Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)([OH:25])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:18]1([O:17][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]([OH:25])=[O:14])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A rapidly stirred solution of 4-benzyloxy-3-cyclopentyloxybenzaldehyde (10.5 g; that is prepared as described in Reference Example 37) in glacial acetic acid (100 mL) is treated with sulfamic acid (4.85 g) and stirred at room temperature for 10 minutes. The solution is then cooled in an ice bath and treated with a solution of sodium chlorite (4.2 g) in water (100 mL) during 15 minutes at 13°-15° C. During the addition a white precipitate forms and, because stirring becomes difficult, a further quantity of glacial acetic acid (60 mL) is added. After warming to room temperature, the solution is stirred for a further 6 hours and further quantities of sodium chlorite (1.6 g) and sulfamic acid (1.7 g) are added. The mixture is poured onto water and the resulting solid is filtered off and dried, to give 3-cyclopentyloxy-4-benzyloxybenzoic acid (10 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid[1-(6-bromo-pyridin-3-yl)-eth-(E)-ylidene]-amide (1.0 g, 3.30 mmol) in THF (25 mL) was dropwised added lithium tri-sec-butylborohydride solution in THF (L-Selectride, 3.30 mL, 3.30 mmol). The mixture darkened in color upon addition of this reagent. After 3 hours, the mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×30 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified via normal phase flash chromatography on silica gel eluting with ethyl acetate-dichloromethane (0-100%) to afford 2-methyl-propane-2-sulfinic acid[(R)-1-(6-bromo-pyridin-3-yl)-ethyl]-amide (700 mg, 70%) as a slightly yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[C:19](=O)([O-])[O-:20].[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20]
Reactant: Cc1ccc(-n2cccc2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cccc2C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To ice-cooled DMF (4.0 g) was added phosphorous oxychloride (8.4 g) dropwise and the mixture was stirred at room temperature for 15 minutes. To the stirred reaction mixture was added a solution of 1-(2-chloro-4-methylphenyl)pyrrole (9.7 g) in DMF (8 ml) dropwise and the mixture was stirred at 50° C. for 1.5 hours followed by addition of ice-water. Stirring was continued for a while and then the mixture was made basic with potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-hexane afforded yellow prisms (7.1 g, 59%), m.p. 111°-112° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])([O-:10])=[O:9]
Reactant: N#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 135 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (2.00 g, 14.2 mmol), 3-aminobenzonitrile (3.35 g, 28.3 mmol) and potassium carbonate (5.88 g, 42.5 mmol) in DMF (30 mL) was stirred at 135° C. for 16 h under a nitrogen atmosphere. After cooling to RT, the reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 25-100% DCM in cyclohexane) then loaded onto an SCX-2 cartridge and washed with DCM to afford 3-(2-nitrophenylamino)benzonitrile as a bright orange foam (2.02 g, 60%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:12](=[O:35])[NH:13][CH2:14][CH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[N:20]=1)[CH2:10][OH:11])(C)(C)C>O1CCOCC1>[NH2:8][C@@H:9]([CH2:10][OH:11])[C:12]([NH:13][CH2:14][CH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[N:20]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NCCc1nc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cs1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(CCNC(=O)[C@@H](N)CO)n3)ccc21

Procedure:
The protecting group is cleaved off as already described using HCl in dioxane starting from 82 mg (0.16 mmol) of ((S)-2-hydroxy-1-{2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]ethylcarbamoyl}ethyl)carbamic acid tert-butyl ester from step c. The product is purified by means of preparative HPLC and is in the form of the formate.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a mixture of ethyl 3-[{(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (335 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (281 mg, 89%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[I:16]I>CO>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]=1[I:16]
Reactant: Nc1ccc(CCO)cc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Nc1ccc(CCO)cc1I
Yield: 36.8 %

Procedure:
To a mixture of 4-aminophenethyl alcohol (20 g, 145.8 mmol) and calcium carbonate (18.2 g, 145.8 mmol) in methanol (200 mL) was added iodine (37 g, 182.3 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 14.1 g (37%) of desired product as a light brown syrup. MS(APCI+): m/z 264.1 (MH+). The compound was taken to Step B without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>C(O)C>[CH2:2]([O:3][C:4]([CH:6]1[CH2:12][C:11]2[C:19]3[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=3)[NH:21][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 97.6 %

Procedure:
4-Cyclohexanonecarboxylic acid ethyl ester (77 g, 450 mmol) and 4-fluorophenylhydrazine hydrochloride (72 g, 443 mmol) were refluxed in 1.25 L of anhydrous ethanol overnight. The resulting yellow solution was cooled, crystals filtered, the filtrate evaporated, the residue partitioned between ethyl acetate and water, organic layer dried over sodium sulfate, evaporated, crystallized from ethyl acetate/heptane to give 113 g (98%) of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:21])[CH:12]=[C:13]([SH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C(N(CC)CC)C.O.II>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:21])[CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:20]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(C=C(S)c1ccccc1)Nc1ccc(C(=O)O)cc1
Agent: II
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1ccc(-n2sc(-c3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.6 %

