Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[O:21][C:22]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[O:21][C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(-c3ccccc3)c(CCC(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionate (1.00 g), lithium hydroxide hydrate (171 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionic acid (918 mg, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 142–143° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][CH:12]=O>CCO>[ClH:10].[Br:9][C:5]1[CH:6]=[C:7]([OH:8])[C:2]2[N:3]([CH:11]=[CH:12][N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Br)cc1O
Reactant: O=CCCl
Solvent: CCO
Product: Cl
Product: Oc1cc(Br)cn2ccnc12
Temperature: 60 °C
Yield: 93.1 %

Procedure:
2-Amino-3-hydroxy-5-bromopyridine (Heterocycles, 41:2799 (1995)) (124 mg, 0.65 mmol) was dissolved in EtOH (3 mL) and added chloroacetaldehyde (0.2 mL, 1.3 mmol, 50% in water) and the resulting solution heated at 60° C. overnight. The solvents were then removed and the solids were crystallized from acetone to give 6-bromoimidazo[1,2-a]pyridin-8-ol hydrochloride (151 mg, 92%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]([N:29]4[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]4)=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCNCC1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Product: O=C(N1CCC(O)CC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Yield: 16 %

Procedure:
The title compound (200 mg, 16%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 4-hydroxypiperidine similarly to the procedure used for example 149. HRMS ESI+ m/z 415.2943 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:29](Cl)(=[O:39])[O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@@H:31]([O:30][C:29]([N:15]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:39])[CH2:32]2
Reactant: Nc1ccccc1
Reactant: CCOC(=O)Cc1cccc(CBr)c1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
A mixture of ethyl 2-[3-(bromomethyl)phenyl]acetate (600 mg, 2.33 mmol), aniline (202 mg, 2.21 mmol) and potassium carbonate (420 mg, 3.04 mmol) in 1V, N-dimethylformamide (15 mL) was heated to 90° C. for 18 hours. After cooling to room temperature, the reaction was filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with brine (3×20 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was dissolved in acetonitrile (5 mL), and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (530 mg, 2.35 mmol) was added. The resulting mixture was heated to 100° C. for 30 minutes under microwave irradiation. The solvent was removed in vacuo, then the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% methanol in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow solid (331 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:21]([F:20])([F:31])[F:32])[CH3:11]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(N)Cc1ccc(Cl)cc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Cl)cc1Cl)NC(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of crude [2-(2,4-dichlorophenyl)-1-methylethyl]amine (about 0.8 g, 3.9 mmol) and triethylamine (0.6 g, 5.9 mmol) in tetrahydrofuran (20 ml) was slowly added dropwise 2-trifluoromethylbenzoyl chloride (0.8 g, 3.8 mmol) at room temperature. After stirring at room temperature for 0.5 hr, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixed solvent of acetone/n-hexane to give a desired compound (white solid, yield; 0.4 g, 27%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH:13](=[C:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>O.C1(C)C=CC=CC=1>[CH:13](=[C:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C=C1CCC(N)CC1
Reactant: COCc1ncnc(Cl)c1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCc1ncnc(NC2CCC(=CC(C)C)CC2)c1OC

Procedure:
3.8 g (20 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine (DE-A 4 116 089), 3.1 g (20 mmol) of 4-iso-butylidene-cyclohexylamine and 3.0 g (30 mmol) of triethylamine were stirred for 3 hours without solvent at 80°-90° C. After cooling, the mixture was taken up in water/toluene, and the organic phase was dried and evaporated on a rotary evaporator. Purification by chromatography (silica gel/ethyl acetate) gave 2.2 g (36% of theory) of a virtually colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:9](=[O:48])[N:8]2[N:49]=[CH:50][CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(C)=O.O.CO.Cl>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:9](=[O:48])[N:8]2[N:49]=[CH:50][CH:51]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccnn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: CCCCc1nc2ccnn2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 67.2 %

Procedure:
A solution of 700 mg of the product of Example 16 in 200 ml of 9:1 acetone-water, 50 ml of methyl alcohol and 2 drops of 5% HCl is refluxed for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is extracted with 3:1 chloroform-methanol. The chloroform layer is dried with anhydrous Na2SO4, filtered and concentrated to a residue which is purified by column chromatography on silica gel by elution with 90% ethyl acetate-hexanes to give 300 mg of the desired product as a solid. M+H=426.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@@H:5]([NH:8][C:9]([C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])[CH2:6][CH3:7].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].N12CCCN=C1CCCCC2>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@@H:5]([N:8]1[C:9](=[O:10])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][C:19]1=[O:20])[CH2:6][CH3:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@@H](CC(=O)OC)NC(=O)c1ncccc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 90.6 %

