Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(O)(=O)C>C(O)C>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol), p-anisaldehyde (69 μL, 0.56 mmol) and glacial acetic acid (31 μl) in ethanol (5 mL) was stirred at room temperature for 1 h. The resultant precipitate was collected by filtration and isolated as a white solid (100 mg, 59%). 1H NMR (CDCl3): 9.05 (s, 1H), 7.72 (s, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.44 (d, J=6.9 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 6.23-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.85 (s, 3H), 3.06 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=9.0 Hz, 1H), 1.51 (d, J=9.0 Hz, 1H), 1.45-1.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([CH3:19])([OH:26])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC1(O)CCNCC1
Solvent: CO
Product: CC1(O)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added 4-methylpiperidin-4-ol (163 mg, 1.413 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (374 mg, 1.034 mmol, 73.2% yield). LC-MS (M+H)+=362.0. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2 H, m), 7.04 (2 H, t, J=8.85 Hz), 4.11-4.30 (3 H, m), 3.48-3.63 (2 H, m), 3.14-3.23 (1 H, m), 3.00-3.12 (1 H, m), 2.54-2.66 (1 H, m), 1.94-2.09 (1 H, m), 1.68 (4 H, t, J=4.12 Hz), 1.28 (3 H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[CH2:6][C:3]1([CH2:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:5][CH2:4]1
Reactant: COC(=O)CC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
To a solution of methyl [1-(hydroxymethyl)cyclopropyl]acetate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to 0° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound appendage 3 as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1.O1CCOCC1>Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COCCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: COCCc1cccc(CO)n1

Procedure:
A solution of 2-(2-methoxyethyl)-6-(triphenylmethoxy)methylpyridine (1.08 g, 2.64 mmol) in 4-M HCl in dioxan (10 mL, 40.0 mmol) was stirred for 4 h and concentrated in vacuo. The residue was partitioned between dichloromethane (15 mL) and saturated NaHCO3 solution (15 mL), the aqueous phase was extracted with dichloromethane (10 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give 6-(2-methoxyethyl)pyridine-2-methanol. A solution of this product in dichloromethane (40 mL) at 0° C. was treated with triphenylphosphine (830 mg, 3.16 mmol) followed portionwise by carbon tetrabromide (1.31 g, 3.96 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO2; isohexane:EtOAc (4:1)] to give the title compound (303 mg, 50%) as a yellow oil; NMR δH (400 MHz, CDCl3) 7.60 (1H, t, J 7.5 Hz), 7.28 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 4.53 (2H, s), 3.76 (2H, t, J 6.5 Hz), 3.35 (3H, s) and 3.05 (2H, t, J 6.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][S:11][C:10]=2[CH:13]=1)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 19.1, 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and 2-(Ethylamino)ethanol were converted to yield 2-(Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanol as light brown oil, MS: 382 (MH+).
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([CH:5]([CH2:8][CH3:9])[CH:6]=O)[CH3:4]>>[CH2:3]([C:5](=[CH:6][N:2]=[CH:6][CH:5]([CH2:8][CH3:9])[CH2:3][CH3:4])[CH2:8][CH3:9])[CH3:4]
Reactant: [NH4+]
Reactant: CCC(C=O)CC
Agent: [OH-]
Product: CCC(=CN=CC(CC)CC)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a sample of 250 grams of 28% ammonium hydroxide was added 215 grams of 2-ethylbutyraldehyde and the heterogeneous mixture was stirred for 18 hours at ambient temperature. The resulting organic layer was separated, and after drying, slowly distilled at atmospheric pressure to yield 148.8 grams of 3,7-diethyl-5-azanona-3,5-diene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2)([O-])=O.O.NN>[Ni].C(O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[CH2:14][CH3:15]
Reactant: CCCN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCN1CCc2cc(N)ccc21

Procedure:
Approximately 400 mg of Raney nickel is added to a mixture of 3.28 g (15.9 mmol) of 5-nitro-1-propylindoline and 4 ml (80 mmol) of hydrazine hydrate in 60 ml of absolute ethanol. The reaction mixture is heated under reflux for 5 hours. After returning to 23° C., a little silica is added to the flask and the solvent is evaporated off under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a Heptane/AcOEt mixture (1/9). A black oil is obtained which is used directly in the following stage.
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][C@H:6](Cl)[CH2:5][N:4]1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:19][NH2:20]>CO>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([N:4]2[CH2:5][C@H:6]3[CH2:7][C@@H:3]2[CH2:2][N:20]3[CH3:19])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](Cl)C[C@@H]2CCl)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3C)cc1
Temperature: 110 °C
Yield: 90 %

