Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and methanesulphonyl chloride (0.125 mL, 1.6 mmol). The reaction mixture was stirred overnight at room temperature, and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water and dried (MgSO4). The dessicant was filtered off and the resulting solution was treated with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to dryness. Column chromatography of the crude product using DCM/MeOH 95:5 as eluent gave 2-(2,4-Dichloro-phenoxy)-N-(1-methanesulfonyl-piperidin-4-yl)-benzamide (86 mg, 72%) as a white solid. LC/MS (APCI) tr=4.56 min, m/z 445.32 (65), 443.31 (M++H, 100). HPLC tr=3.42 min (97.52%) 1H NMR (270 MHz, CDCl3) 1.56-1.69 (2H, m, CH2), 2.06 (2H, m, CH2), 2.75 (3H, s, CH3), 2.86 (2H, m, CH2), 3.68 (2H, m, CH2), 4.09 (1H, m, CH), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.88 (1H, d, J=8.9 Hz, ArH), 7.20-7.28 (2H, m, ArH), 7.38-7.42 (2H, m, ArH+NH), 7.51 (1H, d, J=2.5 Hz, ArH) and 8.15 (1H, dd, J=7.9, 2.0 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 31.47 (CH2), 34.83 (CH3), 44.96 (CH2), 46.28 (CH), 117.76, 120.77, 124.32, 124.83, 125.88, 128.59, 130.44, 130.88, 132.56, 133.04, 149.79, 153.56 (ArC), and 163.97 (C═O).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(O)(=O)C(O)=O.[C:12]1(C)[CH:17]=CC=[CH:14][CH:13]=1>>[CH:1](=[O:5])[C:2]1[C:3](=[CH:17][CH:12]=[CH:13][CH:14]=1)[OH:4]
Reactant: Cc1ccccc1
Reactant: OCCCO
Agent: O=C(O)C(=O)O
Product: O=Cc1ccccc1O

Procedure:
1,3-propanediol (228 g, 3.0 mol), and oxalic acid (4.5 g, 0.05 mol) were added to 400 mL toluene and heated to reflux for 8 hours in an apparatus equipped with a condenser and a Dean-Stark trap. After cooling, the solution was washed with NaHCO3 and distilled water, and the solution was dried over MgSO4. The product precipitated when the solvent was being evaporated. The solid was collected and dissolved in hot hexane. The solution was filtered through Celite® (a filter aid manufactured by Johns Manville Corp.), and the product was crystallized to give 108 g of an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: C=Cc1cc(Cl)c(Br)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(Cl)c(-c2ccccc2Cl)cc1N
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture of 5-bromo-4-chloro-2-vinylbenzenamine (600 mg, 2.6 mmol), 2-chlorophenylboronic acid (1.25 g, 12.9 mmol), Pd(PPh3)4 (300 mg, 0.2 6 mmol), Na2CO3 (1.4 g, 13.0 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (500 mg, 73.1% yield). ESI-MS m/z: 263.1[M+H]+.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[Cl:12][CH2:2][N:3]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4]1
Reactant: N#Cc1ccn(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccn(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The obtained 1-hydroxymethyl-3-cyano-1H-pyrole was dissolved to 3 ml of chloroform, and 2 ml of thionyl chloride was added, followed by stirring at room temperature for 1 hour. After the reaction mixture was cooled to 0° C., it was poured into ice-water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 290 mg of 1-chloromethyl-3-cyano-1H-pyrole.
Reaction SMILES: [OH-].[Li+].C([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:30]([CH2:31][CH2:32][C@:13]12[CH3:14])[C@:26]1([CH:27]([F:29])[F:28])[C:21]([CH2:22][C:23]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)(=O)C1C=CC=CC=1>O1CCCC1.CO>[CH2:35]1[CH2:34][O:33][C:23]2([CH2:24][CH2:25][C@@:26]3([CH:27]([F:29])[F:28])[C:21](=[CH:20][CH2:19][C@@H:18]4[C@@H:30]3[CH2:31][CH2:32][C@@:13]3([CH3:14])[C@H:15]4[CH2:16][CH2:17][C@@H:12]3[OH:11])[CH2:22]2)[O:36]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC5(CC[C@@]43C(F)F)OCCO5)[C@@H]1CC[C@@H]2OC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4CC5(CC[C@@]43C(F)F)OCCO5)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
A solution of this 3,3-ethylenedioxy ester (4.73 g) in 50 ml of tetrahydrofuran is chilled to 0° C., treated with 10 ml of 1N lithium hydroxide in methanol and allowed to warm to room temperature. The reaction is monitored by thin layer chromatography. When all of the ester has been hydrolyzed, the solution is concentrated and diluted with ether. The mixture is washed three times with water and once with brine, dried over magnesium sulfate, and concentrated. The residue is crystallized from ethyl acetate/hexane to yield 3,3-ethylenedioxy-19,19-difluoroandrost-5-en-17β-ol as white crystals.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:20][CH2:21][CH2:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH2:22][CH2:21][OH:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Reactant: OCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Yield: 80.4 %

