Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33]>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.[Cu]I.C(OCC)(=O)C.O>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: OCCC#Cc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C

Procedure:
To 3-(4-bromophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C53) (0.50 g, 1.4 mmol) in a 25 mL vial equipped with a stir bar and cap with septa was added bis(triphenylphosphine)palladium(II) chloride (0.019 g, 0.027 mmol), copper(I) iodide (0.0026 g, 0.014 mmol) and triethylamine (8.5 mL) followed by but-3-yn-1-ol (0.12 mL, 1.6 mmol). The reaction was heated to 60° C. overnight. The reaction was stopped and cooled to room temperature. The reaction mixture was treated with 50% ethyl acetate/water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-50% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided a solid which was dried overnight at 50° C. in vacuo to afford the title compound as a tan solid. It was calculated based on 1H NMR to be mixed with the starting butynol (8%), (0.38 g, 71%): 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.20-8.11 (m, 2H), 7.94-7.88 (m, 2H), 7.83-7.76 (m, 2H), 7.56-7.50 (m, 2H), 3.85 (q, J=6.3 Hz, 2H), 2.74 (t, J=6.2 Hz, 2H), 1.83 (t, J=6.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −62.51; ESIMS m/z 358 ([M+H]+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[S:10]1[CH:14]=[CH:13][N:12]2[CH:15]=[N:16][CH:17]=[C:11]12.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.ClCCl>[C:5]([C:17]1[N:16]=[CH:15][N:12]2[CH:13]=[CH:14][S:10][C:11]=12)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: c1cn2cncc2s1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: ClCCl
Solvent: S=C=S
Product: CCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aluminum chloride (16.0 g) was added to a solution of 12.1 ml of propionyl chloride in 100 ml of carbon disulfide. A solution of 2.48 g of imidazo[5,1-b]thiazole in 100 ml of dichloromethane was added dropwise thereto. The mixture was stirred at room temperature for 18 hr. Propionyl chloride (12.1 ml) and 16.0 g of aluminum chloride were further added thereto, followed by stirring for 24 hr. The reaction solution was poured into 100 g of ice. Dichloromethane (200 ml) was added thereto. Sodium carbonate (100 g) and sodium sulfate (100 g) were added in that order to the mixture with stirring. The insolubles were removed by filtration and washed with dichloromethane. The filtrate was concentrated under the reduced pressure. Ethyl acetate (10 ml) was added to the concentrate. The crystals thus formed were collected by filtration. The filtrate was purified by column chromatography on silica gel (dichloromethane: ethyl acetate=1:1), and then combined with the collected crystals to obtain 2.49 g of 7-propionylimidazo[5,1-b]thiazole.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=3)[O:16][C:15]2([CH3:28])[CH3:27])[CH:8]=1)(=[O:5])=[O:4].O.CO>Br.C(O)(=O)C.ClCCl>[F:29][C:2]([F:1])([F:30])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=3)[O:16][C:15]2([CH3:27])[CH3:28])[CH:8]=1)(=[O:4])=[O:5]
Reactant: COc1ccc2c(c1)C(=O)C(Cc1cccc(NS(=O)(=O)C(F)(F)F)c1)C(C)(C)O2
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)Oc2ccc(O)cc2C(=O)C1Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Yield: 100 %

Procedure:
A mixture of 7.0 g (0.016 mole) of the product of Example 112 in 20 mL 48% hydrobromic acid and 20 mL glacial acetic acid was refluxed for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was, washed with water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 5% methanol in dichloromethane gave 6.9 g (100% of the title product as an oil). NMR (CDCl3 : δ1.46 (d, 6H); 2.85 (m, 1H); 2.95 (m, 2H). MS (Cl, NH3) m/e: 447 (M+ +18, 100), 430 (M+ +1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>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.CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([C:15]2[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([CH3:12])[CH:14]=2)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CC(C)(C)c1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2cc(C(C)(C)C)ncn2)c1
Yield: 96 %

Procedure:
Next, 2.01 g of 4-tert-butyl-6-chloropyrimidine obtained in Step 2, 3.63 g of 3,5-dimethylphenylboronic acid, 2.48 g of sodium carbonate, 0.10 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of DMF were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 0.90 g of 3,5-dimethylphenylboronic acid, 0.64 g of sodium carbonate, and 0.025 g of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 60 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that HtBudmppm (abbreviation), which was the pyrimidine derivative to be produced, was obtained as a pale yellow oil in a yield of 96%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 3 is shown in (k-3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:15](OC(OCC)OCC)C>>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[N:4][C:3]2[C:12]([OH:13])=[N:14][CH:15]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Product: Oc1ncnc2cc(C(F)(F)F)cnc12
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-amino-5-trifluoromethyl-pyridine-2-carboxylic acid amide (500 mg, 2.44 mmol) and triethoxymethane (1.8 g, 12.2 mmol) were heated to 120° C. for 16 h. The mixture was cooled to ambient temperature and treated with low boiling PE. The reaction mixture was stirred for 10 minutes, cooled to 0° C. and the beige solid was collected by filtration (350 mg).
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17](Br)=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[OH:29].[K].[CH3:31]N(C=O)C>O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([Br:28])[C:5]=1[O:29][CH3:31]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: CN(C)C=O
Agent: [K]
Solvent: CI
Solvent: O
Product: COc1c(Br)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1Br
Reaction time: 3 h
Yield: 91 %

