Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH2:32])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][C:43]1[CH:57]=[CH:56][C:46]([CH2:47][N:48]2[CH:52]=[C:51]([C:53](O)=[O:54])[CH:50]=[N:49]2)=[CH:45][CH:44]=1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27](=[O:41])[N:28]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:29]=[C:30]([NH:32][C:53]([C:51]2[CH:50]=[N:49][N:48]([CH2:47][C:46]3[CH:56]=[CH:57][C:43]([CH3:42])=[CH:44][CH:45]=3)[CH:52]=2)=[O:54])[CH:31]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Reactant: Cc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(C(C)(C)O[SiH2]C(C)(C)C)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1

Procedure:
The title compound was prepared by the route outlined in Scheme 8 and using the experimental from Example 20, step 4, with intermediate (8d), 2-[5-amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester (1.0 g, 1.67 mmol) and 1-(4-methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.43 g, 1.99 mmol) which had been synthesised according to the protocol described for intermediate (6e) in example 21. The resultant crude product was purified by flash chromatography on SiO2 with hexane—50% ethyl acetate/hexane (gradient) to afford the title compound as a pink oil, 0.721 g, 54%.
Reaction SMILES: [CH3:1][O:2][C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5](OC)=[O:6].[NH3:13]>CCOCC>[CH3:1][O:2][C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([NH2:13])=[O:6]
Reactant: N
Reactant: COC(=O)C(F)(F)C(F)(F)OC
Solvent: CCOCC
Product: COC(F)(F)C(F)(F)C(N)=O
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A solution of 140 g (0.74 mol) of methyl 3-methoxytetrafluoropropionate in 100 ml of ether was treated at 0° with 15.3 g (0.90 mol) of NH3. The resulting viscous mixture was stirred at 25° overnight and evaporated to dryness at 25° (10 mm). The crude residue was then recrystallized from ether/hexane to give 123.6 g (95%) of 3-methoxytetrafluoropropionamide, mp 78°-80°. An analytical sample was recrystallized from ether/hexane, mp 83°-85°. IR (KBr): 2.95, 3.02 and 3.10 (NH2), 3.37 and 3.49 (sat'd CH), 5.92 (C=O), 6.19 (NH2), 7.5-10μ (CF, C--O). NMR ((CD3)2CO): 1H 6.67 (broad, 2H, NH2) and 3.66 ppm (s, 3H, OCH3); 19F-120.6 (t, JFF 4.7 Hz, 2F, CF2) and -121.8 ppm (t, JFF 4.7 Hz, of d, JHF 2.1 Hz, 2F, CF2).
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2([NH2:12])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:9]2([CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:10]2)[CH:19]=1
Reactant: NC1(Cc2ccccc2)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
Temperature: 140 °C
Yield: 41.2 %

Procedure:
A mixture of 1-(phenylmethyl)cyclopropanamine_hydrochloride (530 mg, 2.88 mmol), 4,6-dichloro-2-pyrimidinamine (295 mg, 1.80 mmol), Et3N (911 mg, 9 mmol) and K2CO3 (249 mg, 1.80 mmol) in ethanol (6 mL) was stirred and heated at 140° C. for 4 hours in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water. The organic layer was separated, dried (Na2SO4), concentrated to dryness and purified by reverse phase chromatography using CH3CN in water from 32% to 42% (0.05% trifluoroacetic acid in water) in 8 min to afford the title compound (204 mg) as a white solid. LC-MS (ES) m/z=275 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@@H:26]([C@H:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH3:27])[N:12]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][C@H:26]([CH3:27])[C@H:28]([OH:29])[CH2:32][OH:31])[N:12]=1
Reactant: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: Cl[Fe](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step yl) (0.13 g) in DCM (5 mL) was added iron (III) chloride hexahydrate (0.26 g). The reaction mixture was stirred at ambient temperature for 1.5 h, then saturated aqueous sodium bicarbonate (1 mL) was added. The layers were separated and the aqueous material extracted with DCM (×3) and ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residual pale yellow solid was slowly precipitated from DCM, filtered and the resulting material washed with minimal cold DCM (2×1 mL) to afford the title compound as a white powder. Yield: 64 mg,
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2nccs2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiazole. The title compound (9 mg) was obtained as a pale solid, m/z 348 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH:29]=[CH2:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:27][OH:28])=[C:24]([CH2:29][CH3:30])[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Agent: [Pd]
Solvent: CCO
Product: CCOc1nc(CC)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Compound B (1.0 g, 2.2 mmol) was dissolved in EtOH (54 mL, 940 mmol), and added to a flask containing palladium (200 mg, 2 mmol) in 10 mL of EtOH. The mixture was degassed and stirred under hydrogen for 1 hour. The palladium was filtered and the solvent was concentrated to yield compound C (1.0 g), which was immediately carried on to the next reaction.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[C:43]([C:40]1[CH:39]=[CH:38][C:37]([CH:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:25][CH:24]=2)=[O:21])=[CH:42][CH:41]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(OCCOCc3ccccc3)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(Cc2ccc(OCCO)cc2)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-propionamide (200 mg, 0.32 mmol) and 10% Pd/C (20 mg) in a solution of methanol/ethyl acetate (60 mL, 4:1) was stirred under an atmosphere of H2 overnight. The mixture was filtered through celite and concentrated under vacuum. The crude was purified by chromatography on silica gel (ISCO cartridge, 40 g), eluting with dichloromethane over 20 minutes to afford 2-(4-tert-Butylphenyl)-N-(4-cyclohexylmethoxyphenyl)-3-[4-(2-hydroxy ethoxy)-phenyl]-propionamide (126 mg, 74%). LC-MS m/z=530 [C34H43NO4+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3].[H-].[Na+].[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:15]=1[C:16](Cl)=[O:17]>CN(C=O)C.O>[N:1]([C:4]1[CH:9]=[C:8]([NH:10][C:16](=[O:17])[C:15]2[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: [N-]=[N+]=Nc1cc(N)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.2 %

