Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[H-].[Na+].I[CH3:18].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH3:18]
Reactant: COC(=O)c1cc2c(F)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(F)cccc2n1C
Yield: 105.2 %

Procedure:
To methyl 4-fluoro-1h-indole-2-carboxylate (1.211 mmol, 234 mg) in N,N-dimethylformamide (10 ml) at 0° C. was added sodium hydride (1.817 mmol, 72.7 mg). The reaction mixture was stirred for one hour at room temperature before iodomethane (1.817 mmol, 0.113 ml, 258 mg) was added. After stirring for three hours water was added and the product was extracted with dichloromethane and concentrated in vacuo to give methyl 4-fluoro-1-methyl-1H-indole-2-carboxylate (264 mg). The latter compound was dissolved in ethanol (5 ml). Then 2 N aqueous sodium hydroxide (5.84 mmol, 2.92 ml) and potassium hydroxide (1.168 mmol, 65.5 mg) were added and the reaction mixture was stirred at 80° C. over night. 2N Hydrochloric acid was added to the reaction mixture and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to give 4-fluoro-1-methyl-1H-indole-2-carboxylic acid (189 mg).
Reaction SMILES: FC(F)(F)C1C(CC2C=CC(N)=CC=2)=CC=CN=1.FC(F)(F)[C:21]1[CH:26]=[C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:24]=[CH:23][N:22]=1.C(OC(=O)CC1C=CC([N+]([O-])=O)=CC=1)C.[Cl:52]C1C=C([N+]([O-])=O)C=CN=1>>[Cl:52][C:21]1[CH:26]=[C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Nc1ccc(Cc2cccnc2C(F)(F)F)cc1
Product: Nc1ccc(Cc2ccnc(Cl)c2)cc1

