Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Dinitroethane (12 g, 0.10 mol) and potassium hydroxide (6 g, 0.11 mol) were dissolved in 100 mL of water to form a first solution. 500 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Butyl acrylate (36 mL, 0.25 mol) was mixed with 300 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 3 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid butyl 4,4-dinitropentanoate (21.5 g, yield: 87%).
Reaction SMILES: C(O)C.[CH3:4][C:5]1([CH3:23])[C:9]([CH3:11])([CH3:10])[O:8][B:7]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([CH3:20])=[O:19])=[CH:14][CH:13]=2)[O:6]1.[BH4-].[Na+]>O>[CH3:11][C:9]1([CH3:10])[C:5]([CH3:4])([CH3:23])[O:6][B:7]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:19])[CH3:20])=[CH:14][CH:13]=2)[O:8]1
Reactant: CC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Into ethanol (5.3 mL), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetone (530 mg, 1.92 mmol) synthesized in Reference Example 4 (4a) was dissolved, to which sodium borohydride (94 mg, 2.50 mmol) was added at 0° C., followed by stirring at room temperature for 30 minutes. To this reaction liquid, water was added, followed by extraction with dichloromethane. The resulting organic layer was dried over sodium sulfate and filtered, and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (483 mg, yield 91%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#N.OS(O)(=O)=O.[OH2:38].[NH4+].[OH-:40]>CO>[C:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:28][N:29]=[N:30][N:31]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)([OH:40])=[O:38]
Reactant: [OH-]
Reactant: O
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CO
Product: CCc1nc2c(C)cc(C(=O)O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 100 °C

Procedure:
To neat 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (20 mg) at RT was added H2SO4 (0.5 mL) and water (0.25 mL). The mixture was heated to 100° C. for 3 hours, cooled to 0° C., then made basic by the addition of NH4OH. After adding methanol (5 mL), the mixture was filtered, concentrated, and purified (SiO2, 60:40:1 CH2Cl2 --CH3OH--NH4OH) to give 17 mg of the title compound as a solid.
Reaction SMILES: S[C:2]1[CH:7]=CC=C[N+]=1[O-].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1.Br.[OH2:18]>C(OC(=O)C)(=O)C>[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1)(=[O:18])[CH3:2]
Reactant: [O-][n+]1ccccc1S
Reactant: Nc1cccc(Br)n1
Reactant: O
Agent: Br
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Br)n1
Temperature: 70 °C

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C. for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C. for 2 hours and at 55° C. for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (1 M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C. and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30](Br)=[O:31].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][NH2:40]>>[C:22]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[C:17]3[C:12](=[C:13]([O:20][CH3:21])[CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[CH2:11][CH2:10][N:9]2[CH2:29][C:30]([NH:40][CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1ccc(OC)c2c1CCNC2C(c1ccccc1)c1ccccc1
Product: COc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2C(c1ccccc1)c1ccccc1

Procedure:
prepared by reaction of 1-(Diphenyl-methyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH3:25][C:26]1[N:30]=[C:29]([C:31]2[N:32]=[N:33][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:35][CH:36]=2)[S:28][N:27]=1.O>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:40]1[CH2:39][CH2:38][N:37]([C:34]2[N:33]=[N:32][C:31]([C:29]3[S:28][N:27]=[C:26]([CH3:25])[N:30]=3)=[CH:36][CH:35]=2)[CH2:42][CH2:41]1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1nsc(-c2ccc(N3CCNCC3)nn2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1nsc(-c2ccc(N3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)nn2)n1
Yield: 45.5 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)-benzoyl chloride (1.1 g) and triethylamine (0.4 g) in DCM (40 ml) was stirred. 3-(3-methyl-1,2,4-thiadiazol-5-yl)-6-(1-piperazinyl)-pyridazine (1.1 g) was added portionwise. The mixture was stirred at room temperature for 3 hours. Triethylamine was added. The mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted three times with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off and dried, yielding 0.91 g (45%) of 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[6-(3-methyl-1,2,4-thiadiazol-5-yl)-3-pyridazinyl]piperazine (compound 131).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=[O:22])[CH2:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[OH:15][CH2:13][CH2:12][CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]([N:8]([CH3:23])[C:7]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1)=[O:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)CC(CCO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Beta-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (11.5 g) in EtOAc (225 mL) was treated with carbonyldiimidazole (11.68 g) and N,N-dimethylaminopyridine (1.0 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (9.74 g) in H2O (150 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (100 mL), sat. NaHCO3 (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (10.4 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a suspension of 16.67 g (0.0379 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) in 500 mL of dimethylformamide was added 8.26 g (0.0612 mole) of 1-hydroxybenzotriazole, 22.44 g (0.0592 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred for 30 minutes and then 6.60 g (0.0580 mole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for an additional and then concentrated under reduced pressure. The residue was partitioned between 800 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with twice with 300 mL of ethyl acetate. The combined organic extracts were washed successively three times with 1 M sodium hydroxide, twice with 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-isopropylamine (190:10:1-160:40:1) to give 15.32 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-39).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][C:6](=[C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1.[CH2:21]1[O:23][CH2:22]1.Cl.[CH2:25]([OH:27])[CH3:26]>>[OH:27][CH2:25][CH2:26][N:11]1[C:10]([CH3:17])([CH3:16])[CH2:9][C:8](=[C:6]2[CH2:5][C:4]([CH3:19])([CH3:18])[N:3]([CH2:22][CH2:21][OH:23])[C:2]([CH3:20])([CH3:1])[CH2:7]2)[CH2:13][C:12]1([CH3:15])[CH3:14]
Reactant: CC1(C)CC(=C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: C1CO1
Reactant: CCO
Agent: Cl
Product: CC1(C)CC(=C2CC(C)(C)N(CCO)C(C)(C)C2)CC(C)(C)N1CCO
Reaction time: 10 h