Procedure:
Compound of Formula (I) in which R1, R2, R4 and R5 =H, Ar1 =Ar2 =phenyl and R3 =4-CO2H A mixture of 1.449 g (0.005 mole) N-(4-carboxyphenyl)-3-mercapto-3-phenylpropenamide (A. Yokoyama, K. Ashida and H. Tanaka, Chem. Pharm. Bull. 12 (6), 690-5 (1964)), 3 mL (excess) triethylamine, 100 mL water and 100 mL ethanol was stirred at room temperature. Added, portionwise, was 1.269 g (0.005 mole) iodine and the mixture stirred at room temperature for 3 hrs. The solution was filtered and the filtrate was acidified to pH 1 with concentrated hydrochloric acid. The resulting solid was filtered and recrystallized twice from ethanol/water to provide 0.350 g (1.180 mmol, 23%) N-(4-carboxyphenyl)-5-phenyl-4-isothiazolin-3-one as a white powder, mp=238°-240° C. NMR (CDCl3 /TMS): 6.6 (S, 1H), 7.5-7.6 (m, 5H), 7.9 (d, 2H), 8.2 (d, 2H). IR (Nujol): 3481, 1698, 1619. High resolution mass spectrum: Calculated; 298.053790. Measured; 298.053472. Anal. calcd. for C16H11NO3S: C 64.65, H 3.70, N 4.71, S 10.77; Found C 64.52, H 3.64, N 4.59, S 10.75.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[C:9]#[CH:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][Mg]Cl>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:11])([C:9]#[CH:10])[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: C#CC(=O)c1cccc(Br)n1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cccc(Br)n1
Temperature: -78 °C

Procedure:
1-(6-Bromopyridin-2-yl)prop-2-yn-1-one (840 mg, 4.00 mmol) was dissolved in THF (20 mL) and cooled to −78° C. Methylmagnesium chloride (3.0 M in THF, 1.60 mL, 4.80 mmol) was added dropwise. The mixture was allowed to warm to room temperature, quenched with saturated NH4Cl, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-50% EtOAc/hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.459 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 6 ml of N,N-dimethylformamide; 0.048 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 30 minutes. 0.294 ml of ethyl 2-bromoisobutyrate was added, followed by stirring in an oil bath (bath temperature 110° C.) for 4 hours. After cooling, 0.048 g of 60% oily sodium hydride and 0.294 ml of ethyl 2-bromoisobutyrate were added, followed.by stirring in an oil bath (bath temperature 110° C.) for 10 hours. After cooling, ice water was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated to yield 0.401 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 5 ml of ethyl acetate; 0.5 ml of a 4 N solution of hydrogen chloride in ethyl acetate was added, followed by concentration; the residue was powdered from diethyl ether; the powder was collected by filtration and dried to yield 0.300 g of the title compound.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]1([C:17](=[N:24][CH2:25][CH:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:37]I>C1COCC1>[C:11]1([C:17](=[N:24][CH2:25][C:26]([CH3:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([O:29][CH3:30])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of LiHMDS in THF cooled to −78° C. was added a solution of methyl 3-(diphenylmethyleneamino)-2-phenylpropanoate (E320) in THF also cooled to approximately −78° C. This solution stirred for 30 min at −78° C., then methyl iodide was added directly and the solution was warmed to 0° C. After 3 h the solution was poured into NH4Cl(sat) and extracted with EtOAc. The combined organics were dried (Na2SO4) filtered, and evaporated. Column chromatography (SiO2, 0-15% EtOAc/Hexanes) gave pure methyl 3-(diphenylmethyleneamino)-2-methyl-2-phenylpropanoate (E321).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(OC2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(OC2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-2-cyclopentyloxy-4-phenyl-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. Off white solid (28.5 mg, 77%). LC-MS: 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][O:7][CH3:8].[CH:10](OCC)=[O:11]>>[CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:10]=[O:11])[CH2:5][CH2:6][O:7][CH3:8]
Reactant: COCCCC(=O)OC
Reactant: CCOC=O
Product: COCCC(C=O)C(=O)OC

