Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:22])([F:21])[CH2:18][CH:19]=O.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:19][CH2:18][C:17]([F:22])([F:21])[F:16])[CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Reactant: O=CCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1CCC(F)(F)F
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of (2S,5R)-1-benzyl-2,5-dimethylpiperazine (2.00 g, 7.21 mmol) in THF (10 mL), MeOH (10 mL), and TEA (1.0 mL) was added 3,3,3-trifluoropropionaldehyde (1.62 g, 14.4 mmol) and AcOH (0.826 mL, 14.4 mmol) followed by sodium cyanoborohydride (0.907 g, 14.4 mmol). The reaction was allowed to stir for 2 h, at which time the reaction was quenched with water (15 mL) then made basic with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated in vacuo to yield a white powder (2.0 g, 90%). Mass Spectrum: Calcd for C16H24N2F3 (M+H): 301. Found: 301.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]#[C:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CO>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]#[C:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(OC)cc1C#Cc1cc(OC)ccc1N
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1C#Cc1cc(OC)ccc1NC(C)=O

Procedure:
Compound 12 (84 mg, 0.27 mmol) was dissolved in MeOH (4 mL), and then acetic anhydride (28 μL, 0.30 mmol) was added. The reaction mixture was refluxed for 30 min. The reaction solvent was removed by evaporation, and then the residue was dissolved in CH2Cl2 (30 mL), and washed with H2O (3×10 mL). The organic layer was collected, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (40% EtOAc in hexanes) to afford methyl 2-((2-acetamido-5-methoxyphenyl)ethynyl)-4-methoxybenzoate in 81.8% (78 mg) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 9.30 (1H, s, NH), 8.51 (1H, d, J=9.6 Hz, Ar), 8.03 (1H, d, J=8.8 Hz, Ar), 7.14 (1H, s, Ar), 7.01 (1H, s, Ar), 6.93 (1H, d, J=9.6 Hz, Ar), 6.89 (1H, d, J=8.8 Hz, Ar), 3.88 (6H, s, 2×OCH3), 3.79 (3H, s, OCH3), 2.39 (3H, s, CH3); 13C-NMR (CDCl3, 100 MHz) δ 169.8, 166.0, 162.7, 154.9, 135.3, 132.8, 126.2, 122.5, 121.2, 118.2, 116.7, 116.2, 114.9, 112.4, 94.6, 91.0, 55.8, 55.7, 52.3, 24.6; MS (ESI) m/z Calcd for C20H19NO5 (M+): 353.1, Found: 352.0 (M−H+). LiOH.H2O (25 mg, 0.60 mmol) was added to a solution of methyl 2-((2-acetamido-5-methoxyphenyl)ethynyl)-4-methoxybenzoate (41 mg, 0.12 mmol) in THF/MeOH/H2O (ratio=3:1:1, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding 1M HCl (aq) and partitioned between EtOAc and sat'd NaH2PO4 (aq). The organic layer was collected, dried over Na2SO4, filtered, concentrated and dried under vacuum to afford compound 13 in 99.5% (40 mg) yield as a brown solid. 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (1H, s, NH), 8.27 (1H, d, J=8.4 Hz, Ar), 8.01 (1H, d, J=8.0 Hz, Ar), 7.19 (1H, s, Ar), 7.08 (1H, s, Ar), 7.06 (1H, d, J=8.0 Hz, Ar), 6.99 (1H, d, J=8.4 Hz, Ar), 3.87 (3H, s, OCH3), 3.77 (3H, s, OCH3), 2.26 (3H, s, CH3); 13C-NMR (DMSO-d6, 100 MHz) δ 169.5, 167.6, 161.4, 154.8, 135.0, 133.1, 124.3, 121.6, 117.5, 116.6, 115.6, 115.2, 113.2, 96.1, 89.8, 56.0, 55.7, 24.5; MS (ESI) m/z Calcd for C19H17NO5 (M+): 339.1, Found: 338.1 (M−H+).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH2:16]>[OH-].[Na+]>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][N:16]1[CH2:3][CH:2]([C:1]([OH:9])=[O:8])[CH2:4][C:5]1=[O:7]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)cc1OC
Temperature: 130 °C
Yield: 67.7 %

