Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[P:28](Cl)(=[O:43])([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][P:28]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([O:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)C(=O)O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](COP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
In 30 ml of dried methylene chloride was dissolved 3.75 g of benzyl N-t-butoxycarbonyl-D-serine, and 1.23 ml of pyridine, 1.86 g of 4-dimethylaminopyridine, and 4.09 g of diphenyl phosphorochloridate were successively added thereto at room temperature, followed by stirring at that temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 2% acetone-containing chloroform) to obtain 5.38 g of benzyl N-t-butoxycarbonyl-O-diphenylphosphono-D-serine as a white solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.C([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])C.CCN(C(C)C)C(C)C.[NH4+].[Cl-].O[Li].O.Cl>C1COCC1.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:34][CH2:33][CH2:32][C:31]([OH:35])=[O:30])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Cl-]
Agent: [Li]O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCNc1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1ccn[nH]1
Temperature: 110 °C
Reaction time: 44 h

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.248 mmol), β-Alanine ethyl ester hydrochloride (267 mg, 1.736 mmol), DIPEA (0.433 mL, 2.480 mmol) and iPrOH (3 mL) were added to a vial, which was sealed and the RM was stirred at 110° C. for 44 h. The RM was treated with saturated aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with sat. aq. Na2CO3 (20 mL) and brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM and EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The resulting ester was dissolved in MeOH (0.5 mL) and THF (1 mL), treated with LiOH.H2O (0.548 mL, 0.548 mmol) and stirred for at RT for 90 min. The RM was acidified with aq. 1 M HCl (4 eq.) and the organic solvents were evaporated off under reduced pressure. The product was filtered off, washed with water and n-hexane and dried to give the title product as a white crystalline solid. HPLC (Condition 7) tR=6.08 min, UPLC-MS (Condition 8) tR=0.98 min, m/z=452 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.62 (t, J=6.45 Hz, 2H) 3.79 (q, J=6.26 Hz, 2H) 6.95 (s, 1H) 7.35 (d, J=8.99 Hz, 2H) 7.85-7.95 (m, J=9.38 Hz, 3H) 8.41 (d, J=1.95 Hz, 1H) 8.67 (d, J=2.35 Hz, 1H) 8.86-9.06 (m, 1H) 10.22 (s, 1H) 12.23 (br. s, 1H) 13.18 (br. s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: Clc1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(Cl)cc2)s1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of diisopropylamine (0.2 mL, 1.538 mmol) in dry THF (5 mL), was added 1.6M n-BuLi in hexanes (0.96 mL, 1.538 mmol) slowly at −78° C. The reaction mixture was stirred for 30 min, 2-(4-chlorophenyl)thiazole (0.2 g, 1.025 mmol) in THF (10.0 mL) added, the mixture stirred for 30 min, a solution of 1-(pyridin-4-yl)ethanone (0.17 mL, 1.538 mmol) in THF (5.0 mL) added, and the mixture was stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (1% methanol in dichloromethane) to obtain 1-(2-(4-chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.1 g, 31% yield) in 99.9% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H), 7.51-7.47 (m, 4H), 6.66 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for [M+H]+ 317.04, found 317.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Nc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Yield: 44 %

