Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:15]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]2[CH3:21])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([N:15]2[C:19]([I:1])=[C:18]([CH3:20])[N:17]=[C:16]2[CH3:21])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2
Reactant: ClI
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1I
Reaction time: 16 h

Procedure:
Iodine monochloride (0.406 g) was added at room temperature to a stirred solution of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.506 g) and sodium acetate (0.328 g) in acetic acid (10 cm3). After 16 hours, volatile material was removed in vacuo and the residue partitioned between aqueous 2M sodium carbonate solution (50 cm3) and dichloromethane (50 cm3). The aqueous phase was further extracted with dichloromethane (2×50 cm3) and the combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from ethyl acetatemethanol to give the title compound, m.p. 242°-245° (0.38 g).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10](C)[CH3:11])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.C1([C@@H]2C[C@H]2C(O)=O)C=CC=CC=1>>[C:6]1([C@@H:5]2[CH2:4][C@H:13]2[C:14]([C:16]2[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=2)=[O:15])[CH:7]=[CH:8][CH:9]=[CH:11][CH:10]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Product: CC(C)c1ccc(C(=O)[C@@H]2C[C@H]2c2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with trans-2-phenylcyclopropylcarboxylic acid, mp 166°-168° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:21][CH3:22])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(N)=O)[CH3:2].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:46])C>O>[CH2:1]([C:3]([CH2:21][CH3:22])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:46])[CH3:2]
Reactant: CC#N
Reactant: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CCC(N)(CC)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-(phenylmethoxy)-benzeneacetamide (Example 266c, 0.77 g) in acetonitrile (6 mL) and water (6 mL) was treated with (bis(trifluoroacetoxy)iodo)benzene (1.113 g) under nitrogen and the reaction stirred at room temperature for 16 h. Further (bis(trifluoroacetoxy)iodo)benzene (1.0 g) was added and the reaction stirred for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified on SCX resin eluting with methanol (discarded) followed by 7N NH3 in methanol. The basic fractions were collected and the volatiles were removed in vacuo to afford subtitle compound (0.83 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[CH3:1])=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: Cc1csc2cccnc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 34.8 %

Procedure:
190 mg of 3-Methyl-thieno[3,2-b]pyridine (1.28 mmol) is dissolved in 3.0 ml of dry THF and cooled to −78° C. 0.62 ml of n-BuLi 2.5M in hexane (1.54 mmol) is added at −78° C. and stirred at −78° C. for 10 min and room temperature for 10 min. The reaction vessel is cooled to −78° C. again and 3.3 ml of 0.5 M ZnCl2 in THF (1.66 mmol) is added at −78C and stirred at room temperature for 15 min. 343 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.0 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) are added and the tube is capped. The tube is heated at 80° C. for overnight. The reaction is quenched by NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 127 mg of the title compound. Yield 35%. mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.79 (dd, 1H, J=4.8 Hz, 1.4 Hz), 8.21 (dd, 1H, J=7.9 Hz, 1.4 Hz), 7.33 (dd, 1H, J=7.9 Hz, 4.8 Hz), 6.76 (s, 1H), 3.38 (m, 1H), 2.55 (s, 6H), 2.47 (s, 3H), 1.89 (m, 4H), 0.92 (t, 6H, J=7.5 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][N:11]1[C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1>CN(C)C(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:16]([C:15]1[N:11]([CH3:10])[N:12]=[C:13]([CH3:19])[CH:14]=1)=[O:17]
Reactant: Nc1cc(O)ccc1Cl
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(O)ccc2Cl)n(C)n1
Yield: 70.3 %

Procedure:
In the same manner as in Reference Example 23 and using 3-amino-4-chlorophenol (920 mg, 6.4 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1170 mg, 7.4 mmol) and N,N-dimethylacetamide (13 mL) as starting materials, N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) was obtained. Using lithium aluminum hydride (1060 mg, 22 mmol), N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) and tetrahydrofuran (40 mL) as starting materials, the title compound (810 mg, 72%) was obtained as a brown solid.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].[NH4+].[Cl-]>C1COCC1>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[CH2:2][C:1]([O:4][CH3:5])=[O:3]
Reactant: COC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 63.4 %

