Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1cccc(F)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-fluoro-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C19H21FO5 [M+Na]+: 371.4.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)c1ccccc1-c1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1c(-c2ccccc2)cccc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
This amide (2.25 g, 10 mmol) and TMEDA (1.2 eq) in THF were mixed and cooled to -78° C. and a 1.3M s-BuLi solution in cyclohexane (2.2 eq) was added dropwise. The resulting reaction mixture was stirred at -78° C. for 30 min and TMSCl (1.2 eq) was added dropwise. The reaction was stirred at -78° C. for 30 min and allowed to warm to -30° C. The reaction was worked up in the usual manner. The crude product was purified by flash chromatography and recrystallization from hexanes to afford the title compound as a white solid (1.15 g, 39%). m.p. 159°-160° C.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([O:35]CC)=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1.[OH-].[Na+]>O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([OH:35])=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Temperature: 25 °C
Yield: 67 %

Procedure:
To 1 mL of an ethanol solution containing 90 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate, 0.3 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 1.5 hours. Then, more 0.3 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 3 hours. After the reaction mixture was cooled to room temperature, water was added, and the solvent was removed under reduced pressure. Water was added, and adjusted to pH 6.7 with 6.0 mol/L hydrochloric acid. The resulting solid was filtered to afford 57 mg of 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([O-:25])=[O:24])[N:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>>[Br:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[CH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: O=C([O-])Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 5) from ethyl ((5-{2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetate and aqueous NaOH.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:9]1([O:17][CH3:18])[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:11][CH3:12]>>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([O:11][CH3:12])[C:9]=1[O:17][CH3:18]
Reactant: COc1ccccc1OC
Reactant: O=Cc1ccncc1
Product: COc1cccc(C(O)c2ccncc2)c1OC

Procedure:
In Scheme N, step a, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrole to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) as described previously in Scheme F, step d.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.FC1N(C)CC[NH+]1C.CN(C=O)C.O.[NH2:45][NH2:46]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([NH:45][NH2:46])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: CN1CC[NH+](C)C1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dried flask was charged with 1.00 g (3 mmol) of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3) and 865 mg (3.3 mmol) of 2-fluoro-1,3-dimethylimidazolidinium hexafluorophosphate, followed by 7.5 mL of anhydrous DMF. The resulting solution was stirred under nitrogen gas with cooling in an ice bath as 0.835 mL of triethylamine was added by syringe through a septum, and this was followed by 0.291 mL (300 mg, 6 mmol) of hydrazine hydrate. After several min, the ice bath was removed, and the mixture was allowed to warm to room temperature. After 1 h, 40 mL of water was added very gradually by syringe, accompanied by vigorous stirring. This resulted in precipitation of product. One hour later, the solid was collected on a filter, washed generously with water, and dried. The crude product was dissolved in dichloromethane-methanol and evaporated onto several grams of silica gel, which was loaded onto the top of a silica gel column. Flash chromatography (1-4% methanol in dichloromethane) provided the title compound as a white solid, mp 168-168.5° C. LC-MS 248 (M+1-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][C:12]([CH3:17])([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][C:12]([CH3:17])([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)CC1(C)C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2,3,3-trimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(#N)C>[N+:28]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH2:10]4)[CH2:8]2)[CH2:14]3)=[CH:6][CH:5]=1)([O-:29])=[O:27]
Reactant: O=[N+]=O
Reactant: COC(=O)CC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COC(=O)CC12CC3CC(C1)CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 0 °C