Procedure:
A mixture of 41.7 g of 2,2,2',2',6,6,6',6'-octamethyl-4,4'-bipiperidylidene, 100g of ethylene oxide, 700 ml of ethanol and 0.06 g of concentrated hydrochloric acid was stirred at 105°-110° C for 10 hours in an autoclave. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was recrystallized from benzene, to give 37.2 g of the desired product as white crystals melting at 226.5°-227.5° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][NH:8][C:7]=1[CH2:17][CH2:18][NH2:19])=[O:5])C.O.[OH-].[Li+].O.[CH2:24]([OH:26])C>>[O:5]=[C:4]1[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH:24]=[O:26])[NH:8][C:7]=2[CH2:17][CH2:18][NH:19]1
Reactant: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Reactant: CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=Cc1[nH]c2c(c1-c1ccccc1)C(=O)NCC2
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
A stirred solution of 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester, lithium hydroxide monohydrate (840 mg, 20 mmol) in ethanol (20 ml) was heated to reflux under an argon atmosphere for 3 hours. The mixture was added with cold water (150 ml), stirred for 10 minutes, extracted with dichloromethane:methanol=5:1(50 ml×7), washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from dichloromethane and methanol to give 4-oxo-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (280 mg, 38.9%) as a red solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+].C(Cl)[Cl:30]>>[Cl:30][C:3]1[CH:2]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:10][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])[CH:4]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: ClCCl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5-chloro-2-hydroxy-benzaldehyde (Aldrich, 7.83 g, 50 mmol) in methylene chloride (150 mL) were added imidazole (Aldrich, 3.72 g, 54.6 mmol) and tert-butyl-dimethyl-chloro-silane (Aldrich, 7.84 g, 52 mmol). The mixture was stirred at room temperature for 5 hrs. A second portion of imidazole (1.2 g) was added and mixture was stirred for 1 hr. The mixture was then poured into saturated sodium bicarbonate solution (150 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2×50 mL). The combined extracts were washed with water, brine and dried over magnesium sulfate. Removal of the solvent gave an off white solid. 13.62 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([C@@H:7]1[CH2:8][C@H:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:10][CH2:11][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(Cl)cc12

Procedure:
Example 2ah, Step 1: A sample of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide was combined with 4,6-dichloroquinazoline (1.2 equivalents) and triethylamine (1.2 equivalents) in ethanol. The resultant solution was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)-2-(6-chloroquinazolin-4-ylamino)acetamide. MS found: (M+H)+=446.44; 1H NMR (400 MHz, CDCl3) δ(TMS): 0.52-1.77 (m, 25H), 2.36-2.48 (m, 1H), 3.92-4.06 (m, 3H), 6.52-6.63 (M, 1H), 7.37-7.55 (m, 3H), 7.70-7.73 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=CC(OC(C)(C)C(O)=O)=C[CH:4]=1)#N.COC(OC)OC.S(=O)(=O)(O)O.[C:28](=O)([O-])[O-].[K+].[K+].[C:34]([O:37][CH:38]([CH3:40])[CH3:39])(=[O:36])[CH3:35]>CO>[CH:38]([O:37][C:34](=[O:36])[CH3:35])([CH3:40])[CH3:39].[CH:3]([CH2:15][C:38]([CH3:39])([CH3:40])[CH3:28])([CH3:4])[CH3:1]
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: CC(=O)OC(C)C
Product: CC(C)CC(C)(C)C
Reaction time: 1.75 h
Yield: 93 %

