Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH3:33][CH2:34][N:35](C(C)C)C(C)C.C(N)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:26])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([NH:35][CH2:34][CH3:33])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Agent: CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-n2cc(C)c3ccc(OCCCl)cc3c2=O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A suspension of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (425 mg) in methylene chloride (8 ml) was cooled to 0° C. and oxalyl chloride (0.2 ml) was added followed by DMF (10 μL) and the reaction mixture was left to stir at room temperature for 1 hour when N,N′-diisopropylethylamine (0.8 ml) and ethylamine (2.28 ml of a 2.0M in THF) were added. The reaction mixture was stirred at room temperature for 17 hours and concentrated. The residue was diluted with ethyl acetate and washed with water (×3), brine, dried (magnesium sulfate) and concentrated to a brown foam which was purified by column chromatography on a silica column eluting using a gradient of iso-hexane to ethyl acetate to give 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-ethyl-4-methylbenzamide as a pale yellow solid (323 mg); NMR Spectrum: (DMSOd6) 1.11 (t, 3H), 2.11 (s, 3H), 2.27 (s, 3H), 3.28 (m, 2H), 4.01 (t, 2H), 4.41 (m, 2H), 7.13 (s, 1H), 7.52 (m, 2H), 7.73-7.78 (m, 3H), 7.89 (d, 1H), 8.50 (t, 1H); Mass Spectrum: M+H+ 399.
Reaction SMILES: [OH:1][CH:2]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11]([CH3:17])=[C:12]([C:14]([OH:16])=O)[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.Cl.[CH2:24]([NH2:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[CH2:24]([NH:26][C:14]([C:12]1[O:13][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[C:10]=2[C:11]=1[CH3:17])=[O:16])[CH3:25]
Reactant: Cc1c(C(=O)O)oc2cccc(OCC(O)CNC(C)C)c12
Reactant: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1oc2cccc(OCC(O)CNC(C)C)c2c1C
Yield: 36.8 %

Procedure:
A solution of 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid (5 mg), ethylamine hydrochloride (42 mg), water-soluble carbodiimide hydrochloride (10 mg), 1-hydroxybenzotriazole (8 mg) and triethylamine (100 μl) in DMF (1 ml) was stirred at room temperature for five hours. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH:H2O=65:30:5 as a developing solvent) to give 4-(2-hydroxy-3-isopropylamino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethylamide (2 mg) as a white powder. MALDI-TOF-MS: m/z 335 (MH+); 1H-NMR (CDCl3): δ 1.27 (3H, t, J=7 Hz), 1.34 (6H, d, J=6 Hz), 2.72 (3H, s), 3.13 (1H, dd, J1=12 Hz, J2=9 Hz), 3.32 (2H, m), 3.49 (2H, dq, J1=7 Hz, J2=6 Hz), 4.05 (1H, dd, J1=10 Hz, J2=6 Hz), 4.15 (1H, dd, J1=10 Hz, J2=5 Hz), 4.53 (1H, br s), 6.55 (1H, d, J=8 Hz), 6.56 (1H, m), 7.00 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].C(Cl)(=O)C>>[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)CCCl
Solvent: CC(=O)Cl
Product: CC(=O)NC(=O)CCCl

Procedure:
A mixture of 0.2 mole 3-chloropropionamide, 35 ml. of acetic anhydride and 1 ml. acetylchloride is refluxed under nitrogen for 1 hour and then concentrated in vacuo to give crude N-acetyl-3-chloropropionamide as an oil which is used in the next step without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:9])[CH3:8].[NH2:20][C:21]1[CH:33]=[C:32]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][C:21]1[CH:33]=[C:32]([CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)Nc1cc(CCc2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 2.7 μL of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were added to 0.13 g of 2-acetoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.45 mL of triethylamine containing 60 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced, pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2-acetoxybenzamido)-4-phenethylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:16]1(=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19](=[O:26])[CH2:18][O:17]1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11](/[CH:14]=[C:18]3\[O:17][C:16](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[C:19]\3=[O:26])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1COC(=O)c2ccccc21
Reactant: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1O/C(=C\[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To the resulting stirred mixture from stage 1, at ambient temperature under argon, was added acetic acid (125 mL), 1H-2-benzopyran-1,4(3H)-dione (compound of formula (III)) (16.2 g, 100 mmol) and ammonium acetate (7.7 g, 100 mmol). The reaction mixture was then heated to 70° C. and distilled for 2 hours. The resulting slurry was cooled to ambient temperature and water (75 mL) added. The slurry was stirred for 30 minutes at ambient temperature then filtered. The filter cake was washed with tert-butyl methyl ether (62.5 mL) and dried to give the title compound as a yellow solid (24.8 g). The material obtained was spectroscopically identical to that obtained in Stage 2, Example 3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Cl:12][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Temperature: 170 °C
Yield: 18.4 %