Procedure:
Methyl 3-phenyl-1-adamantaneacetate, example 1, (78.8 g) was dissolved in acetonitrile (800 mL) and cooled in an ice bath while stirring under a nitrogen atmosphere. Nitronium tetrafluoroborate (40.8 g) in acetonitrile (800 mL) was added dropwise over 45 minutes. The reaction was stirred for 45 minutes after the addition, then poured into ice (985 g). The resulting solid was collected by filtration and dried in vacuo to give methyl 3-(4-nitrophenyl)-1-adamantaneacetate (55.9 g). Mass spectrum: (M+NH4)+@347. Extraction of the aqueous phase with t-butyl methyl ether (2×800 mL) yielded additional material including the lesser products, methyl 3-(2-nitrophenyl)-1-adamantaneacetate; Mass spectrum: (M+NH4)+@347 and methyl 3-(2,4-dinitrophenyl)-1-adamantaneacetate; Mass spectrum: (M+NH4)+@392.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:7][C:8]#[N:9]>N1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:7][C:8]#[N:9])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(O)(CC#N)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Thionyl chloride (2.18 g, 0.018 mol) was slowly added to a stirred solution of 3-hydroxy-3,3-di(4-methoxyphenyl)propanenitrile (4.0 g, 0.014 mol) in pyridine (30 ml) cooled in an ice-salt bath. After the addition was complete the mixture was allowed to warm up to room temperature and stirred for 2 h. ice cold water (100 ml) was added and the mixture extracted with DCM (2×100 ml) The combined organics were washed with 3M hydrochloric acid (1×50 ml, 1×5 ml) , brine (50 ml) , dried over anhydrous sodium sulphate, filtered and evaporated to yield crude 3,3-di(4-methoxyphenyl)-2-propenenitrile (2.95 g, 79%) which was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18]C>CCN(CC)CC.[Cu]I.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>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Nc1cccc(F)c1Br
Reactant: CC#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et3N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)2Cl2 (500 mg) successively at room temperature under N2. The mixture was heated at 80° C. overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL×3). The organic layers were washed with sat. NaCl, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.6, 1H), 7.95 (s, 1H), 7.21 (m, 1H), 6.77 (t, J=7.6 Hz, 1H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22](OCC)=[O:23])([F:21])([F:20])[F:19].CC[O-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][C:22](=[O:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
45.2 g 1-(4-Benzyloxy-phenyl) ethanone (200 mmol) was taken up in THF (250 mL) and treated with CF3CO2Et (30 ml, 250 mmol). The solution was cooled to 0° C. and treated with 2.66 M NaOEt (94 ml, 250 mmol) solution over 1 h. The ice bath was removed and the solution was stirred at room temperature for 4 h. The reaction was poured into 1N HCl (1000 ml) and extracted with EtOAc (1500 ml). The organic layer was washed with brine, dried and evaporated to yield 64.2 g 1-(4-Benzyloxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (200 mmol, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:38])([F:37])[F:36])[C:29]#[N:30]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]2[N:30]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:37])([F:38])[F:36]
Reactant: Cc1ncccc1C(=O)O
Reactant: N#Cc1ccc(OC(F)(F)F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
300 mg 2-methyl-nicotinic acid was suspended in 10 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 3.3 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 1.5 h at 0° C. After this time, it was cooled again to −70° C. and 0.9 g 3-fluoro-4-trifluoromethoxy-benzonitrile (4.1) was added quickly. Then the reaction mixture was stirred for 2 h at −70° C. and then warmed overnight to ambient temperature. The solvent was distilled off, diluted with ethyl acetate, 10 mL phosphate buffer and 5 mL 2N aqueous hydrochloric acid solution (pH 6-7). The formed precipitate was collected and dried. The resulting liquid phase was separated and the water phase extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated and the residue suspended in ether and ethyl acetate. The precipitate was collected, dried and combined with the first precipitate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=O)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:36][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:16][N:15]=2)[CH:12]2[CH2:27][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Temperature: 140 °C
Yield: 72.3 %

Procedure:
The mixture of 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g, 4 mmol), acetic acid (24 μl), and ammonium acetate (1.54 g, 20 mmol) in xylene (20 ml) was heated at 140° C. for 20 hours. The mixture was quenched with saturated sodium carbonate solution, and extracted with EtOAc. The organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.21 g). m/z: 417.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C@H:10]([CH:29]([CH3:31])[CH3:30])[C:11]([N:13]1[CH2:18][CH2:17][C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([OH:19])[C:15]([CH3:28])([CH3:27])[CH2:14]1)=[O:12])=[O:8])(=[O:3])[CH3:2].[CH3:35][N:36]([CH:38](OC)OC)[CH3:37]>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C@@:16]2([OH:19])[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C@H:10]([NH:9][C:7](=[O:8])[C:6]3[CH:32]=[CH:33][CH:34]=[C:4]([C:1](=[O:3])/[CH:2]=[CH:35]/[N:36]([CH3:38])[CH3:37])[CH:5]=3)[CH:29]([CH3:30])[CH3:31])[CH2:14][C:15]2([CH3:28])[CH3:27])=[CH:25][CH:24]=1
Reactant: CC(=O)c1cccc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Reactant: COC(OC)N(C)C
Product: CC(C)[C@@H](NC(=O)c1cccc(C(=O)/C=C/N(C)C)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 105 °C

Procedure:
3-Acetyl-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)benzamide was added DMF-DMA (0.3 mL) and the reaction mixture heated at 105° C. for ˜5 h. The residual DMF-DMA was removed on a rotovap and the crude product was dried on house high vac for ˜3 h to afford N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-((E)-3-(dimethylamino)acryloyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])[CH:6]=O.[NH2:20][OH:21]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19])[CH:6]=[N:20][OH:21]
Reactant: NO
Reactant: COc1cc(C=O)ccc1OCCN1CCNC1=O
Solvent: CCO
Product: COc1cc(C=NO)ccc1OCCN1CCNC1=O
Reaction time: 4.5 h