Procedure:
To a solution of 250 mg of (S)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester in tetrahydrofuran (10 mL) is added 403 mg of 1,1′-carbonyldiimidazole and 0.04 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature and the mixture is stirred at room temperature for 60 h. The reaction mixture is diluted with 50 mL of water and the product is extracted with ethyl acetate (50 mL×3). The combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by flash chromatography on silica gel to give 250 mg (91%) of (S)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(N2CCN(CCO)CC2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Methyl 3-bromo-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate (100 mg, 0.291 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.9 mL). Under ice-cold conditions, sodium hydride (15.2 mg, 0.350 mmol) and benzyl bromide (38 μL, 0.320 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added water under ice-cold conditions, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (43 mg (yield 34.3%)) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: CN1CCC(O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN1CCC(C(c2ccncc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (62 μl, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (31 mg, 33%) as a white solid. The resulting solid was washed with hexane-ether and then, collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21]C)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[CH2:1]([NH:8][C:9](=[O:23])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(/C=C/C=C/C(=O)NCc2ccccc2)ccc1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(/C=C/C=C/c1ccc(O)c(O)c1)NCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-hydroxy-3-methoxyphenyl)-penta-2,4-dienoic acid benzylamide (118 mg, 0.38 mmol) [Example 5] in 50 mL of dichloromethane, 100 μl of boron tribromide (0.95 mmol) was added dropwise at −78° C. The mixture was stirred for 15 min at −78° C. and for 1 h at room temperature. Water (100 ML) was added, the organic layer was separated, dried with Na2SO4 and evaporated.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.[CH3:13][C:14]1([CH3:21])[C:18]([CH3:20])([CH3:19])[O:17][BH:16][O:15]1.C(N(CC)CC)C>O1CCOCC1.C(OCC)(=O)C.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]>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[O:15]2)[CH:7]=1)[CH3:9]
Reactant: CC1(C)OBOC1(C)C
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(B2OC(C)(C)C(C)(C)O2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3-Bromo-5-ethyl-6-methoxy-2-methylpyridine (11.51 g, 50 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.31 g, 64.95 mmol) and triethylamine (21.84 ml, 164.4 mmol) were dissolved under argon in 100 ml of dioxane and then 1,1′bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.94 g, 2.65 mmol) was added. The mixture was stirred at 90° C. for 18 h, cooled and diluted with ethyl acetate, and filtered through silica gel. The solution was cooled to 0° C., mixed with water and extracted twice with ethyl acetate. The dried and concentrated organic phase was chromatographed on silica gel dried at 45° C. in a vacuum drying oven. A pale beige solid (9.94 g, 72%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16](=[O:22])[NH:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:32]>C(Cl)Cl>[CH2:34]([O:33][C:31]([N:20]1[CH2:21][CH:18]([NH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:22])[CH2:19]1)=[O:32])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(=O)Cl
Reactant: O=C(NC1CNC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CC(NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2 g of Azetidin-3-yl-carbamic acid benzyl ester trifluoroacetate (prepared by standard protection and deprotection procedures from 3-Amino-azetidine-1-carboxylic acid tert-butyl ester) in 10 ml of DCM, 1.9 g of triethylamine was added and the mixture was cooled to 0° C. Then, 938 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 1 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: NCc1cccnc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1cccnc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-(aminomethyl)pyridine as in General Procedure 10 to give the title compound. LCMS: m/z=538 (M+H+); retention time=0.59 minutes.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cn1ccc(Br)n1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Product: Cn1ccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 10 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-1H-pyrazole (70 mg, 0.43 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (89-0.43 mmol, Example 146(B)). Microwave conditions. The crude residue was purified by flash, chromatography (cyclohexane/AcOEt 7:3) to yield 12 mg (42 μmol, 10%) of 4-chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:24])[CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)C(O)=O)[CH:5]=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:44]([CH2:47]C)CC)C.[OH2:49]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[O:24][C:47](=[O:49])[NH:44][CH:9]2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2cccc(Cl)n2)O1
Yield: 38 %