Procedure:
A mixture of 1,3-dichloroisoquinoline (5.0 g; see Example 8) and p-anisidine (3.1 g) was heated at a temperature of 170° C. for a period of 2 hours. After cooling the product was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-chloro-1-[N-(4-methoxyphenyl)amino]isoquinoline (1.32 g) mp 101° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])[CH2:28][CH2:29]2)[N:19]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1ccnc(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccnc(N2CCN(C(=O)c3ccsc3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 mL (7.86 mmol) of triethylamine in 30 mL of CH2Cl2 cooled to 0° C. 0.84 g (7.81 mmol) of ethyl chloroformiate are added. The mixture is maintained at 0° C. for 20 minutes and then 1.5 g (7.81 mmol) of 4-methoxy-2-(1-piperazinyl) pyrimidine dissolved in 10 mL of CH2Cl2 are added to the solution. The temperature is allowed to rise to room temperature and the solution continually stirred for 2 hours and the organic phase is washed with H2O, dried over NaSO4 and the solvent evaporated off under reduced pressure. The resulting oil is treated with ethyl ether to yield a solid which is recrystallised from ethanol/H2O to give 0.8 g (2.63 mmol) of 4-methoxy-2-[4-(3-thienylcarbonyl)-1-piperazinyl]pyrimidine. m.p.=90-92° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([N:1]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=3)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=C1CCCNc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Temperature: 50 °C

Procedure:
To a solution of 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one (500 mg, 3.1 mmol) in pyridine (2 ml) is added p-toluenesulfonyl chloride (650 mg, 3.4 mmol), and the mixture is heated at 50° C. for 1 hour. The reaction mixture is poured into 1N HCl (100 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated to a solid. The solid is purified by silica gel column chromatography (eluent, 30% ethyl acetate in hexanes) to give the title compound as a solid. Mass spectrum (ES+): 316 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:4]=1
Reactant: NC1CCOCC1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC2CCOCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A solution of Example C2 (0.200 g, 0.476 mmol) in DCM (5 mL) was treated with mCPBA (0.141 g, 0.571 mmol), stirred at RT for 3 h, treated with 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) and stirred at RT overnight. Additional 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) were added and the mixture stirred at RT for an additional 24 h. The mixture was concentrated to dryness, transferred to a sealed vessel with DMF (10 mL), treated with additional 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, the solids removed via filtration and washed with DCM. The filtrate was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with 5% LiCl (3×), then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (125 mg, 56%). MS (ESI) m/z: 474.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([Cl:16])=[O:6])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Product: Cc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 101.7 %

Procedure:
In this example 2.14 moles of 3-methyl-2-nitrobenzoic acid were refluxed with 6.43 moles (468 ml) of thionyl chloride for three hours and then allowed to stand overnight. The mixture was then again refluxed until the mixture turned a dark brown color. Excess thionyl chloride was removed by evaporation affording 434.4 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2>CCCCCC.C(O)(C)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC(C)O
Product: N[C@H]1Cc2ccc(Br)cc2C1