Procedure:
To a cooled (0° C.) solution of 2-azidopyridin-4-amine (500 mg, 3.7 mmol) in dry DMF (10 ml) was added NaH (178 mg, 7.4 mmol). After stirring for 10 min, a solution 2,4,6-trichlorobenzoyl chloride (1.8 g, 7.4 mmol) in DMF (5 mL) was added dropwise. The reaction was warmed to 25° C. and stirring was continued for 30 min. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (petroleum ether/ethyl acetate=1:1) to afford N-(2-azidopyridin-4-yl)-2,4,6-trichlorobenzamide (180 mg, yield: 14%). LCMS (ESI) m/z: 342.0 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC>C1(C)C=CC=CC=1.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>[Br:12][C:4]1[CH:3]=[C:2]([C:18](=[O:20])[CH3:19])[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
To a solution of 1,3-dibromo-5-(tert-butyl)benzene (664 mg, 2.22 mmol) in toluene (15 mL) were added tri-n-butyl-1-ethoxyvinyl tin (965 mg, 2.66 mmol) and Pd(PPh3)2Cl2 (150 mg 0.22 mmol) under N2. The mixture was stirred at 95° C. for 3 h, evaporated, diluted with 1,4-dioxane and 2N HCl, stirred rapidly at 25° C. for 1 h and then extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by CC to afford compound P49a (310 mg, 55%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1ccccc1I
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccccc1F

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-2-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 12 mg of (8S)-9-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:61][C:62]([CH3:69])([CH3:68])/[CH:63]=[CH:64]/B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:61][C:62]([CH3:69])([CH3:68])[CH:63]=[CH:64][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1
Reactant: NC1=NC2(CO1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: CC(C)(C)/C=C/B(O)O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C=Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 120 °C
Yield: 64 %

Procedure:
A microwave vial was charged with (rac)-2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared in a manner similar to Example 39; 90 mg, 247 μmol), Pd2dba3 (11 mg, 12 μmol), X-Phos (12 mg, 25 μmol), (E)-3,3-dimethylbut-1-enylboronic acid (63 mg, 493 μmol) and potassium phosphate (157 mg, 740 μmol). THF (2 mL) was added and the mixture was heated at 120° C. in microwave reactor for 2 hrs. The mixture was diluted with ethyl acetate and filtered through plug of Celite. After removal of the solvents the residue was purified by flash chromatography on silica gel (12 g Redi-Sep column, 20-100% DCM/MeOH/NH4OH 90:10:1 in DCM) to give 2′-(3,3-dimethylbut-1-enyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (65 mg, 64% yield). This product was hydrogenated at 1 atm of H2 in MeOH/EtOAc mixture using 10% palladium on carbon (53 mg, 49 μmol) for 60 hrs. The reaction mixture was filtered and concentrated in vacuo and was further purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined and dried overnight under high vacuum to give 2′-(3,3-dimethylbutyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as its TFA salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([C:11]2[S:12][CH:13]=[C:14]3[O:19][CH2:18][CH2:17][O:16][C:15]=23)O)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:11]2[S:12][CH:13]=[C:14]3[O:19][CH2:18][CH2:17][O:16][C:15]=23)[CH:5]=[CH:4][N:3]=1
Reactant: OC(Cc1ccnc(Br)c1)c1scc2c1OCCO2
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Brc1cc(C=Cc2scc3c2OCCO3)ccn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
Compound (9) (800 mg, 2.34 mmol) was dissolved in pyridine (2 mL). POCl3 (327 μL, 538 mg, 3.51 mmol) was added and the resulting mixture was cooled to −78° C. Upon addition of water (40 mL) the formation of a precipitate was observed. The cooling bath was removed and the mixture was stirred for 15 min. A precipitate was obtained which was collected upon filtration and washed with petroleum ether/ethyl acetate (20 mL, 1:1) affording pure (10) as a yellow solid (380 mg, 1.17 mmol, 50%), mp 127-129° C. 1H NMR (500 MHz, CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=16.1 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 6.70 (d, J=16.1 Hz, 1H), 6.38 (s, 1H), 4.35-4.33 (m, 2H), 4.27-4.25 (m, 2H).
Reaction SMILES: I[C:2]1[C:3]([O:24]C)=[CH:4][C:5]([O:22]C)=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])=[CH2:27]>CCOCC>[C:29]1([CH:26]([CH3:28])[CH2:27][C:2]2[C:3]([OH:24])=[CH:4][C:5]([OH:22])=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH2:19])[N:11]=[CH:10][CH:9]=3)[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2[N+](=O)[O-])cc1I
Reactant: C=C(C)c1ccccc1
Solvent: CCOCC
Product: CC(Cc1cc(-c2ccnn2-c2ccccc2N)c(O)cc1O)c1ccccc1

