Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:33][C@H:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[OH:39])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(=[O:45])[CH:43]=[CH2:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:32])[NH:33][C@H:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[O:39][CH2:44][CH2:43][C:42]([OH:46])=[O:45])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:32])[NH:33][C@H:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[O:39][CH2:44][CH2:43][C:42]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@H]1O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCO[C@@H]1CCC[C@@H]1NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Product: O=C(O)CCO[C@@H]1CCC[C@@H]1NC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-((1S,2R)-2-hydroxycyclopentyl)urea (16 mg, 0.028 mmol) in THF (1 mL) was added NaH (11 mg, 60% in mineral oil, 0.28 mmol). t-Butyl acrylate (18 mg, 0.14 mmol) was added after 1 min and the reaction mixture stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC Shimadzu-Phenomenex Luna C18 column, 21.2×100 mm eluting with 10-100% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm to give 3-((1R,2S)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclopentyloxy)propanoic acid at the retention time of 8.74 min (1.2 mg, 6% yield) and tert-butyl 3-((1R,2S)-2-(3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)cyclopentyloxy)propanoate at a retention time of 11.32 min (2.5 mg, 14% yield).
Reaction SMILES: [C:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]2)=[C:6]([O:38][CH3:39])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)([CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:36]=[CH:37][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=3[O:38][CH3:39])[CH2:17][CH2:16]2)[C:19]([NH2:21])=[O:20])=[CH:27][CH:26]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(C(N)=O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(C(C)O)ccc1OCCCN1CCC(C(C(N)=O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Using the procedure of Example 20, 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidineacetamide is reduced with sodium borohydride to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[C:13]1[NH:17][C:16](=[S:18])[NH:15][C:14]1=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[CH:12]=[C:13]3[NH:17][C:16](=[S:18])[NH:15][C:14]3=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C=C1NC(=S)NC1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: FC(F)(F)c1ccc2cc3[nH]c(=S)[nH]c3nc2c1
Temperature: 180 °C
Reaction time: 0.3 h
Yield: 55.4 %

Procedure:
A mixture of 5-[[2-amino-4-(trifluoromethyl)phenyl]methylene]-2-thioxo-4-imidazolidinone (3.63 g, 12 mmol), pyridinium tosylate (1.8 g), and diphenyl ether (5.4 g) was heated at 180° C. under an atmosphere of argon. After 18 minutes, the mixture was cooled, chloroform (60 mL) added and the mixture refluxed. After 30 minutes the solid was filtered off and dissolved in a mixture of water (80 mL) and 10% sodium hydroxide solution (5 mL) with warming. Addition of acetic acid afforded a heavy precipitate which was filtered off, washed with water and dried in vacuo to give 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione (1.79 g, 52%), m.p. >320° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[H][H]>C(O)C.C(O)(=O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC#N)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CCN)CC1

Procedure:
A solution of tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (example 89, step a) (1.4 g) in a mixture of ethanol (20 mL) and acetic acid (20 mL) was hydrogenated at 4 atmospheres pressure of hydrogen in the presence of platinum(IV) oxide (0.25 g) for 4 hours. The catalyst was filtered off and the solvents removed under reduced pressure. The residue was partitioned between dilute aqueous NaOH and ethyl acetate and the organic layer dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 1.1 g. Used directly.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:24].[NH2:25][OH:26]>C(O)C>[ClH:24].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:25][OH:26])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CN(CC(C)C(=O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC1CN(CC(C)C(=NO)c2ccc(C(C)(C)C)cc2)CC(C)O1
Temperature: 5 °C
Yield: 95.8 %

