Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.Br[CH2:24][CH:25]([F:27])[F:26].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)C.CN(C)C=O>[F:26][CH:25]([F:27])[CH2:24][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: FC(F)CBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2ccccc2N2CCN(CC(F)F)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), 2-bromo-1,1-difluoroethane (18.1 mg, 0.125 mmol), sodium iodide (1.5 mg, 0.01 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 2 hours at an external temperature of 80° C. After then further adding 2-bromo-1,1-difluoroethane (18.1 mg, 0.125 mmol) to the reaction mixture, it was further stirred for 6 hours and 30 minutes at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The solvent was distilled off by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-(2,2-difluoroethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([OH:16])=[CH:10][C:9]=1[CH3:17])([CH3:6])[CH3:5].[F:19][C:20]([F:39])([F:38])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:24][CH:23]=1.[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH2:32][CH2:31][CH2:30][C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:38])[F:39])=[CH:23][CH:24]=2)=[CH:10][C:9]=1[CH3:17])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C(C)(C)Oc1cc(OC)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1cc(OC)c(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 1D], 2-(4-hydroxy-5-methoxy-2-methyl-phenoxy)-2-methyl-propionic acid methyl ester was reacted with methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) in the presence of NaI and Cs2CO3 in acetonitrile under reflux conditions for 4 h, to give 2-{5-methoxy-2-methyl-4-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-phenoxy}-2-methyl-propionic acid methyl ester as colorless oil.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.CI.[C:20](=O)([O-])O.[Na+]>CS(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][CH3:20])[CH2:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(Br)cc1)N1CC[C@@H](O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CI
Product: CO[C@@H]1CCN(C(=O)c2ccc(Br)cc2)C1
Temperature: 100 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
Sodium hydroxide (10.6 mg, 0.264 mmol) was added to a solution of 54 mg (0.176 mmol) of (R)-(4-bromophenyl)(3-hydroxypyrrolidin-1-yl)methanone in dimethyl sulfoxide (1 ml) synthesized in the same manner as in step (i) of Reference Example 8, 0.11 ml (1.76 mmol) of methyl iodide was then added thereto, and the mixture was stirred at 100° C. for 20 hr. A saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 45 mg (yield 90%) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]4)=[N:26][CH:27]=3)=[N:18][CH:19]=2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+].C(OC)(C)(C)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29]4)=[N:26][CH:27]=3)=[N:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O[C@@H]1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.43 mL (5.32 mmol) pyridine and 2.26 g (0.80 mmol, 15 percent by weight) Dess-Martin-periodinane in DCM are added to a solution of 200 mg (0.53 mmol) (R)-1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-ol in 10 mL DCM. The reaction mixture is stirred for 3 h at RT and added to a solution of semisaturated NaHCO3 solution and tert-butylmethylether. The aqueous phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The product is further reacted without purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]2[N:7]([C:9]([NH2:14])=[C:10]([CH2:12][CH3:13])[N:11]=2)[CH:8]=1.[CH:16](O)=[O:17]>>[Br:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]2[N:7]([C:9]([NH:14][CH:16]=[O:17])=[C:10]([CH2:12][CH3:13])[N:11]=2)[CH:8]=1
Reactant: O=CO
Reactant: CCc1nc2c(C)cc(Br)cn2c1N
Agent: Cl
Product: CCc1nc2c(C)cc(Br)cn2c1NC=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of the above prepared 6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-ylamine hydrochloride (785 g, 2.70 mol, 1 eq.) in formic acid (713 mL, 18.9 mol, 7 eq.) was heated to 80° C. for 2 h. The crude mixture was concentrated in vacuo to low volume (about 400 mL). The residue was brought up in water (1 L) and a 3 M solution of NaOH (2 L), and further basified with a saturated NaHCO3 solution until foaming ceased and pH reached 8-9. After homogenization for 1 h, the precipitate was filtered and washed with water (2×300 mL). Purification was achieved by dissolution in a mixture of toluene and MeOH 3:1 (4 L) followed by concentration in vacuo. Trituration of the residue in a mixture of 200 mL of MeOH and 5 L of DIPE, decantation and filtration of the resulting suspension afforded N-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)formamide (Intermediate Gen-2-d).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][OH:12])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]3[C:8]([O:12][CH2:11][O:10]3)=[CH:9][C:2]=2[O:1][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16]
Reactant: N#Cc1cc(OCO)ccc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)OCO3
Yield: 60.9 %

