Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16]N1C(=O)CCC1.C[Mg]Cl.C[Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH3:16])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Agent: C[Mg]Br
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 150.5 %

Procedure:
To a solution of 5,6-dichloronicotinic acid tert.-butyl ester (3.37 g, 13.6 mmol), Fe(acac)3 (719 mg, 2.04 mmol) and NMP (1.95 mL, 20 mmol) in THF (300 mL), a solution of methylmagnesium chloride in THF (3M, 5.4 mL, 16.3 mmol) is slowly added at −78° C. The brown solution turns turbid and black. Stirring is continued for 1 h at −75° C. before it is warmed to 0° C. The reaction is incomplete and the mixture is cooled again at −70° C. A further batch of methylmagnesium bromide in THF (3M, 5.4 mL, 16.3 mmol) is slowly added at −70° C. The dark green mixture is slowly warmed to −20° C. and carefully quenched with 0.7N aq. HCl (150 mL). The mixture is extracted with ether (5×60 mL). The combined org. extracts are dried over Na2SO4, filtered and evaporated to give crude 5-chloro-6-methyl-nicotinic acid tert.-butyl ester as a yellow oil (4.66 g); LC-MS: tR=1.03 min, [M+1]+=228.22.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.O>CN(C)C=O>[CH3:3][N:4]([CH:20]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrC1C=CCCCC1
Reactant: CNC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)C1C=CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a suspension (10 ml) of sodium hydride (0.24 g, 10 mmoles) in dimethylformamide was added dropwise at 0° C. a dimethylformamide solution (1 ml) of N-methylbenzamide (1.35 g, 10 mmoles). After completion of the addition, the temperature was raised to room temperature, and after stirring for 15 minutes, 3-bromocycloheptene (1.75 g, 10 mmoles) was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, poured into water (20 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.92 g of N-methyl-N-(2-cycloheptenyl)benzamide [Compound (54)].
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.I[CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18].C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[F:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: FC(F)(F)CCCI
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(OCCCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of ethyl 4-hydroxybenzoate (0.46 g, 2.80 mmol), 1-iodo-4,4,4-trifluorobutane (0.67 g, 2.80 mmol) and anhydrous K2CO3 (1.16 g, 8.40 mmol) in methyl ethyl ketone (5 ml) was heated under reflux for 4 h under an atmosphere of argon. On cooling to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between water (15 ml) and Et2O (30 ml). The organic layer was separated, and the aqueous phase extracted with Et2O (2×20 ml). The combined organic extracts were washed with brine (15 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a solid which was purified by flash chromatography (3:1 Hexane/EtOAc) to give the title compound (0.67 g, 87%) as a colourless solid.
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:22]1[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to the free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.29 g. (0.025 mole) of 3-chloro-4-fluorophenyl-isocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give a solid residue. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)- 3-(3-chloro-4-fluorophenyl)urea, m.p. = 131°-132° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[F:38][C:39]([F:60])([F:59])[C:40]1[C:45]([C:46](O)=[O:47])=[CH:44][N:43]=[C:42]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[CH:41]=1.COC(=O)C1C(C(F)(F)F)=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:46]([C:45]2[CH:44]=[N:43][C:42]([C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][CH:50]=3)=[CH:41][C:40]=2[C:39]([F:38])([F:59])[F:60])=[O:47])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 108B]) by saponification in analogy to example 53B]) to give 2-[3-chloro-4-({[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[C:26](=[O:27])[NH:25][N:24]=[CH:23]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>CS(C)=O.O>[CH:35]([N:25]1[C:26](=[O:27])[N:22]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH:23]=[N:24]1)([CH2:37][CH3:38])[CH3:36]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3F)CC2)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a suspension of triazolone 7 (0.11 g, 0.3 mmol) in dimethylsulfoxide (4 mL) was added K2CO3 (0.08 g, 0.6 mmol). The resulting mixture was stirred at room temperature for 1 h. After the addition of 2-bromo butane (0.05 mL, 0.45 mmol), the temperature increased to 80° C. for overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichlormethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product, which was purified by column chromatography to obtain triazolone 8 (0.11 g, 87%). 1H NMR (400 MHz, CDCl3, δH): 7.64 (s, 1H), 7.37 (dd, J=13.0, 2.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J=8.8 Hz, 1H), 6.99-6.97 (m, 2H), 6.88-6.84 (m, 2H), 4.31-4.26 (m, 1H), 3.77 (s, 3H), 3.26 (bs, 8H), 1.86-1.81 (m, 1H), 1.73-1.71 (m, 1H), 1.38 (d, J=6.8 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δC): 154.6, 154.2, 151.6, 139.4, 133.3, 128.4, 119.4, 118.7, 118.0, 114.5, 111.0, 110.8, 55.6, 52.8, 51.0, 50.5, 28.4, 19.3, 10.8.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=O>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]1[O:4][CH2:3][CH:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CC(C)(C)c1ccc(OCC(N)CO)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC2COC(c3c(F)cccc3F)=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
To a mixture of 1.46 g (6.54 mmol.) of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propanol, 0.86 g (8.50 mmol.) of triethylamine and 20 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 1.15 g (6.54 mmol.) of 2,6-difluorobenzoylchloride in 10 ml of anhydrous tetrahydrofuran with stirring at a temperature of from 5° C. to 10° C. for 5 minutes. After addition, the reaction mixture was stirred at room temperature for one hour. After the reaction was completed, the resultant mixture was concentrated under reduced pressure. To the residue, there was added 20 ml of benzene and 10 ml of thionyl chloride and the reaction mixture was refluxed by heating with stirring for 3 hours. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 20 ml of ethanol and further added dropwise 1.4 ml of a 5N aqueous solution of sodium hydroxide with stirring at a temperature of 60° C. for 5 minutes. The reaction mixture was then stirred at the same temperature for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 100 ml of ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 1.72 g of 2-(2,6-diflurophenyl)-4-{[4 -(1,1-dimethylethyl)phenoxy]methyl}-2-oxazoline as a colorless oily substance (nD19.1 1.5391).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=1.C(OCCCC)CCC>>[CH:1]1([NH:7][C:9]2[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COc1cc(F)nc(F)n1
Solvent: CCCCOCCCC
Product: COc1cc(F)nc(NC2CCCCC2)n1
Reaction time: 1 h