Procedure:
3.8 g (13 mmol) of (4-bromophenyl)-(2-nitrophenyl)amine was dissolved in 30 mL of tetrahydrofuran. The resulting solution was stirred at room temperature in the argon atmosphere. During the stirring, a solution of 11 g (64 mmol) of sodium hydrosulfite/30 mL of water was added dropwise. After stirring for 5 hours, 20 mL of ethyl acetate was added, and then a solution of 2.2 g (26 mmol) of sodium hydrogen carbonate/20 mL of water was added. Further, a solution of 2.5 g (18 mmol) of benzoyl chloride/10 mL of ethyl acetate was added dropwise, and the resultant was stirred at room temperature for 1 hour. The resultant was extracted with ethyl acetate, and sequentially washed with an aqueous 10% potassium carbonate solution, water and saturated saline. Thereafter, the solution was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, whereby 2.1 g (yield 45%) of N-[2-(4-bromophenylamino)phenyl]benzamide was obtained.
Reaction SMILES: Cl[CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH:4]1([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH:2]=[CH:3]1
Reactant: ClC1CC(COCc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C1=CC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
[[(3-Chlorocyclobutyl)methoxy]methyl]benzene 82 g, 0.39 mole) in 390 ml of dry dimethylsulfoxide was slowly added to a solution of potassium t-butoxide (132 g, 1.17 mole) in 390 ml of dry dimethylsulfoxide in a water-bath at 18° C. under a dry argon atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into 1600 ml of water and extracted with ether (3×1000 ml). The combined ether extracts were back-extracted with water (4×2000 ml), the extracts were then dried over sodium sulfate, and the volatiles were removed in vacuo. The crude product was divided into two equal portions and each portion was purified on separate 3.5 liter Merck silica columns, eluting with 3% ethyl acetate-hexane. Appropriate fractions were combined and the solvents removed in vacuo yielding 60.0 g of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-:14].[Cl-].[Cl-].O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:2]2[CH:12]=[CH:11][C:5]([Cl:14])=[CH:4][CH:3]=2)[CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a suspension of 4-chlorocinnamic acid (10.0 g, 54.8 mmol) in chlorobenzene (75 mL) at 0° C. was added AlCl3 (12.0 g, 90 mmol) in 4 portions. The mixture was stirred for 10 min at 0° C. then was warmed to 40° C. and stirred for 1 h. Crushed ice (75 g) was added carefully, followed by water (75 mL). The aqueous layer was extracted with DCM (3×). The combined organic extracts were dried (Na2SO4) and concentrated to provide the crude acid as a tan solid. Recrystallization from EtOH provided 7.81 g (48%) of the desired acid as a pale yellow solid. 1H NMR (400 MHz, CDCl3): 7.31-7.22 (m, 4H), 7.14-7.07 (m, 4H), 4.47 (t, J=8.0, 1H), 3.03 (d, J=7.9, 2H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].I[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A mixture of pentane-2,4-dione (4.41 g, 40 mmol), 1-iodo-4-nitrobenzene (5 g, 20 mmol) and potassium carbonate (11 g, 80 mmol) were heated in DMSO (15 ml) at 120° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with water (100 ml), and then extracted with ethyl acetate. The organic layer was washed with water, brine and dried. Evaporation gave a residue which was chromatographed over silica gel eluting with ethyl acetate/pet ether (5:95) to give 3-(4-nitrophenyl)-pentane-2,4-dione (2.67 g, 60%) as solid.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:21][OH:22]>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O.Cl>[CH3:21][O:22][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: -78 °C
Yield: 93.1 %

Procedure:
In a 22 L RBF, charge 4-Chlorosulfonyl-benzoyl chloride (990 g, 4.159 mole) in 8.3 L THF and cool to −78° C. In an addition funnel charge triethylamine (588 ml, 4.159 mole), methanol (168 ml, 4.159 mole), DMAP (5 g, 0.041 mole) and 4 L THF; add this solution dropwise to the reaction keeping the exotherm <−70° C. over 5 hours. After the addition is complete, stir the reaction in a cold bath overnight. Filter the reaction and rinse with 3×500 ml THF. Concentrate under vacuum the filtrate to give a yellow solid. Dissolve the solid in 7 L EtOAc and 7 L 1N HCl. Separate the organic layer and wash with 5 L brine. Dry the organics over Na2SO4, filter and concentrate under vacuum to give a white solid, 4-Chlorosulfonyl-benzoic acid methyl ester. Yield=93.1% (906 g).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH:7]([N:10]([CH:29]([CH3:31])[CH3:30])[CH2:11][CH2:12][O:13][C:14]1[C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=O)[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8]>P(Cl)(Cl)(Cl)=O>[CH:7]([N:10]([CH:29]([CH3:31])[CH3:30])[CH2:11][CH2:12][O:13][C:14]1[C:27]2[C:18](=[N:19][C:20]([Cl:2])=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)N(CCOc1cccc2[nH]c(=O)c3ccccc3c12)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(CCOc1cccc2nc(Cl)c3ccccc3c12)C(C)C