Procedure:
A solution of 2-hydroxy-5-hydroxymethoxy-benzonitrile (0.10 g, 0.61 mmol), 2,2′,4′-trichloroacetophenone (0.16 g, 0.74 mmol, 1.2 eq) and potassium carbonate (0.13 g, 0.92 mmol, 1.5 eq) in 1 mL DMF was stirred overnight at 80° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried with sodium sulfate and filtered through a plug of silica. Concentration in vacuo provided an orange solid, purification of which by RP—HPLC (H2O-MeCN gradient) provided 0.13 g (61%) of (7-amino-1,3,5-trioxa-s-indacen-6-yl)-(2,4-dichloro-phenyl)-methanone as a yellow solid. 1H-NMR (DMSO-d6) δ 7.70-7.69 (m, 1 H), 7.51-7.49, (m 2H), 7.42, (s, 1H) 7.30 (bs, 2H), 7.03 (s, 1H), 6.07 (s, 2H); MS LC-MS (MH+=350.2/352.1), LC-MS RT=3.21 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: Cc1ccc(Cl)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (6 mL) was added to a solution of N-tert-butoxycarbonyl-4-(2-chloro-5-methylphenoxy)piperidine (A, 489 mg) in dichloromethane (20 mL) at room temperature. After stirring at room temperature for 30 min, the reaction mixture was evaporated in vacuo. The residue was partitioned between chloroform and saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo to give the titled compound as yellow crystals, which was used in the next reaction without her purification.
Reaction SMILES: [CH3:1][C:2]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22](=[O:37])[C:23]([CH3:36])([S:25]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=[O:27])=[O:26])[CH3:24])[CH:17]=1)([CH3:15])[CH2:3][O:4][Si](C(C)C)(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[NH4+].[Cl-]>[OH:4][CH2:3][C:2]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22](=[O:37])[C:23]([CH3:24])([S:25]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=[O:27])=[O:26])[CH3:36])[CH:17]=1)([CH3:15])[CH3:1]
Reactant: CC(C)[Si](OCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC2CCOCC2)no1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CCC2CCOCC2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of 190 mg (0.34 mmol) of N-[5-(1,1-dimethyl-2-triisopropylsilanyloxy-ethyl)-isoxazol-3-yl]-2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide in THF (2 mL) are added 1.7 mL (1M solution in THF, 1.7 mmol) of tetrabutylammonium fluoride. The reaction is stirred at room temperature for 18 h and then diluted with 1M aqueous NH4Cl solution (5 mL). The aqueous layer is extracted with DCM (3×25 mL). The combined organic extracts are dried over Na2SO4 and filtered and the filtrate concentrated under reduced pressure to give 46 mg of N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield: 34%, ES-MS: m/z 403 [M+H]Compounds in Table XXXVIII, amide method C, are made according to this procedure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O1CCCC1.O.[OH-].[Li+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH2:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CNc2ccc(CCC(=O)OCC)c(F)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}benzyl)amino]phenyl}propanoate (0.420 g, 0.790 mmol) in a mixture of ethanol (6 mL), tetrahydrofuran (12 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.198 g, 4.74 mmol), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-60% ethyl acetate/hexane) to give the title compound (330 mg, yield 83%) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](N(OC)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:22]=[C:23]([Mg]Br)[CH3:24]>C1COCC1>[C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:8](=[O:9])[C:23]([CH3:24])=[CH2:22])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CON(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Reactant: C=C(C)[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of (S)-tert-butyl (3-(cyclopent-1-en-1-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (81 g, 0.27 mol) in THF (600 mL) was added freshly prepared prop-1-en-2-ylmagnesium bromide (96.0 mL, 1.08 mol) at 0° C. dropwise. After completion of the addition, the reaction mixture was stirred at 0° C. for 2 h then quenched with saturated aqueous ammonium chloride (500 mL). The resulting mixture was extracted with EtOAc (400 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=100:1) to afford (S)-tert-butyl (1-(cyclopent-1-en-1-yl)-4-methyl-3-oxopent-4-en-2-yl)carbamate as colorless oil (39.3 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19].C(OCC)(=O)C>O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:19]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Temperature: 80 °C
Reaction time: 2 h
Yield: 237.3 %

