Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:5]=1[Br:17].C[O-:21].[Na+].Cl>C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:21]
Reactant: C[O-]
Reactant: CC(C)(C)c1cc(Br)c(COC(=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2-Bromo-4-tert-butyl-5-nitro-phenyl)methyl carbonate (72.9 g, 219.5 mmol) was charged to a reactor and DCM (291.6 mL) was added. The yellow reaction solution was cooled using an ice bath. Sodium methoxide (67.04 g, 69.11 mL of 5.4 M, 373.2 mmol) was added portion-wise at 2.2-6.9° C. After complete addition, the reaction was slowly warmed to ambient temperature. When complete, the reaction was cooled to 0° C. and quenched with 1M HCl (373.2 mL, 373.2 mmol). The biphasic mixture was stirred for 20 min and transferred to a seperatory funnel. The organic layer was separated and washed with water (300 mL) followed by brine (300 ml). The organic layer was concentrated and the crude product dried under high vacuum. The product was further purified using Supercritical Fluid Chromatography (SFC) separation on a Berger MultiGram III (Mettler Toledo AutoChem, Newark Del.). The method conditions were 20% methanol at 250 mL/min on a PPU column (30*150) from Princeton Chromatography, 100 bar, 35 C, 220 nm. An injection of 3.5 mL of a 55-70 mg/mL solution was injected. The data was collected using SFC ProNTo software. The purified product received from SFC purification was a methanol solvate. To remove the methanol, an azeotropic distillation was performed. The dark yellow solid, 2-bromo, 4-tertbuyl, 5-nitro phenol methanol solvate, (111.3 g, 0.59.9 mmol) was charged to a 1 L round bottom flask, followed by heptane (500 mL). The slurry is heated to 64° C. to obtain a clear solution. The solvent was distilled under reduced pressure (649 mbar) for 30 minutes and then stripped to dryness. This procedure was repeated three times until no MeOH was detected by 1H-NMR. The product was dried under high vacuum for 16 hours to give the product as a dark yellow semi solid. 1H-NMR (400 MHZ, DMSO-d6) δ 11.2 (bs, OH), 7.69 (s, 1H); 7.03 (s, 1H); 1.30 (s, 9H)
Reaction SMILES: [SH2:1].[CH3:2][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17]#[N:18])[N:7]=1)([CH3:5])[CH3:4].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:5][C:3]([C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=[C:8]([C:17](=[S:1])[NH2:18])[N:7]=1)([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1nc(C#N)nc(C(C)(C)C)c1O
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(C(N)=S)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Hydrogen sulfide is bubbled through a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbonitrile (4.5 g, 19.3 mmol) and triethylamine (4.3 g, 42.4 mmol) in pyridine (20 mL) at room temperature for 6 hours. The reaction mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum and the residue is recrystallized from ether/hexane to give pure 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carbothioamide (3.0 g, 58%); mp 169°-171° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:19])=[CH:16][CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(Br)cc1)c1cccnc1
Reaction time: 0.42 h
Yield: 39.5 %