Procedure:
Methyl acetate (5.09 mL, 64.0 mmol) was added dropwise to a cold (−78° C.) solution of LDA [prepared at 0° C. from i-Pr2NH (10.5 mL, 74.7 mmol) and 2.0 M n-BuLi in hexane (37.3 mL, 74.7 mmol)] in THF (50 mL). After 45 min, the enolate solution was added via cannula to a cold (−78° C.) solution of 2-chlorobenzaldehyde (3.00 g, 21.3 mmol) in THF (50 mL). The reaction mixture was stirred at −78° C. for 1 h. Aqueous saturated NH4Cl solution (15 mL) was then added and the mixture was allowed to warm slowly to room temperature. The mixture was concentrated under reduced pressure. The residue was taken in Et2O (300 mL) and the resulting solution was washed with water (2×50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was partially purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to give the title compound (2.9 g, 63% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=3)[OH:18])[C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1.[OH-:27].[K+]>C(O)(C)(C)C>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:27])=[N:23][CH:24]=3)[OH:18])[C:7]3[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][C:12]=3[C:13]=2[CH:14]=1
Reactant: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
5-[2-(3,6-Dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (600 mg, 1.729 mmol) was dissolved in tert-butanol (12 mL), crushed potassium hydroxide (290 mg, 5.187 mmol) was added, and the mixture heated at 80° C. for 1 h. The reaction was monitored by TLC & LCMS. The reaction mixture was allowed to cool to RT, the solvent was removed under vacuum, and the residue was diluted with water (20 ml) and extracted with EtOAc (2×75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to afford 100 mg of 5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylic acid amide. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.62 (s, 1H), 8.1 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.8 (s, 1H), 5.23 (t, 1H), 4.7 (d, 1H), 4.53 (d, 1H), 4.4 (m, 2H), 3.83 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (s, 3H), 2.43 (s, 3H). Separation by chiral HPLC provides enantiomers II-111a-b.
Reaction SMILES: [S:1]1(=[O:18])(=[O:17])[N:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH:4]2[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[S:1]1(=[O:17])(=[O:18])[N:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(CCS2(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCC2CNCCN21
Yield: 99.3 %

Procedure:
To a solution of 1.5 g of 1,1-dimethylethyl hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide (D9) in 20 ml of dry dichloromethane, under N2 at 0° C., 5 ml of TFA were added drop wise and left to react at 0° C. for 1 h. Then reaction mixture was evaporated under vacuum and crude solid material purified by 50 g SCX cartridge, loading with DCM/MeOH, washing with DCM/MeOH then only with MeOH; product was recovered eluting with 1M NH3 in MeOH. Solvent evaporation gave 0.95 g of pure title compound as white solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 4-phenoxybenzaldehyde (10.0 g, 50 mmol) and 10 mL dry THF was added dropwise to a 0° C. suspension of lithium aluminum hydride (2.1 g, 55.3 mmol) and 100 mL dry THF. The reaction mixture was stirred for 1 hour at 0° C., then was quenched successively with 2.1 mL H2O, 2.1 mL 10% NaOH, and 6.3 mL H2O. The resultant slurry was stirred for 1.5 hours at room temperature, then was filtered through Celite and the filtrate was evaporated under reduced pressure to afford the title compound (9.9 g) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.68 (t, 1H), 4.68 (d, 2H), 7.00 (m, 4H), 7.10 (t, 1H), 7.35 (m, 4H). MS (DCl/NH3) m/e 183 (M+1, --H2O)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:8]2[S:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To 500 ml. of 1,2-dichloroethane were added 24.0 g. (0.10 mole) of 3-phenyl-6-methoxybenzothiophene and 17.1 g. (0.10 mole) of p-methoxybenzoyl chloride. The mixture was cooled to 0° C., and 13.4 g. (0.10 mole) of aluminum chloride were added. The mixture was stirred for 1 hour, and ice then was added to the mixture. The organic layer was separated, washed with water, and evaporated. To the residue were added a mixture of methanol and 5N sodium hydroxide. The mixture was refluxed for 30 minutes and evaporated. To the residue were added ether and water. The ether layer was separated, washed with 1N sodium hydroxide, 1N hydrochloric acid, and aqueous sodium chloride solution. The ether layer then was dried over magnesium sulfate, filtered, and evaporated to give crude product which was recrystallized from methanol to obtain 34.2 g. (91 percent) of the title compound, m.p. 127°-128° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:20][CH2:21][CH2:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH2:22][CH2:21][OH:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ncc[nH]1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Yield: 80.4 %