Procedure:
71.6 g (0.5 mol) of 1-aminocyclohexanecarboxylic acid was added to a solution of 20 g (0.5 mol) of sodium hydroxide in 250 ml of water, and the mixture was stirred at 80° C. for 2 hours. The mixture solution was cooled by ice-water, and 71.8 g (0.2 mol) of 2-furancarbonyl chloride and a solution of 24 g (0.6 mol) of sodium hydroxide in 100 ml in water were simultaneously added thereto for approximately 1 hour. The reaction solution was slowly returned to room temperature, and it was stirred overnight. After 80 ml of ethyl acetate was added to the reaction solution and the mixture was stirred for 1 hour, the insolubles were removed by filtration. The aqueous layer was separately collected, and 49 ml of concentrated hydrochloric acid was added thereto under ice-cooling. The precipitated crystal was collected by filtration and dried under reduced pressure to obtain 112.6 g (95%) of the title compound.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1C=CC=CC=1.Cl.NO>CCO>[N:1]1([C:7]([C:9]2[S:13][C:12]([C:14]#[N:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccncc1
Reactant: O=Cc1ccc(C(=O)N2CCCCC2)s1
Agent: Cl
Agent: NO
Solvent: CCO
Product: N#Cc1ccc(C(=O)N2CCCCC2)s1
Temperature: 145 °C
Yield: 64.9 %

Procedure:
A solution of 5-(Piperidine-1-carbonyl)-thiophene-2-carbaldehyde (Preparative Example 17, 2.23 g, 10 mmol) in EtOH (50 mL) was treated with pyridine (971 μL, 12 mmol, 1.2 eq) followed by hydroxylamine hydrochloride (833 mg, 12 mmol, 1.2 eq) and heated at reflux for 2 hr then evaporated in vacuo. The crude intermediate oxime was then dissolved in acetic anhydride and heated at 145° C. for 16 hr then evaporated in vacuo to a small volume which was partitioned between EtOAc (50 mL) and water (200 mL). The organic layer was further washed with a brine solution (50 mL), dried over MgSO4, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (30 then 50%) as eluant to afford product as a yellow-tinted oil (1.43 g, 65%). 1H NMR (CDCl3) 1.65-1.76 (m, 6 H), 3.64 (br s, 4 H), 7.23 (d, J=4.0, 1 H), 7.56 (d, J=4.0, 1 H). 13C NMR 24.5, 26.2, 44.3 (br), 48.5 (br), 111.9, 113.7, 128.0, 137.0, 144.7, 161.3. LC/MS 5.09 min, [M+1]+ 221.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][C:15]([F:19])=[CH:14]3)[CH2:6][CH2:5]1)(=O)C.[ClH:27]>>[ClH:27].[F:19][C:15]1[CH:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[N:12][N:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]=2[CH:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CC(=O)N1CCC(c2c3ccc(F)cc3nn2Cc2ccccc2)CC1
Agent: Cl
Product: Fc1ccc2c(C3CCNCC3)n(Cc3ccccc3)nc2c1
Reaction time: 6 h
Yield: 25.1 %