Procedure:
4-(2-Chloro-pyridin-4-ylmethyl)-phenylamine was prepared by a method analogous to that described for 4-(2-trifluoromethyl-pyridinylmethyl)-phenylamine (Intermediate 2P), starting from ethyl(4-nitrophenyl)acetate and 2-chloro-4-nitro-pyridine. 1H NMR (CHCl3-d) δ 8.23 (dd, J=5.1, 0.5 Hz, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.95 (m, 2H), 6.65 (m, 2H), 3.83 (s, 2H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([O-:13])([O-])[O:9][CH2:10][CH3:11].[F:14][CH:15]([F:37])[O:16][C:17]1[C:18]([F:36])=[C:19]([C:28]([N+:33]([O-:35])=[O:34])=[C:29]([F:32])[C:30]=1[F:31])[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=O)=[O:21]>>[F:37][CH:15]([F:14])[O:16][C:17]1[C:18]([F:36])=[C:19]([C:28]([N+:33]([O-:35])=[O:34])=[C:29]([F:32])[C:30]=1[F:31])[C:20]([C:22](=[CH:23][O:25][CH2:26][CH3:27])[C:8]([O:9][CH2:10][CH3:11])=[O:13])=[O:21]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
38 ml of acetic anhydride and 11 ml of ethyl orthoformate were added to the whole of the ethyl 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoylacetate [(XV), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=X'=F] prepared as described in step (b) above, and then the mixture was heated under reflux for 3 hours; the excess acetic anhydride and ethyl orthoformate were then removed by evaporation under reduced pressure, to give 20.6 g of ethyl 2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyacrylate as a red liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][OH:24])[CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=NN=N1.CC#N.C(N(C(C)C)[P:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(C)C.[OH:51]O>C1COCC1.C(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][O:24][P:37](=[O:51])([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OO
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: CCCCCCCCOc1ccc(C2CN(CCO)CCO2)cc1
Agent: c1nnn[nH]1
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C2CN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CCO2)cc1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethanol (1.33 g; 4.0 mmol) in a mixture of THF (15 mL) and CH2Cl2 (15 mL) was added a tetrazole solution in CH3CN (17.6 mL; 0.45 mol/L; 7.9 mmol) at RT. The resulting mixture was stirred for 30 minutes and subsequently di-tert-butyl N,N-diisopropylphosphoramidite (2.00 ml; 6.3 mmol) was added and stirred overnight at RT. Subsequently, an aqueous hydrogen peroxide solution (1.80 ml; 300 g/1; 15.9 mmol) was added and the mixture stirred at RT for another 15 min. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford phosphoric acid di-tert-butyl ester 2-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-ethyl ester (0.71 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH:16]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:16]([C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]=3[CH3:13])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: Cc1cccc(C)c1C=O
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3c(C)cccc3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-diaminobenzoic acid methyl ester (5.2 g) and 2,6-dimethylbenzaldehyde (4.2 g) in DMSO (50 mL) was added Yb(OTf)3 (3.9 g). The mixture was stirred at room temperature for 18 h. The mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester as a red solid; MS (ESI)m/z 281 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[NH2:40][C@@H:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:42]([NH:44][CH3:45])=[O:43]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:40][C@@H:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:42]([NH:44][CH3:45])=[O:43])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=404.3 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@:19]([OH:35])([C@H:26]([N:28]1[CH:32]=[C:31]([CH2:33][OH:34])[N:30]=[N:29]1)[CH3:27])[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@:19]([OH:35])([C@H:26]([N:28]1[CH:32]=[C:31]([CH:33]=[O:34])[N:30]=[N:29]1)[CH3:27])[CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: C[C@@H](n1cc(CO)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](n1cc(C=O)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
Dimethylsulfoxide (1.08 ml) was added dropwise at -78° C. to a solution of oxalyl chloride (1 ml) in dichloro-methane (30 ml), followed by stirring for 10 minutes. To the mixture was added dropwise over the period of 5 minutes a solution of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (2 g) in dichloro-methane (30 ml), followed by stirring for 15 minutes at -78° C. and then for 1 hour at -45° C. To the mixture was added triethylamine (5 ml), followed by stirring for 20 minutes at 0° C. To the mixture was added a saturated aqueous ammonium chloride solution (20 ml). The mixture was extracted with dichloromethane (40 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: ethyl acetate/dichloromethane=3:1) to give Compound 71 (1.49 g), which was crystallized from diisopropyl ether to yield a colorless crystalline powder.
Reaction SMILES: O.[Cl:2][C:3]1[N:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([CH:7](C(OCC)=O)C(OCC)=O)=[O:6].Cl>CS(C)=O>[Cl:2][C:3]1[C:4]([C:5](=[O:6])[CH3:7])=[CH:18][CH:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cccnc1Cl
Temperature: 130 °C
Yield: 56 %

Procedure:
Water (1.3 mL) was added to a solution of diethyl 2-(2-chloronicotinoyl)malonate (31.7 mmol) in dimethylsulfoxide (50 mL). The pH of the reaction mixture was added adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture was heated at 130° C. for 2 h. The reaction mixture was then quenched with ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (1/20 ethyl acetate/petroleum ether to provide 1-(2-chloropyridin-3-yl)ethanone in 56% yield as light yellow oil.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:37]3[CH2:42][CH2:41][CH:40]([C:43]([F:46])([F:45])[F:44])[CH2:39][CH2:38]3)=[O:36])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].C(=O)([O-])[O-].[K+].[K+].C[Si]([N:57]=[C:58]=O)(C)C>CC(C)=O>[CH3:58][NH:57][C:3]([N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:9]([Cl:8])=[CH:10][C:11]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([N:37]5[CH2:38][CH2:39][CH:40]([C:43]([F:46])([F:44])[F:45])[CH2:41][CH2:42]5)=[O:36])=[CH:33][CH:34]=4)=[CH:12][C:13]=3[Cl:28])[C:17]2=[O:27])[CH2:26][CH2:25]1)=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCNCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A solution of (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 30) (112 mg, 0.16 mmol) and potassium carbonate (40 mg, 0.32 mmol) in Acetone (5 mL) is treated with Trimethylsilyl-isocyanate (30 mg, 0.24 mmol). The reaction is stirred overnight at room temperature. The reaction is quenched with 1N HCl and extracted with Et2O. The organic is washed with brine, dried over MgSO4, and filtered. The crude is purified by silica gel column chromatography using Hexanes:EtOAc to elute pure product. The solvent is removed to afford 0.038 g (38%) of product. MS (m/e): 626 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:34])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].ClCl.ClCCl.CO.N>>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([NH:34][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Cl:1])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Cl
Agent: ClCl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2Cl)cc1Cl
Product: Cl