Procedure:
Iodomethane (0.383 mL, 6.16.mmol) was added to a stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (2.13 g, 4.4 mmol), potassium carbobnate (0.669 g, 4.34 mmol) and DMF (15 mL) at room temperature under a dry nitrogen atmosphere. After 3 h, the reaction mixture was diluted with water and the resulting solid was filtered and washed with water. The solid was taken up in dichloromethane and silica gel (40 mL) was added. The solvent was removed and the adsorbate was flash chromatographed (90:10 petroleum ether:dichloromethane) to provide the title compound as a white solid (2.0 g, 91%): mp 238.5-239.5° C.: NMR (CDCl3); δ 8.36 (ddd, J=8, 1, 1 Hz, 1H), 7.84 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.60 (s, 2H), 7.58 (ddd, J=8, 1, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.45 (ddd, J=8, 7, 1 Hz, 1H), 7.20 (ddd, J=8, 7, 1 Hz, 1H), 6.80 (ddd, J=8, 1, 1 Hz, 1H), 4.11 (s, 3H, CH3); MS (EI): [M+], 3 bromine isotope pattern, 574 (35%), 576 (95%) 578 (100%) 580 (45%); Anal. Calc. for C23H13Br3OS: C, 47.87, H, 2.27, N, 0.00. Found: C, 47.73, H, 1.88, N, 0.03.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)([NH:14][S@@](C(C)(C)C)=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.Cl>CO.O1CCOCC1.CCOC(C)=O>[NH2:14][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[C:23]([F:31])[CH:22]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C[C@](N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
(S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-((R)-2-methylpropan-2-ylsulfinamido)propanoate (0.075 g, 0.16 mmol) was dissolved in MeOH (2 mL). At RT, 4.0M HCl in dioxane (2 mL) was added and the reaction mixture stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL), transferred to a separation funnel and washed with 1.0M NaOH (ca.20 mL). The organic portion was dried over anhydrous Na2SO4, decanted and concentrated yielding (S)-methyl 3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate as a colorless oil, (0.062 g, crude quantitative yield). LCMS: 1.37 min [M+1] 377.1 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]1([CH2:50][NH:51][C:52]([C:54]2[NH:55][C:56]3[C:61]([CH:62]=2)=[CH:60][CH:59]=[CH:58][C:57]=3[N:63]([CH3:72])[S:64]([C:67]2[S:68][CH:69]=[CH:70][CH:71]=2)(=[O:66])=[O:65])=O)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:72][N:63]([C:57]1[CH:58]=[CH:59][CH:60]=[C:61]2[C:56]=1[NH:55][C:54]([C:52]1[S:43][C:44]3([CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:50][N:51]=1)=[CH:62]2)[S:64]([C:67]1[S:68][CH:69]=[CH:70][CH:71]=1)(=[O:66])=[O:65]
Reactant: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCOCC3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC4(CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
To a solution of triphenylphosphine oxide (1.15 g) in acetonitrile (20 ml) was slowly added trifluoromethanesulfonic anhydride (0.35 ml) at 0° C., and the mixture was stirred for 10 min. N-{[4-(Benzylthio)tetrahydro-2H-pyran-4-yl]methyl}-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.76 g) was added, and the reaction mixture was stirred at 10° C. for 1 hr. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.22 g, yield 36%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 189-191° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: Cc1c(N)ccc(C#N)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of (2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (51C) (661 mg, 2.0 mmol) in 5% DMF in CH2Cl2 (10 mL) at rt was added 4-amino-2-chloro-3-methyl-benzonitrile (340 mg, 2.04 mmol) followed by NaBH(OAc)3 (636 mg, 3.0 mmol) and HOAc (180 μL, 3 mmol). The reaction was stirred under nitrogen at rt for 18 h. Additional portions of NaBH(OAc)3 (424 mg, 2.0 mmol) and HOAc (120 μL, 2 mmol) were added, and the reaction was stirred for an additional 18 h. The reaction was diluted with EtOAc (50 mL) and the organic layer was washed with saturated aqueous NaHCO3 (50 ml), dried (MgSO4), filtered and concentrated. Purification via flash chromatography (silica gel, 0 to 15% EtOAc/hexanes) provided the title compound (605 mg, 1.26 mmol, 63%). MS m/z 480 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O.O1CCOCC1>[C:16]([NH:1][C@H:2]([CH2:6][O:7][CH:8]([F:10])[F:9])[C:3]([OH:5])=[O:4])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](COC(F)F)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N[C@H](COC(F)F)C(=O)O
Yield: 67 %