Procedure:
2.93 g of (S)-5-bromo-indan-2-ylamine were prepared as described for the (R)enantiomer starting from 12.5 of racemic 5-bromo-indan-2-ylamine and the corresponding (1R)-(−)-campher-sulfonic acid. The enantiomeric purity was checked via chiral HPLC on a DAICEL Chiralcel OJ column (4.6×250 mm) using n-hexane:isopropanol:triethylamine (90:10:0.1) as eluent: 99% (S)-1% (R).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15]>C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][CH2:4][CH2:15][C:14](=[O:16])[C:8]=2[CH:9]=1
Reactant: CC(=O)c1cc(F)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Weighed out Sodium Hydride (561 mg, 23.4 mmol) into a nitrogen purged round bottom flask and added 10 mL THF. Placed the solution under nitrogen and added 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethanone (4.07 g, 15.6 mmol) in 15 mL THF. Let stir at room temperature overnight. Concentrated in vacuo and flashed 0 to 50% ethyl acetate/hexanes. NMR confirmed product as 7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.58 g, 56.2% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])[CH:3]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2cc(NC(=O)c3ccccn3)c3cn[nH]c3c2)cc1

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-pyridinecarboxamide (70 mg, 0.22 mmol), [4-(acetylamino)phenyl]boronic acid (47 mg, 0.26 mmol), Pd(dppf)Cl2 (22 mg, 0.027 mmol) and 2 M sodium carbonate (aq) (0.328 ml, 0.656 mmol) in 1,4-dioxane (1.5 ml) and water (1.5 ml) were heated in a Biotage microwave at 150° C. for 30 mins. The reaction was washed through a silica cartridge eluting with MeOH. The solvent was removed in vacuo. The residue was purified by HPLC using the method described below to afford the title compound.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([N:15]2[CH2:18][C:17]4([CH2:23][CH2:22][N:21](C(OCC5C=CC=CC=5)=O)[CH2:20][CH2:19]4)[CH2:16]2)[CH2:10][CH2:9]3)[N:3]=[CH:4][CH:5]=1>CO.[Pd]>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([N:15]2[CH2:16][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:18]2)[CH2:10][CH2:9]3)[N:3]=[CH:4][CH:5]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CN([C@@H]1CCc3cc(-n4nccn4)ccc31)C2
Agent: [Pd]
Solvent: CO
Product: c1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)n1
Reaction time: 6 h

Procedure:
In a Parr® shaker bottle, a solution of benzyl 2-(R)-5-(2H-1,2,3-triazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6-1b, 1.20 g, 2.7 mmol) in MeOH (30 mL) was treated with 10% Pd/C (50% wet for safety, 600 mg). The mixture was hydrogenated at 45 psi for 6 hours. The reaction was filtered through a pad of Celite® and concentrated to afford 2-((R)-5-(2H-1,2,3-triazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane as a glass-like solid (690 mg, 82%). MS (ES+) 310.0 (M+H)+. 1H NMR (CD3OD) δ 0.95 (s, 1H), 1.27-1.32 (m 2H), 1.88-1.92 (m, 3H), 2.26-2.30 (m, 1H), 2.97-3.01 (m, 5H), 3.13 (s, 3H), 3.33-3.51 (m, 1H), 4.07 (br s, 1H), 7.50 (s, 2H), 7.90 (s, 3H).
Reaction SMILES: ClC1C(C)=C(Cl)C2C(=CC=CC=2F)N=1.Cl[C:16]1[C:25]([CH3:26])=[C:24]([Cl:27])[C:23]2[C:18](=[CH:19][C:20]([F:28])=[CH:21][CH:22]=2)[N:17]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[Cl:27][C:24]1[C:23]2[C:18](=[CH:19][C:20]([F:28])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:31]2[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:30]=2[F:29])[C:25]=1[CH3:26]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: Cc1c(Cl)nc2cccc(F)c2c1Cl
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl

Procedure:
Essentially prepared according to Procedure F using a mixture of 2,4-dichloro-5-fluoro-3-methylquinoline and 2,4-dichloro-7-fluoro-3-methylquinoline (˜1:4 mixture) (690 mg, 3.00 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=335.0 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH3:31])=[O:28])=[CH:16][CH:15]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[Li+].[OH-]>CO.O>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH:30]([O:29][C:27]([NH:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([C:8]2[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=2)=[CH:19][CH:18]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1-c1ccc(-c2onc(C)c2NC(=O)OC(C)c2ccccc2Cl)cc1
Reaction time: 2 h