Procedure:
Prepared analogously to Example 3.8.a. from (3-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-(2-diethylaminoethoxy)phenylamine. Yield: 0.35 g (68% of theory); melting point: 195° C.-200° C.; C27H26Cl2N2O2*HCl (M=517.87); calc.: molecular ion peak (M+H)+: 481/3/5 (Cl2); found: molecular ion peak (M+H)+: 481/3/5 (Cl2); Rf value: 0.6 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][C:12]2[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[F:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][C:12]2[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
10% Sodium hydroxide aqueous solution 0.2 mL was added to a suspension of ethanol 2.0 mL of methyl 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoate 0.10 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoic acid 70 mg of white solid.
Reaction SMILES: C([CH:4]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:5]([CH3:9])(O)[C:6]#[CH:7])(C)=C.[O:15]1[CH2:19][CH2:18]CC1.O.[C:21](=O)(O)[O-].[Na+]>C(OCC)C.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:9][C:5](=[CH:4][CH:10]=[CH:11][CH:12]([CH3:13])[CH3:14])[CH2:6][CH:7]=[CH:21][C:19](=[O:15])[CH3:18]
Reactant: C1CCOC1
Reactant: C#CC(C)(O)C(CC=C(C)C)C(=C)C
Reactant: O=C([O-])O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)C=CCC(C)=CC=CC(C)C
Yield: 57 %

Procedure:
4-Isopropenyl-3,7-dimethyl-6-octen-1-yn-3-ol (0.192 g; 10-3 mole) is kept at a temperature in the region of 40° C. and protected from light in the presence of silver trifluoromethanesulphonate (0.257 g; 10-3 mole) in a mixture (3:1 by volume) of tetrahydrofuran and water (10 cc). After 20 hours the reaction mixture is diluted with ethyl ether (20 cc) and treated with a saturated solution of sodium bicarbonate (5 cc). After separation, the organic phase is washed with demineralised water until neutral, and then dried over magnesium sulphate. After filtration, evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa) and purification by chromatography on alumina, 6,10-dimethyl-3,6,8-undecatrien-2-one (0.110 g) is obtained in a yield of 57%, having the following characteristics:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:22][C:23]1[N:28]=[CH:27][C:26](I)=[CH:25][N:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:1]#[C:2][C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)=[CH:4][N:5]=3)[CH:8]=2)=[CH:13][CH:14]=1
Reactant: Nc1ncc(I)cn1
Reactant: C#Cc1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Nc1ncc(C#Cc2cnc3ccc(-c4ccc(C(F)(F)F)cc4)cn23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.24) (300 mg, 1.0 mmol) and commercially available 2-amino-5-iodopyrimidine (230 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (270 mg, 67%). MS (ISP) 380.3 [(M+H)+]; mp 244–246° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[N:16]1[C:25]2[C:20](=[CH:21][C:22]([I:27])=[CH:23][C:24]=2[F:26])[C:19](=[O:28])[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:17]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[F:26][C:24]1[CH:23]=[C:22]([I:27])[CH:21]=[C:20]2[C:25]=1[N:16]([NH:15][CH3:13])[CH:17]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:19]2=[O:28]
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(NC)c2c(F)cc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.9 %