Procedure:
A Parr bottle was charged with 0.5 g (1.29 mmol) of (2R,4S)-2-chloromethyl-4-chloro-1-(4-toluenesulfonyl)pyrrolidine and 6 ml of methanol and the bottle was tared. Methylamine gas was then bubbled through the methanol solution until 0.4 g (12.9 mol) of the gas had dissolved. The bottle was then sealed and heated to 110° C. After heating for 16 hours, the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were partitioned between 50 ml of methylene chloride and 40 ml of 10% aqueous NaOH solution. The layers were separated and the organic layer was washed with 40 additional milliliters of 10% aqueous NaOH solution, and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 309 mg of the desired product which represents a 90% yield. M.P.=82°-87° C. [α]D =-16.8° (c=1.038, CH3OH).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH3:12]>>[C:1]([NH:5][C:6](=[O:11])/[CH:7]=[C:8](\[NH2:12])/[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CC(=O)NC(C)(C)C
Reactant: N
Product: C/C(N)=C/C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-t-butyl-3-ketobutanamide (0.29 g) was dissolved in saturated ethanolic ammonia (15 ml) and stirred overnight at room temperature. The solution was evaporated to yield N-t-butyl-3-aminocrotonamide which was used directly. The crude residue was dissolved in ethanol (8 ml), 2-chlorobenzaldehyde (0.28 g) and ethyl 4-[2-(2-methylbenzimidazol-1-yl)ethoxy]-3-ketobutanoate (0.61 g) were added. The mixture was heated at reflux overnight, cooled and the solvent removed under reduced pressure. The residue was chromatographed on silica eluting with 4% diethylamine in ethyl acetate. The fractions containing the product were combined and evaporated. The residue was re-chromatographed on silica eluting with 5% methanol in ethyl acetate. The fractions containing the product were combined and evaporated to yield the title compound (0.17 g, 15%). m.p. 157°-161° C. Found: C, 65.66; H, 6.68; N, 9.74. C31H37C1N4O4 requires C, 65.89; H, 6.60; N, 9.91%.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Br:13][C:14]1[CH:15]=[C:16]([CH2:21][NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:17]([NH2:20])=[N:18][CH:19]=1>O1CCOCC1>[Br:13][C:14]1[CH:19]=[N:18][C:17]2[NH:20][C:6](=[O:7])[N:22]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH2:21][C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1CCN(CCNCc2cc(Br)cnc2N)CC1
Solvent: C1COCCO1
Product: CN1CCN(CCN2Cc3cc(Br)cnc3NC2=O)CC1
Reaction time: 8 h

Procedure:
CDI (815 mg, 5.0 mmol) was added to a solution of 5-bromo-3-((2-(4-methylpiperazin-1-yl)ethylamino)methyl)pyridin-2-amine (550 mg, 1.67 mmol) in dioxane (13 mL). The reaction mixture was stirred overnight at reflux. After concentration to dryness, the residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (10:0:0.1 to 9:1:0.1) as eluent. The title product was obtained as a yellow solid (430 mg, 72%).
Reaction SMILES: CS(O[CH2:6][C:7]([F:19])([F:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.CN(C=O)C.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>O>[CH2:11]([O:10][CH2:9][CH2:8][C:7]([F:19])([F:18])[CH2:6][N:29]1[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCC(F)(F)CCOCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Temperature: 120 °C

Procedure:
The compound 1-methanesulfonyloxy-2,2-difluoro-4-benzyloxybutane (21.8 g, 74.1 mM), dry DMF (100 mL), and potassium phthalimide (15.26 g, 10% excess) are stirred and heated under nitrogen, at 120° C. for 5 days. Following the addition of water (500 mL), the mixture is extracted with ether. The organic phase is washed with 1N CCl followed by water (twice), dried (Na2SO4) and concentrated to a volume of about 100 mL. Upon addition of petroleum ether, crystallization occurs. After chilling for 3 hours at 5° C., beige crystals of the compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide are obtained, filtered and washed with petroleum ether: 18 g (70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of 4-bromophenol (3.30 g, 20.0 mmol), triphenylphoshine (5.25 g, 20.0 mmol) and N-(2-hydroxyethyl)morpholine (2.51 g, 19.1 mmol) in THF (30 mL) was added diisopropyl azodicarboxylate (3.94 mL, 20.0 mmol) over 10 min. The reaction mixture was stirred at room temperature for 2 h, and then hydrochloric acid (50 mL, 1N) was added. The mixture was extracted with diethyl ether (2×50 mL), and then the pH was adjusted to 10 with 2N aq. NaOH. The mixture was then extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford N-(4-bromophenoxyethyl)morpholine (4.54 g, 15.9 mmol) as a white solid.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)#N.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:22]1CCCC1>>[OH:9][CH:6]1[CH2:7][CH2:8][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH:1]=[O:22])[CH2:4][CH2:5]1
Reactant: N#CC1(c2ccccc2)CCC(O)CC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=CC1(c2ccccc2)CCC(O)CC1