Procedure:
Phosphorous pentachloride (173 mg., 0.83 mM), phosphorous oxychloride (80 ml.) and 3,8-bis[(β-diisopropylamino(ethoxy]-6(5H)-phenanthridinone (2.0 g., 4.15 mM) were reacted according to the procedure of Example VII to give 1.66 g. of the title product; M.P. 88° C.-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[Cl:18][C:19]1[CH:23]=[N:22][N:21]([CH3:24])[C:20]=1[NH2:25]>>[Cl:18][C:19]1[CH:23]=[N:22][N:21]([CH3:24])[C:20]=1[NH:25][C:15]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]2[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=12)=[O:17]
Reactant: Cn1ncc(Cl)c1N
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Product: COCc1cc2c(C(=O)Nc3c(Cl)cnn3C)ccc(OC)c2o1

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (0.14 g) and 4-chloro-2-methyl-2H-pyrazol-3-ylamine (78 mg). Purification by column chromatography on silica eluting with 50%-75% ethyl acetate in hexane afforded the title compound as an off white solid (34 mg).
Reaction SMILES: [Cl:1]C1C=C(C=C(I)C=1)C(N)=N.F[C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16].IC1C=C(C=CC=1)C(N)=N>>[Cl:1][C:13]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16]
Reactant: N=C(N)c1cc(I)ccc1F
Reactant: N=C(N)c1cc(Cl)cc(I)c1
Agent: N=C(N)c1cccc(I)c1
Product: N=C(N)c1cc(I)ccc1Cl

Procedure:
3-Chloro-5-iodo-benzamidine, 2-fluoro-5-iodo-benzamidine as well as 3-iodo-benzamidine may be prepared analogously.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9]S(C)=O)=[C:4]([NH:14][CH3:15])[CH:3]=1>C(O)(=O)C.C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH3:9])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(Cl)ccc1C(=O)CS(C)=O
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc(Cl)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-[4-chloro-2-(methylamino)phenyl-2-methylsulphinylethanone (17 g) in a mixture of glacial acetic acid (35 ml) and absolute ethanol (35 ml) was added dropwise over 20 minutes to a stirred suspension of zinc dust (22.5 g) in acetic acid (20 ml) and absolute ethanol (35 ml) under nitrogen at ambient temperature. After stirring at ambient temperature for 24 hours, the reaction mixture was filtered through diatomaceous earth (sold under the trade name CELITE) and the filter bed was washed with glacial acetic acid (200 ml). Water (600 ml) was added to the combined filtrate and washing and the mixture was extracted with dichloromethane (3×200 ml). The combined extracts were dried over magnesium sulphate and the solvent was removed by distillation to give the novel compound 4'-chloro-2'-(methylamino)acetophenone, m.p. 65°-66°.
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)C>CO>[N:9]1[CH:8]=[C:7]([CH2:6][C:5]([NH2:1])=[O:4])[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=12
Reactant: N
Reactant: CCOC(=O)Cc1cnc2ccccn12
Solvent: CO
Product: NC(=O)Cc1cnc2ccccn12
Temperature: 100 °C

