Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[N:26]=[C:25]([CH3:27])[N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:16][CH:17]1[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+].[N:43]#[C:44]Br>CO>[CH:17]1([CH2:16][N:15]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:14]2[N:13]=[C:12]3[N:24]([CH3:28])[C:25]([CH3:27])=[N:26][C:11]3=[CH:10][C:9]=2[CH2:8][N:7]([CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=2)[C:44]#[N:43])[CH2:18][CH2:19]1
Reactant: Cc1nc2cc(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
A mixture of {6-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl}-bis-cyclopropylmethyl-amine (0.220 g, 0.41 mol) and sodium bicarbonate (0.071 mg, 0.83 mol.) in methanol (8 mL) was stirred at 0° C. for 15 min. Cyanogen bromide (0.053 g, 0.05 mol) was added and continued to stir at room temperature for 1.5 h. Methanol was removed under reduced pressure, extracted with ethyl acetate (250 mL), washed with water (250 mL×2) and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 0.220 g of colorless gummy compound.
Reaction SMILES: C(OC([N:11]1[CH2:24][CH2:23][C:14]2([C:18](=[O:19])[N:17]([O:20][CH3:21])[C:16](=[S:22])[CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(OCC)C.[BrH:30]>C(O)(=O)C>[BrH:30].[CH3:21][O:20][N:17]1[C:16](=[S:22])[CH2:15][C:14]2([CH2:23][CH2:24][NH:11][CH2:12][CH2:13]2)[C:18]1=[O:19]
Reactant: CON1C(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)CC1=S
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CON1C(=O)C2(CCNCC2)CC1=S
Reaction time: 0.33 h

Procedure:
In an acetic acid solution (5 ml) of 25% hydrogen bromide was dissolved 8-benzyloxycarbonyl-2-methoxy-2,8-diazaspiro[4,5]decane-3-thion-1-one (0.5 g), and the solution was left standing at room temperature for 20 minutes. To the solution was added ethyl ether (100 ml), and resulting precipitates were collected by filtration, followed by recrystallization from ethanol to obtain 0.4 g of a pale yellow solid, m.p. 235° to 237° C.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br-].[Br:23][C:24]1[CH:25]=[CH:26][C:27]2[C:36]([CH:37]=1)=[S+:35][C:34]1[C:29](=[CH:30][CH:31]=[C:32](Br)[CH:33]=1)[N:28]=2>C(Cl)(Cl)Cl>[Br-:23].[CH2:12]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:24]1[CH:25]=[CH:26][C:27]2[C:36]([CH:37]=1)=[S+:35][C:34]1[C:29](=[CH:30][CH:31]=[C:32]([N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:33]=1)[N:28]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Brc1ccc2nc3ccc(Br)cc3[s+]c2c1
Reactant: CCCCCCCCCCNCCCCCCCCCC
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCN(CCCCCCCCCC)c1ccc2nc3ccc(N(CCCCCCCCCC)CCCCCCCCCC)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.7 g (5.72 mmol) of didecylamine in 20 mL of CHCl3 was added 0.63 g (1.43 mmol) of 22. The reaction mixture was stirred at room temperature for 2 h under argon and concentrated under diminished pressure to give 3,7-bis(didecylamino)phenothiazin-5-ium bromide (CPD-14): mass spectrum (MALDI-TOF), m/z 788.69 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1

Procedure:
In a 100 ml round-bottomed flask, 1 eq. of the compound obtained in Step B is dissolved in 20 ml of CCl4. 1 eq. of N-bromosuccinimide and 0.04 eq. of benzoyl peroxide are then added, and the mixture is irradiated by means of a halogen lamp and maintained at reflux for 4 hours. At the end of the reaction, the insoluble material is filtered off, and the carbon tetrachloride is evaporated off. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(Cl)CCCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (200 mg, 0.486 mmol) was dissolved in dichloromethane (3 ml) and triethylamine (203 μl, 1.46 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (69 μl, 0.535 mmol). The reaction was stirred under nitrogen at room temperature for 2 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (259 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: CN(C)Cc1ccc(CCN)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:19])=[C:3](/[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21].C(OCC)(OCC)OCC>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:9](=[O:18])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:19])[N:1]=[C:20]2[CH3:21])=[CH:16][CH:15]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)/C(C(=O)Nc1ccc(Cl)cc1)=C(/C)N
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)nc(C)n(-c2ccc(Cl)cc2)c1=O
Yield: 42 %

Procedure:
This compound is prepared in 42% yield from ethyl 3-amino-2-(4-chlorophenylcarbamoyl)crotonate in a manner analogous to Example 1 substituting triethyl orthoacetate for triethyl orthoformate.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20](OCC)=[O:21])=[C:17]=[O:18]>>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[C:20](=[O:21])[CH:19]([CH:25]([CH3:27])[CH3:26])[NH:16][C:17]3=[O:18])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: CCOC(=O)C(N=C=O)C(C)C
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C(C)C)C2=O)cn1
Yield: 30 %

