Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:15][CH2:16][CH3:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][OH:14].Cl[C:19]1[C:20](=[O:25])[C:21](=[O:24])[C:22]=1[CH3:23].CCN(CC)CC.[K+].[Br-]>CN(C=O)C.O>[CH2:16]([S:15][C:3]1[C:2]([NH:1][C:19]2[C:20](=[O:25])[C:21](=[O:24])[C:22]=2[CH3:23])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][NH:7]2)[CH3:17]
Reactant: Cc1c(Cl)c(=O)c1=O
Reactant: CCSc1c(N)ccc2[nH]cc(CCCO)c12
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCO)c12
Temperature: 23 °C
Reaction time: 50 h

Procedure:
A mixture of 3-(5-amino-4-ethylthio-3-indolyl)-1-propanol (0.93 g, 3.7 mmol), 3-chloro-4-methyl-1,2-dioxocyclobut-3-ene (0.58 g, 4.4 mmol) and Et3N (0.62 ml, 4.4 mmol) in DMF (50 ml) was stirred at 23° C. for 50 h before adding water (200 ml). The aqueous solution was extracted with EtOAc (3×75 ml). The organic extracts were washed with water (50 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using first a mixture of CH2Cl2 :EtOAc (1:4) and then EtOAc:Et3N (49:1). Appropriate fractions were concentrated in vacuo leaving yellow crystals, 0.815 g, m.p. 119° C., 64%. 1H NMR (DMSO-d6) δ (ppm): 11.17, 11.11, 10.80 and 10.51 (4 br s, 2H indolic NH, and 5-NH), 7.4 (br s, 1H), 7.26 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.40 (t, J=5.2 Hz, 1H, OH), 3.46 (t, J=3.5 Hz, 2H after D2O exchange), 2.95-3.10 (m, 2H, CH2CH2CH2O), 2.66 (br s, 2H, CH3CH 2 S), 2.26 (br s, 1H, CH3 on dioxocyclobutene), 1.7-1.9 (m, 2H, CH2CH2CH2O), 1.59 (br s, 2H, CH3 on dioxocyclobutene), 0.9-1.1 (m, 3H, CH3CH2S). IR (KBr) n:3420, 3300-3000, 1775, 1728, 1620, 1580 and 1400 cm-1. Anal. calcd. for: C18H20N2O3S: C 62.77; H 5.85; N 8.13; S 9.31. Found: C 62.75; H 5.85; N 8.20; S 9.25.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:30]([F:33])([F:32])[F:31])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O>CO.C(O)(C)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:30]([F:33])([F:32])[F:31])[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(COc1cc(-c2ccc([N+](=O)[O-])cc2)nc2cccc(C(F)(F)F)c12)N1CCOCC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(C(F)(F)F)cccc3n2)cc1
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
4-{[2-(4-Nitrophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (6.6 g) dissolved in methanol (=b 132 cc) is hydrogenated for three hours thirty minutes at atmospheric pressure in the presence of an 8N solution (6.6 cc) of gaseous hydrochloric acid in isopropanol and palladium (0.66 g) supported on charcoal (10% palladium). Distilled water (240 cc) is then added, the mixture is stirred for 10 minutes and the catalyst is thereafter filtered off. Normal aqueous sodium hydroxide solution (45 cc) is added an the precipitate is filtered off, washed with distilled water (3×100 cc) and dried under reduced pressure. The precipitate is dissolved while hot in a cyclohexane/ethyl acetate mixture (50:50 by volume). The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up on petroleum ether, filtered off and dried. 4-{[2-(4-Aminophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (3.16 g,), m.p. 174° C., is thereby obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])(C)(C)C.[Li][CH2:35][CH2:36][CH2:37]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[F:15][C:12]([F:14])([F:13])[C:7]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:37][CH:36]=[CH2:35])=[CH:20][CH:21]=1)([OH:6])[C:8]([F:10])([F:11])[F:9]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CS(=O)(=O)c2ccccc2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CN1CCCN(C)C1=O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Tert-Butyl(dimethyl)[2,2,2-trifluoro-1-{4-[(phenylsulfonyl)methyl]phenyl}-1-(trifluoromethyl)ethoxy]silane (378 mg, 0.74 mmol) was dissolved in anhydrous THF (10 mL) under argon and cooled to −78° C. 1.6M BuLi solution in hexanes (0.5 