Procedure:
3-Bromopyridine (0.4 ml, 4.0 mmol) was dissolved in 15 ml of tetrahydrofuran in an argon atmosphere. n-Butyllithium (1.58 M n-hexane solution, 2.4 ml, 3.8 mmol) was added to the solution at −78° C., and the mixture was stirred for 25 min. Subsequently, a solution of 502 mg (2.7 mmol) of 4-bromobenzaldehyde in tetrahydrofuran (2 ml) was added dropwise thereto at −78° C., and the mixture was stirred at −78° C. for one hr, was stirred under ice cooling for one hr, and was then stirred at room temperature for one hr. The reaction solution was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with a saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with 5 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 282 mg (yield 40%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([OH:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 25 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with (3-hydroxy-5-(trifluoromethyl)phenyl)boronic acid (70 mg, 0.34 mmol), sodium carbonate (108 mg, 1.02 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (6 mg, 0.01 mmol) according to the method described in the Preparation 17. The residue was purified by reverse phase using SP1® Purification System to give 30 mg (25% yield) of the title compound as a solid. Purity 98%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=3)=[CH:5][CH:4]=2)=[CH:20][CH:19]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccc(Cl)cc3)cc2)no1
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 4-chlorophenol (21 mg, 0.16 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(4-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (29 mg, 82%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.50-7.65 (m, 3H), 7.26-7.38 (m, 2H), 6.97-7.11 (m, 2H), 5.17 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)=[O:8]
Reactant: NCC1CCCCN1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
contacting the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.O>CS(C)=O>[CH3:12][O:13][CH2:14][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccn1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11.8 g. (0.1 mole) of 2-pyridylacetonitrile in dry dimethylsulfoxide at 10° C. is added 0.1 mole of sodium hydride (dispersed in mineral oil). After 20 minutes, 0.1 mole of chloromethyl methyl ether is added with cooling and the mixture is kept at 10° C. for 2 hours, then allowed to warm to room temperature overnight. The reaction mixture is poured into water and extracted with ether. The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum and distilled to give 3-methoxy-2-(2-pyridyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[Na+].Cl.[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of 200 g (1.4 mole) of 2-chlorobenzaldehyde in 500 ml of acetone is treated with 200 ml of water, cooled in an ice bath, then treated with 40 ml of 10% NaOH by drops. The mixture is kept below 40° C. After the addition is complete the mixture is stirred at 25° C. for 1.5 hours, then acidified with 10% HCl. The mixture is diluted with water and extracted with benzene. 0.5 g of toluene-sulfonic acid is added to the benzene solution and the mixture refluxed under a water separator. A total of 6 ml of water is collected. The mixture is cooled, shaken with bicarbonate, dried (Na2SO4), and evaporated. Distillation gives 150 g (60%) of 4-(2-chlorophenyl)-but-3-ene-2-one, b.p. 106°-120° C. @ 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(O)=O>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:16]=2)[CH:3]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
Sodium tiracetoxyl-borohydride (985 mg, 4.65 mmol) was added to a solution of 6-chloro-pyrimidin-4-ylamine (200 mg, 1.55 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (682 mg, 3.1 mmol) in 25 ml of DCE. 1 ml of HOAc was added, and the mixture was stirred overnight at 50° C., followed by addition of 25 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 5:1) to give 64 mg of (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 12%.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:45]=[CH:46][CH:47]=4)[O:39][CH2:40][C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:45]=[CH:46][CH:47]=4)[O:39][CH2:40][C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(OCC(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(OCC(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of methyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenoxy}acetate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the precipitated crystals were collected by filtration to give {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenoxy}acetic acid as colorless crystals (0.18 g, yield 72%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 166-168° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([OH:21])[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>>[O:17]1[C:18]2[CH:19]=[CH:20][C:12]([CH2:11][O:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[CH:13][C:14]=2[O:15][CH2:16]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cnccc1OCc1ccc2c(c1)OCO2

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 and piperonyl alcohol (3.45 ml, 18.92 mmol), the titled compound was obtained as a yellow solid. (3.08 g, 88.6%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)cc1
Yield: 76.2 %

Procedure:
A solution of 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 4-(methyloxy)benzenesulfonyl chloride, (0.025 g, 0.13 mmol) and DIPEA (0.05 mL, 0.25 mmol) in CH2Cl2 (2 mL) was stirred overnight. The solvent was concentrated and purification was accomplished by RP-HPLC (water/acetonitrile/0.1% TFA). The desired fractions were lyophilized and EtOAc (25 mL) and sat. NaHCO3 (10 mL) were added. The layers were separated and the aqueous layer extracted with EtOAc (2×10 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to afford N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-4-(methyloxy)benzenesulfonamide (0.030 g, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.03 (t, 1H), 7.80 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.38 (dd, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 6.99-7.10 (m, 3H), 3.96 (d, 2H), 3.78 (s, 3H). MS: m/z 485 (M+23).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=O)C.[NH3:18]>>[C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[NH2:18]
Reactant: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N
Product: CC(C(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-proline (2 g.) is dissolved in 10% methanolic ammonia and the mixture stored at room temperature in a pressure flask. When thin layer chromatographic analysis indicates that all the starting material has been converted to the amide, the mixture is concentrated to dryness, and the residual ammonium salt is converted to the free acid with ion exchange resin (Dowex 50 hydrogen form) to obtain 1-(2-carbamoylpropanoyl)-L-proline, yield 1.1 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](OC)=[O:12].[BH4-].[Li+].O>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][OH:12]
Reactant: COC(=O)c1cc2ccccc2n1C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CO)cc2ccccc21
Yield: 99.9 %

