Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@H:9]([C:17]([C:19]1([NH2:33])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][C:20]1([C:29]([O:31][CH3:32])=[O:30])[CH2:21]3)[CH2:25]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:17]([C:19]1([NH2:33])[CH:26]2[CH2:25][CH:24]3[CH2:23][CH:22]([CH2:21][C:20]1([C:29]([O:31][CH3:32])=[O:30])[CH2:28]3)[CH2:27]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C12CC3CC(CC(C3)C1(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C12CC3CC(CC(C3)C1(N)C(=O)[C@@H](N)Cc1ccccc1)C2

Procedure:
To a solution of 1.862 g of methyl Boc-L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A) in 10 ml of methylene chloride is added 5 ml of trifluoracetic acid. After 15 minutes at room temperature the reaction mixture is concentrated to a small volume and 5 ml of cold potassium carbonate is added. The mixture is extracted twice with 20 ml of chloroform. The combined chloroform extracts are dried over sodium sulfate to give methyl L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A) as a crystalline solid melting at 160°-167° C. Under a nitrogen atmosphere at -50° C. a dry (1 g of 4 A sieves) solution of 1.878 g of Boc-L-tyrosyl-D-methionyl-glycine and 0.444 ml of N-methylmorpholine in 25 ml of tetrahydrofuran is stirred while 0.52 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to -10° C. for 10 minutes then cooled to -40° C. and 1.24 g of methyl L-phenylalanyl- 2-amino-1-adamantanecarboxylate is added. The reaction mixture is stirred overnight at room temperature. Upon the addition of water a solid separates and is collected by filtration, washed and dried. The residue is dissolved in methanol, filtered through Filter Cel, concentrated and diluted with equal volumes of ethyl acetate and ether. The solid which precipitates is collected by filtration, washed with ether and dried to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-2-amino-1-adamantanecarboxylate (Isomer A). 2.34 Grams of this compound is dissolved in 10 ml of acetic acid and 20 ml of a 5 N solution of hydrogen chloride in dioxane is added. The reaction mixture is concentrated under a stream of nitrogen for 11/2 hours and diluted with 150 ml of ether. The solid which forms is collected, dissolved in methanol, concentrated to about 10 ml and diluted with 40 ml of water then allowed to stand overnight at room temperature. The solution is filtered and lyophilized to give methyl L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-2-amino-1-adamantanecarboxylate hydrochloride (Isomer A) which is represented by the following formula ##STR47##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.[N:27]([CH2:30][CH3:31])=[C:28]=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([NH:27][C:28]([N:18]1[CH2:17][C:16]2=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]2)[N:9]2[C@H:5]([CH2:6][CH2:7][CH2:8]2)[C:4]2[C:22](=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[O:21][CH2:20][CH2:19]1)=[O:29])[CH3:31]
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5.5 mg, 0.016 mmol) was added isocyanatoethane (1.5 mg, 0.022 mmol), followed by DIEA (1.9 μL, 0.011 mmol). After stirring at ambient temperature overnight the reaction was concentrated and purified by reverse-phase column chromatography, eluting with 0-80% acetonitrile/H2O to afford the title compound (3.3 mg, 50% yield). MS (apci) m/z=425.4 (M+H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=1[O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:14]=1)#[N:5]
Reactant: N#Cc1ccc(O)cc1C(F)(F)F
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-hydroxy-2-(trifluoromethyl)-benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]\[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[CH2:26][CH2:25][CH3:24])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccccc1CCCCBr
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCCC(c1ccccc1OC)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO3 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g, m.p.=132°-133° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:28]([Cl:30])=[O:29])[C@H:10]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]2[N:27]=[CH:26][O:25][N:24]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[O:25]1[CH:26]=[N:27][C:23]([C@H:13]2[NH:14][CH2:15][C@H:10]([N:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:28]([Cl:30])=[O:29])[CH2:11][CH2:12]2)=[N:24]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncon1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cl)N(OCc1ccccc1)[C@@H]1CC[C@@H](c2ncon2)NC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.5 %

Procedure:
A mixture of (2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.6 g), and 4 N HCl in dioxane (18 mL), was stirred at rt for 2 hrs. The solvent was then removed under vacuum to give (3R,6S)-6-(1,2,4-oxadiazol-3-yl)piperidin-3-yl(benzyloxy)carbamic chloride (1.4 g) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 301.0.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1nnc(C)s1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1nnc(C)s1
Yield: 100.6 %

