Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:29].[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)#[CH:32].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:22]2[CH:27]=[CH:26][C:25]([C:32]#[C:31][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:24][CH:23]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(I)cc2)cc1C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(OC/C=C(/c2ccccc2)c2ccc(C#Cc3ccccn3)cc2)cc1C

Procedure:
A solution of (Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (283 mg, 0.55 mmol), 2-Ethynyl-pyridine (0.167 ml. 1.65 mmol), bis(triphenylphosphine) palladium(II) chloride (0.015 g, 0.022 mmol), copper(I) iodide (0.31 mg, 0.002 mmol) in dry triethylamine (4 ml) were heated to 120° C. by microwave irradiation for 20 min. The cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding {2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-acetic acid methyl ester as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13](O)=[O:14].CN(C)C=O.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([Cl:31])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-[2-(2,5-Dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetic acid (9.40 g, 30 mmol, E/Z=20/80) was dissolved in dimethylformamide (DMF)(0.11 g, 1.5 mmol) and toluene (20 ml). A solution of 95% thionyl chloride (4.13 g, 33 mmol) and toluene (10 ml) was added dropwise at 60° C. over 5 hours. The mixture was stirred at 60° C. for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to a total amount of 30 g to give crude 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](C)=[CH:11][C:10]([C:14]([O:16]CC)=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccn(-c2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxylate (4.28 g, 17.8 mmol) in 2N NaOH (17.85 ml) was refluxed for 16 hours. The reaction was cooled to room temperature, neutralized with 10% citric acid and extracted with ethylacetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(3-bromophenyl)-1H-pyrazole-3-carboxylic acid (3.29 g, 89%).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][C:15]2[C:16]([CH3:31])=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:33]([F:36])([F:35])[F:34])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:32][N:13]([CH2:14][C:15]1[C:16]([CH3:31])=[N:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([C:33]([F:34])([F:35])[F:36])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CN(C)c1ccc(OCC(=O)O)c(C(F)(F)F)c1
Reaction time: 3.5 h

Procedure:
0.046 g (0.087 mmol) of the above prepared [rac]-(4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester was dissolved in 0.52 ml of THF/EtOH=1/1, treated with 0.26 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 3.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after recrystallisation from AcOEt/hexane, 0.039 g of the title compound as off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:22][C:23]([F:26])([F:25])[F:24])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)#[CH:2]>CCO.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([O:22][C:23]([F:26])([F:24])[F:25])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH3:2]
Reactant: C#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(CC)c2OC1C(F)(F)F
Reaction time: 3 h

Procedure:
A mixture of ethyl 8-ethynyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21f, Step 2 (12.2 g, 32.0 mmole) and 10% Pd/C (1.22 g) in absolute EtOH (250 mL) was hydrogenated at 30 psi for 3 h. The catalyst was then removed by filtration and the solution concentrated in vacuo to give the product in assumed quantitative yield as an off-white solid. The solid was carried on without further purification: EIHRMS m/z 384.0759 (M+, C16H14F6O4, Calc'd 384.0796).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]>CCCCCC.CC(O)C>[NH2:1][C:2]1[C:3]([CH3:35])=[C:4]([CH3:34])[C:5]2[O:9][C@:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:32]=1[CH3:33]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1N)C[C@](C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2

Procedure:
1-[(5-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphenylmethyl)-4-piperidinamine was subjected to preparative high-performance liquid chromatography (column: CHIRALCEL OD (20×250 mm, Daicel Chemical Industry, Ltd.), mobile phase: hexane-2-propanol=95:5); flow rate: 80 mL/min., column temperature: 30° C.) to provide the title compound. [α]D −21.4° (c 0.496, ethanol)
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.CC(C)=[O:15].O>>[C:2]12([OH:15])[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1
Reactant: CC(C)=O
Reactant: BrC12CCCC(C1)C1CCC2C1
Solvent: O
Product: OC12CCCC(C1)C1CCC2C1
Reaction time: 1 h
Yield: 95 %

