Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14]O)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:22][CH2:14][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([CH:7]=1)[O:5][CH2:4][C:3]1[C:2]([CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:20]
Reactant: COc1ccc(CO)cc1OCc1c(C)cccc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CBr)cc1OCc1c(C)cccc1C
Reaction time: 1.5 h

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-4-methoxyphenyl)methanol (Step C, 5.23 g, 20.4 mmol) and CBr4 (10.16 g, 30.6 mmol) in dry CH2Cl2 (20 ml) was added portion wise triphenylphosphine (8.03 g, 30.64 mmol) at 0° C. The reaction mixture was stirred for 1.5 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[C:3]=1[F:26].[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:6]=2[CH:5]=[C:4]([CH3:25])[C:3]=1[F:26]
Reactant: Cc1cc2c([nH]c(=O)n2C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F

Procedure:
1,1-Dimethylethyl 4-(4,5-difluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate D22 (150 mg, 0.4 mmol) was dissolved in dichloromethane (5 ml) and treated with HCl in 1,4-dioxane (1 ml×4M) at room temperature for 4 h. Solvent was then evaporated to afford the title compound, 120 mg. M++H=268.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=1.[C-:14]#[N:15].[Na+]>CS(C)=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:14]#[N:15])=[CH:4][C:5]=1[C:10]([F:13])([F:12])[F:11]
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
3.94 g of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (14.4 mmol) and 1.06 g sodium cyanide (21.6 mmol) were suspended in 12 ml DMSO under argon and stirring and heated to 50° C. for 1 h. The reaction mixture was then poured on water/ice and extracted four times with DCM. The combined organic phases were washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 3.188 g of (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile as a dark red oil, which was directly used in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:17][C:9]1[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[CH:7]=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCc2ccccc2)c(C=O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1.17 g (5.0 mmol) of 2,4-di-tert-butyl-6-hydroxybenzaldehyde (from Step A of Example 35) in 10 mL of dry DMF was added 0.25 g (10.4 mmol) of powdered sodium hydride and the resulting mixture was stirred for 30 min under a nitrogen atmosphere. Benzyl bromide (1.0 g, 5.9 mmol) was then added and the resulting mixture was stirred for an additional 3 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ether and water. The aqueous layer was re extracted with ether and the organic layers were then combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0-10% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C([O-])([O-])=O.[K+].[K+].CC(C)=O>[Cl-].[Na+].O>[CH2:18]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc2cc(C(=O)OCC)[nH]c2c1

Procedure:
Ethyl 6-hydroxy-1H-indole-2-carboxylate (4.6 g, 0.02 M) was heated under reflux with allylbromide (3 g, 2.2 ml, 0.025 M), K2CO3 (4.14 g 0.03 M) and acetone (150 ml) for 20 hours. On cooling the mixture was poured into brine and extracted into ethyl acetate, washed with brine, dried over magnesium sulphate and evaporated to dryness. The resulting crude brown solid was purified by extraction into hot 60°-80° petroleum ether to yield a yellow solid which was dried in vacuo, 4 g, 72%, mp 89°-91°.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:11][CH2:12][OH:13])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[H-].[Na+].Cl[CH2:17][C:18](=[O:26])[CH2:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21].Cl>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][CH2:17][C:18](=[O:26])[CH2:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: CC(C)OC(=O)CC(=O)CCl
Reactant: Cc1nc2cnccc2n1CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2cnccc2n1CCOCC(=O)CC(=O)OC(C)C
Yield: 58.2 %

Procedure:
2-Methyl-1-(2-hydroxyethyl)-imidazo[4,5-c]pyridine (5 g, 28.5 mmole) was added to a suspension of sodium hydride (60% oil dispersion, 2.3 g, 57 mmole) in dry tetrahydrofuran (100 ml) and the mixture was sonicated for 2 hours at room temperature. A solution of isopropyl 4-chloroacetoacetate (5.1 g, 28.5 mmole) in tetrahydrofuran (100 ml) was added dropwise under nitrogen with sonication and the mixture was sonicated for 5 hours at room temperature. 2N Hydrochloric acid (100 ml) was added and the tetrahydrofuran removed under reduced pressure. The aqueous solution was washed with methylene chloride (2×50 ml), neutralised with potassium carbonate and extracted with ethyl acetate (3×25 ml). The combined extracts were washed with water, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate containing 10% isopropyl alcohol to yield isopropyl 4-[2-(2-methyl-1-imidazo[4,5-c]pyridyl)ethoxy]-3-ketobutanoate (5.3 g, 58%). Rf (silica; methanol, ethyl acetate 1:4) 0.13; N.M.R. (CDCl3) δ=1.05 (d, J=6 Hz, 6H); 2.50 (s, 3H); 3.15 (s, 2H); 3.67 (t, J=5.5 Hz, 2H); 3.93 (s, 2H); 4.19 (t, J=5.5 Hz, 2H); 4.8 (m, 1H); 7.11-8.19 (m, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:26]=[CH:25][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([NH:24][C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:22][CH2:23]3)=[O:17])=[CH:25][CH:26]=2)=[N:2]1
Reactant: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Reactant: O=C(Cl)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCOCC1
Reaction time: 4 h
Yield: 0.3 %