Procedure:
Benzyl 4-(4-iodobutyl)phenyl ether (14.29 g), 2-(2-hydroxyethyl)imidazole (13.1 g), and potassium carbonate (5.39 g) were stirred in DMF (390 ml)at 60° C. for 16 hours. After cooling, the insoluble matter was filtered off; the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was purified by column chromatography (eluent: ethyl acetate-methanol=19:1→9:1). The eluate was recrystallized from ethyl acetate-methanol to yield the titled compound (10.99 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:27][CH2:28][CH3:29])[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[CH2:15][CH2:14]3)[CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46](Cl)(=[O:48])=[O:47]>C1COCC1>[N:21]1([C:19]([N:16]2[CH2:15][CH2:14][CH:13]([N:12]([CH2:27][CH2:28][CH3:29])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([O:1][S:46]([C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=5[Cl:39])(=[O:48])=[O:47])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[O:20])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3ccccc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a 0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solution was allowed to stir for 24 h at 25° C. under N2. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford 2-Chloro-benzenesulfonic acid 7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester 40 (5.1 mg), [M+H]+=690.
Reaction SMILES: C(C([NH:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[CH:36]=[C:35]([F:41])[C:34]=1[F:42])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=O)(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:13][C@H:14]([C:18]([NH:20][CH:21]([CH:30]([OH:43])[CH2:31][O:32][C:33]1[C:34]([F:42])=[C:35]([F:41])[CH:36]=[C:37]([F:40])[C:38]=1[F:39])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:19])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)[C@H](NC(=O)C(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of N-[(carbobenzyloxycarbonyl)valinyl]-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (6.12 g, 10.50 mmol) in MeOH (300 ml) was added 10% palladium on carbon (0.92 g) at room temperature. The reaction was stirred for 3 hours under hydrogen (1 atm), then filtered through a pad of celite. The filter cake was washed with MeOH. The filtrate was concentrated in vacuo to provide the titled product as a viscous yellow oil (4.69 g, 10.30 mmol, 98%). MS C20H20N2O5, [M+Na]+ =475, [M−H]− =451.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:24]1([CH:30]2[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:24]1([C@@H:30]2[CH2:35][CH2:34][C@H:33]([O:23][C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[CH:14]=[C:13]([CH2:12][N:9]3[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)[CH:22]=[CH:21]4)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OC1CCC(c2ccccc2)CC1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](c5ccccc5)CC4)ccc3c2)CC1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
A mixture of 1-(6-hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.400 g, 1.28 mmol), 4-phenyl-cyclohexanol (0.2479 g, 1.406 mmol) and triphenylphosphine (0.6695 g, 2.553 mmol) in toluene (5 mL, 40 mmol) was stirred for 20 min, then diisopropyl azodicarboxylate (0.32 mL, 1.5 mmol) was added dropwise at 0° C. The solution was stirred at reflux overnight. The reaction was added silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give product as an oil (0.3 g, 50%). LCMS: Rt=1.75 min, m/z=472.45 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)[N:10](C1CCCCO1)[N:9]=[CH:8]2.C(OC(N1C=C(C2C=C3C(C=NN3C3CCCCO3)=CC=2OC2C=CC([N+]([O-])=O)=CC=2F)C=N1)=O)(C)(C)C.C([O-])(O)=O.[Na+].CCOC(C)=O>CCOC(C)=O.CCO>[NH:16]1[CH:15]=[C:14]([C:13]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][NH:10]3)=[CH:6][C:5]=2[O:4][C:3]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:2]=2[F:1])[CH:18]=[N:17]1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2-c2cn[nH]c2)c(F)c1
Agent: CC(C)(C)OC(=O)n1cc(-c2cc3c(cnn3C3CCCCO3)cc2Oc2ccc([N+](=O)[O-])cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc3cn[nH]c3cc2-c2cn[nH]c2)c(F)c1
Yield: 265.6 %