Procedure:
Bubble ammonia through a solution of (imidazo[1,2-a]pyridin-3-yl)acetic acid ethyl ester (10.0 g, 48.96 mmol) in methanol (30 ml) at 0° C. Heat the reaction mixture in a sealed tube at 100° C. for 2 hours. Concentrate the reaction mixture under reduced pressure. Triturate with ethyl acetate to give the title compound as a white solid.
Reaction SMILES: B(Br)(Br)Br.CO.[CH3:7][O:8][C:9]([C:11]1([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:10]>ClCCl>[CH3:7][O:8][C:9]([C:11]1([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)=[O:10]
Reactant: COC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution consisting of boron tribromide (114 mL of a 1 M solution in dichloromethane) and dichloromethane (100 mL) is cooled in an ice/salt/methanol bath to −10° C. and a solution consisting of 1-[3-(4-methoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (10 g) dichloromethane (150 mL) is added dropwise while the temperature is maintained at −10° C. over 1 hour. The reaction mixture is allowed to warm to 0° C. and stirred for 4 hours until all starting material is consumed. The solution is cooled to −10° C. and 5% sodium bicarbonate solution (250 mL) is added slowly by addition funnel while maintaining the temperature below 0° C. The reaction flask is removed from the cold bath and water added, the organic layer is separated, dried, and concentrated to give 1-[3-(4-hydroxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (9.6 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:31][C:30]=1[F:29]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=568.3 [M+H+].
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C[NH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:28]4[CH:33]=[C:32]([NH2:34])[C:31]([F:35])=[CH:30][C:29]=4[CH3:36])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:28]3[CH:33]=[C:32]([NH2:34])[C:31]([F:35])=[CH:30][C:29]=3[CH3:36])[C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(N)cc1-c1cc2cnc(N)cc2n(C)c1=O
Temperature: 50 °C
Yield: 52.9 %

Procedure:
Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (0.8 g, 1.9 mmol) in DCM (10 mL) and the reaction mixture was refluxed at 50° C. for 2 hour. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized with saturated aq NaHCO3 to pH 7-8. Then the aqueous layer was extracted with EtOAc (3×50 mL), the extracts were dried (Na2SO4) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (0.3 g, 53% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.29 (s, 1H), 7.57 (s, 1 H), 6.83 (d, J=12.4 Hz, 1 H), 6.56 (d, J=9.6 Hz, 1 H), 6.48 (s, 2 H), 6.24 (s, 1 H), 4.87 (s, 2 H), 3.45 (s, 3 H), 1.94 (s, 3 H); MS (ESI) m/z: 299.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2,6-Dichloro-9-[(1R,4S)-4-(5-ethyl-tetrazol-2-yl)-cyclopent-2-enyl]-9H-purine (step 1) (0.2 g, 0.57 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (0.088 g, 0.68 mmol) is added followed by 2,2-diphenylethylamine (0.123 g, 0.63 mmol) and the reaction mixture is stirred at 50° C. for 4 hours. The solvent is removed in vacuo and residue is partitioned between dichloromethane (20 mL) and 2M HCl (20 mL). The organic layer is washed with sat. NaHCO3 (20 mL), water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.20 (br s, 1H), 7.30-7.10 (m, 10H), 6.30 (m, 1H), 6.20 (m, 1H), 5.95 (m, 1H), 5.80 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 3.35 (m, 1H), 2.85 (q, 2H), 2.20 (m, 1H), 1.30 (t, 3H), MS (ES+) m/e 512 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C>[CH3:32][O:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:25]([F:28])([F:26])[F:27]
Reactant: CI
Reactant: OC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanol (Example 34, 0.05 g, 0.132 mmol) was taken into DMF (3 mL). Next, NaH (0.011 g, 0.264 mmol, 60% dispersion) was added and stirred for 1 hour at room temperature. Next, iodomethane (0.04 ml, 0.66 mmol) was added and allowed to stir for 30 minutes. The reaction was quenched with water then extracted with ether. The combined organics were dried over magnesium sulfate and concentrated. The resulting material was purified via column chromatography using 5% ethyl acetate in hexane as the eluent to yield 0.039 g (75%) of desired product as a white solid. MS (ESI) m/z 394 ([M+H]+); Anal. Calcd for C24H18F3NO: C, 73.27; H, 4.61; N, 3.56. Found: C, 73.15; H, 4.16; N, 3.41.