Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[C:20]([F:22])[C:19]([NH2:23])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:20]1[C:19]([NH2:23])=[CH:18][CH:17]=[C:16]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=3[CH:8]=2)[N:21]=1
Reactant: Nc1ccc(Br)nc1F
Reactant: COc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(N)c(F)n3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
5-Methoxybenzofuran boronic acid (345 mg, 1.80 mmol), 6-bromo-2-fluoro-pyridin-3-ylamine (286.5 mg, 1.50 mmol), Pd(PPh3)2Cl2 (25.2 mg, 0.036 mmol) and Et3N (475.5 μL, 3.41 mmol) were mixed in EtOH (10 mL) in a microwave vial. The reaction mixture was stirred at 140° C. for 10 minutes in a microwave reactor. The volatiles were then removed under reduced pressure and water was added (20 mL). The product was extracted with ethyl acetate (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of the crude product by flash column chromatography using 25% ethyl acetate in hexane gave 2-fluoro-6-(5-methoxy-benzofuran-2-yl)-pyridin-3-ylamine (268 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.58 (d, J=7.6 Hz, 1 H), 7.39 (d, J=9.0 Hz, 1H), 7.15 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.88 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H). ESMS: m/z 259.47 [M+1]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 98.3 %

Procedure:
A mixture of morpholine (50 g, 0.6 mol) and 4-fluorobenzonitrile (24 g, 0.2 mol) is heated at 120° C. The conversion of the 4-fluorobenzonitrile is complete after 5 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 37 g of the title-compound. Yield: 95%; m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32](OCC)=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH3:44]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32](=[O:33])[NH2:44])[CH2:29][CH2:30][CH2:31]3)[N:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(N)=O)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
50 mg of 4-((S)-4-Carboxy-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester were dissolved in 1 ml of a 8 M solution of ammonia in methanol. After 16 h at RT the solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[C:5]([C:16]([OH:18])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][C:9]2[C:4](=[C:5]([C:16]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:18])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cccc2cc(C(F)(F)F)c(Cl)nc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cccc2cc(C(F)(F)F)c(Cl)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2-chloro-3-(trifluoromethyl)quinoline-8-carboxylic acid (165 mg, 0.60 mmol), 3-aminopyridine (73 mg, 0.78 mmol), HATU (365 mg, 0.96 mmol), DIPEA (312 mg, 2.4 mmol) in CH2Cl2 (4 ml) was stirred at room temperature under N2 overnight. The reaction mixture was washed with water (5 mL) and brine (3×5 mL). The organic solution was dried, concentrated, and purified by silica gel column chromatography (25% ethyl acetate in pentane to give 2-chloro-N-(pyridin-3-yl)-3-(trifluoromethyl)quinoline-8-carboxamide as a white solid. (36 mg 65% yield.)
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)=[O:13])[N:10]=[C:6]2[C:5]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]3)=[N:42][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>>[O:27]1[CH2:28][CH2:29][N:24]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([NH:11][C:12]([C:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=4)=[O:13])[N:10]=3)[C:2]([C:38]3[CH:39]=[CH:40][C:41]([N:44]4[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]4)=[N:42][CH:43]=3)=[CH:3][N:4]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=C(Nc1cn2c(Br)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(NC(=O)c5ccc6ccccc6n5)cn34)cn2)CC1

Procedure:
Compound 21d was prepared from compound 21c and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate using the reaction conditions described in Example 1, Step G, and substituting K2CO3 as the base. Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H37N9O4: 636.3 (M+H). Found 636.4.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:19])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:9]1[CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:19])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)c2ccccn2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O)c2ccccn2c1=O
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 1-t-butyldimethylsiloxy-3-ethoxycarbonyl-4H-quinolizin-4-one (3.32 g) in tetrahydrofuran (100 ml) was added a solution of tetra-n-butylammonium fluoride (1M, 11.47 ml) at 0° C. The mixture was stirred for one hour and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was filtered and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 1-hydroxy-3-ethoxycarbonyl-4H-quinolizin-4-one (1.13 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH2:35])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:23][C:24]([F:37])([CH3:36])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: CC(F)(F)COc1ccc(CCN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ccc(CCNc2ncc(C#N)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 30 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, 0.28 mmol), 2-(4-(2,2-difluoropropoxyl)phenyl)ethanamine (70 mg crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to give the title product (38.6 mg, 0.084 mmol, 28% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.15-7.97 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.39-4.22 (m, 1H), 4.12 (t, J=11.6 Hz, 2H), 3.66-3.49 (m, 2H), 3.41-3.35 (m, 1H), 2.88-2.77 (t, J=7.2 Hz, 2H), 1.96-1.82 (m, 1H), 1.80-1.42 (m, 8H), 1.03-0.95 (m, 6H). MS (ESI) m/z 460.2 [M+H]+.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:6][CH2:5]1)#[N:2].[CH2:28]([Li])CCC.CI.O.C(OCC)(=O)C>O1CCCC1>[C:1]([CH:3]=[C:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][N:22]([CH3:28])[C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH2:8][CH2:9]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC(=O)N(C)C[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Yield: 44 %