Procedure:
Compound 64 (500 mg, 1.19 mmol) was dissolved in dichloromethane, and the solution was added with triethylamine (0.498 mL, 3.57 mmol), 4-morpholinecarbonyl chloride (468 mg, 2.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200.2 mg, 1.04 mmol) at 0° C., followed by stirring for 4 hours to obtain Compound 99 (1.5 mg, 0.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Brc1cncnc1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, MS (ISP): m/e=325.0 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-Bromopyridine.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](O)=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:12][OH:13]>O=[Mn]=O>[CH2:1]([C:5]1[NH:6][C:7]([CH:12]=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(O)[nH]1
Reactant: CO
Agent: O=[Mn]=O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-butyl-4-chloro-5-hydroxyimdazole (5.0 g, 26,5 mMol) in methanol (300 ml) were added MnO2 (57.6 g, 0.663 mol) and 3A° powdered molecular sieves (oven dried in vacuo) (4.5 g), and the mixture was stirred at room temperature for 20 h. The reaction was filtered through a pad of celite. The filterate was evaporated in vacuo to give the pure desired aldehyde (purity checked on TIC using EtOAc-Hexane 1:3) in quantitative yield (4.9 g, white solid). This material was used directly in the subsequent steps as described below.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:31][C:30]([F:32])([F:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3C(F)(F)F)cc2)no1
Temperature: 40 °C
Yield: 1.8 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 40 mg, 0.196 mmol) was dissolved in DMF (1 mL). K2CO3 (19 mg, 0.14 mmol), tetrabutylammonium iodide (7 mg, 0.02 mmol), and 1-chloromethyl-2-trifluoromethyl-benzene (36 μL, 0.25 mmol) were added. The reaction mixture was heated at 40° C. for 14 h. The reaction mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The organic layer was dried (Na2SO4), filtered, evaporated, and purified by chromatography (30% EtOAc/hexanes) to give 3-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.3 mg, 2%) as a white solid. HRMS Calcd. for C18H14F3N2O3 (M+H)+, 363.0951. Found: 363.0950.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:8]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:15]([O:17]CC)=[O:16].O>CCO>[Cl:3][C:4]1[N:8]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=[CH:6][C:5]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2ncccn2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(-c2ncccn2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1 N aqueous sodium hydroxide solution (2.0 mL) is added to a suspension of ethyl 5-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (250 mg, 1.11 mmol) in 5.0 mL of EtOH. The reaction mixture is stirred at RT for 1 h. Water is added, and the solution is washed with EtOAc. The aqueous layer is cooled to 0° C. and acidified to pH=2-3 with conc. HCl. The precipitated solid is collected by vacuum filtration and dried in vacuo to give the title compound as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[CH:32][C:31]([CH2:34][N:35]5[CH2:36][CH2:37][N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH2:40]5)=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 347 was prepared as an off-white solid (TFA salt) from compound 4 and compound 348 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.57 (1 H, s), 9.27 (1 H, s), 8.60 (2 H, s), 8.47 (1 H, d, J=2.0 Hz), 8.32-8.43 (1 H, m), 8.07 (1 H, dd, J=8.8, 2.2 Hz), 5.46 (1 H, dq, J=9.0, 8.9 Hz), 4.12-4.28 (4 H, m), 3.65 (2 H, br. s.), 2.96-3.21 (8 H, m), 2.48-2.61 (2 H, m), 2.15-2.31 (4 H, m), 1.85-1.99 (2 H, m), 1.28 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 515.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]=2[CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)COc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A solution of 6-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (2.08 g, 11.6 mmol) dissolved in 12.5 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.52 g, 12.8 mmol) suspended in 25 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes and then ethyl bromoacetate (1.54 mL, 13.9 mmol) was added to the mixture and stirred vigorously for 1.5 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.5 min and m/e 265 [M+1]+. The reaction was quenched by adding 5 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation, and the crude residue was purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 50 mL/min, A: methylene chloride, B: methanol, B: 10% for 5 min, 80% for 30 min; detection at 214 nm) to give ethyl [6-(methyloxy)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (1.82 g, 6.9 mmol, 60%). MS (ES) m/e 265 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[NH:20][CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:26]([N:34]=C=O)(=[O:33])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[N:20]([C:26]([NH2:34])=[O:33])[CH2:19][CH2:18][CH2:17]4)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Fc1ccc(OCc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(COc4ccc(F)cc4)c3)cnc21
Temperature: 50 °C
Yield: 71.6 %

