Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH2:14]Br)[C:9]#[N:10]>CN(C=O)C>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH2:14][N:1]=[N+:2]=[N-:3])[C:9]#[N:10]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
Sodium azide (Aldrich, 0.63 g, 9.8 mmol) was added to a solution of 3-fluoro-4-(bromomethyl)benzonitrile (compound 5-3, 1.4 g, 6.5 mmol) in DMF (15 ml). After stirring at ambient temperature for 20 hours, the reaction mixture was partitioned in EtOAc and water (100 ml, each). Organic layer was then dried (MgSO4), and solvent was removed under vacuum to give the title compound (0.995 g, 86%). 1H NMR (CDCl3): δ 4.50 (s, 2H), 7.38 (d, 2H, J=8.1 Hz), 7.52 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C([O-])(O)=O.[Na+].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][N:7]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=[C:6]2[CH:5]=1)=[O:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-amino-isonicotinic acid methyl ester (5 g, 32 mmol), w-bromoacetophenone (6.47 g, 32 mmol), NaHCO3 (2.95 g, 35 mmol) and methanol (30 ml) was heated under an atmosphere of argon to reflux (3 h). After cooling, water (20 ml) was added, the mixture was stirred at r.t. (15 min), and filtered. The obtained solid was washed (water, methanol, diethyl ether) and dried under vacuum. The product (6.8 g, 85%) was used in the next step without further purification. MS (m/e)=253.2 [M+H+].
Reaction SMILES: [C:1]1([C:7]2([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-phenyl-cyclopentanecarbaldehyde (277) (11.5 g, 71.82 mmol) in methanol (150 mL) was added NaBH4 at 0° C. portion-wise and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (20 mL). Subsequently, the methanol was removed, the residue diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL) and the separated organic part was dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 5-10% ethyl acetate in hexane) to get (1-phenyl-cyclopentyl)-methanol] (278) (10 g, 79.0%) as a white solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 43 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with t-butyl-1-piperazinecarboxylate as described in Step 2 of Example 29 to afford 4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazine-1-carboxylic acid tert-butyl ester (43% yield) as a yellow solid. ESI/MS 300 (M), 306 [M−CO2C(CH3)3], 350 [M−C(CH3)3], 406 (M+H; RT=3.89 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=9 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.22 (8H, 2 br m); 1.37 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:31][CH3:32])=[C:10](\[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([N:16]1[C:17]2[C:13](=[CH:12][C:11](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[C:9](/[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])\[CH2:31][CH3:32])=[CH:19][CH:18]=2)[CH:14]=[N:15]1)(=[O:35])[CH3:34]
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2c(cnn2C(C)=O)c1)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (0.25 g, 0.56 mmol; Compound 195) in DCM (5.6 mL) at room temperature, acetic anhydride (57 mg, 0.56 mmol) was added followed by N,N-dimethylpyridin-4-amine (6 mg, 0.056 mmol). The reaction was stirred at room temperature over the weekend, quenched with water, and then extracted with DCM (2×50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column using 0-20% ethyl acetate in hexanes to afford the title compound. 1H NMR (400 MHz, DMSO-d6): δ 12.34 (br, 1H), 8.52 (s, 1H), 8.30 (d, 1H), 7.80 (s, 1H), 7.50 (d, 1H), 7.45-7.40 (m, 5H), 7.20-7.10 (m, 1H), 6.94 (d, 2H), 6.39 (d, 1H), 2.77 (s, 3H), 2.34 (q, 2H), 0.87 (t, 3H); LCMS: 489 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1

Procedure:
Prepared according to procedure A using 3-fluoroaniline (18 mL, 187 mmol), pyridine (31 mL, 374 mmol) and diethyl methylmalonate (48 mL, 281 mmol). The crude was purified by column chromatography on silica (using a gradient of hexane:EtOAc, 1:0 to 3:1 as eluent) to give ethyl 3-(3-fluorophenylamino)-2-methyl-3-oxopropanoate as a light brown solid. Mass Spectrum (ESI) m/e=240.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].[CH2:21]([NH:23][C:24](=[O:44])[NH:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[N:31][C:26]([NH:25][C:24](=[O:44])[NH:23][CH2:21][CH3:22])=[CH:27][C:28]=4[C:35]4[S:36][CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:39]=4)=[CH:11][N:10]=3)[C:5](=[O:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]2)[CH2:14][CH2:13]1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(C2CC2)c2ncc(Br)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3C2CC2)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
In a round bottomed flask, ethyl 6-bromo-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 16, 200 mg, 0.59 mmol), 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 367 mg, 0.83 mmol) and sodium carbonate (125 mg, 1.18 mmol) were combined and suspended in dimethylformamide (10 mL). Argon gas was purged through the above suspension for 15 min. At the end of this period, tetrakis (triphenylphosphine) palladium (68 mg, 0.05 mM) was added under argon atmosphere and the reaction mixture was heated to 40° C. for 6 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water and stirred for 30 min to obtain a solid which was filtered and washed with water and dried to afford 70 mg (20%) of ethyl 1-cyclopropyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)cc1
Yield: 35.2 %

Procedure:
Compound 40 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH3:18])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@H]1C
Product: COC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@H]1C

Procedure:
The procedure of Reference Example 2 was repeated by using the thus synthesized methyl (3R*,4S*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate crude product (12.28 g) and benzyl chloroformate (21.3 mL, 149.3 mmol) to obtain 4.23 g (14.52 mmol, 2 steps, 15%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5](=[CH:9][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[CH:14][CH:15]=1)[C:6]([CH3:8])=O)(=[O:4])=[O:3].[CH3:17][O:18][C:19](=[O:24])/[CH:20]=[C:21](\[NH2:23])/[CH3:22]>C(O)C>[CH3:17][O:18][C:19]([C:20]1[CH:9]([C:10]2[CH:11]=[N+:12]([O-:16])[CH:13]=[CH:14][CH:15]=2)[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:8])[NH:23][C:21]=1[CH3:22])=[O:24]
Reactant: CC(=O)C(=Cc1ccc[n+]([O-])c1)S(C)(=O)=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(S(C)(=O)=O)C1c1ccc[n+]([O-])c1

Procedure:
A mixture of 22.5 g of 1-methylsulphonyl-1-(1-oxido-3-pyridylmethylene)-acetone, 16.5 g of 3-aminocrotonic acid methyl ester and 45 g of molecular sieve (Union Carbide, 3 Å) in 250 ml of absolute ethanol is boiled under reflux for 18 hours. The resulting suspension is filtered, the filter residue is washed with chloroform and the filtrate is concentrated by evaporation under reduced pressure. The oily residue is dried by the addition of toluene and renewed concentration by evaporation under reduced pressure. The residue is chromatographed over approximately 50 to 100 times the amount of silica gel, a mixture of chloroform and methanol (9:1) being used as the liquid phase. Once the starting materials and intermediate have been removed by washing, the desired product is eluted; the corresponding fractions are combined and concentrated by evaporation and the residue is recrystallised from a mixture of isopropanol and diethyl ether. In this manner 2,6-dimethyl-5-methylsulphonyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3-carboxylic acid methyl ester having a melting point of 236°-238° is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a stirred solution of 1-(t-butoxycarbonyl)-2-pyrrolidinone (11.9 g, 64.3 mmol) in dry THF (190 mL) at −78° C. was added a solution of LiHMDS (1.0M in toluene, 135 mL, 135 mmol). After stirring at −78° C. for 2 hours, benzoyl chloride (7.5 mL, 64.3 