Procedure:
The compound obtained in Example 9 (1 mmol) was treated with n-butyl lithium (1.6 M in hexane, 1.6 mmol), methyl iodide (2 mmol) in 10 ml tetrahydrofuran at −78° C. temperature. The reaction mixture was with ethyl acetate water mixture. The organic layer was evaporated to give a crude compound, which was chromatographed on a silica gel to give the titled compound in 44% yield.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH3:27])[C:14]2[CH:18]([CH2:19][C:20]([O:22]CC)=[O:21])[O:17][B:16]([OH:25])[C:15]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.O>[C:1]([O:5][C:6]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH3:27])[C:14]2[CH:18]([CH2:19][C:20]([OH:22])=[O:21])[O:17][B:16]([OH:25])[C:15]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCC(=O)OC(C)(C)C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 2-(6-(2-(tert-butoxycarbonyl)ethoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (80 mg, 0.2 mmol) in 16 mL of THF/H2O (1/1) was added LiOH (42 mg, 1.0 mmol) in 5 mL of H2O at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1 N HCl to pH=5. The resulting mixture was extracted with EtOAc (3×20 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as an off-white powder (60 mg, yield: 82.2%). 1H NMR (400 MHz, DMSO) δ12.23 (s, 1H), 9.09 (s, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.45-5.42 (m, 1H), 3.96-3.93 (m, 2H), 3.27-3.31 (m, 2H), 3.00-3.04 (m, 1H), 2.25 (s, 3H), 2.08-2.02 (m, 1H), 1.39 (s, 9H); MS (ESI) m/z=366 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])(=[O:13])C.[Na+].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:13]
Reactant: CC(=O)[O-]
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: OCc1ccc(Cl)cc1Cl
Reaction time: 25 h
Yield: 94.6 %

Procedure:
2,4-Dichlorobenzyl chloride (100 g) was added to a solution of sodium acetate (208.8 g) and tetrabutylammonium hydrogen sulphate (2 g) in water. The mixture was heated under reflux with stirring for 25 hours. Aqueous sodium hydroxide (50 ml. of 70% w/v solution) was added and the refluxing continued for 30 minutes. The mixture was cooled and the solid collected by filtration, washed with water and dried in vacuo to give 2,4-dichlorobenzyl alcohol, having a purity of 99.3%, in a yield of 94.6%.
Reaction SMILES: [C:1]([N:10]1[C@@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][O:12][C:11]1=[O:22])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].C(N(C(C)C)CC)(C)C.[O:32]1[CH2:37]CCOO1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:32][CH2:37][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:1]([N:10]1[C@@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][O:12][C:11]1=[O:22])=[O:9]
Reactant: C1COOOC1
Reactant: C=CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S)-3-(7-octenoyl)-4-benzyl-1,3-oxazolidin-2-one (2.24 g, 7.59 mmol) and titanium (IV) chloride (1M in dichloromethane, 8.0 mL, 7.97 mmol) in dichloromethane (35 mL) at 0° C. was added dropwise diisopropylethylamine (1.5 mL, 8.35 mmol). After stirring at 0° C. for 1 hour, the resulting titanium enolate was then reacted with a solution of trioxane (0.82 g, 9.11 mmol) in dichloromethane (7 mL), followed by the addition of a solution of titanium (IV) chloride (1M in dichloromethane, 8.0 mL, 7.97 mmol). The reaction mixture was then stirred at 0° C. for 4 h. The reaction mixture was then quenched with saturated ammonium chloride (50 mL). The aqueous layer was extracted with dichloromethane (100 mL×2). The organic extracts were washed with brine, and dried over MgSO4, filtered and concentrated in vacuo to yield the title compound. MH+332.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:16]([O:17]COCC[Si](CC)(CC)CC)=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])=[CH:5][CH:4]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2ncccc2OCOCC[Si](CC)(CC)CC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ncccc2O)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a solution of 4-ethylphenyl-[3-[2-(triethylsilyl)ethoxymethoxy]]pyridin-2-yl-methanol (2.35 g, 6.54 mmol) in THF-water (25:1; 60 mL), p-toluenesulfonic acid monohydrate (2.8 g, 16.4 mmol) was added and stirred at room temperature for 20 hours and at 40° C. for 4 hours. After cooling the reaction mixture to room temperature, saturated sodium bicarbonate solution (100 mL) was added and the resulting mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 4-ethylphenyl-3-hydroxypyridin-2-yl-methanol (0.62 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([N:16]([CH:17]3[CH2:18][CH2:19]3)[S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:39])[F:40])[CH:30]=3)(=[O:37])=[O:36])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@@H]3CC[C@H](NC4CC4)[C@@H]3C2)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3aS*,4S*,6aR*)-2-Benzyl-N-cyclopropyloctahydrocyclopenta[c]pyrrol-4-amine (382 mg, 1.490 mmol) from Example 198, triethylamine (312 μL, 2.235 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (262 μL, 1.639 mmol) were combined in tetrahydrofuran (7 mL). A catalytic amount of (dimethylamino)pyridine was added, and the reaction mixture was stirred at room temperature overnight. The solvent was reduced in volume, and the crude material applied to silica gel and eluted with 20% to 100% ethyl acetate/hexanes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.46 (s, 1H), 8.31 (d, J=7.9, 1H), 7.93 (d, J=7.8, 1H), 7.74 (t, J=7.9, 1H), 7.41 (d, J=7.2, 2H), 7.36 (t, J=7.4, 2H), 7.29 (t, J=7.2, 1H), 3.97 (ddd, J=6.1, 7.7, 13.5, 1H), 3.54-3.45 (m, 2H), 3.17 (dt, J=5.9, 11.8, 1H), 2.82 (dd, J=3.6, 9.7, 1H), 2.55 (t, J=8.2, 1H), 2.51-2.43 (m, 2H), 2.36-2.22 (m, 2H), 1.88-1.82 (m, 1H), 1.57 (dt, J=5.9, 11.6, 1H), 1.43-1.32 (m, 3H), 1.05-0.98 (m, 1H), 0.80 (ddd, J=6.9, 9.8, 12.4, 1H), 0.73-0.65 (m, 1H); MS (ESI+) m/z 465 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:22]([Cl:38])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:38][C:22]1[CH:21]=[C:20]([N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: Fc1ccc2c(c1)CNCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3ccc(F)cc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (151 mg, 1.35 mmol), 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride (122 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: C[C@H](O)c1ccccc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1F