Procedure:
10.1 g (0.102 mol) of cyclohexylamine were added at 0°-to 2° C. to a mixture of 7.3 g (0.05 mol) of 2,4-difluoro-6-methoxypyrimidine in 50 ml of methyl t.-butyl ether within 15 minutes. After 1 hour at 0° C. and 3 hours at 25° C., the resulting precipitate was filtered off, and the filtrate was washed with water, dried over magnesium sulfate and concentrated. 8.3 g (73.8% of theory) of the title compound were isolated as an oil (nD23 =1.5211) after chromatography of the residue obtained in this way.
Reaction SMILES: [I:1][C:2]1[C:10]2[S:9][C:8]([CH2:11][O:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1N.N(OC(C)(C)C)=O.O>C1COCC1>[I:1][C:2]1[C:10]2[S:9][C:8]([CH2:11][O:12][CH3:13])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nc2ccc(N)c(I)c2s1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Product: COCc1nc2cccc(I)c2s1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a cooled (0° C.) solution of 7-iodo-2-methoxymethyl-benzothiazol-6-ylamine (1.8 g, 5.62 mmol) in THF under nitrogen was added tert-butyl nitrite (3.3 mL, 28.1 mmol) dropwise. The reaction mixture stirred 3 h at 50° C. Water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water and brine, dried over sodium sulfate, and concentrated. Purification of the residue by column chromatography afforded 1.0 g (60%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.90 (d, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.19-7.21 (m, 1H), 4.8 (s, 2H), 3.58 (s, 3H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Ic1ccccc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccc1)O2
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 2.3 g (10 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6ol, 3.06 g (15 mmol) of iodobenzene, 0.39 g of triphenylphosphine. 95 mg of cuprous iodide 3 ml of triethylamine and 100 ml of acetonitrile was degassed with argon for 10 minutes. palladium acetate. 110 mg (0.5 mmol), was then added and stirring under argon was continued for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and evaporated. The crude product was chromatographed over 100 g of silica gel (Merck 70-230 mesh) using methylene chloride for elution. The clean fractions were combined and evaporated and the residue was crystallized from hexane to yield 2.1 g (68 %) of rac-3,4-dihydro-2,5,7,8-tetramethyl-2-(phenylethynyl)-2H-1-benzopyran-6-ol with m.p. 109-111° C. The analytical sample was recrystallized from hexane and had m.p. 111°-113° C. Anal. Calcd. for C21H22O2 : C, 82.32; H, 7.24 Found ; C, 82.02; H, 7.30
Reaction SMILES: O[C@H:2]([CH3:18])[C@H:3]([NH:7][C:8]([O:10][C:11]1([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9])[C:4]([OH:6])=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:17][C:11]1([O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C[C@@H](O)[C@H](NC(=O)OC1(C)CCCCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1(C)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a round bottomed flask equipped with a magnetic stirrer and a dropping funnel (2S,3R)-3-hydroxy-2-[(1-methylcyclohexoxy)carbonylamino]-butanoic acid (0.503 g, 1.95 mmol) was dissolved in anhydrous CH2Cl2 (50 mL). The clear yellow solution was cooled to 0° C., PyBOP (1.22 g, 2.34 mmol) was added, followed by a dropwise addition of Et3N solution (0.815 mL, 5.85 mmol) in anhydrous CH2Cl2 (5 mL), over a period of 10 min. The crude mixture was stirred at 0° C. for 1 h then overnight at rt. The reaction was quenched by addition of 5% NaHCO3 solution (50 mL) and the corresponding mixture was vigorously stirred for 10 min. The two phases were separated and the organic one collected, dried over Na2SO4 and concentrated to dryness to leave an oil, which was purified by typical chromatography eluting with petroleum ether/AcOEt mixtures (from 9:1 to 7:3). The title compound was obtained as white solid (0.070 g, 15%). m.p.: 92-93° C. MS (ESI) m/z: 242.2 [M−H]+; (ESI) m/z: 240.1 [M−H]−. 1H NMR (DMSO-d6): δ 1.15-1.60 (m, 8H) 1.35 (d, J=6.3 Hz, 3H), 1.42 (s, 3H), 2.02 (m, 2H), 4.83 (m, 1H), 5.35 (dd, J=9.2, 6.3 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].CCN(CC)CC>C1(C)C=CC=CC=1>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: Cc1ccccc1NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reaction time: 0.25 h

