Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:11])[CH2:9][O:10][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of (S)-1-(3-Chloro-phenyl)-ethane-1,2-diol (9.83 g, 0.057 mol) and triethylamine (11.8 ml, 0.086 mol) a solution of TsCl (10.87 g, 0.057 mol) in dichloromethane (50 ml) was added at 0° C. over 30 min. The mixture was stirred at 0° C. for 4 h. Precipitate formed was removed by filtration, the filtrate was washed with water (50 ml), dried over Na2SO4, evaporated. The residue vas dissolved in CH2Cl2 (200 ml), filtered through a SiO2 pad, evaporated. Colorless oil, 16.34 g (0.050 mol, 88%). 1H NMR (300 MHz, DMSO) δ 7.67 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.20-7.35 (m, 4H), 5.90 (d, J=4.9 Hz, 1H), 4.79 (q, J=5.1 Hz, 1H), 4.03 (m, 2H), 2.41 (s, 3H)
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].O[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>N(C(OCC)=O)=NC(OCC)=O>[CH:1]([O:4][CH2:5][CH2:6][O:7][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCO
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(C=O)cc1
Yield: 81.7 %

Procedure:
To a solution of 2-isopropoxyethanol (600 mg, 5.76 mmol), p-hydroxybenzaldehyde (0.78 g, 6.34 mM) and triphenylphosphine in THF (20 ml) (1.6 g, 6.1 mmol), diethyl azodicarboxylate (40% in toluene) was added at 0° C. over 10 minutes while stirring. Then, the mixture was stirred at room temperature for 18 hours until the initial reaction product of 2-isopropoxyethanol and p-hydroxybenzaldehyde disappeared. The resulting solution was concentrated and purified by silica gel chromatography (hexane:ethylacetate=5:1) to obtain 4-(2-isopropoxyethoxy)benzaldehyde as yellow oil (0.98 g, yield: 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 3 mL 50% aqueous tetrahydrofuran were added 0.43 mL (0.86 mMol) 2N sodium hydroxide followed by 0.065 mL (0.56 mMol) benzoyl chloride and the resulting mixture was stirred at room temperature. After about 4 hours the reaction mixture was partitioned between dichloromethane and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane (2-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.095 gm (66%) of the title compound. A portion was recrystallized from ethanol/water to provide an analytical sample.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:25])[CH2:21][C:22](=[NH:24])[NH2:23])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]([C:21]1[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:23][C:22]=1[NH2:24])=[O:25])[CH3:18]
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1ccccc1
Yield: 69 %

Procedure:
Upon heating a solution of 20.8 of benzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 2 hours, 2-amino-4,6-diphenyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 159°C (ethanol) is obtained. Yield: 69 percent of theory.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:29]1[CH:28]=[C:27]([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Lithium hydroxide monohydrate (0.030 g, 0.72 mmol) was added to a stirred solution of {4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (10 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.082 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H), 10.60 (br. s, 1 H), 8.00 (dd, J=8.80, 6.80 Hz, 1 H), 7.88-7.92 (m, 3 H), 7.45 (d, J=8.31 Hz, 2 H), 7.29-7.40 (m, 2 H), 7.09-7.17 (m, 3 H), 6.52 (d, J=11.74 Hz, 1 H), 3.83 (s, 2 H), 2.00 (s, 3 H). MS calcd. for C25H18FClNO4S [(M−H)−] 482, obsd. 482.3.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:17])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:17])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1sc(N2CC[C@H](N)[C@H](OC)C2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Yield: 84.4 %

Procedure:
The same operation as in Example (221c) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-3-methylthiophene-2-carboxylate obtained in Example (245c) (50 mg, 0.18 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (46 mg, 0.26 mmol), WSC hydrochloride (101 mg, 0.53 mmol), 1-hydroxybenzotriazole (26 mg, 0.19 mmol) and N-methylmorpholine (0.04 mL, 0.35 mmol), to obtain 67 mg of the title compound as a white solid (86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[C:16]([N+:28]([O-])=O)[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:26])[CH3:27])=[C:16]([NH2:28])[CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(NC(C(C)C)C(C)C)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](NC(=O)c1ccc(NC(C(C)C)C(C)C)c(N)c1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
1.35 g of (S)-2-[4-(1-Isopropyl-2-methyl-propylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester were dissolved in 14 ml ethanol, 0.30 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 4 h. The catalyst was removed by filtration over celite, and the reaction mixture was concentrated to yield 1.00 g (79%) of (S)-2-[3-Amino-4-(1-isopropyl-2-methyl-propylamino)-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester as a viscous oil, which was used without further purification.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O1CCCCC1[O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.O1CCCCC1OC1C=CC(Br)=CC=1.[Mg]>O1CCCC1.Cl[Cu].C(OCC)C>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:30]1[CH:29]=[CH:28][C:27]([OH:26])=[CH:32][CH:31]=1
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Agent: Cl[Cu]
Agent: Brc1ccc(OC2CCCCO2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCCCCCCCCCc1ccc(O)cc1
Yield: 36 %