Procedure:
6-[5-(4-Fluoro-phenoxymethyl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine (32 mg, 0.096 mmol) and benzoyl isocyanate (24 mg, 0.14 mmol) are mixed in 1.0 mL of DCM and the mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in 1.0 mL of EtOH. K2CO3 (23 mg, 0.16 mmol) is added and the mixture is heated at 80° C. for 45 min. Then the solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (75 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 26 mg of the titled product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][NH:19]4)[N:11]=2)=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][CH2:18][NH:19]4)[N:11]=2)=[CH:6][C:5]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OC
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1OC
Yield: 100 %

Procedure:
When the product of Step C was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound 100% yield. 1H-NMR (CDCl3) 1.5 (tr, 3H, J=3.98 Hz); 3.6 (tr, 2H, J=7.79 Hz); 3.8 (tr, 2H, J=8.87 Hz); 3.99 (s, 3H); 4.19 (q, 2H, J=14, 7 Hz); 6.97 (d, 1H, J=8.5 Hz); 7.17 (d, 1H, J=7.79 Hz); 7.32 (tr, 1H, J=7.82 Hz); 7.66 (d, 1H, J=1.92 Hz); 7.67 (dd, 1H, J=1.97, 8.41 Hz), 7.89 (d, 1H, J=7.78 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1Cl
Reactant: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)CC2)cc1Cl
Yield: 84 %

Procedure:
This compound was prepared in 84% yield by reaction of 3-(3-chloro-4-methoxybenzoyl)propionic acid with hydrazine hydrate in ethanolic solution at reflux temperature for 5 hours. It had mp 194°-195°C after crystallisation from ethanol.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15].N#N.Cl>CCOC(C)=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]2[O:7][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:4]=2[CH2:5][CH2:6]1
Reactant: O=C=NC(=O)Cl
Reactant: CC1(c2ccccc2)CCCC1=O
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)CCc2c1oc(=O)[nH]c2=O
Temperature: 58 °C
Reaction time: 1.75 h
Yield: 43 %

Procedure:
Combined 2-methyl-2-phenylcyclopentanone (Intermediate V(1) (705.5 mg, 4.05 mmol) and carbonisocyanatidic chloride (1700 mg, 8.06 mmol), flushed with N2, and sealed in a sealed tube. Heated at 58° C. for 1 h, then 130° C. for 1.75 h. Let cool to rt. Carefully opened the tube (HCl), and dissolved the residue in EtOAc. Partitioned with NaHCO3 (aq), and extracted 3 times into EtOAc. Washed combined organic layers with brine, dried over MgSO4, filtered, and concentrated in vacuo. Loaded the residue onto Silica gel and eluted with an EtOAc/Hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (43% yield)LC-MS (M+H)+=244.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (1 H, br. s.), 7.32-7.38 (2 H, m), 7.26-7.30 (3 H, m), 2.69-2.75 (2 H, m), 2.43-2.52 (1 H, m), 2.21-2.29 (1 H, m), 1.68 (3 H, s).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>O.C1(C)C=CC=CC=1.C(O)C.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>[C:22]1([C:8]2[N:13]=[CH:12][C:11]([C:14]3([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: OB(O)c1ccccc1
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: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccccc3)nc2)CC1

Procedure:
Sodium carbonate (42.4 mg, 0.400 mmol) in water (0.20 mL) was added to a mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (45.1 mg, 0.200 mmol), Phenylboronic acid (24.4 mg, 0.200 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.15 mg) in toluene (200.0 μL) and ethanol (100.0 μL). The resulting mixture was irradiated by microwave at 120° C. for 15 minutes. Ethyl acetate (5 mL) was then added to the mixture. The resulting mixture was washed with water followed by brine. The organic layer was dried over Na2SO4, then filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate/hexane to give ethyl 1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NC[C@H](O)[CH2:37][OH:38].CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH2:37][OH:38])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: NC[C@H](O)CO
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 43 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(−)-3-amino-1,2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (404.3 mg, 43%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.31 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0630 (M+H C22H21BrF2N3O5 requires 524.0627).
Reaction SMILES: CS(O[CH:6](C)[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)(OC)OC)(=O)=O.[C:23](=[O:26])(O)[O-:24].[Na+].CO>O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:7]([CH3:6])[C:23]([OH:24])=[O:26])=[CH:17][CH:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)OS(C)(=O)=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 72.3 %

Procedure:
A mixture of 17 g of 1-(4-isobutylphenyl)-1,1-dimethoxyprop-2-yl methanesulfonate from Example 21, 16.5 g of sodium bicarbonate, 170 ml of methanol and 135 ml of water is heated to 67°-70° C. and held at reflux for 23 hours. Then the methanol is distilled from the reaction mixture and the aqueous phase remaining is extracted with 150 ml of methylene chloride. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with 150 ml of methylene chloride. The organic phase is dried over magnesium sulfate, and the solvent evaporated to yield 7.67 g of 2-(4-isobutylphenyl)propionic acid (melting point: 73°-75° C.).