified by column chromatography on silica gel using a 7:3 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield the pure 1-[4-(trans-4-hydroxycyclohexyl)phenyl]-4-pentylbicyclo[2.2.2]octane (1.2 g, 80 per cent).