Procedure:
Prepared as in Example 10-41 from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 10-41a) and ethyl 2-isocyanato-3-methylbutanoate. Yield: 30%. 1H NMR (CDCl3, 400 MHz): δ 0.96-0.94 (d, 3H, J=7.2 Hz), 1.09-1.07 (d, 3H, J=8 Hz), 2.19 (s, 3H), 2.26-2.22 (m, 1H), 2.40 (s, 3H), 4.02 (s, 1H), 5.05 (s, 2H), 5.53 (bs, 1H), 7.90 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.1 μM.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][C:20]=1[F:21]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:22][O:23][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,4-dif-luorophenyl)methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[O:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[O:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1oc2ccccc2c1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 3-(4-methylphenyl)benzo[b]furan-2-carbonitrile (239 mg), N-bromosuccinimide (182 mg), and 2,2'-azobisisobutyronitrile (10 mg) in carbon tetrachloride (5 ml) was refluxed for 5 hours and cooled to ambient temperature. The precipitates were filtered off. The filtrate was washed with aqueous sodium bicarbonate solution (×3), dried, and concentrated in vacuo to give a yellow oil, which was crystallized from n-hexane to yield 3-(4-bromomethylphenyl)benzo[b]furan-2-carbonitrile (300 mg) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:45])[O:3][C:4]1[CH:5]=[C:6]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:20]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][CH:9]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[F:45][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(OC(F)F)cc2-c2nc(C)nc(N)n2)cn1
Yield: 74 %

Procedure:
A solution of 4-(5-(difluoromethoxy)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.022 g, 0.036 mmol) in trifluoroacetic acid (Aldrich) (0.531 mL, 7.15 mmol) and trifluoromethane sulfonic acid (TCI) (3.16 μL, 0.036 mmol) was heated at 80° C. for 20 min. The reaction mixture was concentrated and the residue was first diluted with sat. NaHCO3 (8 mL) then extracted with CHCl3 (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 10% to 20% acetone in hexanes) to give the product as a yellow solid (0.010 g). m/z (ESI, +ve ion) 376.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.65 (s, 1H); 8.67 (br. s., 1H); 8.35 (br. s., 1H); 8.20 (br. s., 1H); 8.09 (d, J=9.94 Hz, 1H); 6.79 (d, J=8.92 Hz, 1H); 6.11-6.75 (m, 1H); 5.41 (br. s., 2H); 3.95 (s, 3H); 2.58 (s, 3H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II.[CH2:13]1COC[CH2:14]1>>[CH:2]1([C:1]([OH:10])=[O:9])[CH2:14][CH2:13][CH:5]([C:6]([OH:8])=[O:7])[CH:4]=[CH:3]1
Reactant: C1CCOC1
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Product: O=C(O)C1C=CC(C(=O)O)CC1
Temperature: 160 °C
Yield: 75 %

Procedure:
In a Parr reactor, a mixture of cis,trans muconic acid (8.18 g, 57.6 mmol), I2 (293 mg, 1.15 mmol, 2.0 mole percent), and THF (120 ml, 0.48 M) is heated to 160° C. for 25 hours under ethylene pressure (pRT=252 psi (1.74 MPa)). After cooling to room temperature, a white solid is found to be suspended in a weakly yellow solution. The solution is filtered to remove the precipitated trans,trans muconic acid and all solvent is evaporated on a rotary evaporator. The residue is suspended in hot ethyl acetate/dioxane; after cooling to room temperature, the precipitated solid is removed by filtration and the filtrate is evaporated to dryness to yield cyclohex-2-ene-1,4-dicarboxylic acid (7.22 g, 42.4 mmol, 75 percent).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Sc1ccc(Br)cc1
Product: CN1CCN(c2cc(Sc3ccc(Br)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of 2.0 g. 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 5.0 g. of p-bromothiophenol is heated in an oil bath maintaining the temperature at 160°C. for three hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. Upon recrystallization from absolute ethanol, there is obtained 4-(4-bromophenylthio)-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[O:37]1[CH2:38][CH2:39][N:34]([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:35][CH2:36]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.6 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (31 mg, 0.070 mmol) and morpholine (0.012 mL, 1.4 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (31 mg, 15 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 7 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 50-100% EtOAc/hexanes) to furnish methyl 6-(2-(3-(4′-(morpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a light yellow oil (21 mg, 58%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.04-8.02 (m, 2H), 7.97 (t, 1H, J=7.8 Hz), 7.52 (d, 4H, J=8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.04 (s, 3H), 3.73 (t, 4H, J=4.5 Hz), 3.54 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.16 (t, 2H, J=7.6 Hz), 2.48 (s, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.8, 139.3, 139.0, 138.2, 136.7, 129.6, 128.9, 128.0, 127.1, 126.8, 125.2, 123.3, 67.0, 63.1, 53.6, 53.1, 40.6, 29.3; HR ESI-TOF m/z 512.2173 (M+H+, C30H29N3O5, requires 512.2180).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)(=O)C.II>C1(C)C=CC=CC=1.[Zn].[Pd]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:8])[CH2:18][C:17]1[CH:16]=[CH:15][C:14]([OH:13])=[CH:21][CH:20]=1)[CH3:7]
Reactant: CC(=O)Oc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Pd]
Agent: II
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Reaction time: 24 h
Yield: 14.6 %

