Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].C(OCC1C=CC(C(O)=O)=CC=1)CC=C.[CH:29]([OH:32])([CH3:31])[CH3:30]>>[CH:29]([O:32][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([CH3:31])[CH3:30]
Reactant: CC(C)O
Reactant: O=C(O)c1cccc(CCl)c1
Agent: C=CCCOCc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OCc1cccc(C(=O)O)c1

Procedure:
The reaction of isopropanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-isopropoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.49 (s, OCH2C6H4—); 3.653 (m, CH(CH3)2); 1.14 (d, CH(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 139.79; 131.56; 130.68; 128.43; 128.08; 127.92; 70.54; 68.50; 22.02 (2 C).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:3]1[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cc(Cl)cnc1N
Temperature: 150 °C
Yield: 44.9 %

Procedure:
A mixture of 3-bromo-5-chloro-2-pyridinamine (C. W. Murtiashaw, R. Breitenbach, S. W. Goldstein, S. L. Pezzullo, J. Quallich, R. Sarges, J. Org. Chem., 1992, 57, 1930) (8.56 g, 41.4 mmol), t-butyl acrylate (12 ml, 82 mmol), tri-o-tolylphosphine (2.92 g, 9.6 mmol) and palladium acetate (540 mg, 2.4 mmol) in triethylamine (130 ml) was heated in a sealed bomb to 150° C. for 10 hours. The reaction mixture was filtered, the residue washed with EtOAc and the combined filtrates evaporated to a dark brown oil. Purification by column chromatography upon silica gel using hexane-EtOAc (7:3) as eluant and subsequent crystallisation from hexane at −78° C. gave the title compound as a bright yellow solid (4.75 g, 18.6 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1.[C:13]([O-:16])(=[O:15])[CH3:14].[Na+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:16][CH2:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([Cl:12])[C:6]=2[S:5][CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: Clc1ncnc2c(CBr)csc12
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1csc2c(Cl)ncnc12
Temperature: 35 °C
Reaction time: 4 h

Procedure:
7-(Bromomethyl)-4-chlorothieno[3,2-d]pyrimidine (9.17 g, 33.0 mmol) was dissolved in DMF (54 mL) and then sodium acetate (27 g, 330 mmol) and potassium iodide (10.96 g, 66.0 mmol) were added thereto. The reaction mixture was stirred at 35° C. for 4 hours, diluted with ethyl acetate and washed with sat. sodium thiosulfate solution 5 times. The reaction mixture was dried with MgSO4, filtered, concentrated and purified by silica gel chromatography to obtain to obtain the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](OC)=[O:14])[C@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)C>[CH2:20]([N:10]1[C@@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C1OC[C@@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =+27.7° at c=1.0 in DMF, 368 mg) in toluene (2 ml) and isopropanol (3 ml) was added dropwise to a suspension of sodium borohydride (100 mg) in toluene at 5°-10° C. The obtained mixture was allowed to warm up to room temperature and to react at the same temperature for 18 hours. Then, 1N hydrochloric acid (10 ml) was added dropwise to the mixture. The mixture was stirred at 55°-60° C. for 30 minutes. Aqueous layer was separated from organic layer and extracted once with toluene (15 ml). The organic layers were combined, washed successively with water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated to give (3aR,6aS)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (301 mg). M.P., 116°-118° C. [α]D25 =-61.8° (c=1, CHCl 3).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH2:9]>>[CH3:8][NH:9][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: CN
Product: CNC1CCCCC1O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Cyclohexene oxide (147 g, 1.5 mol) was dissolved in a ethanolic 8 M methylamine solution (750 ml) and stirred at 40° C. for 16 h. The reaction mixture was concentrated in vacuo to give racemic 2-methylaminocyclohexanol as a slightly brown oil (195 g, 100%). According to GC-analysis this product was 99+% pure and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][OH:33])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.2 g) was dissolved in 25 ml of ethyl acetate, to which 0.29 ml of methanesulfonyl chloride and 0.53 ml of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (15 ml×2) and 15 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1). The desired fraction was concentrated and the residue was recrystallized from a mixture of 5 ml of diisopropyl ether and 10 ml of hexane to give 1.26 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1nocc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nocc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
A dry flask was charged with 3-Methyl-isoxazole-4-carboxylic acid (0.500 g, 3.9339 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (39 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.992 g, 3.932 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF (5 mL) and collected to afford the 3-Methyl-isoxazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.938 g, 2.60 mmol, 66%).
Reaction SMILES: O[C:2](=[O:23])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.O[N:25]1[C:29]2C=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.Cl.CN(C)CCCN=C=NCC.N1CCCCC1>C(Cl)Cl>[N:25]1([C:2](=[O:23])[CH2:3][CH2:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)[N:8]=[C:7]([C:21]#[N:22])[N:6]=2)[CH2:31][CH2:32][CH2:33][CH2:28][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: N#Cc1nc(CCC(=O)O)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N#Cc1nc(CCC(=O)N2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-hydroxy-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (64 mg) in DCM (6 mL) was added 1-hydroxybenzotriazole (30 mg) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (38 mg). The solution was stirred at room temperature for 15 min and piperidine (22 mg) added. After standing for 18 h, the reaction mixture was washed with HCl (1M, 2×5 ml), H2O then brine and dried with sodium sulfate. After removal of solvent, crystallisation from a trace of acetone/ether gave 4-(3-piperidin-1-yl-3-oxopropyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid, 35 mg.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][CH3:14])#[N:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34]>ClCCl>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[OH:34])=[O:10])=[CH:6][C:5]=1[O:13][CH3:14])#[N:2]
Reactant: COc1cc(C(=O)O)ccc1CC#N
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCCC[C@H]2O)ccc1CC#N
Reaction time: 2 h

