Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:17][N:18]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)[CH2:19][CH2:20][O:21]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN2CCOC(CN[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (100 mg, 0.305 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 4-formylbenzoate (60.0 mg, 0.365 mmol) and sodium triacetoxyborohydride (97 mg, 0.457 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was then quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved into methanol (3.00 mL) and sodium hydroxide (6M, 0.5 mL, 3.00 mmol) was added. The mixture was stirred at room temperature for 18 h and purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 81 mg of product (HCl salt) as white solid. MS: (M+H)+=367.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.36 (m, 1H), 1.50 (br. s., 1H), 2.93 (br. s., 2H), 3.10 (br. s., 2H), 3.35 (br. s., 2H), 4.05 (br. s., 2H), 4.36 (br. s., 2H), 7.10-7.39 (m, 5H), 7.74 (br. s., 2H) 8.01 (m, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH:43]1[CH2:45][CH2:44]1.C(OCC)(=O)C>C(#N)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:42][CH:43]5[CH2:45][CH2:44]5)[CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrCC1CC1
Reactant: Oc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1cc(OCC2CC2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (400 mg, 0.88 mmol) in acetonitrile (80 mL) was added cesium carbonate (315 mg, 0.97 mmol) and (bromomethyl)-cyclopropane (0.26 mL, 2.64 mmol). The reaction mixture was heated at reflux for 6 hours. After the reaction was cooled to room temperature, ethyl acetate was added and the organic phase was washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by purification with silica gel chromatography (3:2 hexanes/ethyl acetate) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (320 mg, 71%) as yellow solid. 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.78 (d, 1H), 7.33 (m, 2H), 7.18 (m, 2H), 6.98 (m, 1H), 6.30 (d, 1H), 6.02 (m, 2H), 5.08 (d, 1), 4.35 (m, 1H), 3.99 (m, 1H), 3.80 (d, 2H), 2.014 (m, 4H), 1.83–1.55 (m, 12H), 1.22 (m, 1H), 0.61 (m, 2H), 0.35 (m, 2H). MS m/z 509 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([CH:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=2)[C:20]1=[O:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1c2ccc(Br)cc2CCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under dry N2, diisopropylamine (1.7 ml, 0.012 mol) was dissolved in tetrahydrofuran (20 ml) and cooled to -78° C. Butyl lithium (6.88 ml of 1.6 M in hexane, 0.011 mol) was added, and the mixture stirred at -20° C for 0.5 hour and then recooled to -78° C. 6-Bromo-3,4-dihydro-1(2H)-naphthalenone (2.25 g, 0.010 mol; J. Am. Chem. Soc. v. 102, p. 7920, 1980), dissolved in tetrahydrofuran (10 ml) was added, the mixture warmed to -20° C. over 0.5 hour and stirred at that temperature for 15 minutes. Finally benzyl bromide (1.3 ml, 0.011 mol) was added, the mixture warmed over 1 hour to ambient temperature, and stirred at that temperature for 16 hours. The reaction was quenched with two volumes of 10% HCl and extracted with 150 ml ether. The organic layer was washed with 100 ml saturated brine, dried (MgSO4), stripped in vacuo, and the residue chromatographed on silica gel using 1:1 hexane:CH2Cl2 as eluant, monitoring by tlc (1:2 hexane:CH2CL2). Recovered was 380 mg of bis-benzylated product (Rf 0.58), 750 mg of title product (Rf 0.50) and 1.1 g of starting material (Rf 0.28), suitable for recycling.