Procedure:
To a solution of 5-(2-fluoro-4-nitrophenoxy)-6-(1H-pyrazol-4-yl)-1-(tetrahydropyran-2-yl)-1H-indazole (900 mg, 2.13 mmol) and 4-[5-(2-fluoro-4-nitro-phenoxy)-1-(tetrahydropyran-2-yl)-1H-indazol-6-yl]-pyrazole-1-carboxylic acid tert-butyl ester (3.1 g, 5.92 mmol) in EtOAc/EtOH (75 mL/75 mL) is added stannous chloride dihydrate (10 g, 52.74 mmol). The reaction mixture is stirred at reflux overnight. After it is cooled and basified with saturated aqueous NaHCO3 to pH 8-9, the mixture is extracted with EtOAc (100 mL). The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting first with PE:EtOAc (1:1) and then with EtOAc to give the product (1.75 g, 71.0% yield). MS (m/z): 310.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Product: COC(=O)c1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a 500 mL round bottomed flask equipped with a stirring bar, reflux condenser and a drying tube was added 3-methyl-4-aminobenzoic acid (8.00 g, 52.92 mmol) and anhydrous methanol (300 mL). This solution was saturated with anhydrous HCl gas and the mixture was stirred at ambient temperature for 26 h. The methanol and HCl were removed in vacuo and the solid product was suspended in 400 mL of EtOAc. This mixture was made basic by careful addition of aqueous NaHCO3 solution. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give methyl 3-methyl-4-aminobenzoate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:13][CH2:12][CH2:11][C:10]#[C:9][OH:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: C#CCCCCO
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OC#CCCCCc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3-chloroiodobenzene (14.3 g, 60 mmol), tetrakis(triphenylphosphine) palladium (2.1 g, 1.8 mmol) and 5-hexyn-1-ol (5.9 g, 60 mmol) in triethylamine (120 ml) was stirred at 25° C. for 3H and partitioned between water and ether. The
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:1]([CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CC[C@H]3CN(c4ncccn4)CCN3C2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
A solution of 0.385 g (1.55 mmol) of (7R,9aS)-7-hydroxymethyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 4), 0.220 g (2.34 mmol) of phenol, and 0.488 g (1.86 mmol) of triphenylphosphine in 30 mL of dry THF was treated with 0.324 g (1.86 mmol) of diethyl azodicarboxylate, and the mixture stirred at 23° C. for 16 h. The solvent was evaporated, the residue dissolved in ethyl ether and treated with HCl(g) in ether. The precipitate was collected on a Buchner funnel, and washed with 1:1 ether:ethyl acetate three times. The solid was dissolved in water, basified with 1M NaOH and extracted with chloroform. The organic layer was washed with 1M NaOH (2×) and water (1×), dried (magnesium sulfate), filtered and evaporated to give 0.310 g of (7R,9aS)-7-phenoxymethyl-2,3,4,6,7,8,9,9a-octahydro-2-pyrimidin-2-yl-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 203°-205° C. 13C NMR (base, CDCl3): δ 27.0, 29.0, 36.4, 43.6, 49.1, 54.9, 58.8, 60.8, 70.9, 109.8, 114.5, 120.6, 129.4, 157.7, 159.0, 161.5. HRMS calcd for C19H24N4O: 324.195. Found: 324.194.