Procedure:
The 4-(cyanomethyl)-3-methoxybenzoic acid (0.33 g, 1.7 mmol) was suspended in anhydrous dichloromethane (5 mL) and treated with oxalyl chloride (0.3 mL, 3.5 mmol) followed by few drops of DMF at 22° C. under argon. After 2 h stirring, the resulting solution was concentrated to dryness, dissolved in dichloromethane (5 mL), and added slowly to a solution of trans-2-aminocyclohexanol hydrochloride (0.26 g, 1.7 mmol) and TEA (0.5 mL, 3.5 mmol) in anhydrous dichloromethane (10 mL). After 20 min stirring, filtered off salt, and concentrated to afford 4-(cyanomethyl)-N-[(2R)-2-hydroxycyclohexyl]-3-methoxybenzamide as a yellow solid. MS (ESI) 289 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3]CCCC1CCCC1=O.OCCCCCC1CCCC1=O.[C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])(=[O:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)C)(=O)C>>[C:2]([O:39][C:35]1[CH2:36][CH2:37][CH2:38][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])(=[O:1])[CH3:3]
Reactant: O=C1CCCC1CCCCCO
Reactant: CC(=O)OCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1

Procedure:
A solution of 400 g. (2.04 moles, of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 1 l. of acetic anhydride is refluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO4), and evaporated to yield 452 g. of an oil.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19](=[S:20])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: S=C=NC1CCCCC1
Reactant: Nc1ccc(NNC=O)cc1
Product: O=CNNc1ccc(NC(=S)NC2CCCCC2)cc1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-aminophenyl)hydrazine (7.5 g, 0.05 mole) and cyclohexyl isothiocyanate (7.1 g, 0.05 mole). Yield 9.6 g (66%), m.p. 158°-160° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[F:24][C:13]([F:12])([F:23])[C:14]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:8][O:15]1
Reactant: C[S+](C)C
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1ccc(C2(C(F)(F)F)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(O)CCCCCO.C(OC=C)(=O)C.[CH:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]C=C)=[CH2:22]>C1(C)C=CC=CC=1>[CH:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH2:22]
Reactant: C=COCCCCCCOC=C
Agent: O=C([O-])[O-]
Agent: OCCCCCCO
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COCCCCCCO
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and sodium carbonate (64 mg, 0.6 mmol) in toluene (1.0 ml), 1,6-hexanediol (118 mg, 1 mmol) and vinyl acetate (344 mg, 4 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1,6-bis(vinyloxy)hexane and 6-vinyloxy-1-hexanol were produced in yields of 87% and 2%, respectively, with a conversion from 1,6-hexanediol of 97%.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([OH:19])=O)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[S:40]1[C:44]2([CH2:48][CH:47]([C:49]([OH:51])=[O:50])[NH:46][CH2:45]2)[S:43][CH2:42][CH2:41]1>C(#N)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:46]1[C@H:47]([C:49]([OH:51])=[O:50])[CH2:48][C:44]2([S:40][CH2:41][CH2:42][S:43]2)[CH2:45]1)=[O:19])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: O=C(O)C1CC2(CN1)SCCS2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A mixture of 2.0 g of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid and 1.1 g of carbonyldiimidazole in acetonitrile is stirred under argon at 0° C. for 1 hour and then treated with 1.9 g of triethylamine and 1.7 g of 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, hydrochloride. After 4.5 hours the acetonitrile is stripped and the residue is partitioned between ethyl acetate and 1 N HCl. The organic phase is washed with brine, dried (MgSO4), and the solvent is stripped to give 3.2 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(N(CC)CC)C>>[C:11]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C(Cl)C1=CCCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)O)cc1)C1=CCCCC1