Procedure:
Suitable reaction conditions are: 2-(4-cyanophenoxy)-2-methylpropionic acid (or compound (viii)) (1 wt) was dissolved in methanol and trimethylorthoformate (TMOF, 1 vol) with stirring under nitrogen1. Sulfuric acid (98%, 0.08 vol, 0.32 eq) was then added, and the mixture was heated to reflux with HPLC monitoring. The reaction was typically complete after approx 1.5-2 hrs at reflux. The batch was cooled, and added to a stirred suspension of potassium carbonate (0.65 eq) in isopropyl acetate and then concentrated in vacuo to a total volume of approx 4 vol. Isopropyl acetate was added, and the slurry concentrated in vacuo to a total volume of approx 4 vol. Isopropyl acetate (4 vol) and water (5 vol) was added, the resultant biphasic solution was separated, and the organics were washed with water. The product was obtained by crystallisation from isopropylacetate/iso-octane with seeding. Expected yield: 93% theory, 99% w/w. Suitable reaction conditions for compound of formula (II) where X is H are: The compound (vii) is suspended in IMS containing AcOH, and treated with 10% Pd/C catalyst (50% wet, 0.1 wt). Hydrogenated at room temp for 60-90 mins until essentially complete by HPLC. The aminoacid precipitates during the reduction to give a fairly thick slurry at the end of the reaction. This is diluted with water and heated to obtain a complete solution. Filtered through celite to remove catalyst and washed through with 1:1 aq IMS. The filtrate and washings are concentrated in vacuo to ca 10 vols, and treated with cHCl (1 vol). Reconcentrated in vacuo to ca 4 vols, by which time a thick slurry results. This is collected by vacuum filtration and washed with water and dried at 50C in vacuo to constant weight. Yield is 70-75% as hydrochloride salt.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH2:12]([C@H:14]([NH:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:25]=1[O:40][CH2:41][CH2:42][NH2:43])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[O:40]([CH:25]([CH3:24])[CH3:26])[CH:41]([CH3:42])[CH3:3].[CH2:12]([C@H:14]([NH:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:25]=1[O:40][CH2:41][CH2:42][NH:43][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: O=C(O)Cc1ccccn1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)OC(C)C
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)Cc2ccccn2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 15.3 %

Procedure:
Prepared as described in Example 26 from 0.41 g (2.4 mmol) of 2-pyridylacetic acid hydrochloride, 1.0 g (2.4 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4), 0.33 ml (2.4 mmol) of TEA, 0.64 g (4.7 mmol) of HOBT and 0.58 g (2.8 mmol) of DCC. The work up and the purification of the reaction mixture were conducted as described in Example 26. After trituration with i-Pr2O, 0.10 g of the title compound were obtained.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]CCCCCCC.C(O)C.C(C=O)=O.[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:31][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:12][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:7]1[N:8]=[N:9][NH:10][CH:11]=1
Reactant: Cc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: Cc1ccccc1-c1c[nH]nn1
Agent: O=CC=O
Solvent: CCO
Product: Cc1ccccc1NCCCCCCCC/C=C\CCCCCCCCc1c[nH]nn1
Temperature: 115 °C

Procedure:
Approximately 80 grams (0.6 mole) tolyltriazole (Sherwin Williams Co.), 167 grams (0.6 mole) oleyl amine (Armak-O, Armak Chemical Co.), 100 ml ethanol, and 100 ml toluene were charged to a 1 liter flask equipped with an agitator, Dean-Stark apparatus and dropping funnel. This mixture was stirred to a homogeneous mixture. Glyoxal (43.5 grams, 0.3 mole, 40% in water) was added dropwise and then stirred at room temperature for 12 hours. Water was then azeotropically removed by heating to 115° C. The dark brown product (261 grams) was isolated by filtration and removal of solvent under reduced pressure.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH:20]=[O:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[OH:8])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher et al, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3 mol) was dissolved in THF (250 ml) and cooled to −40° C. The solution was treated with a 2M solution of lithuim diusopropylamide in THF (200 ml, 0.4 mol) and stirred for 45 minutes maintaining a temperature of −40 to −20° C., before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32 mol) in THF (250 ml). The mixture was allowed to warm to room temperature then stirred for a further 18 hours. After re-cooling to 0° C. the reaction was quenched with saturated ammonium chloride solution (500 ml), and the resulting two phase mixture separated. The aqueous phase was extracted with ethyl acetate and the combined organics concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and concentrated under reduced pressure to an oil (129 g). The oil was dissolved in THF (300 ml) and a 1M solution of tetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. The solution was stirred at room temperature for 45 minutes, then concentrated to an oil under reduced pressure. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and evaporated under reduced pressure. The oil was triturated with hexane and the resulting solid filtered and washed with hexane to afford the title compound (67.58 g 79%) as a tan solid; MS(AP+) m/e 284/286/288 [M+H]+.