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44][CH2:43]2)=[CH:38][C:32]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:41]=[CH:40][C:39]([C@H:42]4[CH2:43][CH2:44][C@H:45]([OH:48])[CH2:46][CH2:47]4)=[CH:38][C:32]=3[C:33](=[O:34])[N:35]([CH3:36])[CH3:37])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CN(C)C(=O)c1cc(C2CCC(O)CC2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)cc3C(=O)N(C)C)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.20 g, 0.45 mmol) and 2-amino-5-(4-hydroxycyclohexyl)-N,N-dimethylbenzamide (Compound 173A, 0.130 g, 0.496 mmol). The reaction mixture was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash unit eluting with 0 to 5% MeOH in DCM to afford the individual trans and cis isomers. Cis: 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.86 (d, J=8.34 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.26 (dd, J=1.77, 8.59 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (t, J=1.89 Hz, 1H), 6.73 (d, J=7.83 Hz, 1H), 3.92-4.01 (m, 4H), 3.89 (br. s., 1H), 3.77 (s, 3H), 3.13-3.23 (m, 2H), 2.91 (d, J=15.16 Hz, 6H), 2.56 (t, J=11.87 Hz, 1H), 1.79-1.92 (m, 2H), 1.70-1.78 (m, 2H), 1.49-1.61 (m, 4H), 1.18 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 681.2723 [MH+]. HPLC: tR=1.45 min (UPLC TOF MS: polar—3 min). Trans: 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=8.84 Hz, 1H), 7.58 (d, J=8.08 Hz, 1H), 7.26 (dd, J=2.02, 8.34 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J=7.83 Hz, 1H), 4.57 (d, J=4.55 Hz, 1H), 3.91-4.01 (m, 4H), 3.76 (s, 3H), 3.40-3.54 (m, 1H), 3.14-3.23 (m, 2H), 2.91 (d, J=18.95 Hz, 6H), 1.93 (d, J=9.35 Hz, 2H), 1.79 (d, J=12.38 Hz, 2H), 1.45-1.58 (m, 2H), 1.22-1.35 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 680.2332 [MH+]. HPLC: tR=1.40 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[N:5][N:6]=1.[CH2:8]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][NH:9]1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[Br:1][C:2]1[S:3][C:4]([N:9]2[CH2:8][C:11]3([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[CH2:10]2)=[N:5][N:6]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(Br)s1)C2
Temperature: 120 °C
Yield: 87.8 %

Procedure:
A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (245 mg, 1.004 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (290 mg, 1.105 mmol) and DIPEA (702 μL, 1.02 mmol) in dioxane (2.5 mL) was heated at 120° C. for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with DCM (20 mL), and the organic phase was concentrated onto silica gel. The crude material was purified by flash chromatography using a 24 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a yellow oil (343 mg, 88% yield). LC-MS: Rt 1.25 min; MS m/z 391.2 [M+2]+ [Method A]. 1H NMR (400 MHz, Chloroform-d) δ 3.87 (s, 4H), 3.34-3.43 (m, 4H), 1.73-1.85 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)CCNC2CN1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2cc(O)ccc21

Procedure:
Prepared as Ex. No. 5, from 6 g (15.23 mmoles) of 1-(pyrrolidin-1-yl)methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 4.1 g (20.0 mmoles) of 3,4-dichlorophenylacetic acid, 5.4 ml (38.42 mmoles) of triethylamine and 6.2 g (30.24 mmoles) of dicyclohexylcarbodiimide in 145 ml of dry chloroform.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([C:26](=[O:28])[CH3:27])[N:23]([CH3:29])[C:22]=2[CH:30]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[C:26]([C:24]1[N:23]([CH3:29])[C:22]2[CH:30]=[C:18]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:19]=[CH:20][C:21]=2[N:25]=1)(=[O:28])[CH3:27]
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: CC(=O)c1nc2ccc(Br)cc2n1C
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (312 mg), 1-(6-bromo-1-methyl-1H-benzimidazol-2-yl)ethanone (360 mg), N,N′-dimethylethylenediamine (0.141 ml), copper iodide (250 mg) and potassium carbonate (393 mg) in DMSO (3 ml) was stirred at 150° C. for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH/IPA to give the title compound (54.6 mg) as a pale orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:18][OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: COCCOC
Product: O=C(NC1(CO)CCCCC1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in DME (15 mL) at 4° C. was slowly added isobutyl chloroformate (2.14 mL, 16.5 mmol) and the reaction mixture was stirred for 5 min, then filtered into a pre-cooled (4° C.) flask. Sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) wag added followed immediately by water (500 mL). The reaction was then warmed to 20° C. and stirred for 30 min. The reaction mixture was extracted with CH2Cl2 and concentrated under reduced pressure to yield 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 100%): TLC (25% EtOAc/hex) Rf0.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:9]([OH:16])[C:10]([CH3:15])([CH3:14])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1>[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:9]([OH:16])[C:10]([CH3:15])([CH3:14])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(C)(C)C(O)C(c1cccc(Cl)c1)n1ccnc1