Procedure:
Ethyl 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (anti isomer) (1.2 g.) and 1 N aqueous solution of sodium hydroxide (10.5 ml.) were treated according to a similar manner to that of Example 1(a) (5) to give 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (anti isomer) (1.06 g.), mp 173° to 174° C. (dec.).
Reaction SMILES: [CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16]C=O)[C@H:4]1[S:3]2.[OH-].[K+]>CO.O>[CH3:1][C:2]12[CH2:10][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[CH:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[OH:16])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]1S2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(O)c3ccccc3)[C@H]1S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.3 %

Procedure:
To a solution of 2-methyl-2,3-methylene-6-(2-phenyl-2-formyloxyacetamido)penam-3-carboxylic acid (1.1 g.) in methanol (10 ml.) and water (7 ml.) was added dropwise 1N-potassium hydroxide aqueous solution adjusting to pH 7 to 8, and the mixture was stirred for 10 minutes at room temperature. After the reaction was completed, methanol was distilled off from the reaction mixture under reduced pressure. The residual solution was acidified by adding 1N-hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off from the extract under reduced pressure and the residue was pulverized by n-hexane to give 2-methyl-2,3-methylene-6-(2-phenyl-2-hydroxyacetamido)penam-3-carboxylic acid (0.4 g.).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.CCCCCCC>[C:55]([N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:19][CH:20]=2)[CH2:50][CH2:51]1)(=[O:57])[CH3:56]
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 23.5 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Dichloromethane (225.0 mL) and 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25° C. Triphenylphosphine (72.2 g, 275 m mol) and 1-[4-(2-hydroxy-ethyl)piperazin-1-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25° C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30° C. over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30° C. to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25° C. and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25° C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:6]2[C:10]=1[O:9][CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:7]2.Cl[C:26]1[N:35]=[CH:34][C:33]2[N:32]([CH3:36])[C:31](=[O:37])[C@@H:30]([CH2:38][CH3:39])[N:29]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:28]=2[N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:40]1([N:29]2[C:28]3[N:27]=[C:26]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([C:15]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[O:16])=[C:6]5[C:10]=4[O:9][CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:7]5)[N:35]=[CH:34][C:33]=3[N:32]([CH3:36])[C:31](=[O:37])[C@H:30]2[CH2:38][CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CN(C)CC1Cc2c(C(=O)OCc3ccccc3)ccc(N)c2O1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OCc4ccccc4)c4c3OC(CN(C)C)C4)nc2N1C1CCCC1
Yield: 34.2 %

Procedure:
Benzyl 7-amino-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29g (212 mg, 0.65 mmol) was dissolved in 20 mL of 4-methyl-2-pentanol followed by the addition of (7R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7H-pteridin-6-one 1o (230 mg, 0.78 mmol) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol). The reaction solution was heated to reflux for 3 hours with stirring and concentrated under reduced pressure. The resulting residue was added with 30 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (50 ml×3). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-(dimethylaminomethyl)-2,3-dihydrobenzofuran-4-carboxylate 29h (0.13 g, yield: 34.2%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([O:30][C:28]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:26])[CH:6]=1)[CH3:25])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C)C(=O)OCc1ccccc1

Procedure:
{2′-[(Benzyloxycarbonyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-27) was prepared by following the procedures of Example 7 and using (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(OC)cc3)cc2OC1C(F)(F)F
Temperature: 105 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A 50 mL flask was charged with the substituted ethyl 2H-1-benzopyran-3-carboxylate from Step 2 (1.44 g, 4.43 mmol), 4-methoxyphenol (0.62 g, 4.99 mmol), K2CO3 (0.84 g, 6.07 mmol), and DMSO (10 mL). The reaction was stirred at 105° C. for 18 hours, poured into water extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated in vacuo, to give a brown oil which was passed through a column of silica gel with 5% ethyl acetate/hexanes to give a yellow solid (0.78 g, 41%): mp 115.8–117.0° C. 1H NMR (CDCl3/300 MHz) 7.66 (s, 1H), 7.32 (s, 1H), 7.04 (d, 2H, J=9.3 Hz), 6.98 (d, 2H, J=9.1 Hz), 6.38 (s, 1H), 5.65 (q, 1H, J=6.8 Hz), 4.33 (m, 2H), 3.86 (s, 3H), 1.37 (t, 3H, J=7.2 Hz). 19F NMR (CDCl3/282 MHz) −78.9 (d, J=6.5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=1)=C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:47])([F:48])[F:49])=[CH:41][CH:40]=3)=[O:35])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccc(OC(F)(F)F)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-(4-(trifluoromethoxy)phenyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (40 mg, 0.13 mmol) and 1-isocyanato-4-(trifluoromethoxy)benzene (27.2 mg, 0.13 mmol) according to General Procedure G to give 25 mg (37.2%) of white solid. Anal. Calcd. for C26H30F3N5O2 m/z 501.2, found: 502.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.7 (s, 1H), 7.49 (d, J=9 Hz, 2H), 7.40 (d, J=8.9 Hz, 2H), 7.23 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 6.13 (d, J=7.4 Hz, 1H), 3.87 (d, J=11.8 Hz, 1H), 3.76 (d, J=12.9 Hz, 1H), 3.28 (m, 1H), 2.79 (m, 1H), 2.60 (m, 2H), 2.44 (m, 2H), 1.91 (m, 1H), 1.65 (m, 3H), 1.48 (m, 1H), 1.24 (m, 6H), 1.11 (m, 1H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[Na+].Cl>O>[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)c1ccccc1
Yield: 91.4 %