Procedure:
0.4 g of CuCl and 29 g of 11-(tetrahydropyran-2-yloxy)-1-bromoundecane (B) were added to a filtered solution of 4-(tetrahydropyran-2-yloxy)phenyl magnesium bromide (A), prepared from 20.0 g of 4-(tetrahydropyran-2-yloxy)-1-bromobenzene and 3.16 g of magnesium, in 100 ml of tetrahydrofuran. After refluxing for 2 days, the reaction mixture was mixed with 100 ml of diethyl ether, followed by extraction with 100 ml of a saturated NH4Cl solution. After evaporation, the intermediate product C was refluxed for one hour with 40 ml of methanol and 1 ml of saturated hydrochloric acid. 15 ml of a saturated solution of NaHCO3 was added and the methanol was evaporated. 100 ml of diethyl ether was added. 7.4 g of 4-(11-hydroxyundecyl) phenol (D, 36%) was obtained after extraction with 50 ml of saturated sodium chloride, drying over magnesium sulphate, evaporation and recrystallisation from toluene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([OH:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2onc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1noc2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N,N-dimethylformamide is stirred for 30 minutes, treated with methyl bromoacetate (3.96 g, 0.0260 mol), stirred overnight at room temperature, and poured into an acidic ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and a (1:1) to (4:1) methylene chloride/hexanes gradient gives the title product as a white solid (2.80 g, mp 72-73.5° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:26]2[CH2:32]Br>CN(C)C=O>[F:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[C:26]2[CH2:32][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CNCc1ccc(C(C)(C)C)cc1
Reactant: Fc1cc(F)c2cccc(CBr)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.3 g of N-methyl-4-tert.butylbenzylamine, 0.25 g of potassium carbonate and 5 ml of abs. dimethylformamide (DMF) are added dropwise 0.4 g of 5,7-difluoro-1-bromomethylnaphthalene and the mixture stirred overnight at RT. The solvent is removed under vacuum and the residue partitioned between ether and water. The organic phase is dried and evaporated. The pure product is obtained as an oil following chromatography on silica gel (eluant:hexane/ethylacetate=95/5).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([OH:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:20][O:21][C:22](=[O:43])[CH2:23][N:24]([CH2:36][C@@H:37]([NH2:42])[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:43])[CH2:23][N:24]([CH2:36][C@@H:37]([NH:42][C:14](=[O:16])[CH2:13][C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:18][CH:17]=2)[CH:9]=[N:10][CH:11]=1)[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Reactant: CC[C@H](C)[C@H](N)CN(CC(=O)OC)Cc1cccc2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid (220 mg,0.533 mmol) and the amine hydrochloride salt from step C (212 mg,0.533 mmol), HOBT (72 mg, 0.533 mmol), and N-methylmorpholine (117 μl, 1.11 mmol) in DMF (2 ml) was added EDC (764 mg, 3.99 mmol). The reaction was stirred at room temperature for 72 hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine, dried (Na2SO4). and evaporated in vacuo. The residue was chromatographed (SiO2, 3-4% MeOH in CH2Cl2, gradient elution) to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1coc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1coc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 6-methoxybenzofuran-3-carboxylate (498 mg, 2.42 mmol) was dissolved in dichloromethane (100 mL) then cooled to −10 C. A solution of 1M boron tribromide in dichloromethane (9.67 mL, 9.67 mmol) was added slowly via syringe. The dark purple reaction mixture was warmed to RT over 3 h then continued stirring at RT for an additional 4 h. The mixture was slowly quenched with aqueous 1N hydrochloric acid until it became colorless. The mixture was diluted with dichloromethane and washed with water (2×) and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The remaining orange-brown solid was purified by silica gel chromatography (1:4 EtOAc/hexane) to afford methyl 6-hydroxybenzofuran-3-carboxylate as an off-white solid. MS (ESI, neg. ion) m/z: 191.1 (M−1).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:15])[CH2:6][O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][CH:13]=1)=[N+:2]=[N-:3].[H-].[Na+]>C1COCC1>[N:1]([CH2:4][C@@H:5]1[O:15][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[O:7][CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@H](O)COc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H]1COc2cccnc2O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Dissolve (2S)-1-azido-3-[(2-chloro-3-pyridyl)oxy]propan-2-ol (40.28 g, 176.17 mmol) in THF (880 mL) and slowly add sodium hydride (60% dispersion in mineral oil; 14.09 g, 352.35 mmol). Heat the mixture to 90° C. and stir for 2 hours at that temperature. Slowly pour the mixture into 1 liter of packed ice to quench the reaction. Remove the dioxanes under reduced pressure and extract the resulting mixture with EtOAc (3×). Dry the combined extracts over Na2SO4; filter; and concentrate the filtrate under reduced pressure. Purify via flash column chromatography using 2×330 g silica gel, eluting with a gradient of 0-75% of Et2O in hexanes. Combine the product fractions and remove solvents under reduced pressure to provide the title compound as a yellow solid (7.5 g., 22.15%). MS (m/z): 193 (M+1).
Reaction SMILES: [CH2:1]([N:8]([C:16]12[CH2:23][CH2:22][C:19]([CH:24]([C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[C:28]4[N:33]([Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:34]=[CH:35][C:27]=34)[OH:25])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([N:8]([C:16]12[CH2:23][CH2:22][C:19]([C:24]([C:26]3[C:27]4[CH:35]=[CH:34][N:33]([Si:36]([CH:43]([CH3:45])[CH3:44])([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:41])[CH3:42])[C:28]=4[N:29]=[CH:30][C:31]=3[Cl:32])=[O:25])([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C34CCC(N(Cc5ccccc5)C(=O)OC(C)(C)C)(CC3)CC4)c(Cl)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C34CCC(N(Cc5ccccc5)C(=O)OC(C)(C)C)(CC3)CC4)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.26 g, 1.93 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.64 g, 3.86 mmol). The reaction was stirred at ambient temperature for about 3 h and was diluted with DCM (10 mL). The mixture was washed with saturated aqueous NaHCO3 (2×15 mL), brine (15 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The resulting oil was purified by silica gel chromatography eluting with a gradient of 0-25% EtOAc in heptane to give tert-butyl benzyl(4-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-bicyclo[2.2.2]octan-1-yl)carbamate (0.965 g, 77%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.32-7.24 (m, 3H), 7.23-7.08 (m, 3H), 6.23 (d, J=3.5, 1H), 4.53 (s, 2H), 2.13-2.03 (m, 6H), 1.95-1.83 (m, 6H), 1.81-1.74 (m, 3H), 1.41 (s, 9H), 1.12-1.06 (m, 18H).
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]([O:18]CC)=O)[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH3:21].CO>>[OH:1][C:2]1([CH2:15][C:16]([NH2:21])=[O:18])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: CCOC(=O)CC1(O)CCN(Cc2ccccc2)CC1
Solvent: CO
Product: NC(=O)CC1(O)CCN(Cc2ccccc2)CC1