mmol) was added dropwise over 5 minutes while keeping the temperature below −50° C. The mixture was stirred at −78° C. for 4 hours, and the reaction was then quenched with a saturated aqueous NH4Cl solution (200 mL). The mixture was diluted with EtOAc (300 mL) and the organic layer was washed with saturated NaHCO3 (200 mL×2) and saturated aqueous NaCl (200 mL). The organic layer was dried over MgSO4, filtered and concentrated, and the crude product was purified by flash column chromatography (20-60% EtOAc in hexanes) to afford the title compound (14.5 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[CH:20]([O:26][C:27]([CH3:29])=[O:28])[CH2:19]4)[N:12]=[N:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:30]N(C)C=O>CI>[F:3][C:4]1[C:9]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[C:20]([CH3:30])([O:26][C:27]([CH3:29])=[O:28])[CH2:19]4)[N:12]=[N:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: CC(=O)OC1Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(=O)OC1(C)Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, 3 mg of 60% of sodium hydride was added to 1 ml solution of dimethylformamide with 10 mg of 1-(2-fluoropyridine-3-yl)-4-(1-oxo-2-methylcarbonyloxy-indane-5-yl)-5-methyl-1H-[1,2,3]triazole, obtained in Example 45. After stirring 30 min at room temperature, 5 drops of methyl iodide was added and the mixture was further stirred for 1 hour at room temperature.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:21])=[N:15]2)=[CH:10][CH:9]=1>O1CCOCC1.CO>[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH:21]=[O:2])=[N:15]2)=[CH:10][CH:9]=1
Reactant: COCOc1ccc2ccc(C)nc2c1[N+](=O)[O-]
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: CO
Product: COCOc1ccc2ccc(C=O)nc2c1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 20 h
Yield: 58.8 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, selenium dioxide (11 mg, 0.099 mmol) was added to a solution of 8a (22.1 mg, 0.089 mmol) in dioxane (2 mL) at 85° C. The reaction was stirred for 20 h at 85° C., then cooled, diluted with methanol, and vacuum filtered. The filtrate was collected and concentrated, leaving a yellow solid, which was purified by column chromatography (4:6 EtOAc/hexane) to provide 9a (13.7 mg, 0.0523 mmol, 59%) as a yellow solid: 1H NMR (CDCl3) δ 10.15 (1H, s), 8.35 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=8 Hz), 8.00 (1H, d, J=9.6 Hz), 7.76 (1H, d, J=9.2 Hz), 5.43 (2H, s), 3.56 (3H, s); 13C NMR (CDCl3) δ 193.25, 154.14, 149.28, 140.47, 137.83, 137.55, 130.64, 125.26, 119.33, 117.34, 95.45, 57.24; FTIR (neat) 2858, 1715, 1529, 1263, 1197, 1155, 1061, 935, 918, 849, 806, 771, 658 cm−1; MS (ESI) m/z calculated for (C12H10N2O5+H)+ 263, found 263; HRMS (ESI) m/z calculated for (C12H10N2O5+H)+ 263.0668, found 263.0662.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42].CCN(CC)CC>C(Cl)Cl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:23][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:37])=[CH:34][C:33]=1[C:41]([F:42])([F:43])[F:44]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (30 mg, 0.079 mmol) in CH2Cl2 (0.2 mL) was added 4-fluoro-3-(trifluoromethyl)benzoyl chloride (0.048 mL, 0.158 mmol), followed by Et3N (0.04 mL, 0.158 mmol). The resulting mixture was stirred at room temperature for 5 h. The crude product was purified on a preparative HPLC column type using 30 to 100% CH3CN in H2O with 0.1% TFA for 10 minutes as mobile phase. The solvent was removed under reduced pressure to afford (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (35 mg, 80% yield) as white powder. LC-MS (ESI) 568.30 (M+H), retention time=4.27 min (0-100% MeOH in H2O with 0.1% TFA in a 4-min run); Analytical HPLC: 3.95 min (0-100% CH3CN in H2O with 0.1% TFA in a 4-min run, purity 100%); 1H NMR (400 MHz, CD3OD) δ ppm 3.88-4.01 (m, 1H), 4.10 (d, J=13.18 Hz, 1H), 6.69 (d, J=7.47 Hz, 2H), 6.97-7.51 (m, 11H), 7.99 (d, J=5.71 Hz, 2H), 8.90 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12](N)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.C(Cl)[Cl:39]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12]([Cl:39])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1