Procedure:
In a similar manner as described for example B31, 2.31 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.92 g of (1S)-1-(2-fluorophenyl)ethanol, 3.67 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.53 g of di-tert-butyl azodicarboxylate in 65 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:6][CH2:7][C:8]([NH:10]/[C:12](=[CH:16]\[CH3:17])/[C:13]([OH:15])=[O:14])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)CCC1CCCC1
Reactant: CCC(=O)C(=O)O
Product: C/C=C(\NC(=O)CCC1CCCC1)C(=O)O
Reaction time: 8 h

Procedure:
A solution of 1.41 g (10 mmole) of 3-cyclopentylpropionamide and 1.53 g (15 mmole) of 2-ketobutyric acid was stirred and refluxed under a small Dean-Stark trap. After 8 hrs. the solution was cooled, resulting in heavy crystallization. The solid was collected on a filter and washed with toluene and CH2Cl2. Yield of white crystals=1.44 g, mp 180.5°-182° (prelim. softening). The material was recrystallized from methyl ethyl ketone. Yield of white needles=0.63 g (28%), mp 184°-185° (slight prelim. softening). Tlc (4:1 toluene-AcOH) now showed a single spot, and NMR indicated essentially pure Z-isomer.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:30][O:31][CH2:32][CH2:33]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:30][O:31][CH2:32][CH2:33][O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1
Reactant: COCCBr
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), 2-bromoethyl methyl ether (0.070 mL, 0.75 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column-chromatography eluting with hexane/AcOEt (1/2) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 (1H, dd, J=1.9, 7.9 Hz), 7.20 (1H, s), 7.34-7.45 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 8.29 (1H, s). LC-MS (ESI) m/z 457 [M+H]+. Anal. Calcd for C23H19F3N4O3.0.25H2O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:5]2[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:4]=2[NH:3]1.[ClH:29]>CO.C(O)C>[ClH:29].[NH:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5]3[CH:20]=[C:21]([O:24][C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:23][C:4]=3[NH:3][C:2]2=[O:1])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(OC(F)(F)F)cc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: O=c1[nH]c2ccc(OC(F)(F)F)cc2n1C1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl 4-{2-oxo-6-[(trifluoromethyl)oxy]-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D31) (1.54 g) in methanol (20 mL) was treated with a saturated solution of hydrogen chloride in ethanol (10 mL). The mixture was stirred for 1 hour when the solvent was removed to give the title compound as a white solid (1.28 g).