Procedure:
10 Grams (4.4 millimoles) of 1-bromotricyclo [4.3.1.12,5 ] undecane are dissolved in acetone-water (145 ml - 95 ml) and the solution is refluxed under stirring for one hour. After allowing the solution to cool, the solution is extracted with petroleum ether and the extract is dried with anhydrous magnesium sulfate. The solvent is distilled out. The residue is purified by sublimation to obtain 0.69 g (yield 95%) of tricyclo [4.3.1.12,5 ] undecane-1-ol as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[CH:3]1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=c1cc[nH]c2c([N+](=O)[O-])cccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a stirred mixture of 1,4-dihydro-4-oxo-8-nitroquinoline (10 g) in dimethylformamide (100 ml) was dropwise added N-bromosuccinimide (9.83 g) over the period of 2 minutes under ice-cooling, and the mixture was stirred for 30 minutes at 4° C. Water was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was washed with water and hot ethanol to give 3-bromo-1,4-dihydro-8-nitro-4-oxoquinoline (12.12 g).
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.[NH2:21][C:22]1[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=1>C1COCC1.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>[NH:15]1[C:16]2[C:12](=[C:11]([C:25]3[CH:24]=[N:23][C:22]([NH2:21])=[N:27][CH:26]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: Nc1ncc(Br)cn1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cccc3[nH]ccc23)cn1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Pd(PPh3)4 (285 mg, 0.25 mmol) and a freshly prepared sodium hydroxide solution (985 mg in 12 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.21 mmol) and 2-amino-5-bromopyrimidine (1.71 g, 9.85 mmol) in THF (30 mL). The reaction mixture was degassed and then purged three times with nitrogen and then refluxed overnight with stirring under nitrogen. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (300 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give 1.4 g (82%) of 5-(1H-indol-4-yl)-pyrimidin-2-ylamine as a white solid.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:29][C:30]3[NH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[C:34]([C:39]#[N:40])[CH:33]=4)[C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:29][C:30]3[NH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[C:34]([C:39]#[N:40])[CH:33]=4)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)C(Cc1cc2ccc(C#N)cc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(Cc3cc4ccc(C#N)cc4[nH]3)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
An aqueous solution containing 3 g of sodium hydroxide dissolved in 10 ml of water was added to 100 ml of a methanol solution containing 22 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionate, and the resulting mixture was stirred at room temperature for 24 hours. After distilling off the solvent, the remaining portion was adjusted to pH 4-5 with citric acid and then extracted with ethyl acetate. By drying the extract to distill off the solvent, 20 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionic acid was obtained.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([CH2:16]OS(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>C(Cl)Cl>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([CH2:16][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:14][CH:15]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(COS(C)(=O)=O)nc1-c1ccccc1
Reactant: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CN2CCCCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a solution of 0.40 g (0.73 mmol) methanesulfonic acid 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-phenyl-pyrimidin-2-ylmethyl ester in 5 ml CH2Cl2 added 0.11 ml (1.1 mmol) piperidine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 10:1) to give 0.32 g (81%) 4-phenyl-2-piperidin-1-ylmethyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a pale yellow waxy solid, MS (ISP): 537.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[OH-:10].[Cs+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1ccc(I)cc1
Agent: [Cs+]
Product: COc1ccc(O)cc1
Yield: 90 %

Procedure:
Following general operating mode A, 4-methoxyiodobenzene (246 mg, 1.0 mmol) is caused to react with cesium hydroxide to give the expected product in the form of a white solid with a yield of 90% (eluent: ethyl acetate/heptanes 20:80).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([C:15]([O:17]C)=[O:16])[CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO.C(OC(=O)C)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)c(=O)n(C2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1cc(C(=O)O)cn(C2CCCC2)c1=O

Procedure:
A mixture of Methyl 5-cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (290 mg, 1.2 mmol) and 1N sodium hydroxide (6 mL, 6.0 mmol) in methanol (12 mL) was heated to reflux for 1 h and brought to RT. The mixture was concentrated and the residue obtained was dissolved in ethylacetate (20 mL), acidified with 1N hydrochloric acid (pH ˜5). The organic phase was separated, dried over magnesium sulfate and concentrated to afford the title compound as a light yellow solid. MS m/z: 233 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:26]=[C:25](F)[CH:24]=[C:23]2[C:18]=1[C:19]([NH2:28])=[N:20][CH:21]=[N:22]2>CN(C=O)C>[NH2:28][C:19]1[C:18]2[C:23](=[CH:24][C:25]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:26][C:17]=2[F:16])[N:22]=[CH:21][N:20]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1ncnc2cc(F)cc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(F)c3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.61 mmol, 107.6 mg) is dissolved in 5 mL DMF. To this solution is added sodium hydride (60% suspension in mineral oil) (0.77 mmol, 30.8 mg) and the mixture is stirred at rt for 5 min. and then 5,7-Difluoro-quinazolin-4-ylamine (0.55 mmol, 100 mg) is added. The reaction is stirred at 50° C. for 22 h. The reaction is cooled and quenched by pouring into 100 ml sat. NH4Cl aq. and extracted 3 times with 20 mL CH2Cl2. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-15% MeOH in CH2Cl2. 1-(4-Amino-5-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (35 mg, LC/MS m/z=339 [M+H]+) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:16][CH2:13][CH:14]=[CH2:15])=[O:8]
Reactant: O=C(Cl)C=Cc1cccc(F)c1
Reactant: C=CCN
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCNC(=O)C=Cc1cccc(F)c1
Reaction time: 72 h