mL, 0.85 mmol) was added and the reaction was allowed to warm to 0° C. After 30 min at 0° C., the reaction was cooled to −78° C. and DMPU (0.26 mL, 2.1 mmol) was added, followed by allyl bromide (0.07 mL, 0.81 mmol). The reaction was allowed to warm to 0° C. and monitored by thin layer chromatography. The reaction was quenched with saturated NH4Cl and diluted with ethyl acetate. The layers were separated and the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (6:1 hexanes/EtOAc) afforded the protected sulfone as a colorless oil. The sulfone was deprotected as described in Example 2 step 3. Purification by flash chromatography (6:1 hexanes/EtOAc) afforded the title compound as a white solid (266 mg, 82%): mp=148° C. 1H NMR (CDCl3) δ 7.55 (m, 3H), 7.45 (d, 2H), 7.33 (t, 2H), 7.17 (d, 2H), 5.55 (m, 1H), 5.04 (m, 2H), 4.14 (dd, 1H), 3.51 (br s, 1H), 3.21 (m, 1H), 2.93 (m, 1H). Anal. Calc. for C19H16O3SF6: C, 52.06; H, 3.68. Found: 52.04; H, 3.45. HRMS (M+NH4+) Calc.: 456.1068. Found: 456.1075.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:21]([OH:23])=[O:22])=[CH:5][N:6]2[C:11]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[N:9][CH:8]=[N:7]2)[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:24][O:22][C:21]([C:4]1[C:3]([CH2:1][CH3:2])=[C:11]2[N:6]([CH:5]=1)[N:7]=[CH:8][N:9]=[C:10]2[NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCc1c(C(=O)O)cn2ncnc(Nc3ccc(OC)nc3)c12
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCc1c(C(=O)OC)cn2ncnc(Nc3ccc(OC)nc3)c12

Procedure:
To a solution of Example 84 (3 mg, 0.01 mmol) in methanol (0.3 mL) and toluene (0.7 mL) was added trimethylsilyl diazomethane (100 μL of 2.0 M solution in THF). After 30 min. acetic acid and methanol were added and the reaction mixture was concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 20% ethyl acetate in hexanes to provide 3 mg of white solid. MS: [M+H]+=328.1; 1H NMR (CDCl3): δ 8.30 (s, 1H), 7.94-7.90 (m, 3H), 7.01 (s, 1H), −6.81 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.32 (q, J=7.6 Hz, 2H), 1.56 (t, J=7.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=3)[N:11]=2)[CH:3]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].CCCCCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[F:16][C:15]1[C:10]([NH:9][C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:7]=[CH:6][C:5]=2[OH:8])=[N:11][C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:20][CH:19]=2)=[N:13][CH:14]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cc(N)ccc3O)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1ccc(O)c(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 3.2 %

Procedure:
To a 25 mL 3-neck RBF previously equipped with a magnetic stirrer and CaCl2 guard tube was added 4-amino-2-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenol (0.075 g in 5 mL DCM) and it was cooled to −40° C. and acryloyl chloride (0.019 g in 3 mL DCM) was slowly added. The reaction was warmed to room temperature and stirred for 30 min. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 30 min. The reaction mixture was poured in water (100 mL) and basified using sodium bicarbonate. The mixture was extracted with DCM (2×25 mL) and the combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by preparative-HPLC to give 2.7 mg of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)-4-hydroxyphenyl)acrylamide. 1H NMR: DMSO-d6 (400 MHz) 3.25 (s, 3H), 3.58 (s, 2H), 3.91 (s, 2H), 5.70 (d, 1H, J=10), 6.20 (d, 1H, J=16.8), 6.39 (dd, 1H, J=10.4, 17.2), 6.65 (d, 2H, J=8.8), 6.87 (d, 1H, J=8.8), 7.45 (m, 3H), 7.78 (s, 1H), 8.01 (s, 1H), 8.21 (s, 1H), 8.48 (s, 1H), 8.92 (s, 1H), 9.98 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:25]=2[N:26]=1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:28]3[CH:29]=[CH:30][C:24]4[S:23][C:22]([CH3:21])=[N:26][C:25]=4[CH:27]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: Cc1nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2s1