Procedure:
To a solution of 3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (3.1 g, 8.6 mmol) in tetrahydrofuran (100 ml) were added diphenylphosphoryl azide (2.0 ml, 9.5 mmol) and triethylamine (1.8 ml, 12.9 mmol), and the mixture was heated under reflux for 1 hr. The reaction solution was allowed to cool, water (150 ml) was added, and the mixture was extracted with ethyl acetate (150 ml×2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give 5-(6-chloro-2-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1.18 g, 38%, (4RS,5RS) form: (4RS,5SR) form=3:2).
Reaction SMILES: [C:1]1([S:11]([NH2:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(=O)CC.O.CCOC(C)=O>[C:1]1([S:11]([NH:14][C:22](=[O:23])[O:24][CH2:25][CH3:26])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cccc2ccccc12
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1cccc2ccccc12
Yield: 65.8 %

Procedure:
A mixture of 1-naphthalene sulfonamide (769 mg, 3.67 mmol) and potassium carbonate (563 mg, 4.07 mmol) in 2-butanone (9 ml) was heated under reflux for 30 min. Ethyl chloroformate (430 mg, 3.96 mmol) was added dropwise and the resulting solution was heated under reflux for 3 h. The mixture was cooled and diluted with H2O (30 ml) and AcOEt (10 ml). The aqueous layer was collected and adjusted to pH 2 by addition of 1N HCl (aq). Extraction with AcOEt (2×20 ml) and concentration of the dried organic extracts afforded ethyl 1-naphthylsulfonylcarbamate (674 mg, 67%) as a white solid. 1H NMR (DMSO-d6): δ 12.35 (bs, 1H), 8.57 (1H, d, J 8.6), 8.29 (2H, m), 8.11 (1H, d, J 7.7), 7.71 (3H, m), 3.90 (2H, q, J 7.1), 0.99 (3H, t, J 7.1).
Reaction SMILES: [CH3:1][C@@H:2]([O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrBr.[Br:20]C1C=CC(OC[C@@H](C)CC)=C(C=1)C#N>C(Cl)(Cl)Cl>[Br:20][C:15]1[CH:16]=[CH:17][C:10]([O:9][C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CCCCCC[C@@H](C)Oc1ccccc1C#N
Reactant: CC[C@H](C)COc1ccc(Br)cc1C#N
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCC[C@@H](C)Oc1ccc(Br)cc1C#N

Procedure:
Quantities: compound 40 (12.34 g, 0.054 mol), bromine (17.15 g, 0.0107 mol), chloroform (100 ml). The experimental procedure was as described for the preparation of compound 41. The crude product was purified by column chromatography (20% petrol/dichloromethane) to give a fawn oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[CH2:10][OH:11].C([Cu])#N.CN([CH:18]=[O:19])C>O>[OH:8][C:5]1[C:4]([CH3:9])=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:18](=[O:19])[O:11][CH2:10]2
Reactant: CN(C)C=O
Reactant: Cc1c(O)ccc(Br)c1CO
Agent: N#C[Cu]
Solvent: O
Product: Cc1c(O)ccc2c1COC2=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
To a 2 L 3 neck flask equipped with overhead stirrer, N2 inlet, and condenser were charged 4-bromo-3-hydroxymethyl-2-methyl phenol (100 g, 461 mmol), CuCN (83.0 g, 921 mmol), and DMF (500 mL). The solution was sparged with N2 for 15 min then heated to 145° C. to obtain a homogeneous solution. The solution was aged at 145° C. for 2 h, then the reaction mixture was cooled to 95° C. 41.5 mL water was added (sparged with N2), and the reaction aged for 20 h. The reaction was cooled to RT then the solids filtered through solka flok and the cake washed with 50 mL DMF. To a 3 L flask containing 1 L EtOAc was added the DMF filtrate. A precipitate coating formed in bottom of flask. The DMF/EtOAc suspension was filtered through solka flok and the cake was washed with 250 mL EtOAc. The resulting filtrate was washed with 5% brine solution (3×500 mL). The aqueous layers were extracted with 500 mL EtOAc and the combined organics were dried over MgSO4, filtered and evaporated. The solids were slurried in 250 mL MTBE at RT then filtered and washed with 100 mL MTBE. The solids were dried under vacuum at RT, providing 5-hydroxy-4-methyl-3H-isobenzofuran-1-one.