Procedure:
To a stirred mixture of 15.8 parts of a sodium hydride dispersion 50% and 660 parts of dimethyl sulfoxide were added portionwise 78.4 parts of 1-acetyl-4-(6-fluoro-2H-indazol-3-yl)piperidine under nitrogen atmosphere. Upon complete addition, stirring was continued for 1 hour at room temperature. 42 Parts of chloromethylbenzene were added dropwise during 45 minutes. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into crushed ice and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of methylbenzene and methanol (90:10 by volume) as eluent. The first fraction was collected and the eluent was evaporated, yielding 91 parts (86.3%) of 1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl]piperidine as a residue (int. 1). b) A mixture of 8 parts of 1-acetyl-4-[6-fluoro-2-(phenylmethyl)-2H-indazol-3-yl] piperdine and 70 parts of a hydrochloric acid solution 6N was stirred for 6 hours at reflux temperature. The reaction mixture was evaporated and the oily residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (25.1%) of 6-fluoro-2-(phenylmethyl)-3-(4-piperidinyl)-2H-indazole monohydrochloride; mp.>300° C. (int. 2).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[C:11]([C:13]1[CH:35]=[CH:34][C:16]([O:17][C:18]2[CH:19]=[C:20]([NH2:33])[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=3)[CH:23]=2)=[CH:15][CH:14]=1)#[N:12]>>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[CH:21]=[C:20]([NH:33][C:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:6]3)=[O:10])[CH:19]=[C:18]([O:17][C:16]3[CH:34]=[CH:35][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[CH:23]=2)=[CH:26][CH:27]=1)#[N:32]
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: C[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1

Procedure:
Following the procedure of Example 107(e) trans-4-methyl-cyclohexanecarboxylic acid 0.21 g (1.52 mmol) and [3,5-bis-(4-cyano-phenoxy)-phenyl]-amine (0.50 g, 1.52 mmol) were used to afford 0.65 g of the required product. Percentage purity (LCMS): 85.4%, (M+1)=451.1+1.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([Cl:30])[C:24]=1[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([Cl:30])[C:24]=1[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC(C)(C)C)c(OC(C)(C)C)c2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)Oc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(Cl)c1OC(C)(C)C
Yield: 65 %

Procedure:
4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid (AAA-048) (110 mg, 64%) was prepared from methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (175 mg, 0.403 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (6 mL) was used instead of THF: m/z 418 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.78 (1H, br s). 10.49 (1H, s), 7.93 (2H, d), 7.87 (2H, d), 7.85 (1H, d), 7.59 (1H, d), 1.40 (9H, s), 1.34 (9H, s).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:26][OH:27])=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[F:25])[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[C:3]([CH2:26][OH:27])=[C:4]([CH2:9][NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:12]=3[F:25])[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:31][CH:32]=1)#[N:37]
Reactant: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2F)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2F)c(CO)c1OCc1ccc(C#N)cc1
Yield: 33 %

Procedure:
The coupling of 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridine-3-ylmethyl)-amino]-3′-fluoro-biphenyl-4-carbonitrile (61) (250 mg, 0.69 mmol) and α-bromo-p-tolunitrile (149 mg, 0.76 mmol), as described in Example 1, gave 4′-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-3′-fluoro-biphenyl-4-carbonitrile (62) (109 mg, 33% yield).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([O:32]CC)=[O:31])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([OH:32])=[O:31])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of ethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate (300 mg), 1N aqueous sodium hydroxide (1.32 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at room temperature. To the reaction mixture were added 1N hydrochloric acid (1.32 ml) and then water. The resulting crystalline precipitate was collected by filtration and washed with ether. Recrystallization from tetrahydrofuran gave 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]-phenyl]propyl]-2-imidazolecarboxylic acid (176 mg, 63%) as colorless prisms, mp 116° C. (decomp.).