Procedure:
Benzyl 4-(4-iodobutyl)phenyl ether (14.29 g), 2-(2-hydroxyethyl)imidazole (13.1 g) and potassium carbonate (5.39 g) were stirred in DMF (390 ml) at 60° C. for 16 hours. After cooling, the insoluble matter was filtered off; the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated brine. Under reduced pressure, the solvent was distilled off; the residue was purified by column chromatography (eluent:ethyl acetate:methanol=19:1 to 9:1). The eluate was recrystallized from ethyl acetate-methanol to give the titled compound (10.99 g) as colorless crystals.
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8]1([P:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([SH:16])=[S:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:1]1([S:16][P:14]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: BrC1CCCCC1
Product: S=P(SC1CCCCC1)(C1CCCCC1)C1CCCCC1

Procedure:
Cyclohexylbromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain cyclohexyldicyclohexylphosphinodithioate, m.p. 82°-85° C, which on testing lasted 1250 hours* longer than the control. The average number of hours required to reach failure was 3.5 times that of the control.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4][CH2:3]1.ClC(Cl)C.Cl.[F:17][C:18]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:19]=1[CH2:20][O:21][C:22]1[C:23]2[N:24]([C:28]([C:32](Cl)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1>C(N(CC)CC)C>[C:10]([C:2]1([NH:1][C:32]([C:28]2[N:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:20][C:19]4[C:18]([F:17])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])[C:23]3=[N:30][C:29]=2[CH3:31])=[O:33])[CH2:7][O:6][C:5]([CH3:8])([CH3:9])[O:4][CH2:3]1)#[N:11]
Reactant: CC1(C)OCC(N)(C#N)CO1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(C#N)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Under an argon gas flow, to a mixture of 10.4 g of 5-amino-2,2-dimethyl-1,3-dioxane-5-carbonitrile, 27.8 ml of triethylamine, and 280 ml of dichloroethane were added 27.2 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride and 12 ml of dichloroethane at room temperature, followed by stirring at 70° C. for 2 hours. After leaving to be cooled to room temperature, the insoluble materials were separated by filtration and washed with dichloroethane. The filtrate was washed with a 10% aqueous citric acid solution three times, and the aqueous layer was extracted with chloroform. The organic layer was combined, washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was azeotropic distilled with ethyl acetate twice. To the obtained residue was added THF, and the insoluble materials were separated by filtration and washed with THF. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 27.7 g of N-(5-cyano-2,2-dimethyl-1,3-dioxan-5-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([N:13]([CH2:29][CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH3:12].C1N2CCN(CC2)C1>C(#N)C>[CH2:29]([N:13]([CH2:11][CH3:12])[S:14]([C:17]1[C:18]([S:23]([NH:26][C:27]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:28])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH3:30]
Reactant: COc1cc(C)nc(N)n1
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Yield: 34.2 %