Procedure:
To a solution of 3-methoxy-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde (25.6 g, 0.097 mol) in EtOH (250 mL) at 52° C. is added a solution of hydroxylamine (10.2 g, 0.155 mol, 50% in water, Aldrich) in EtOH (20 mL). The reaction medium is then stirred for 4.5 hours between 50 and 60° C. The reaction medium is then concentrated under reduced pressure (Tbath=42° C., 60 mbar) so as to obtain a residue of 70-80 mL. The precipitate obtained is filtered, washed with an EtOH/water mixture (twice 5 mL/15 mL) and dried under atmospheric pressure at room temperature.
Reaction SMILES: [Cl-].[NH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][NH3+:13])=[O:4].[OH:14][C:15]1[C:16]([C:31](O)=[O:32])=[N:17][C:18]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>>[NH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:12][NH:13][C:31]([C:16]1[C:15]([OH:14])=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[N:23]2)=[C:18]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[N:17]=1)=[O:32])=[O:4]
Reactant: CN(c1nc(C(=O)O)c(O)c2ncccc12)S(C)(=O)=O
Reactant: NC(=O)c1cc(F)ccc1C[NH3+]
Agent: [Cl-]
Product: CN(c1nc(C(=O)NCc2ccc(F)cc2C(N)=O)c(O)c2ncccc12)S(C)(=O)=O

Procedure:
In a similar manner as described for Example 7, Step 3, [2-(aminocarbonyl)4-fluorophenyl]methanaminium chloride (from Example 9, Step 3) was coupled with 8-hydroxy-5-[methyl(methylsulfonyl)amino]-1,6-naphthyridine-7-carboxylic acid (from Example 5, Step 3) to afford the title compound.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(OCCO)C>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][OH:33])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Reactant: Nc1ccc(CCO)cc1
Solvent: CCOCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[4-(1-tertbutoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.53 g, 4.0 mmol) and 4-aminophenethyl alcohol (1.10 g, 8.0 mmol) in 2-ethoxyethanol (15 ml) was heated to reflux for 18 h. The reaction was cooled to room temperature, trifluoroacetic acid (2 ml) added and the reaction stirred for 30 min. Solvent was removed in vacuo and the residue partitioned between CH2Cl2 (100 ml) and saturated, aqueous Na2CO3 (80 ml). The aqueous layer was re-extracted with CH2Cl2 (2×80 ml) and the combined CH2Cl2 layer washed with aqueous Na2CO3 (80 ml), brine (80 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 10-15% methanol in CH2Cl2) to give the title compound as a buff solid (1.30 g) m.p. 162-163°. δH (d6DMSO) 9.74 (1H, s), 8.55 (1H, s), 7.76 (2H, d, J 8.5 Hz), 7.68 (2H, d, J 8.5 Hz), 7.62 (2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 4.57 (1H, bs), 3.55 (2H, m), 2.65 (2H, t, J 7.2 Hz), 1.41 (6H, s); MS (ESI) 383 (MH+, 35Cl, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.[Cu]I.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>[CH2:12]([N:11]([CH2:15][CH2:16][CH3:17])[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)[CH2:13][CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CCCN(CCC)C1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1

Procedure:
Using General Procedure D; [1-(4-bromophenyl)-cyclopropyl]-dipropylamine (Intermediate 121, 150.0 mg, 0.50 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (35.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5d. The title compound was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:21](OC)=[O:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[Al].[Li].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([CH2:21][OH:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(=O)c1cccc2c(-c3ccc(F)cc3)n(Cc3ccc(C)cc3C)nc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cn2nc3c(CO)cccc3c2-c2ccc(F)cc2)c(C)c1
Yield: 99.9 %

Procedure:
A solution of methyl 2-(2,4-dimethylbenzyl)-3-(4-fluorophenyl)-2H-indazole-7-carboxylate (0.100 g, 0.25 mmol) and lithium aluminum (0.1 g, 0.25 mmol) in 5 mL THF was stirred at ambient temperature for 1 hour. Excess hydride was decomposed by the addition of 0.1 mL H2O, 0.1 mL 1N NaOH, 0.3 mL H2O and 100 mg of Na2SO4. The solids were filtered and the filtrate concentrated in vacuo to give 0.09 g of product as a light yellow solid.