Procedure:
To (4′-{4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester (0.105 g, 0.20 mmol) in methanol (20 mL) was added 1N aqueous LiOH (5 mL, 5 mmol), and the reaction was stirred for 2 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(Cl)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:1](#[N:4])[CH:2]=[CH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: N#CC=Cc1ccccc1
Yield: 540 %

Procedure:
The procedure described in Example 1 is repeated, except that 3.31 g (0.0625 mol) of acrylonitrile, 7.02 g (0.05 mol) of benzoyl chloride, 11.6 g (0.0625 mol) of tri-n-butylamine, 100 ml of p-xylene and 0.1122 g (0.0005 mol) of palladium acetate are used. After a reaction time of 2 hours at 120° C., 3.47 g (0.27 mol) of cinnamonitrile are obtained, corresponding to a yield of 54% of theory. Boiling point=134°-136° C./17×102Pa.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:11]1[NH:12][N:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:10][C:9]1[C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(C#N)c1F
Reactant: c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C#N)c1-n1nccn1
Temperature: 120 °C
Yield: 27.5 %

Procedure:
To a mixture of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6 mmol) and 2H-1,2,3-triazole (2.04 g, 29.6 mmol) in DMF (80 mL) was added potassium carbonate (8.26 g, 59.2 mmol). The resulting mixture was heated to 120° C. for 2 h. The mixture was cooled, diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (SiO2, ethyl acetate/hexanes, gradient 0-50%) to yield the title compound (1.5 g, 26%). MS (ESI) mass calcd. for C10H8N4, 184.2; m/z found, 185.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.95 (s, 2H), 7.66 (d, J=7.7, 0.7 Hz, 1H), 7.59 (d, J=7.8, 0.6 Hz, 1H), 7.50 (dd, J=9.8, 5.7 Hz, 1H), 2.20 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([CH3:10])[CH:3]=1.OS(O)(=O)=O.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:22]>O>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([F:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [H+]
Solvent: O
Product: Cc1cc(Br)cc(C)c1F
Yield: 71.1 %

Procedure:
To a mixture of 4-Bromo-2,6-dimethylaniline (8.3 g, 42 mmol) at 5° C. and H2O (50 mL) was added conc H2SO4 (6.25 mL). NaNO2 (4.1 g) was added in portions until an excess was indicated by starch iodide paper. Water (30 mL) was added to make the mixture homogeneous. After transferring to a plastic container, HBF4 (50%, 13.7 g) was added dropwise with stirring. The resultant white precipitate was collected by vacuum filtration, washed with H2O (30 mL), MeOH (30 mL), and Et2O (60 mL), and dried over P2O5 under vacuum for 16 h. The solid was then heated in a glass flask with an open flame until all the solid had decomposed. The remaining liquid was diluted with Et2O (50 mL) and 0.5 M NaOH (30 mL). The organic layer was separated, washed with 0.5 M NaOH (25 mL), H2O (25 mL), brine (25 mL), dried (MgSO4), and concentrated in vacuo yielding 6.06 g (72%) of 1-bromo-4-fluoro-3,5-dimethylbenzene as a pale yellow liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[BH4-].[Na+].[Cl-].[Na+]>C(O)C.C(Cl)Cl.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(-c2ccco2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: OCc1cccc(-c2ccco2)c1
Yield: 101.3 %

Procedure:
A solution of 3.0 g (0.017 mol) of 3-(2-furanyl)benzaldehyde and 0.66 g (0.017 mol) of sodium borohydride in 30 mL of ethanol was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residual oil. The oil was dissolved in a mixture of methylene chloride and water, and was saturated with solid sodium chloride, then extracted with three portions of 100 mL each of methylene chloride. The combined extracts were dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 3.0 g of 3-(2-furanyl)-phenylmethanol.