Reactant: ClCCl
Agent: CC(C)(C)ON=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: COCOCCCCCCCCCCc1nc(Cl)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
To a stirred solution containing 240 mg (0.58 mmol) of 5-(benzyloxy)-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidin-2-amine in 10 mL of anhydrous DCM were added 1.10 g (5.80 mmol) of benzyltrimethylammonium chloride followed by 696 μL (5.80 mmol) of t-butyl nitrite. The reaction mixture was stirred at 23° C. protected from light for 15 h. The mixture was filtered and the filtrate was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 44 mg (16%); silica gel TLC Rf 0.45 (4:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br s, 12H), 1.55 (quint, 2H, J=7.2 Hz), 1.65 (quint, 2H, J=6.8 Hz), 2.42 (s, 3H), 2.67 (dd, 2H, J=8.0, 8.0 Hz), 3.33 (s, 3H), 3.47 (t, 2H, J=6.8 Hz), 4.59 (s, 2H), 4.83 (s, 2H) and 7.37 (m, 5H); 13C NMR (CDCl3) δ 19.32, 26.16, 28.14, 29.25, 29.35, 29.35, 29.47, 29.51, 29.71, 31.92, 55.04, 67.85, 76.03, 96.36, 128.08, 128.73, 128.73, 128.77, 128.77, 135.73, 149.01, 154.24, 163.79 and 167.41; mass spectrum (APCI), m/z (M+H)+435.2411 (C24H36N2O3Cl requires 435.2415)
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C)C=O>[Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:16])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Br)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-bromoethyl)benzoic acid (50.7 mg, 0.221 mmol) in methylene chloride (4.0 mL, 62 mmol) was added 2.0 M of oxalyl chloride in methylene chloride (0.25 mL) followed by 3 drops of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for one hour, and then evaporated in vacuo to remove dichloromethane and excess oxalyl chloride. The crude product was carried forward without purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].C(O)C>O>[OH:19][CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2nc(C)c(CBr)nc2cc1OC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2nc(C)c(CO)nc2cc1OC

Procedure:
8.9 g (30 mmols) of 2-(bromomethyl)-6,7-dimethoxy-3-methyl-quinoxaline are suspended in a mixture of 158 g (1.5 mols) of sodium carbonate, 350 ml of water and 100 ml of ethanol. The suspension is boiled under reflux for four hours. 300 ml of water are then added and the resulting mixture is extracted with three times 120 ml of chloroform. The organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo. The solid residue is recrystallised from methanol. This gives 3.5 g (50%) of a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(O)c1CNc1cccn2c(C)c(C)nc12
Temperature: -73 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
8-(2-methoxy-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.14 g, 0.48 mmol) was solved in methylene chloride (9 ml) and the mixture was cooled to −73° C. Boron tribromide in methylene chloride (1M) (2.37 ml, 2.37 mmol) was added dropwise and the mixture was stirred for 20 h. in a nitrogen atmosphere and the temperature was allowed to raise to room temperature. The reaction mixture was cooled on ice and ice, water and methylene chloride were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure to give 0.077 g (57%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[CH:24]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[OH:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][CH:26]([CH:24]([OH:25])[C:23]([F:31])([F:32])[F:22])[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OC(C1CCNC1)C(F)(F)F
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(C(O)C(F)(F)F)C1
Yield: 45.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN of corresponding free base: 943906-23-8, 14.5 mg, 70.4 μmol) to obtain the title compound (14 mg, 46%) as colorless liquid, MS (EI): m/e=436.4 [MH+].