Agent: [Pt]
Product: C=CCC(C)(C)C(O)C(c1cccc(Cl)c1)n1ccnc1

Procedure:
In the same fashion as described in Example 26, 1.43 g of 1-(3-chlorophenyl)-3,3-dimethyl-1-(1-imidazolyl)-2-hexanol of melting point 97° C. were obtained through hydrogenation on a 5 mmol scale of 1-(3-chlorophenyl)-3,3-dimethyl-1-(1-imidazolyl)-5-hexen-2-ol (compound according to Example 2) with 200 mg of sulfidized 5% platinum on activated charcoal as catalyst.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>ClCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.15 g, 0.41 mmol) in dichloromethane (3 mL) and DMF (1 mL) was added HATU (0.23 g, 0.62 mmol). The mixture was stirred for 15 mins followed by addition of 2,2,2-trifluoroethylamine (0.08 g, 0.82 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a white ppt which was filtered and dried under high vacuum to give the title compound as a white powder (0.109, 55%). 1H NMR (400 MHz, CDCl3) δ7.34-7.25 (m, 3H), 7.12 (t, J=7.5 Hz, 2H), 7.01 (t, J=7.7 Hz, 3H), 6.91 (t, J=8.4 Hz, 3H), 6.54 (d, J=8.4 Hz, 2H), 5.81 (s, 1H), 4.29 (s, 2H), 4.01-3.88 (m, 3H), 2.48-2.43 (m, 1H), 1.62-1.49 (m, 2H), 1.27-1.20 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])(=O)C>[OH-].[Na+]>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[OH:4])=[N:11][CH:12]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1O
Yield: 63.5 %

Procedure:
2-Acetoxy-N-(5-chloropyridin-2-yl)benzamide (1.45 g, 5 mmol) was saponified in aqueous methanolic NaOH. Standard acid-base workup gave 1.06 g of crude crystalline product which was recrystallized from acetone to give N-(5-chloropyridin-2-yl)-2-hydroxybenzamide (0.79 g, 63% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([F:21])([F:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])(=O)C.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.C(OCC)C>[F:21][C:7]([F:20])([CH2:6][CH2:5][OH:4])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]
Reactant: CC(=O)OCCC(F)(F)CN1C(=O)c2ccccc2C1=O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
The above N-(4-acetoxy-2,2-difluorobutyl)phthalimide (3.84 g, 12.9 mmol) was dissolved in THF (65 mL) and cooled to −78° C. A solution of DIBAL-H (32.3 mL, 1.0 M in hexanes, 32.3 mmol) was added slowly and the solution allowed to stir 0.5 h. Saturated aqueous NH4Cl solution (15 mL) was then added and the solution was warmed to room temperature. MgSO4 (15 g) and diethyl ether (200 mL) were added, and the mixture was filtered through celite, washing with excess 1:1 Et2O/THF (1 L). The filtrate was then concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel (1:2 EtOAc/hexanes) to give the desired N-(2,2-difluoro-4-hydroxybutyl)phthalimide as a pale yellow solid (1.47 g, 45%). 1H NMR (CDCl3) δ 1.97 (t, OH, J=6.0 Hz), 2.22 (tt, 2H, J=16.5, 6.0 Hz), 3.95 (q, 2H, J=6.0 Hz), 4.19 (t, 2H, J=15 Hz), 7.75 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][NH:11][C:12](=[O:15])[CH2:13][Cl:14])=O)[CH:5]=[N:6][CH:7]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[O:15][C:12]([CH2:13][Cl:14])=[N:11][N:10]=2)[CH:3]=1
Reactant: O=C(CCl)NNC(=O)c1cncc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1nnc(-c2cncc(Br)c2)o1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
A suspension of 5-bromo-N′-(chloroacetyl)-3-pyridinecarbohydrazide (3.65 g, 12.48 mmol) in POCl3 (20 mL) was heated at 110° C. for 1.5 h. Upon cooling, the mixture was concentrated in vacuo. The residue was diluted with EtOAc and sat'd NaHCO3 solution was added slowly while stirring. The pH of the aqueous phase was adjusted to ˜8 by addition of sat'd K2CO3 solution. The phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) to afford the title compound as a light yellow solid (2.01 g, 59% yield): MS (ES) m/z 274 and 276 (M+1 Br isotopes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])C)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[O-]Cl.[Na+].[OH-].[Na+].S(S([O-])=O)([O-])(=O)=[O:20].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:20])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(=O)c1cc(Br)c2c(c1)CCC2