Product: Cc1nc2cc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)ccc2s1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (31 mg, 0.104 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (22 mg, 0.114 mmol), (R)-4-((R)-1-(3-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.28 was isolated, following column chromatography.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CC(C)C(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (example 149) (115 mg, 0.279 mmol) and triethylamine 0.558 mmol) in anhydrous DMF (2 ml) was stirred at RT for 1 hour. After this time, isobutyryl chloride (35 μl, 0.335 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between water and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (60 mg, 45%).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:10]([OH:12])=O)=[N:5][CH:6]=[C:7]([Br:9])[CH:8]=1.CC[N:15]([CH2:18]C)CC.CN([C:23]([O:27]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:23][O:27][CH2:18][NH:15][C:10]([C:4]1[C:3]([F:2])=[CH:8][C:7]([Br:9])=[CH:6][N:5]=1)=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ncc(Br)cc1F
Reactant: CCN(CC)CC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COCNC(=O)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 3-fluoro-5-bromopyridine carboxylic acid hydrochloride (1.83 g, 6.5 mmol), N—O-dimethyl hydroxylamine hydrochloride (824 mg, 8.45 mmol), Et3N (2.3 mL, 16.25 mmol) and HATU (3.2 g, 8.45 mmol) in dry DMF (30 mL) was stirred at room temperature under N2 for 16 h. Further HATU (900 mg, 2.4 mmol) was added and the reaction stirred for a further 6 h. The solvent was removed in vacuo and the crude partitioned between saturated NaHCO3 (aq) and EtOAc. The aqueous was extracted with additional EtOAc (×3) and the combined organics washed with brine dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (gradient: 20%-80% EtOAc in petroleum ether 40-60:EtOAc) yielded 3-fluoro-5-bromopyridine carboxylic acid methoxymethylamide as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([N:13](C1C=CC=CC=1)[C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH3:15])=[O:12].C=O.[C:34](O)(=O)[CH3:35]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][C:35]1[CH:34]=[CH:5][CH:4]=[CH:3][CH:11]=1)=[O:12]
Reactant: CC(=O)O
Reactant: C[C@@H](C(=O)N[C@H](C=O)CC(=O)O)N(C(=O)c1cc2ccccc2n1C)c1ccccc1
Agent: C=O
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@H](C=O)CC(=O)O)cc2ccccc21
Yield: 25 %

Procedure:
(3S)-3-[(1-Methylindole-2-carbonyl)phenyl-alaninyl]amino-4-oxobutanoic acid, semicarbazone (116 mg, 0.25 mmol) were dissolved in methanol (3 mL), formaldehyde (1 mL, 37% wt. aq) and acetic acid (1 mL) and the resulting solution was stirred for 9 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo, diluted with water, and extracted twice with ethyl acetate. The ethyl acetate solution was washed with brine, dried over sodium sulfate and concentrated to give a crude product which was triturated with ether to afford the title product as a brown powder (26 mg, 25%). TLC (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf=0.33; MS for C23H21N3O5; M+H+=422; M−H+=420.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:24][N:23]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3ccnc(C)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=303.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH:29]=O>>[F:25][C:26]([F:39])([F:40])[C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:28]=1[CH2:29][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:7]2[C:6]3[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[N:9][C:8]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2,5-bis(trifluoromethyl)benzaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 558.