Procedure:
88.0%. B. 4-(1-cyclohexene-1-carbonylamino)-benzoic acid was prepared as described in Example 1 from 16.6 g (0.121 mol) of p-aminobenzoic acid with 22.0 g (0.152 mol) of 1-cyclohexene-1-carboxylic acid chloride and 21.3 ml (0.152 mol) of triethylamine. Recrystallization from THF/n-pentane.
Reaction SMILES: C[N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29].N1CCCCC1>C(O)C>[CH3:16][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:24]1[NH:25][CH:26]=[C:20]2[C:21]=1[CH2:22][CH2:23][NH:18][C:19]2=[O:29])(=[O:4])=[O:5]
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [NH:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([N:25]([CH3:27])[CH3:26])=[CH:7][CH:8]=2)[O:3]1.N[C:29]1OC2C(C(C3C=C(OC)C(OC)=C(Br)C=3)C=1C#N)=CC=CC=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)([CH3:29])[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(N(C)C)ccc23)cc(Br)c1OC
Reactant: COc1cc(C2C(C#N)=C(N)Oc3ccccc32)cc(Br)c1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C2(C)C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reaction time: 0.25 h
Yield: 79 %

Procedure:
2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-chromene: 4 Å Molecular sieves (20 mg) was added to 2-amino-3-cyano-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene (20 mg, 0.05 mmol) in dichloromethane (1 mL). The solution was stirred for 15 min. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (10 mg, 0.05 mmol, 1 eq.) was added and stirred continuously at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with sodium bicarbonate saturated solution (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to yield 17 mg (79%) of the desired compound. 1H NMR (DMSO-d6): 8.33 (s, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 6.87 (d, J=9.1 Hz, 1H), 6.56 (dd, J=2.5, 9.1 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.03 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([Li])CCC>>[F:1][C:2]1[C:3]([F:8])=[C:4]([Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]=[CH:6][C:7]=1[Si:10]([CH3:12])([CH3:11])[CH3:9]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F

Procedure:
4-Alkoxy-2-fluoro-3-phenoxyphenylacetic acid compounds were prepared from o-difluorobenzene (SCHEME 5). A mixture ortho-difluorobenzene (23a) and trimethylsilylchloride was treated with butyl lithium to produce 2,3-difluoro-1,4-bis-trimethylsilanyl-benzene (23b) which was brominated to afford 23c. Selective monometallation of 23c with iso-propylmagnesium chloride-lithium chloride complex and quenching the organomagnesium compound with DMF afforded 23d. Reaction of 23d with a phenol in the presence of K2CO3 resulted in displacement of the fluorine atom adjacent to the aldehyde to afford 24a. The aldehyde was subjected to a Baeyer-Villiger oxidation with trifluoroperacetic acid which underwent concomitant hydrolysis to the phenol 24b which was alkylated with Cs2CO3 and methyl iodide to afford the methoxy substituted analog 24c. Metallation of the remaining bromine substituent with iso-PrMgCl/LiI/THF and allylation of the resulting Grignard reagent afforded 25a which was oxidatively cleaved with NaIO4/Ru(III)Cl3 to produce the phenylacetic acid 25b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Cl:20])=[C:22]([N+:30]([O-:32])=[O:31])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
2-(4-chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 mL) followed by the addition of DIEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) dropwise in 10 mL of DCM. After stirring for 30 minutes, the reaction was loaded onto silica gel and eluted with hexanes/ethyl acetate (2/1) to yield N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (4.0 g, 86% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:1][C:2]1([CH2:15][NH:16][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:31])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(CNC(=O)C2CCCCC2)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(2.6 g, described in Example 3), triethylamine (1.34 g), cyclohexylcarbonyl chloride (1.94 g) and dry tetrahydrofuran (60 ml) is stirred at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (3.8 g); mp 174°-175° C.; nmr (CDCl3) δ0.85-2.25(m), 1.55(s), 2.81(m), 3.79(m), 4.00(m), 5.96(t), 6.9-7.2(m) and 9.71(s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]=1[O:14][CH3:15].[C:17]([Mg]Cl)#[CH:18]>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:13])[C:17]#[CH:18])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COC(=O)COc1ccc(C=O)cc1OC
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCC(=O)OC)c(OC)c1

Procedure:
[4-(1-Hydroxy-2-propynyl)-2-methoxy-phenoxy]-acetic acid methyl ester was prepared according to Method A above (except the Grignard reagent was added at −78° C.) from (4-formyl-2-methoxy-phenoxy)-acetic acid methyl ester (0.645 g, 2.9 mmol) (from Example 45) in THF (30 mL) and ethynylmagnesium chloride (3.45 mmol, 7 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 525 mg, 72%).