Procedure:
A solution of o-tolyl-hydrazine hydrochloride (0.3 mmol) in 0.5 mL of toluene with 4,4-dimethyl-3-oxopentanenitrile (375 mg, 3 mmol, 10 equiv) and Et3N (84 μL, 0.6 mmol, 2 equiv) is stirred at 110° C. overnight. The solvent is evaporated and the residue taken up in EtOAC and washed with saturated NaHCO3 and brine. The organic layer is then concentrated and the residue diluted in 1 mL of ethanol and 1 mL of 1M HCl. The mixture was left at rt for 15 min and then it was concentrated. 5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-ylamine is used crude in the preparation of Example 34.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccn2)CC1
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (1.33 g, 5.66 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 120° C. for 68 h. After cooling to room temperature the reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) at 100° C. for 2 h to give the crude title compound (1.28 g, 96%) as white solid, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH3:32])[S:30][CH:31]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:27]3[CH:28]=[C:29]([CH3:32])[S:30][CH:31]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1cc(Br)cs1
Product: Cc1cc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)cs1

Procedure:
Prepared in analogy to Example A23(b) from 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 4-bromo-2-methylthiophene (commercial). Light yellow solid. MS (m/e): 315.2 ([M]+, 100%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].Cl>CN(C=O)C.O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: CC(C)(N)CC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)O)NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 32.4 %

Procedure:
To a mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 3-amino-3-methyl-butyric acid (Oakwood) (199 mg, 1.7 mmol) in DMF (3 mL) was added sodium methoxide solid (73 mg, 1.36 mmoL). The mixture was gently refluxed for 2 h. After cooled, it was diluted with water (100 mL) and acidified by 1 N HCl aqueous solution to pH=3-4. Precipitate was collected and dried in vacuo. The crude product was purified by silica gel chromatography, eluting with 20%-100% EtOAc-hexanes, to provide the title compound (42 mg, 0.11 mmol) in 33% yield. LC-MS ESI−: 379.04 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.P(=O)(O)(O)O>O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[CH:15][C:14]([OH:18])=[O:17])[C:7]2=[O:12]
Reactant: O=C1CCCc2c(F)cccc21
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Solvent: O
Product: O=C(O)C=C1CCc2c(F)cccc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 5-fluoro-3,4-dihydro-1(2H)-naphthalenone (10 g), glyoxylic acid monohydrate (6.2 g) and 85% phosphoric acid (10 ml) was stirred at 90° C. for three hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to give (5-fluoro-3,4-dihydro-1-oxo-2(1H)-naphthalenylidene)acetic acid (13 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccc(CC3CCCC3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of methyl 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}biphenyl-3-carboxylate (204 mg) and 10% Pd/C (wet) (50 mg) in EtOAc (3 ml) and MeOH (3 ml) was stirred under hydrogen atmosphere at room temperature for 14 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 12:1 to 6:1) to give methyl 3′-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}biphenyl-3-carboxylate (172.1 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1(OC)[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[CH:7]=1
Reactant: COC1(OC)CC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC1=CC(=O)NC1=O
Yield: 70.5 %

Procedure:
To a solution of 3,3-dimethoxypyrrolidine-2,5-dione (12.3 g, 77 mmol) in toluene (500 mL) was added TsOH·water (1.46 g, 7.7 mmol). A Dean Stark Trap was attached and the reaction mixture was refluxed overnight. TLC (petroleum ether/EtOAc=1/1) showed the reaction was complete. The mixture was concentrated and purified by column chromatography (from petroleum ether/EtOAc=2/1 to petroleum ether/EtOAc=1/1) to afford 3-methoxy-1H-pyrrole-2,5-dione (6.9 g, 70% yield) as an orange solid.
Reaction SMILES: Cl.C[N:3]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C@H:5]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[CH2:4]1.[Cl:29]C(OC(Cl)C)=O>ClCCCl>[ClH:29].[CH2:27]1[O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][C@H:5]3[C@H:6]([C:9]4[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=4)[CH2:7][CH2:8][NH:3][CH2:4]3)=[CH:21][C:22]=2[O:28]1
Reactant: CN1CC[C@@H](c2ccc([N+](=O)[O-])cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Yield: 64.7 %

Procedure:
Was prepared from compound (1) (2.4 g) by treatment with 1-chloroethyl chloroformate (1.02 g) in 1,2-dichloroethane (100 ml) as described by Olofson et. al (J. Org. Chem. 49 (1984) 2081). Rinse up on a silica gel column gave 1.5 g of compound (6). M.p. 95°-100° C.