Procedure:
A solution of 5.05 g of methyl 1-methylindole-2-carboxylate (prepared as described in Preparation 22) in 20 ml of anhydrous tetrahydrofuran was added dropwise to a mixture of 1.85 g of lithium borohydride and 80 ml of anhydrous tetrahydrofuran, and the resulting mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 4.30 g of the title compound, melting at 92.8°-95.2° C.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][NH:8][CH:3]([CH2:4][CH2:5]2)[CH2:2]1.[ClH:9].O.[OH-].[K+].[C:13]1([C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:22][CH2:23]Br)[C:20]#[N:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[ClH:9].[C:25]1([C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH2:22][CH2:23][N:8]2[CH2:7][CH:6]3[CH2:5][CH2:4][CH:3]2[CH2:2][CH2:1]3)[C:20]#[N:21])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C1CC2CCC1CN2
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 0.85 part of 2-azabicyclo-[2.2.2.]octane hydrochloride in 20 parts of water is added 0.71 part of potassium hydroxide under a nitrogen atmosphere. Then, 1.90 parts of 2,2-diphenyl-4-bromobutyronitrile is added, and the mixture heated to reflux for 3.5 hours. This reaction mixture is cooled to about 60° C., whereupon 13 parts of benzene is added. The aqueous layer is separated and extracted with 15 parts of benzene. To the combined benzene extracts is added dropwise 2 parts by volume of a solution of hydrochloric acid in isopropanol. The volume of this solution is reduced by heating on a steam bath. Cooling affords a white precipitate which is washed with benzene and dried at 100° C. for about 2 hours. The resulting product, 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile hydrochloride, is obtained in approximately 76.8% yield. This product melts at about 194° - 197° C., and is represented by the following structural formula. ##STR11##
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-])#[N:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[N:4]=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: Cc1cc[n+]([O-])c(C#N)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(C#N)c1
Yield: 80.8 %

Procedure:
A mixture of 2-cyano-4-methylpyridine-1-oxide (4.03 g, 30 mmol) in phosphoryl trichloride (80 mL, 858 mmol) was heated to reflux overnight. The solvent was removed in vacuo. The residue was treated with ice and its pH made basic using saturated NaOH solution at 0° C. The aqueous layer was extracted with DCM (3×). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound (3.7 g, 81%). ESI-MS m/z [M+H]+ 153.6.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](C1NN=CC=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:37]1[CH:38]=[N:33][CH:34]=[N:35][CH:36]=1)[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc2nc(-c3ccn[nH]3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3cncnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid (87) was prepared following the procedure used for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 70 except that pyrimidin-5-ylboronic acid was used instead of 1H-pyrazol-5-ylboronic acid. 1H-NMR: 400 MHz, (CD3CN) δ: 9.52 (br s, 2 H), 9.26 (s, 1 H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1 H), 7.83 (d, J=9.2 Hz, 1 H), 7.60 (m, 3 H), 7.37 (d, J=7.6 Hz, 1 H), 5.27 (s, 1 H), 2.65 9s, 3 H), 0.99 (s, 9 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H25ClN3O3: 462.15. found: 462.45.
Reaction SMILES: C(O)(=O)C.[N+:5]([CH:8]([CH3:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10])([O-])=O>C(O)(C)C>[NH2:5][CH:8]([CH3:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10]
Reactant: CC(C(O)c1ccccc1)[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(N)C(O)c1ccccc1

Procedure:
In the practice of this invention, the 2-nitro-1-phenyl-1-propanol is dissolved in a lower alkyl alcohol, preferably isopropyl alcohol. The mixture is placed in a vessel suitable for high pressure reactions and equipped with agitation means, e.g. a rocking bomb or a stirred bomb. Acetic acid is added to the solution to produce the acetate salt of 2-amino-1-phenyl-1-propanol during the reduction reaction.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11]O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cn2ccccc2n1
Solvent: ClCCl
Product: ClCCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A mixture of 2-(imidazo[1,2-a]pyridin-2-yl)ethanol (400 mg, 2.466 mmol) from Example a4) and SOCl2 (2 mL, 27.4 mmol) in DCM (10 mL) was stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (3×100 mL) and washed with saturated NaHCO3 solution (6 mL×4) and brine (6 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Pre-TLC (PE/EA=1/1, v/v) to give the title compound as an oil (300 mg, yield 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].N.O1CCOCC1.[Li+].C[Si]([N-:39][Si](C)(C)C)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([NH2:39])=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(N)=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (280 mg, 0.746 mmol) was dissolved in tetrahydrofuran (THF) (5 mL) and to this solution was added ammonia in dioxane (0.5 M) (4.47 mL, 2.237 mmol), followed by LiHMDS in THF (1 M, 0.895 mL, 0.895 mmol). The reaction was left to stir overnight at room temperature, under nitrogen. The reaction was quenched with water (1 mL) then combined with a previous identical trial reaction on a smaller (0.075 mmol) scale, for workup. The crude was concentrated in vacuo, then the product was extracted to the organic phase of an aqueous work up between ethyl acetate (15 mL) and brine (10 mL). The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the crude product, 263 mg. No further purification was undertaken. LCMS [LCMS1] Rt 1.14 min, m/z (ES+) 361 (M+H).