Procedure:
A mixture of 6.0 g (46 mmols) of itaconic acid and 7.7 g (46 mmols) of 3,4-dimethoxybenzylamine was heated at 130° C. for 2 hours in a nitrogen atmosphere. After cooling to about 100° C., 70 ml of 10% sodium hydroxide were added to the viscous reaction mixture, while mechanically stirring, and the resulting mixture was then cooled to room temperature. In order to remove any insoluble matter, the sodium salt solution was extracted with 50 to 100 ml of ethyl acetate, and the aqueous phase was acidified with dilute hydrochloric acid. The oil precipitated thereby was taken up in methylene chloride, and the methylene chloride phase was dried and concentrated by evaporation. The residue crystallized when ether was added. 8.7 g (68% of theory) of 1-(3,4-dimethoxybenzyl)-4-carboxy-pyrrolidin-2-one were obtained. Melting point: 176°-178° C.
Reaction SMILES: [Br:1]Br.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].C(OCC)(=O)C>[Br:1][C:8]1[CH:7]=[C:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a suspension of iron powder (0.0669 g, 1.20 mmol) in bromine (2.05 mL, 39.9 mmol) at 0° C. was added methyl p-tolyl sulfone (0.340 g, 2.00 mmol). The reaction was warmed up to RT and stirred for 2 h. The mixture was poured into an ice-cold 1 M solution of sodium thiosulfate and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 545 mg of crude material. The crude material was purified by column chromatography (3/1 Hex/ethyl acetate to 1/1 ethyl acetate/hexanes) to give 374 mg of 2-bromo-1-methyl-4-(methylsulfonyl)benzene as a white solid. ES+=251.0 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1.[CH3:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][CH2:30][N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1>CN1C(=O)CCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:32]([NH:31][CH2:30][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([CH3:24])=[CH:35][CH:34]=3)=[S:33])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Reactant: Cc1ccc(CCN=C=S)cc1
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1ccc(CCNC(=S)Nc2ccc3c(c2)c(C(F)(F)F)cc(=O)n3C)cc1
Reaction time: 168 h
Yield: 20 %

Procedure:
6-Amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 200 μL of a 0.2 M solution in NMP, 40 μmol) was treated with pyridine (20 μL of a 0.2 M solution in NMP, 4 μmol) & 4-methylphenethyl isothiocyanate (240 μL of a 0.2 M solution in NMP, 48 μmol). After 7 d, the mixture was concentrated, then the residue was washed with MeCN (2×150 μL) to give the title compound (3.3 mg, 20%): RT=1.87 min; m/z (ES+)=420.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1.C(N(CC)CC)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:41](=[O:42])[CH2:40][Cl:39])[C:22]=3[CH3:28])=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1
Reactant: O=C(Cl)CCl
Reactant: Cc1c(N)cccc1Cc1nc2n(-c3c(Cl)cc(Cl)cc3Cl)[nH]c(C(C)C)c-2c(=O)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cccc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Part A: To a stirred, cooled (0° C.) solution of 110 mg (0.23 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 4 mL of THF was added 0.084 mL (0.6 mmol) of triethylamine followed by 0.024 mL (0.3 mmol) of chloroacetyl chloride. The solution was stirred 2 h, warming to ambient temperature. The reaction was quenched by dropwise addition of 5 mL of 0.5 N aq. HCl, and the resulting solid was collected by filtration. The product was washed with water then 1:1 ether-hexanes and air-dried to afford 96 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methyl benzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 237-238° C. 1H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 9.69(s, 1H); 7.93(s, 2H); 7.15(d, 1H, J=7.3 Hz); 7.07(t, 1H, J=7.7 Hz); 6.95(d, 1H, J=8.7 Hz); 4.25(s, 2H); 3.90(s, 2H); 3.20-3.33(m, 1H); 2.07(s, 3H); 1.30(d, 6H, J=6.9 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=[O:14])[C@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8]1.[CH3:22][CH2:23]O>>[O:6]=[C:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH2:22][CH3:23])=[O:14])[C@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8]1
Reactant: CCO
Reactant: O=C1CC[C@@H](C(=O)O)[C@H](c2ccccc2)C1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1CCC(=O)C[C@H]1c1ccccc1
Reaction time: 14 h
Yield: 31 %