Procedure:
A solution of 3-fluorocinnamoyl chloride (3.7 g) in dry toluene (35 ml) was added with stirring to allylamine (8 ml) in dry benzene (100 ml). The reaction mixture was allowed to stand at room temperature for three days. After evaporation of the solvents under reduced pressure the residue was triturated with water containing a small amount of sodium carbonate and washed with water. Recrystallization from ethanol: water gave 3-fluoro-N-allylcinnamamide (3.3 g), m.p. 84.5-87° C. as fine white needles. Elemental analysis, nmr and ir spectra were consistent with the structure assignment.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1(c2ccc(N)cc2)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-cyclopropanecarbonitrile (500 mg, 2.65 mmol, Journal of the American Chemical Society, 71, 2031-5; 1949) in 7 mL of EtOH-2.5 mL of EtOAc was added 350 mg 5% Pd—C. The mixture was stirred under 1 atm of H2 overnight. The reaction was filtered, concentrated in vacuo and then purified using preparative thin layer chromatography (CHCl3) to afford the title compound as an oil (96 mg, 23%). Mass spectrum (ESI, m/z): Cald. C10H10N2, 159.0, found 159.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](O)=[CH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2].C(O)(=O)C.[CH3:25][NH2:26]>CCO>[CH2:1]([O:3][C:4](=[O:20])[C:5]([NH:26][CH3:25])=[CH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: CN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC(=O)c1c[nH]c2ccc(Cl)cc12)NC
Yield: 37.5 %

Procedure:
To a solution of 0.59 g (2.0 mmol) of 4-(5-chloroindol-3-yl)-2-hydroxy-4-oxo-2-butenoic acid ethyl ester prepared in Example 1(1) in 95% EtOH (10 ml) was added 0.55 g (6.0 mmol) of methylamine acetate. After refluxing for 2.5 hours, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with water, dried, and then concentrated. The resulting residue was chromatographed on silica gel (ethyl acetate as eluant) to give 0.23 g of the titled compound as oil. Yield: 38%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([S:21](Cl)(=[O:23])=[O:22])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:2]([NH:3][S:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:12][CH:13]=2)(=[O:23])=[O:22])[CH2:7][CH2:6]1)(=[O:27])[CH2:12][CH2:11][CH3:20]
Reactant: CC(C)N=C=O
Reactant: Cc1ncccc1C(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3cccnc3C)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-[(2-methyl-pyridine-3-carbonyl)-amino]-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 8.68 (d, 1H), 8.59 (d, 1H), 8.31 (d, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.73 (m, 2H), 7.41 (m, 1H), 4.00 (d, 1H), 3.61 (d, 1H), 3.23 (m, 1H), 2.93 (t, 1H), 2.66 (s, 3H), 2.59 (m, 1H), 2.17 (t, 2H), 1.48 (m, 2H), 1.43 (m, 2H), 1.19 (m, 2H), 0.82 (m, 2H). LC/MS m/z 494 (M−H)−, 496 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:17]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(O)c1ccc2c(ccn2C)c1OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCC(=O)c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To activated 4 Å molecular sieves (4.3 g, 250 mg/mmol) was added a solution of 1-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)butan-1-ol obtained above (ca. 17.22 mmol) in DCM (90 mL). The mixture was cooled to 0° C. before NMO (3.00 g, 25.61 mmol) and TPAP (300 mg, 0.85 mmol, 5 mol %) were added subsequently. The reaction was stirred at 0° C. for 15 min and then allowed to warm to room temperature. After 2 h complete conversion of staring material was observed. Molecular sieves were filtered off and were washed with DCM. The mother liquor was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 5-15% gradient). 1-(4-(Benzyloxy)-1-methyl-1H-indol-5-yl)butan-1-one was obtained as a white solid (4.85 g) in 92% yield over 2 steps.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[CH2:12]([C:10]1[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]([OH:25])=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[N:11]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A mixture of 4-butyl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (41 mg, 0.12 mmol) and glycine (175 mg, 2.32 mmol) in 0.5 M sodium methoxide/methanol (4.4 mL) was refluxed for 48 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (19 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.19 (br s, 1H), 8.17 (m, 2H), 7.63 (m, 3H), 4.05 (d, J=5.8 Hz, 2H), 3.33 (m, 2H), 1.88 (m, 2H), 1.41 (m, 2H), 0.97 (t, J=7.2 Hz, 3H); MS: (+) m/z 386.13 (M+1), (−) m/z 384.13 (M−1).