Procedure:
A thus produced 4-cyano-4-phenylcyclohexanol (b) obtained in step (1) is directly reduced, e.g., with lithium aluminum hydride (in a solvent such as tetrahydrofuran) at elevated (reflux) temperature, to give a corresponding 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c). This compound is also prepared via the tetrahydropyranyl ether of (b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[C:29]([CH3:33])([CH3:32])[CH:30]=[O:31].CC(C)=[O:36]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:16])[NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[C:29]([CH3:33])([CH3:32])[C:30]([OH:36])=[O:31]
Reactant: CC(C)=O
Reactant: CC(C)(C=O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Product: CC(C)(C(=O)O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of crude (±)-7-bromo-N-(2-adamantyl)-3-(2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (40 mg, 0.0778 mmol) in dry acetone was added H2Cr2O7 (234 mg, 0.8 mmol), and the solution was stirred for 1 h. 0.5 Treatment of the mixture with NaBH4 and concentration afforded the crude product which was purified by preparative HPLC to give (±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoic acid (1.55 mg, 5%). LC-MS Method 5 tR=1.504 min, m/z=531; 1H NMR: (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43 (m, 2H), 1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H), 2.51-2.61 (m, 1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m; 2H), 7.01 (m, 1H), 7.21-7.33 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[CH2:16]([O:8][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1CCCOC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A cooled (0° C.) solution of tetrahydro-pyran-3-carboxylic acid (2.831 g, 21.752 mmol) in dichloromethane (60 mL) and N,N-dimethylformamide (5 drops) was treated with oxalyl chloride (2.0 mL, 23.927 mmol). After stirring at room temperature for 2 h, benzyl alcohol (2.5 mL, 23.927 mmol) was added. After stirring at room temperature for 2 h and standing overnight, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (4.587 g, 96%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.58-1.88 (m, 3H), 2.03-2.13 (m, 1H), 2.62-2.72 (m, 1H), 3.47 (ddd, J=11.4, 9.6, 3.4 Hz, 1H), 3.63 (dd, J=11.4, 9.1 Hz, 1H), 3.85 (app dt, J=11.1, 3.8 Hz, 1H), 4.06 (ddd, J=11.4, 4.0, 1.6 Hz, 1H), 5.12, 5.17 (ABq, JAB=12.5 Hz, 2H), 7.31-7.46 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2].C1C[O:29]CC1>CCO>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)(=[O:29])[NH2:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1cc(C(N)=O)nc2ccc(C(F)(F)F)cc12
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 2-((2-cyano-6-(trifluoromethyl)quinolin-4-yl)amino)acetate (329 mg, 0.94 mmol) from above step A, in EtOH (3 mL) water (600 uL) and THF (5 mL) was added hydrido(dimethylphosphinous acid-kp)[hydrogen bis(dimethylphosphinito-kp)]platinum(ii) (80 mg, 0.18 mmol) and stirred at 75° C. for 3 h. The mixture was filtered to remove the white solid that had formed and the filtrate was evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CNC.C(N(CC)CC)C>C1COCC1>[CH3:14][N:15]([CH3:16])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N(C)C)cc1
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a soln. of 4-(methoxycarbonyl)benzoic acid (100 mg, 0.555 mmol) in THF (5 ml) was added HATU (211 mg, 0.555 mmol), dimethylamine (0.278 ml, 0.555 mmol) and triethylamine (0.077 ml, 0.555 mmol) at r.t. The mixture was stirred at r.t for 4 hrs. Evaporated to remove the solvent. The residue was dissolved in EtOAc (10 ml), washed w/water (3×), brine. Dried (Na2SO4), and evaporated to afford methyl 4-(dimethylcarbamoyl)benzoate (100 mg, 0.458 mmol, 83% yield) as solid. 1H-NMR (CD3OD, 500 MHz): δ 8.10 (1H, d, J=6.4 Hz), 7.55 (1H, d, J=6.4 Hz), 3.94 (3H, s), 3.13 (3H, s), 2.99 (3H, s). m/e (M+H): 208.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:18])=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:30][N:29]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (37 mg, 0.15 mmol), was dissolved in DMF (2 mL), 5-(pyridazin-3-yl)pyridin-2-amine (31 mg, 0.18 mmol) and DIEA (131 uL, 0.75 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (86 mg, 0.23 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 213. MS m/z 404.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 11.11 (s, 1H), 9.22 (dd, 1H), 9.13 (dd, 1H), 8.55 (dd, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 8.02 (d, 1H), 7.83-7.78 (m, 1H), 7.71-7.65 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.35 (m, 3H), 3.90 (s, 2H).
Reaction SMILES: CN(C=O)C.O=[C:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[N:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:15]=[CH:14]2)[CH2:9][CH2:8]1>CCOCC>[CH:10]1([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[N:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:15]=[CH:14]2)[CH2:9][CH2:8][CH2:7][CH2:12][CH2:11]1
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCC(=O)CC2)n1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)n1
Reaction time: 48 h

Procedure:
The product of the preceding example, DMF (10 mL), the product of example 1 (b) (1.59 g, 5.5 mmol) and KCO3 (0.308 g, 2.23 mmol) were combined and stirred for 2 days, diluted with Et2O and filtered. The filtrate was concentrated under high vacuum to a brown paste. Trituration with Et2O and hexane (1:1, 200 mL) afforded the title compound as a tan solid. Crystallization from EtOAc/hexane (1:4) afforded 0.631 g (39% from the product of example 1(d). ESP+ (Mass Spec) m/z 353 (MH+). mp=207-208.