Procedure:
(2R)-2-Amino-3-(difluoromethoxy)propanoic acid (680 mg, 4.39 mmol) was mixed with sodium bicarbonate (738 mg. 8.78 mmol) and acetic anhydride (491 mg, 4.82 mmol) in water (10 mL) and dioxane (10 mL) at 0° C. to room temperature overnight. The reaction mixture was acidified with 1N HCl to pH2, concentrated and extracted with ethyl acetate, and concentrated again to give (2R)-2-(Acetylamino)-3-(difluoromethoxy)propanoic acid (580 mg, 82.3%) as a colorless sticky oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 6.40 (d, 1H), 6.24 (wt, 1H), 4.88 (m, 1H), 4.36 (dd, 1H), 4.22 (dd, 1H), 2.12 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]#[N:33].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:16][C:15]([C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[CH2:26][CH2:27][CH2:28][CH3:29])=[N:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCC#N)ccc3c2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
A mixture of ({1-bromo-6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (71 mg, 0.141 mmol), prepared in the previous step, sodium azide (27.8 mg, 0.427 mmol) and ammonium chloride (25 mg, 0.467 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 3 h. Following the reaction by MS, starting material remained. Additional sodium azide (25 mg, 0.38 mmol) and ammonium chloride (25 mg, 0.467 mmol) were added and the reaction stirred at 100° C. for two more hours. This procedure was repeated four additional times until the MS showed that the reaction went to completion. The reaction was filtered, acidified with 5 mL of 1N HCl and then diluted with 10 mL of H2O. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (52 mg, 67%) as a brown solid, mp 235-237° C. Elemental Analysis for C27H22BrN5O3+0.23 mol H2O Calc'd: C, 59.12; H, 4.07; N, 12.77. Found: C, 59.36; H, 4.27; N, 12.23.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1(O)[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[OH:52][CH:49]1[CH2:50][CH2:51][CH:47]([O:1][C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]3[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:13]3)=[N:6][CH:7]=2)[CH2:48]1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OC1CCC(O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OC5CCC(O)C5)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.28 mmol) of 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one are dissolved in 6 ml of DMF, and 277 mg (0.83 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 33 mg (0.32 mmol) of 1,3-cyclopentanediol are added. The reaction mixture is shaken at room temperature for 15 min, and 196 mg (0.83 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mix-ture was shaken at room temperature for 3 h, a further 277 mg (0.83 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 196 mg (0.83 mmol) of di-tert-butyl azodicarboxylate were added, and the mixture was shaken at room temperature for 18 h. The reaction mixture is filtered off through kieselguhr with suction and washed with acetonitrile. The filtrate is evaporated and purified by means of preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH:3]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][O:9][C:4]2[CH:3]=[C:2]([NH:1][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)cc(OCCc2ccc(C#N)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(OCCc2ccc(C#N)cc2)c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a cold solution (ice:water temperature) of amino-[3-2-(4-cyanophenyl)ethoxy]-5-methylbenzene (0.13 g; 0.50 mmol; from step (iii) above) in pyridine (5 mL) was added benzenesulfonyl chloride (71 μL; 0.55 mmol). After 2 hours stirring, NaHCO3/aq (sat.) was added, and the solution extracted with EtOAc. The combined organic phases were dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:1)) to give 0.19 g (97%) of the sub-title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH3:20])=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[NH:23][C:21]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([C:41]3[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=3)=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:19][CH3:20])=[O:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(Cl)nc2)c2ccccc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(-c3cnn(C)c3)nc2)c2ccccc12
Temperature: 100 °C

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (Example 3, 0.050 g, 0.12 mmol) in 3 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.24 mL, 0.24 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.037 g, 0.18 mmol), and bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 0.0078 mmol). The reaction was heated at 100° C. for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 470.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.59 (s, 1H), 8.26-8.23 (m, 1H), 8.12 (d, J=7.1 Hz, 1H), 8.07-7.89 (m, 3H), 7.85-7.82 (m, 1H), 7.70-7.61 (m, 3H), 4.52 (s, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 3.98 (br s, 1H), 3.57-3.51 (m, 1H), 2.16-2.13 (m, 2H), 1.79 (br s, 2H), 1.50-1.21 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>ClCCCl>[C:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][NH:11][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: COc1ccc(CNCCNC(=O)OC(C)(C)C)cc1
Yield: 11.7 %

Procedure:
This compound was made in a manner analogous to that set forth in Step D of Example 5, using 3.0 grams (0.022 mole) of 4-methoxybenzaldehyde, 3.6 grams (0.022 mole) of N-(2-aminoethyl)(tert-butoxy)carboxamide (known compound), 7.0 grams (0.033 mole) of sodium triacetoxyborohydride and 5.3 grams (0.044 mole) of magnesium sulfate in 30 mL of 1,2-dichloroethane. The reaction product was purified with column chromatography on silica gel. Elution was accomplished using mixtures of 2% to 5% methanol in methylene chloride as eluants. Appropriate fractions were combined and concentrated under reduced pressure, yielding 0.72 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional material.