Procedure:
A mixture of 0.8 g of 2-amino-4-methoxy-6-methylpyrimidine, 2.8 g of the crude sulfonyl isocyanate from Example 4 and a few crystals of DABCO in 25 ml of acetonitrile was stirred at room temperature for 16 hours. A small amount of unreacted aminopyrimidine was filtered off and the filtrate concentrated in-vacuo to give a hard glass. Crystallization from methanol gave 0.9 g of N,N-diethyl-N'[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-1,2-benzenedisulfonamide as a white solid, m.p. 170°-2°.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][CH2:24][C:25]#[C:26][Mg]Br>>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[O:14])[C:26]#[C:25][CH2:24][O:23][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C=O)cn2c1C
Reactant: Br[Mg]C#CCOC1CCCCO1
Product: CCc1c(OC)nc2nc(C(=O)C#CCOC3CCCCO3)cn2c1C

Procedure:
6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-carboxaldehyde and 3-(tetrahydropyran-2-yloxy)-1-propynyl-magnesium bromide [J. Chem. Soc., 1950, 3646] were reacted by the method of Step A of Example 1 to obtain 1-(6-ethyl-7-methoxy-5-methylimidazol[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Yield: 80.9 %

Procedure:
Following the procedure for Intermediate 1 using 5-fluoro-2-methylbenzenesulfonyl chloride (10.0 g, 48 mmol), triethylamine (13.9 mL, 100 mmol) and morpholine (8.37 g, 96 mmol) gave the title compound as white solid (10.07 g, 81% yield). 1H NMR (300 MHz, CDCl3) δ: 7.58 (1H, dd, J=8.6, 2.7 Hz), 7.27 (1H, dd, J=8.4, 5.1 Hz), 7.15 (1H, td, J=8.1, 2.8 Hz), 3.72-3.68 (4H, m), 3.16-3.13 (4H, m), 2.57 (3H, s). LCMS (M+H) calcd for C11H15FNO3S: 260.07; found: 260.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl-:22].C(OC([N:30]1[CH:34]2[CH2:35][NH2+:36][CH2:37][CH:33]2[CH2:32][CH2:31]1)=O)(C)(C)C.Cl>>[Cl-:22].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:36]2[CH2:37][CH:33]3[CH:34]([NH2+:30][CH2:31][CH2:32]3)[CH2:35]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2C[NH2+]CC21
Agent: Cl
Agent: [Cl-]
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CC4CC[NH2+]C4C3)cccc2c1

Procedure:
0.088 g of 5-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydropyrrolo[3,4-b]pyrrol-1-ium chloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with 1-(tert-butoxycarbonyl)-octahydropyrrolo[2,3-c]pyrrol-5-ium chloride and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isoproanol.
Reaction SMILES: [C:1]([C:4]1[C:12](=[O:13])[N:11]2[C:7]([S:8][C:9]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=32)=[N:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CC(N(C)C)=O>[NH:35]1[C:34]([NH:33][C:1]([C:4]2[C:12](=[O:13])[N:11]3[C:7]([S:8][C:9]4[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]=43)=[N:6][CH:5]=2)=[O:3])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O

Procedure:
3-Carboxy-7-nitro-4-oxo-4H-pyrimido[2,1-b]benzothiazole (1.34 g.) and 827 mg. of 1,1'-carbonyldiimidazole are added to 60 ml. of dimethylacetamide, and the suspension heated on a steam bath for 15 min. To the resulting solution is added 434 mg. of 5-aminotetrazole and the heating continued for 20 min. The suspension is cooled and filtered. The desired product can be further purified by recrystallization from dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1=O
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 4-hydroxy-9-cis-retinoic acid (16 mg, 0.05 mmole) in CH2Cl2 (1.5 ml) was added Dess-Martin reagent [see Dess and Martin in J. Org. Chem. 48:4155 (1983)] (42 mg, 0.1 mmole) in one portion at 25° C. After stirring for 5 minutes, the mixture was diluted with 10 ml of ether and to this was added saturated aqueous NaHCO3 (5 ml) containing Na2 SO3 (55 mg). The mixture was stirred for 20 minutes to dissolve the solid and the layers separated. The ether layer was washed with H2O (2×5 ml), brine (5 ml) and dried (MgSO4). The solvent was recovered under reduced pressure and residue was subjected to flash column chromatography (silica, 60% ether in Hexane) to give 4-keto-9-cis-retinoic acid (14 mg. 90%), characterized as follows: TLC rf=0.6 (silica, 80% ether in hexane);1HNMR (400 mHz, CDCl3) δ7.05 (dd, J=16, 12 Hz, 1H, olefinic), 6.82 (d, J=16 Hz, 1 H, olefinic), 6.32 (d, J=16 Hz, 1H, olefinic), 6.30 (d, J=16 Hz, 1H, olefinic), 6.20 (d, J=12 Hz, 1H, olefinic), 5.80 (s, 1H, olefinic), 2.5 (t, J=7 Hz, 2H, CH2—CO), 2.31 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.9 (s, 3H, CH3), 1.89 (m, 2H, CH2), 1.20 (s, 6H, 2×CH3).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH2:22]>C(Cl)(Cl)Cl>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:22][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccc2ccccc2c1
Temperature: 180 °C
Reaction time: 8 h