Procedure:
Sulfuric acid (0.073 ml, 1.375 mmol) was added to a mixture of (trans)-4-oxo-2-phenylcyclohexanecarboxylic acid (1.5 g, 6.87 mmol) in EtOH (15 ml). The reaction was aged at 77° C. for 14 h. The cooled reaction was quenched with NaOH (1N) and extracted three times with CH2Cl2. The combined organic layers were dried under reduced pressure and purified via silica gel column chromatography (0-40% EtOAc:Hexanes) to afford ethyl(trans)-4-oxo-2-phenylcyclohexanecarboxylate (526 mg, 31%) as a colorless oil. MS ESI: [M+H]+ m/z 247.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[Cl:28])[N:24]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:23]=[C:22]2[NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:23][N:24]2[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:20][C:19]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(CC)cc3)cc12
Yield: 104.1 %

Procedure:
504 mg of 4-ethylphenylboronic acid, 664 mg of sodium carbonate in 20 cm 3 of distilled water and 202 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 75 cm3 of dioxane. The mixture is refluxed for 18 hours and then the temperature is allowed to return to room temperature to add 75 cm3 of ethyl acetate and 50 cm3 of water, and the reaction medium is filtered through a sinter funnel packed with Celite. The filtrate is separated by settling and the organic phase is washed successively with 50 cm3 of water, with 50 cm3 of saturated aqueous sodium chloride solution, separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), and then dried (90 Pa; 50° C.) to give 1.1 g of N-[6-chloro-5-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2C(=O)O1>CC1C=CC=CC=1C>[CH2:6]([O:5][C:1]([C:2]1[CH:3]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[N:8]=1)=[O:4])[CH3:7]
Reactant: O=C1ONN2CCCCC12
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCCC2

Procedure:
Ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino[1,2-c][1,2,3]oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1-1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%).
Reaction SMILES: CI.[NH:3]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][N:5]=[N:4]1.[CH2:18](N(CC)CC)C>C(#N)C>[CH3:18][N:6]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:3][N:4]=[N:5]1
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CI
Product: Cn1nnnc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of methyl iodide (34.1 ml, 0.5 mol) in acetonitrile (100 ml) was added dropwise, over lh, to a solution of 4-(1H-tetrazol-5-ylmethyl)nitrobenzene (20.5 g, 0.1 mmol), and triethylamine (18.7 ml, 0.25 mol), in acetonitrile (500 ml), at room temperature. The mixture was stirred for 3h, the solvent removed under vacuum and residue dissolved in EtOAc (500 ml). The solution was washed with water (2x) and brine (1x) and the solvent evaporated. The crude product was chromatographed through silica-gel eluting with EtOAc/hexane (1:1)→EtOAc (100%) to give 2 components. The more polar product (7.9 g) was identified as the desired 1-methyl substituted tetrazole. The less polar product (7.0 g) was identified as being the 2-substitution product; 5 (360 MHz, CDCl3, more polar isomer) 3.94 (3H, s, CH3), 4.40 (2H, s, CH2), 7.42 (2H, d, J=8.7 Hz, Ar--H), 8.21 (2H, d, J=8.7Hz, Ar--H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[C:13](=O)([O-])[O-].[Na+].[Na+]>C=O.C(O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:7])[N:8]([CH3:13])[CH2:9][O:12][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1COc2cc(F)ccc2C1=O