Procedure:
9.5 g (0.03 mole) of p-tert.-butyl-2-methyl-3-(2,6-dimethyl-morpholin-4-yl)-propiophenone were heated under reflux with 3.6 g (0.05 mole) of hydroxylamine hydrochloride in 80 ml of ethanol for 20 hours. After cooling to 5° C., the mixture was filtered. The filtrate was concentrated, the residue was suspended in dilute sodium hydroxide solution and the suspension was extracted with chloroform. Ethereal hydrochloric acid was added to the organic phase and the reaction product which had precipitated was filtered off. 10.6 g (96% of theory) of p-tert.-butyl-2-methyl-3-(2,6-dimethyl-morpholin-4-yl)-propiophenone oxime hydrochloride of melting point 214° to 16° C. were obtained.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:16])[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)[CH3:8]>O.C1COCC1.CO>[I:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([CH3:8])[C:6]([OH:16])=[O:5])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)c1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.610 g (14.6 mmol) Lithiumhydroxide monohydrate in 15 mL water are added to 2.12 g (7.31 mmol) 2-(4-iodo-phenyl)-propionic acid methyl ester (Bioorg. Med. Chem. Lett. 2010, 20, 896) in 20 mL THF and 12 mL MeOH at 0° C. Cooling is removed and the mixture is stirred at rt for 2 h. After that time, the mixture is acidified with 1 N HCl to pH˜1 and extracted with DCM. The organic layer is washed with brine, dried over sodium sulphate and the solvent is evaporated. The product is used without further purification in Example IV.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3([OH:23])[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:9][CH:8]=2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]3([OH:23])[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)no1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(-c2ccc(CCC3(O)CN4CCC3CC4)cc2)no1
Reaction time: 4 h
Yield: 24.3 %

Procedure:
A mixture of 3-[2-(4-(5-methyl-1,2,4-oxadiazole-3-yl)phenyl)ethynyl]-3-hydroxyquinuclidine (0.61 g) and 5% Pd on carbon (60 mg) in ethanol (100 ml) was hydrogenated at atmospheric pressure for 4 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane containing 1% ammonia (density, 0.88 g/cm3), to give 3-[2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)ethyl]-3-hydroxyquinuclidine (0.15 g) as a solid, m.p. 165°-167° C.; NMR: 1.2-2.1(7H,m), 2.9-2.65(8H,m), 2.65(3H,s), 4.5(1H,s), 7.4(2H,d) and 7.9(2H,d); m/z 314 (M+H).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](N)=[O:4].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:14][C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC(C)(O)C(N)=O
Reactant: CCCCCCO
Product: CCCCCCOC(=O)C(C)(C)O
Yield: 51.8 %

Procedure:
A mixture of 20.6 g of α-hydroxy-isobutyramide and 204 g of n-hexyl alcohol was heated in the presence of 0.45 g of PbO for 6 hours at 200° C. in an autoclave. On working up by distillation, 19.5 g (= 51.8 percent of theory) of α-hydroxy-isobutyric acid-n-hexyl-ester were obtained. The amide conversion is 75 percent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:22]/[C:23]2[NH:24][CH:25]=[CH:26][C:27]=2[O:28][CH3:29])/[C:15](=[O:21])[NH:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(N)c3)c21
Yield: 64.2 %

Procedure:
Using Method S above, 3-aminophenyl boronic acid (0.16 g, 1.0 mmol) (Lancaster) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.3 g, 0.94 mmol) (Starting Material 7) using (Ph3P)4Pd (0.11 g) as catalyst in aqueous 2M Na2CO3 (0.94 mL, 1.88 mmol) and DME (20 mL) at reflux for 1 day to produce (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 0.2 g, 65%).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]2([CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[C:16](=[O:30])[O:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C>[C:20]1([CH:19]2[C:12]3([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[O:15][C:16](=[O:30])[C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]2=3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1OC2(CCNCC2)C(c2ccccc2)c2ccccc21