Procedure:
3 g of 3-fluoro-4-nitrophenol and 8.2 g of 2-naphthylamine were mixed and stirred for 8 hours at 180° C. The raw mixture was taken up in chloroform and washed with 2N aqueous hydrochloric acid. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:19]([F:22])([F:21])[F:20])=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]2[C:15](O)=[O:16].CCN(CC)CC.Cl.[F:31][C:32]([F:51])([F:50])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)=[O:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:51][C:32]([F:50])([F:31])[C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH:44]2[CH2:49][CH2:48][N:47]([C:15]([C:7]3[C:6]4[C:10](=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][C:19]([F:22])([F:20])[F:21])[N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH:8]=3)=[O:16])[CH2:46][CH2:45]2)[CH:38]=1)=[O:34]
Reactant: O=C(NCc1ccc(F)c(C2CCNCC2)c1)C(F)(F)F
Reactant: COCCn1cc(C(=O)O)c2c(OC(F)(F)F)ccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)C(F)(F)F)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 8 (19.1 g, 59.6 mmol), Et3N (24.8 mL, 177.9 mmol), 2,2,2-trifluoro-N-(4-fluoro-3-piperidin-4-yl-benzyl)-acetamide hydrochloride (11, 26.4 g, 77.5 mmol) (14), and EDCI (17.1 g, 89.3 mmol) in CH2Cl2 is stirred at rt overnight. Both TLC and LC/MS indicate that the reaction is completed. The mixture is partitioned between H2O and CH2Cl2. The two layers are separated, and the organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (40/60 to 0/100) as eluant to give 9 (36 g, 99%) as a white foam. 1H NMR (CDCl3) δ 7.37 (s, 1H), 7.20-7.10 (m, 2H), 7.10-6.85 (m, 4H), 4.95 (br s, 1H), 4.60-4.35 (m, 4H), 3.90 (br s, 1 H), 3.73 (t, J=5.0 Hz, 2H), 3.32 (s, 3H), 3.25-2.70 (m, 3H), 2.05-1.50(m, 4H); 19F NMR (CDCl3) δ −57.54 (s, 3F), −75.39 (s, 3F), −119.31 (s, 1F), −134.96 (d, J=11.3 Hz, 1F); MS 608 (M+1, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[OH:43][CH2:42][C:41]([NH:40][S:37]([C:33]1[CH:32]=[C:31]([NH:30][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])[CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:38])([CH3:45])[CH3:44]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 646.4 [(M+H+]; mp 268° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([NH:15][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCCCO1
Reactant: CCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)CCCCO
Temperature: 110 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Delta valerolactone (40 g, 0.4 mole) was added dropwise with stirring to n heptylamine (50.6 g, 0.44 mole) so that the temperature of the mixture was maintained at 85° to 90° C. Heat was applied and the temperature raised to 110° C. over 20 minutes after which the temperature was maintained at 110° to 115° C. for a further 6 hours (after 3 hours N.M.R. indicated that the reaction was 90 to 95% complete). Toluene (200 ml, 173 g) was added and the solution cooled to 0° C. with stirring. After 1 hour at 0° C., the solid was collected and washed successively with ice cold toluene (50 ml, 43 g) and n-heptane (50 ml, 34 g). The material was dried at room temperature overnight to give the product. (81.6 g (95% yield) m.p. 53° to 54° C.).