Procedure:
In 5 ml of water is dissolved 350 mg of sodium 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionate, followed by the addition of 2-N hydrochloric acid. The oily substance separated out is extracted with ether. The extract is washed with water and the solvent is distilled off. The described procedure gives 300 mg of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionic acid, as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH2:22][CH3:23])[CH2:10]2)[CH:7]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C1(C)C=CC=CC=1>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C@@H:11]([CH2:22][CH3:23])[CH2:10]2)[CH:7]=1
Reactant: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product from example 69 part e) (2 g) in dichloromethane (100 ml) was added trifluoroacetic acid (100 ml). The mixture was stirred at RT for 24 h. Toluene (100 ml) was added and reaction was concentrated (bath temp <40° C.) in vacuo to give the sub-titled compound as a yellow oil (3.10 g).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][C:6](=[N:9][OH:10])[CH2:7][CH3:8])[CH3:3].CO.C[O-].[Na+].O1C[CH2:19][CH2:18][CH2:17]1.C(Br)C=C>>[CH3:1][C:2](=[CH:4][CH2:5][C:6](=[N:9][O:10][CH2:19][CH:18]=[CH2:17])[CH2:7][CH3:8])[CH3:3]
Reactant: CCC(CC=C(C)C)=NO
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CO
Product: C=CCON=C(CC)CC=C(C)C
Temperature: 0 °C

Procedure:
A reactor was charged with 1 mole of 2-methyl-5-hydroxyimino-2-heptene, 8 moles of methanol containing 1.2 moles of sodium methylate, and 10 moles of tetrahydrofuran (THF). The mixture was cooled to 0° C., and with stirring, 1.3 moles of allyl bromide was added dropwise over 5 minutes. The mixture was stirred at room temperature for one day. The reaction mixture was concentrated, and 40 parts of methylene chloride was added. The mixture was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give 2-methyl-5-allyloxyimino-2-heptene in a yield of 80 mole %. Identification of this compound was performed by using IR, NMR and mass spectra (the same techniques were used to identify compounds appearing hereinafter).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:10])[C:5]([O:7]CC)=[O:6]>O.CO>[CH3:10][C:4]([S:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)([CH3:3])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)Sc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Sc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.7 grams NaOH in 5 ml of water was added dropwise to a solution of 8.79 grams of ethyl 2-methyl-2-(4-pyridinylthio)propionate in 15 ml methanol. The solution was stirred at room temperature overnight, and then concentrated in vacuo to remove methanol. Concentrated HCl was added to the sodium salt and the mixture triturated with isopropanol and heated on the steam bath. The mixture was then cooled and filtered to remove sodium chloride. The filtrate was concentrated in vacuo and the resulting gummy solid dissolved by adding hot isopropanol. The mixture was cooled and filtered to give the title compound. The filtrate upon concentration and cooling gave a further yield of the title compound. M.P. 190°-192° C.; 1NMR and IR were both in agreement for the titled compound.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:34][CH3:35])[C:16]=1[CH2:36][C:37]1[CH:38]=[N:39][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:41][CH:42]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnc(C)n3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (614.1 mg, 3.509 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.830 g, 1.75 mmol, Intermediate 45: step f) in dry THF (5 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by trituration with dichloromethane to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J=2.1 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.0, 2.1 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.41 (dd, J=8.8, 2.1 Hz, 1H), 6.15 (s, 2H), 5.47 (s, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 3.40 (s, 6H), 2.29 (s, 6H); MS m/e 571.0 [M+H]+.