Procedure:
A mixture of 4-fluoro-2-hydroxy-N-methyl-benzamide (0.3 g, 1.77 mmol) in formaldehyde (37% aq. soln) (2 mL) and formic acid (2 mL) was refluxed for 1 hour then poured onto ice. The mixture was neutralised with sodium carbonate and extracted into chloroform (3×30 mL). The combined organics were dried (MgSO4), and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 10-50% ethyl acetate in isohexane to give the desired compound as a white solid (0.24 g).
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]2)=C[CH:4]=1.C([O-])(=O)C.[NH4+:22]>>[NH2:22][C:11]1[CH2:10][C:9]2([CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]2)[CH2:14][C:13](=[O:15])[CH:12]=1
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: NC1=CC(=O)CC2(CCCCC2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) spiro[5.5]undecane-2,4-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([C:24]#N)[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C([OH:29])(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([CH:24]=[O:29])[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1(c2ccc3ncccc3c2)CC1
Reactant: CC(C)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=CC1(c2ccc3ncccc3c2)CC1
Temperature: -2.5 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (1M in THF, 96 mL, 96 mmol) was added to a solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 63.9 mmol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to −5 to 0° C., and stirred at that temperature for 3 h. The reaction mixture was cooled to −60° C. Isopropyl alcohol (10 mL) was carefully added dropwise. After stirring for 30 min, the reaction mixture was warmed to −5 to 0° C. The reaction mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered through a pad of silica gel eluting with 40% ethyl acetate in hexanes. The filtrate was concentrated to yield the desired product. (12 g, 95.1%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:36]([CH:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1)[CH2:38][CH3:39])[CH3:37]
Reactant: CCC(Br)CC
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(CC)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 3-bromopentane (1.40 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.98 g, 84%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)#[CH:15].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general coupling procedure, (4-iodo-phenylethynyl)-trimethyl-silane (Maya et al., Chem. Mater., 2004, 16:2987-2997) (0.75 g, 2.50 mmol) was coupled to 4-ethynyl-phenylamine (Fan et al., J. Am. Chem. Soc., 2002, 124:5550) (0.35 g, 3.00 mmol) using PdCl2(PPh3)2 (0.09 g, 0.13 mmol), CuI (0.05 g, 0.25 mmol), TEA (3 mL), and THF (10 mL). The reaction was stirred at 40° C. overnight. The mixture was poured into H2O and extracted (3×) with CH2Cl2, dried using anhydrous MgSO4, and concentrated in vacuo. Column chromatography, silica gel (CH2Cl2) afforded 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine as a yellow solid (0.64 g). Following the general deprotection of TMS-protected alkynes, 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine (0.64 g, 2.21 mmol) was dissolved in a mixture of CH2Cl2 (15 mL), MeOH (15 mL), and K2CO3 (1.53 g, 11.05 mmol). The product 6, was afforded without additional purification as an orange solid (0.47 g, 87%, 2 steps). 1H NMR (400 MHz, (CD3)2CO) δ 7.45 (m, 4H), 7.25 (d, J=6.7 Hz, 2H), 6.68 (d, J=6.7 Hz, 2H), 5.09 (s, 2H), 3.77 (s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:16]1[CH:32]=[CH:31][C:19]([O:20][CH2:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:18][C:17]=1[N+:33]([O-])=O.[C@@H:36]12[C:45](=O)[O:44][C:42](=[O:43])[C@@H:37]1[CH2:38][CH2:39][CH2:40][CH2:41]2>>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:20][C:19]1[CH:31]=[CH:32][C:16]2[N:14]([CH2:13][C:10]3[CH:11]=[CH:12][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[C:45]([C@H:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]3[C:42]([OH:44])=[O:43])=[N:33][C:17]=2[CH:18]=1
Reactant: NCc1ccc(N2CCCCC2)cc1
Reactant: O=[N+]([O-])c1cc(OCc2nc3ccccc3s2)ccc1F
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(N2CCCCC2)cc1

Procedure:
The title compound was prepared using analogous conditions described in Example 208 using (4-(piperidin-1-yl)phenyl)methanamine and 2-((4-fluoro-3-nitrophenoxy)methyl)benzo[d]thiazole in step B and cis-1,2-cyclohexanedicarboxylic anhydride in step D using conventional heating. MS (ESI): mass calcd. for C34H36N4O3S, 580.76; m/z found, 581.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.21 (s, 1H), 7.99-7.94 (m, 2H), 7.55-7.48 (m, 1H), 7.45-7.39 (m, 1H), 7.34-7.28 (m, 2H), 7.04 (dd, J=8.9, 2.4 Hz, 2H), 6.92-6.87 (m, 2H), 5.54 (s, 2H), 5.45 (d, J=16.6 Hz, 1H), 5.38 (d, J=16.6 Hz, 1H), 3.59-3.51 (m, 1H), 3.11-3.04 (m, 4H), 2.89-2.82 (m, 1H), 2.38-2.26 (m, 1H), 2.10-1.99 (m, 1H), 1.86-1.70 (m, 4H), 1.70-1.60 (m, 4H), 1.60-1.35 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:25])[CH2:21][NH:22][CH2:23][CH3:24])=[C:4]([F:26])[CH:3]=1.[CH3:27][OH:28].C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]2[C:20](=[O:25])[CH2:21][N:22]([CH2:23][CH3:24])[C:27]2=[O:28])=[C:4]([F:26])[CH:3]=1
Reactant: CO
Reactant: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN1CC(=O)N(c2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)C1=O

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide (0.82 g) and 1,11-carbonyldiimidazole (0.43 g) in toluene (20 ml) was heated at reflux for 2 hours, cooled and processed. Column chromatography on silica gel eluting with 2.5% methanol-methylene chloride gave a buff colored solid (0.8 g), mp 162-3° C. 1H NMR (CDCl3, TMS): 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m).