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)c1cc(Br)c2c(c1)CCC2
Temperature: 50 °C
Yield: 98.2 %

Procedure:
1-(7-bromo-2,3-dihydro-1H-inden-5-yl)ethanone (8.6 g, 36 mmol) was dissolved in dimethoxyethane (100 mL) and to the solution were added NaClO aq (200 mL 1M, 200 mmol) and NaOH aq (20 mL 10 M, 200 mmol). The mixture was heated to 50° C. for 1 h and then diluted with water (200 mL). Sodium pyrosulfite (5.7 g, 30 mmol) was added. The mixture was washed with ether, acidified with concentrated HCl and then extracted twice with ether (150 mL). The organic solution was washed with brine, dried and then the solvent was evaporated. The solid residue was treated with cold CH2Cl2 (−40° C.), then filtered off and dried. There was obtained 7.1 g (82%) of 7-bromoindane-5-carboxylic acid as a solid material. 1H NMR (300 MHz, CD3OD): 2.0-2.2 (q, 2H), 2.9 (t, 2H), 3.1 (t, 2H), 7.8 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([OH:8])=[CH:7][C:2]=3[F:1])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: Oc1ccc2cc(-c3cc(F)c(O)cc3F)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.84 mmol) and NCS. (295 mg, 2.21 mmol) in THF (37 mL) according to method Cto yield 370 mg (66%) of yellowish solid: mp:203–204° C.; 1H NMR (DMSO-d6): δ 6.90 (1H, dd, J=11.90 Hz, J=7.50 Hz), 7.32 (1H, d, J=8.88 Hz), 7.49 (1H, dd, J=11.87 Hz, J=7.60 Hz), 7.72–7.76 (1H, m), 7.84 (1H, d, J=8.97 Hz), 8.03 (1H, s), 8.06 (1H, d, 8.87 Hz), 10.58 (2H, s); MS (ESI) m/z 305/307 (M−H)−; HRMS calcd for C16H9ClF2O2 306.02591, observed 305.01863 (M−H)−.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.B.C1COCC1>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])([CH2:20][CH2:21]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: B
Solvent: C1CCOC1
Product: OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanoic acid (115 mg, 0.307 mmol) in dry THF (1 mL) at 0° C. under N2 was added BH3.THF (0.461 ml, 0.461 mmol) over a period of 3 min. The resulting mixture was stirred at 0° C. for 30 min and at room temperature 3 h. The reaction was cooled to 0° C. and quenched with water carefully. The mixture was extracted with ethyl acetate. The organic layer was washed with sat′d aqueous NaHCO3, water, dried, and the concentrated in vacuo to afford the title compound (111 mg, 100% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.04-7.00 (m, 1H), 6.94 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.98-3.91 (m, 1H), 3.83 (s, 2H), 3.67 (t, J=6.5 Hz, 2H), 3.64-3.58 (m, 1H), 2.04 (t, J=7.8 Hz, 5H), 1.90-1.83 (m, 2H), 1.75-1.50 (m, 10H), 1.38-1.26 (m, 2H), 1.22-1.15 (m, 2H).
Reaction SMILES: ClC1C=CC=C2C(OC(=O)C=12)=[O:6].[N+:13]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=[O:23])[C:17]=12)=[O:20])([O-:15])=[O:14].ClCl.C1(=O)OC(=O)C2=CC=CC=C12>>[N+:13]([C:16]1[CH:26]=[CH:25][CH:24]=[C:18]([C:19]([OH:6])=[O:20])[C:17]=1[C:22]([OH:21])=[O:23])([O-:15])=[O:14]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: ClCl
Agent: O=C1OC(=O)c2ccccc21
Product: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
3-Chlorophthalic anhydride can also be prepared from 3-nitrophthalic anhydride by replacement of the nitro group by chlorine. The 3-nitrophthalic anhydride needed for this is prepared in three process steps by nitration of phthalic anhydride in moderate yield, by isomer separation of the nitrophthalic acids formed, by fractional crystallization and by conversion to the anhydride of the 3-nitrophthalic acid obtained (M. S. Newman, P. G. Scheurer, J. Am. Chem. Soc. 78 (1956), 5005; Organic Syntheses, Coil. Vol. 1 (1932), 399-401). This multistage and complicated route, which additionally gives poor yields, is not very suitable for industrial use.