Procedure:
Prepared by the procedure described in Example 3, Step A from 1'-benzyl-1,4-dihydro-4-phenylspiro(3H-2-benzopyran-3,4'-piperidine)-1-one hydrochloride, (8 mg, 0.019 mmol) and ethanol (5 mL). Reaction time: 45 minutes. Yield 5.5 mg (98.5%). FAB-MS calc. for C19H19NO2 293; found 294 (M+H, 93%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:41])C(=O)C1.[NH4+].[Cl-].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:30][CH3:31])([CH2:32][CH3:33])[CH2:28][CH3:29])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[C:10]([I:41])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)c(I)cn2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 1 g (2.1 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole in 7 mL DMF was treated portionwise at 0° C. with 1.94 g (8.6 mmol) of NIS and stirred for 2 hrs at 65° C. The mixture was poured into a mixture of a saturated aqueous solution of NH4Cl containing NaS2O3 and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 1.1 g (72%) of 1-benzyl-3-iodo-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole, of which 50 mg were dissolved in 1 mL of MeOH and treated with 0.2 mL of 2M NaOMe in MeOH. After stirring for 30 min at RT, the crude mixture was distributed between aqueous HCl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 30 mg of 2-(1-benzyl-3-iodo-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, light brown solid, MS 498 (M−H)−.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:21][C@H:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:23])[CH2:11][CH2:12]2)C1C=CC=CC=1.[ClH:44]>CO.C(OCC)C.[OH-].[Pd+2].[OH-]>[ClH:44].[F:32][C:30]([F:31])([F:33])[C:28]1[CH:29]=[C:24]([C@@H:22]([O:21][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:15][C@H:14]3[N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH3:23])[CH:25]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:27]=1
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](n3cnnn3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: C[C@H](O[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2n1cnnn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-6-(1H-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane (Example 135; 158 mg, 0.26 mmol) was dissolved in methanol (5 ml) and 2N hydrochloric acid (0.5 ml) and 10% palladium hydroxide (40 mg) added and the mixture hydrogenated at 50 psi for 30 minutes. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by thin layer chromatography [5% methanol in dichloromethane] to give a white solid. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60° C. (41 mg, 28%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]12[CH2:14][NH:13][CH2:12][CH:11]1[CH2:10][O:9][NH:8]2.Cl[C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([F:24])=[C:18]([CH3:25])[N:17]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:24][C:19]1[C:20]([O:22][CH3:23])=[N:21][C:16]([N:13]2[CH2:12][CH:11]3[C:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)([NH:8][O:9][CH2:10]3)[CH2:14]2)=[N:17][C:18]=1[CH3:25]
Reactant: c1cnc(C23CNCC2CON3)cn1
Reactant: COc1nc(Cl)nc(C)c1F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(N2CC3CONC3(c3cnccn3)C2)nc(C)c1F
Temperature: 110 °C
Yield: 38.4 %

Procedure:
To a stirred solution of 6a-pyrazin-2-yl-1,3,3a,4,5,6-hexahydropyrrolo[3,4-c]isoxazole (1.4 g, 7.28 mmol) in 1,4-dioxane (30 mL) is added 2-chloro-5-fluoro-4-methoxy-6-methyl-pyrimidine (5.14 g, 29.13 mmol) and diisopropylethylamine (5.7 mL, 32.77 mmol). The resulting solution is heated at 110° C. for 4 hours. The reaction is cooled and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (0.93 g, 38%). ES/MS (m/e): 333 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH:21][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:15][CH:14]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: COc1ccc(C(CN)N2CCOCC2)cc1
Product: COc1ccc(C(CNC(=O)c2ccccc2C)N2CCOCC2)cc1

Procedure:
From 2-methylbenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1cccc2ccc(O)cc12
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1cccc2ccc(O)cc12
Yield: 71.8 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 1.93 g (0.01 mol) of 3-nitrophthalic anhydride, 1.59 g (0.01 mol) of 1-amino-7-naphthol and 30 ml of acetic acid is refluxed for 17 hours. The resulting suspension is stirred with 300 ml of water, then filtered and the filter residue is then washed with water and dried. 2.9 g of crude product are obtained and are extracted with chloroform. The chloroform extract is stirred with 4 g of silica gel, filtered with suction whilst hot, and evaporated to dryness. 2.4 g (72% of theory) of 1-(3-nitrophthalimidyl)-7-hydroxynaphthalene are obtained; melting point 136°-7° C.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:16]([O:18]CC)=[O:17])#[N:2].C([OH:23])C.[OH-].[K+]>O>[C:16]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:23])([OH:18])=[O:17]
Reactant: CCO
Reactant: CCOC(=O)c1cnn(-c2ccc(C)c(C)c2)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-n2ncc(C(=O)O)c2C(N)=O)cc1C