Procedure:
A solution of trifluroacetic acid (6.40 g) in methylene chloride (5 mL) is added dropwise over a 4 minute period to a solution of ethyl 1-((tert-butoxycarbonyl)(methyl)amino)-8-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Preparation 34, 1.10 g) in methylene chloride (20 mL) at room temperature. After 3.5 h, the mixture is poured into a mixture of saturated sodium bicarbonate solution (125 mL) and water (50 mL), and extracted two times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated at reduced pressure. The resulting gummy solid is stirred with diethyl ether at room temperature to afford 0.857 g (98%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([N:21]1[CH2:25][C:24](=[O:26])[NH:23][S:22]1(=[O:28])=[O:27])=[CH:5]2.[CH3:29][C:30]([CH3:36])([CH2:33][CH:34]=[CH2:35])[CH2:31][OH:32]>>[OH:32][CH2:31][C:30]([CH3:36])([CH3:29])[CH2:33][CH2:34][CH2:35][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([N:21]1[CH2:25][C:24](=[O:26])[NH:23][S:22]1(=[O:27])=[O:28])=[CH:5]2
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OC(=O)c2ccccc2)S(=O)(=O)N1
Reactant: C=CCC(C)(C)CO
Product: CC(C)(CO)CCCc1ccc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 8, step A, from benzoic acid 6-bromo-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl ester and 2,2-dimethylpent-4-en-1-ol: Retention time=1.30 min (Method A); (M−H)−=495.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20](C(=O)C(F)(F)F)=[CH:19][CH:18]=2)[N:7]=1)=[O:4].[C:31](OC(=O)CC)(=O)[CH2:32]C>CN(C)C1C=CN=CC=1.O>[C:17]1([N:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:6]([NH:5][C:3](=[O:4])[CH2:31][CH3:32])=[N:7]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCC(=O)NC1=NN(c2ccccc2)C(c2ccccc2)C1

Procedure:
A mixture of 10.0 g. of 3-amino-1,5-diphenyl-2-pyrazoline (prepared in Example 4), 30.0 ml. of propionic anhydride and 500 mg. of 4-dimethylaminopyridine is heated on a steam bath for 3 hours. The mixture is poured into water to separate an oil. The oil crystallizes and the solid is collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over anhydrous sodium sulfate then is columnized and recrystallized twice as for Example 26 (A) to give 6.0 g. of the product of the Example as colorless plates, m.p. 148.0°-148.5° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.BrCCO[Si]([C:29](C)([CH3:31])[CH3:30])(C)C.CCN(C(C)C)C(C)C.[I-].[K+]>CN(C=O)C>[CH3:30][CH:29]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 50 °C

Procedure:
A solution of 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (500 mg, 1.59 mmol) in DMF (15.0 mL) was charged with (2-bromoethoxy)-tert-butyldimethylsilane (0.376 mL, 1.75 mmol), DIPEA (0.694 mL, 3.99 mmol) and potassium iodide (26 mg, 0.16 mmol) and was heated at 50° C. for 16 h. The DMF was then concentrated in vacuo. The product was purified by flash chromatography (0 to 15% MeOH:EtOAc) to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 7.90 (s, 1H), 7.69 (s, 1H), 4.31 (td, J=7.71, 15.41 Hz, 1H), 3.88 (t, J=5.68 Hz, 2H), 3.28 (br s, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 2.76-2.84 (m, 2H), 2.51-2.67 (m, 2H), 2.10-2.19 (m, 4H), 1.31 (s, 12H), 0.91-0.94 (m, 9H); MS (ESI): 436.28 [M+H]+; HPLC tR=1.26 min (TOF polar—3 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8](O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a mixture of (R)-tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)(methyl)carbamate (2.0 g, 7.00 mmol) in THF (23.33 mL) was added phthalimide (1.339 g, 9.10 mmol) and PPh3 (3 mmol of PPh3/1 g of resin, 2.34 g, 7.02 mmol). Then DTBAD (1.660 g, 7.21 mmol) in THF was slowly added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite® and washed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with sat. Na2CO3, water and brine, dried over sodium sulfate, filtered off, and concentrated. The crude product was purified by flash chromatography to afford (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol, 67.5%). LCMS (m/z): 315.1 (MH+-100), 1.19 min.