Procedure:
The title compound was prepared from 4-methoxy-butyric acid methyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.
Reaction SMILES: C1(P(=[CH:20][C:21]#[N:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:23]1[CH:24]=[CH:25][C:26]([CH:31]=O)=[C:27]([CH:29]=[O:30])[CH:28]=1>ClCCl>[CH:29]([C:27]1[CH:28]=[CH:23][CH:24]=[CH:25][C:26]=1[CH:31]=[CH:20][C:21]#[N:22])=[O:30]
Reactant: O=Cc1ccccc1C=O
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#CC=Cc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of triphenylphosphoranylidene acetonitrile (13 g) in dry dichloromethane (20 ml) was added to a solution of ortho phthalaldehyde (5.4 g) in dry dichloromethane (20 ml), at 0°. The solution was stirred at room temperature for 1 h, then the solvent evaporated and the oil taken up with diethyl ether. The solid was filtered, washed with ether and the solution evaporated to dryness to give a yellow oil, which was eluted on a silica gel column (gradient petrol ether/diethyl ether, 1:1) to give the (E)-isomer of the title compound (0.9 g) and the (Z)-isomer of the title compound (2 g) (eluted first) as white solids which were recrystallized from petrol ether/diethyl ether (9:1).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:19]([CH2:18][NH:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)#[N:20]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: N#CCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 2.11 g (10 mmol) 3,3-diphenylpropylamine (Aldrich), (0.54 g, 4.54 mmol) bromoacetonitrile (Aldrich), and 2.5 g potassium carbonate in 5 ml acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed with water, the solvent evaporated, and the residue chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 1.24 g (yield 50%) N-cyanomethyl-3,3-diphenylpropylamine as an oil which solidified on standing. 1H NMR (CDCl3, 300 MHz) 7.45-7.10 (m, 10 H), 4.05 (t, 1 H), 3.50 (s, 2 H), 2.67 (t, 2 H), 2.23 (dt, 2H); 13C NMR (CDCl3, 75 MHz) 144.25, 128.53, 127.68, 126.33, 117.72, 48.58, 47.13, 37.19, 35.14.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[F:9][C:10]1[CH:17]=[CH:16][C:15](O)=[CH:14][C:11]=1[CH2:12][OH:13]>>[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:11]=1[CH2:12][OH:13]
Reactant: OCCc1cccs1
Reactant: OCc1cc(O)ccc1F
Product: OCc1cc(OCCc2cccs2)ccc1F

Procedure:
2-Fluoro-5-[2-(2-thienyl)]ethoxybenzyl alcohol was prepared from 2-thiophene-ethanol (0.5 g) and 2-fluoro-5-hydroxybenzyl alcohol according to the procedure described in Example 152 to give the product as a clear oil (0.12 g); δH (400 MHz, CDCl3) 7.16 (1H, dd, J 5, 1.5 Hz), 6.98–6.92 (3H, m), 6.91 (1H, m), 6.78 (1H, dt, J 9, 3.5 Hz), 4.70 (2H, d, J 6 Hz), 4.15 (2H, t, J 6.5 Hz) and 3.28 (2H, dt, J 6.5, 1 Hz); HPLC (XTERRA, 50/80%, 220 nm) 97% (3.49 min).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][NH:14][CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 120a (1.14 g, 2.62 mmol), methylene chloride (10 mL) and trifluoroacetic acid (10 mL). The solution was stirred for 2 h at room temperature. After this time, the solution was concentrated under reduced pressure. The residue was partitioned between methylene chloride (100 mL) and 1 M aqueous dibasic potassium phosphate (30 mL). The aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The organic extracts were combined, washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to afford a 68% yield (600 mg) of 153a as an off-white solid: mp 170-171° C.; 1H NMR (300 MHz, DMSO-d6) d 9.30 (s, 1H), 7.62 (m, 2H), 7.31 (s, 1H), 6.97 (d, 1H, J=7.8 Hz), 4.10 (br s, 1H), 3.83 (s, 2H), 3.43 (s, 3H), 2.96 (t, 2H, J=5.7 Hz), 2.68 (t, 2H, J=5.7 Hz); MS (ESI+) m/z 334.0 (M+H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:8]=1>>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:9]1[N:8]=[C:7]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[C:11]([O:13][CH3:14])[N:10]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from methane sulfonamide (0.11 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.12 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]2[O:12][C:11](=[O:13])[C@@:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1([C@H:34]([N:36]=[C:37]=[O:38])[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:20]([C:7]1[C:8]([OH:12])=[C:9]([C@@:10]2([C:14]([F:16])([F:15])[F:17])[O:18][C:37](=[O:38])[N:36]([C@@H:34]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH3:35])[C:11]2=[O:13])[CH:19]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2c(c1)[C@](O)(C(F)(F)F)C(=O)O2
Reactant: C[C@@H](N=C=O)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@H](c1cccc2ccccc12)N1C(=O)O[C@@](c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)(C(F)(F)F)C1=O
Yield: 37.9 %

Procedure:
(R)-(+)-5,7-Di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (100 mg, 0.3 mmol), (R)-(−)-1-(1-naphthyl)ethyl isocyanate (58 uL, 0.33 mmol), and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) were heated at reflux in toluene (1 mL) for 1 h under nitrogen. The resulting solution was evaporated to dryness and the residue purified by chromatography on silica gel with a gradient of ethyl acetate in heptane from 0% to 100% in 20 min. and then with heptane/DCM 3:1. One obtained 60 mg (37%) of white crystals. Crystals suitable for X-ray analysis were obtained by slow evaporation of a solution in dichloromethane.