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][N:25]([CH3:43])[C:26](=[O:42])[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:30]5[CH:31]=[CH:32][C:27]([C:26]([N:25]([CH3:43])[CH3:24])=[O:42])=[CH:28][CH:29]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Temperature: 150 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (0.10 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 mmol), K2CO3 (240 μL, 1M), Pd-FibreCat (7 mg), and DMF (1 mL) were combined. The mixture was heated at 150° C. for 5 min (5 min ramp time) in a microwave reactor. After cooling, the mixture was filtered and purified by prep-HPLC to provide 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,N-dimethyl-benzamide. ESI-MS m/z calc. 442.2. found 443.5 (M+1)+; Retention time 3.12 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.02-1.08 (m, 2H), 1.37-1.44 (m, 2H), 2.17 (s, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 6.01 (s, 2H), 6.87-6.93 (m, 2H), 6.98 (d, J=1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H), 7.40-7.52 (m, 4H), 8.75 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(O)=O>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:16]=2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
Sodium tiracetoxyl-borohydride (985 mg, 4.65 mmol) was added to a solution of 6-chloro-pyrimidin-4-ylamine (200 mg, 1.55 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (682 mg, 3.1 mmol) in 25 ml of DCE. 1 ml of HOAc was added, and the mixture was stirred overnight at 50° C., followed by addition of 25 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 5:1) to give 64 mg of (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 12%.
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]=1[O-:24].[CH2:25]1COCC1>>[Cl:21][C:18]1[CH:17]=[C:16]([CH2:22][CH3:23])[N+:15]([O-:24])=[C:14]([O:10][C:3]2[CH:2]=[C:7]([CH3:25])[C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])[C:19]=1[CH3:20]
Reactant: CCc1cc(Cl)c(C)c(Cl)[n+]1[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(Cl)c(C)c(Oc2cc(C)c(C)cc2C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,4,6-trimethylphenol in dry THF was added NaH and stirred at room temperature for 20 minutes. A solution of 2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and the resulting mixture was heated at reflux for 1.5 hour. The mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the title compound which was used directly for the next step reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[CH3:27].[C:29](OCC)(=O)[CH3:30]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:19][CH2:26][CH3:27])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([O:18][CH2:29][CH3:30])=[O:17])=[CH:5]2
Reactant: CCBr
Reactant: CCOC(C)=O
Reactant: O=C(O)C1=Cc2c(ccc(Cl)c2O)OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2OCC)OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 6-chloro-5-hydroxyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (0.5g, 1.7 mmol) and cesium carbonate (800 mg, 0.94 mmol) in 10 mL of DMF was added ethyl bromide(0.80 mnL, 6.2 mmol). The mixture was stirred at room temperature overnight. To the reaction was added 150 mL of ethyl acetate, the resulting organic solution was washed with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with EtOAc/hexane mixture. It gave 0.4 g of white solid. Part of the product was further purified on reverse phase HPLC for analytical characterization. LC-MS(ES+) 351.3(M+1, 100), 19F NMR(CDCl3/400 Hz) −78.782(d, J=6.8 Hz); 1H NMR (CDCl3/400 Hz) 7.94(s, 1H), 7.27(d, J=8.8 Hz, 1H), 6.70(d, J=8.8 Hz, 1H), 5.66(q, J=6.8 Hz, 1H), 4.32(m, 2H), 4.10(m, 2H), 1.42(t, J=7.2 Hz, 3H), 1.34(t, J=7.2 Hz, 3H); 13C NMR(CDCl3/400 Hz) 163.8, 153.2, 152.6, 133.5, 132.0, 123.5(q, J=287.6 Hz), 121.2, 117.2, 115.6, 112.6, 71.4, 70.5(q, J=33.2 Hz), 61.8, 15.5, 14.4. High resolution MS(ES+) m/e calc. for C15H15ClF3O4: 351.0605(M+H), 351.0641(M+H, observed).