Procedure:
A 2.5 g. portion of ethyl 5-cyano-1-(3,4-dimethylphenyl)-4-pyrazolecarboxylate was hydrolysed in 50 ml. of ethanol and 12 ml. of water with 1.3 g. of potassium hydroxide under reflux for 21/4 hours. The mixture was then cooled and poured into 300 ml. of water. The aqueous mixture was filtered, made acid with concentrated hydrochloric acid, and filtered. The solids were dried and recrystallized from ethanol/water to obtain 1.62 g. of the desired product, m.p. 231°-232.5°. Its elemental analysis was as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([O:32]C)=O)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH3:41]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH:30]([OH:32])[CH3:41])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(O)c1ccccc1-c1ccc(COC2C3CCC(CC2c2ccc(Cl)cc2)N3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A solution of 0.330 g (0.71 mmol) of methyl (1RS,2RS,3RS,5SR)-4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-carboxylate in 10 ml of ether was slowly added dropwise to a suspension of 33 mg of lithium aluminium hydride in 5 ml of ether and the mixture was stirred at room temperature for 4 hours. After the addition of aqueous ether and subsequently water the phases were separated, the organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 140:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There was obtained 0.210 g (68% of theory) of [4'-[3-(4-chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-yloxymethyl]-biphenyl-2-yl]-ethanol as a colourless foam, Rf : 0.18 (methylene chloride:methanol:ammonia=140:10:1), MS: 434 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[N:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:19]1[CH:28]=[CH:27][C:22](C(OC)=O)=[CH:21][CH:20]=1)=[O:7])(C)(C)C.F[C:30](F)(F)[C:31]([OH:33])=[O:32]>ClCCl>[C:31]([CH2:30][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]3[C:9]=2[CH2:8][C:6]([OH:5])=[O:7])=[CH:28][CH:27]=1)([OH:33])=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(-c2nc3ccc(C)cn3c2CC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(CC(=O)O)cc3)c(CC(=O)O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 10 (3.1 g, 8.15 mmol) in dichloromethane (50 ml) was added to trifluoroacetic acid (25 ml). Following stirring at room temperature for 2 h the solution was concentrated to dryness. Potassium carbonate (10%) solution (100 ml) was added and the solution washed with diethyl ether (2×50 ml) and acidified to pH 6 with HCl (6M). The precipitate was filtered, washed with diethyl ether and recrystallized to give [2-(4-carboxymethylphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]acetic acid 11 as a white solid (1.65 g, 62%).
Reaction SMILES: [C:1]([CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[NH2-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]Cl>>[Cl:18][CH2:19][CH2:20][CH2:21][C:3]1([C:1]#[N:2])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: N#CC1c2ccccc2-c2ccccc21
Reactant: ClCCCCl
Agent: [NH2-]
Agent: [Na+]
Product: N#CC1(CCCCl)c2ccccc2-c2ccccc21

Procedure:
9-cyanofluorene was reacted with sodium amide and 1,3-dichloropropane to give 9-(3-chloropropyl)-9-cyanofluorene. A solution of 10.0 g. of 9-(3-chloropropyl)-9-cyanofluorene in 200 ml. of morpholine containing 2.0 g. of potassium iodide was stirred at 160° C. for sixteen hours. After cooling the reaction mixture to room temperature, the solution was diluted with 500 ml. of water, and the aqueous mixture was extracted several times with ethylacetate. The organic extracts were combined, washed with water, and the product was extracted therefrom into 0.6N hydrochloric acid. The aqueous acid layer was separated and made alkaline by the addition of 10 percent sodium hydroxide solution. The alkaline solution was extracted with fresh ethyl acetate, and the extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-morpholinopropyl)-9-cyanofluorene.