Procedure:
A slurry containing 24.6 g of zinc dust in 100 ml dry toluene was treated dropwise with a solution containing 73.5 g of ethyl bromoisobutyrate and 65 g of 4-acetoxybenzaldehyde in 200 ml dry toluene. A crystal of iodine was added to initiate the reaction and the mixture was heated to reflux overnight. An additional equivalent of ethyl bromoisobutyrate was added and reflux was continued for 24 hours. After cooling, the filtrate was hydrogenated over palladium and the residue purified by flash chromatography to give 12.2 g of 3-(4-hydroxyphenyl)-2,2-dimethylpropanoic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)[N:12]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)OCO4)n2)c1
Yield: 73.1 %

Procedure:
Using Method F with 200 mg (0.33 mmol) 4a and 138 mg (1.0 mmol) 3,4-methylendioxyaniline, 84 mg (29.0%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 2.08 (s, 3H, CH3CO), 5.99 (s, 2H, OCH2O), 6.91 (d, 1H, Harom 5, J=8.40), 7.32 (q, 1H, Harom 6, Jo=8.43, Jm=1.99), 7.40 (d, 1H, Harom 2, J=1.85), 7.43 (t, 1H, Harom 5′, J=7.87), 7.65 (d, 1H, Harom 4′ or 6′, J=8.93), 7.68 (d, 1H, Harom 6′ or 4′, J=7.83), 8.12 (s, 1H, HP5), 8.30 (s, 1H, Harom 2′), 8.35 (s, 1H, HP3), 9.42 (s, 1H, NHamino), 10.09 (s, 1H, NHamido); MS, (C19H16N4O3), m/z: 349.1 [M++1, 100].
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:21]Br>C1(C)C=CC=CC=1>[Br:21][CH2:9][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: BrBr
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)C(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 4.20 g. of 1,1-diphenyl-2-propanone in 25 ml. of acetic acid is heated at 60°-70° C. and 1.0 ml. of bromine in 8 ml. of acetic acid is added dropwise. The reaction mixture is held at 60°-70° C. for one hour and then poured into ice. Toluene is added. The toluene layer is separated, washed with water, dried over magnesium sulfate and concentrated to obtain 1-bromo-3,3-diphenyl-2-propanone.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]=[C:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]1([C:7](=[N:9][C@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=N[C@@H](C)c1ccccc1)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=N[C@H](C)C(F)(F)F)c1ccccc1

Procedure:
To crude (S)-(1-phenylethyl)-(2′,2′,2′-trifluoro-1-methylethylidene)-amine (1410 g, 4.54 mol theory) and washings with 20 g of toluene at room temperature, add DBU (1050 g, 6.897 mol) in portions to keep temperature below 60° C. Heat the reaction at 60° C. overnight (14 h) under nitrogen until the starting material rearranges to the desired intermediate (2460 g of solution). MS (ES+) m/z: 216.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2N1
Product: CC(=O)N1C(=O)Cc2ccccc21

Procedure:
1,3-Dihydro-2H-indol-2-one (35.6 g, 0.268 mol) suspended in acetic anhydride (30 mls) and mixture refluxed for 20 hours. Filtered and washed with diethyl ether (50 mls) dried in vacuo at 80 deg C. to give a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[C:6]2[N:11]=[C:10]3[N:12]([CH3:16])[C:13]([CH3:15])=[N:14][C:9]3=[CH:8][C:7]=2[CH2:17][N:18]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:19]#[N:20])[CH2:3][CH2:2]1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:35][C:32]([F:33])([F:34])[C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=1)[CH2:21][N:18]([CH2:17][C:7]1[CH:8]=[C:9]2[N:14]=[C:13]([CH3:15])[N:12]([CH3:16])[C:10]2=[N:11][C:6]=1[N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:36][CH:37]1[CH2:39][CH2:38]1)[C:19]1[N:40]=[N:41][NH:42][N:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc2n1C
Temperature: 90 °C
Yield: 926.6 %

Procedure:
A mixture of [5-(bis-cyclopropylmethyl-amino)-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-6-ylmethyl]-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.220 g, 0.04 mmol), sodium azide (0.130 g, 2 mmol.) and ammonium chloride (0.106 g, 2 mmol) were taken in DMF (15 mL) and heated at 90° C. for 2 h. The reaction mixture was taken in ethyl acetate (250 mL) and washed with water (250 mL×4) and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 0.220 g of colorless gummy liquid.