Procedure:
A solution of ethyl [4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetate (15 g, 54.15 mmol) [prepared according to Caroon, J. M.; et al. J. Med. Chem. 1981, 24,1320.] in 7N NH3-MeOH (16 mL) was heated to 100° C. in a sealed tube for 3d. The solution was cooled and concentrated and the residue washed with DCM providing the title compound (4 g, 30%) as a white solid which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: O=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8]1)=[O:6].O.C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[C:16]1([C:2]2[O:6][C:5]([CH:7]3[CH2:12][CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8]3)=[N:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)N1CCC(C(=O)NCC(=O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(c2ncc(-c3ccccc3)o2)CC1

Procedure:
A suspension of 1-acetyl-piperidine-4-carboxylic acid (2-oxo-2-phenyl-ethyl)-amide (1.1 g, 3.8 mmol), prepared as in Part A, in conc. H2SO4 (20 mL) is warmed to 65° C. for 1 h. The warm solution is poured into H2O (250 mL), which is neutralized with solid NaHCO3. This solution is extracted with EtOAc (2×200 mL) and the combined organic extracts are dried (MgSO4) and concentrated to afford 1-[4-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone as a clear oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]([C:29]([F:32])([F:31])[F:30])=[N:11][C:12]([N:15]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([O:27]C)=[O:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:7]([C:9]2[C:10]([C:29]([F:30])([F:31])[F:32])=[N:11][C:12]([N:15]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CCCN2c1ncc(C(=O)N2CCOCC2)c(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCCN2c1ncc(C(=O)N2CCOCC2)c(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a mixture of methyl 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg) and methanol (2 mL) was added a 1 M aqueous sodium hydroxide solution (670 μL) at room temperature, followed by stirring at 60° C. for 3 hours. To the reaction mixture were added 1 M hydrochloric acid and water, followed by stirring at room temperature for 30 minutes, and then the resulting precipitate was filtered and washed with water to obtain 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (95 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([OH:13])=O)[CH:3]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1OCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1OCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold suspension of 4-chloro-o-tolyloxyacetic acid (17.4 mmol) in 40 mL of dry dichloromethane was added oxalyl chloride (39.15 mmol) followed by one drop of N,N-dimethylformamide. Bubbling immediately began. After 30 minutes, the reaction mixture was warmed in a 45° oil bath for 1.5 hours. The solution was cooled to room temperature and all volatiles were removed by evaporation. Dry nitrogen gas was introduced into the evaporator and more dry dichloromethane was added. This was evaporated again in vacuo. Finally, dry toluene was added to the residue and this was evaporated at reduced pressure. The prepared acid chloride was used without further purification in the following step.