Procedure:
12.8 Analogous reaction of 5-[5-iodo-2,4-dimethoxyphenyl]1-(2-nitrophenyl)-1H-pyrazole with isopropenylbenzene, hydrogenation and ether cleavage gives the compound 5-{5-(2-phenylpropyl)-2,4-dihydroxyphenyl}-1-(2-aminophenyl)-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[CH2:20]([Mg]Cl)[CH2:21][CH3:22]>C1COCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[N:3]=1
Reactant: CCC[Mg]Cl
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C=O
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.600 g (2.26 mmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde (example 3A]) was dissolved in 11.3 ml of abs. THF and treated at −78° C. with 1.2 ml of 2M propyl magnesium chloride solution (in EtOEt, 1.06 eq.). After stirring for 15 Min. at 0° C., the reaction mixture was carefully poured onto crashed ice/NH4Cl, extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded then 0.281 g of the title compound as white crystals of mp. 83–85° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[NH:17][C:18](=O)[CH:19]([CH3:21])[CH3:20].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC.ClCCl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CNc1cc(Cl)ccc1CO
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a suspension of 3.96 g (105 mmol) of lithium aluminum hydride in 200 ml of dry ether was dropwise added under chilling with ice for 15 min. a solution of 9.50 g (37 mmol) of methyl-4-chloro-2-(isobutyrylamino)benzoate obtained in b) above in a mixture of 20 ml of dry dichloromethane and 20 ml of dry ether. The mixture was then stirred for 30 min., and heated under reflux for 30 min. To the mixture was dropwise added under chilling with ice a saturated aqueous sodium sulfate. The organic portion was taken out by decantation, and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 7.28 g of the desired compound as a residual colorless oil.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCNC(=O)OCc3ccccc3)cc2)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(CCN)cc2)c(C)c1
Yield: 87.6 %

Procedure:
A mixture of methyl 4′-[2-[[(benzyloxy)carbonyl]-amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (650 mg), ammonium formate (500 mg) and palladium on carbon powder (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 2 hours. The reaction mixture was filtrated and poured into water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 4′-(2-aminoethyl)-2-methyl-1,1′-biphenyl-4-carboxylate (380 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[OH:12][S:13]([OH:16])(=[O:15])=[O:14].[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[S:13]([OH:16])([OH:15])(=[O:14])=[O:12].[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=2)[CH2:4]1
Reactant: NC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (60 mL) was charged into a flask, cooled in an ice/water bath, and 2-aminoindane hydrochloride (10.08 g) was added cautiously, followed by H2SO4 (6.0 mL) and HNO3 (3.0 mL). The ice bath was removed, and the mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was then placed in an ice water bath for the slow addition of diethyl ether (300 mL) over 35 minutes. The mixture was stirred at room temperature overnight, then the solids were filtered and dried in vacuo to give 15.43 g of 2-amino-5-nitro-indane sulfate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[C:25]2[N:26]=[N:27][NH:28][N:29]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([C:25]5[N:26]=[N:27][NH:28][N:29]=5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(-c3nn[nH]n3)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2-c2nn[nH]n2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
4-Bromochlorobenzene (3.2 g, 16.62 mmol) was dissolved in dry THF (20 mL). After bringing the reaction temperature down to -78° C. with an acetone/dry ice bath, nBuLi (15.58 mL, 1.6M, 1.5 equiv.) was added slowly and stirred at -78° C. for 30 min. Tributyltinchloride (6.77 mL, 1.5 equiv.) was added and stirred overnight while bringing the reaction to room temperature. Reaction mixture was quenched by stirring the reaction flask open in air for 1 hour after which THF was rotavaporated off. Product was obtained as an oil (7.35g, 97%) after passing the mixture through a quick silica gel column eluting with 100% hexanes.