Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.P(Br)(Br)[Br:16].C(Cl)Cl.O>CCCCCC.C(OCC)(=O)C>[CH:12]1[CH:13]=[CH:14][C:9]([C:1]2[CH:6]=[CH:5][C:4]([CH2:7][Br:16])=[CH:3][CH:2]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: BrCc1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A suspension of 4-biphenylmethanol (62.9 g, 340 mmol) in hexane (650 mL) is treated with phosphorus tribromide (16 mL, 171 mmol) dropwise over 10 minutes. After 20 minutes CH2Cl2 (200 mL) is added to dissolve the remaining solid. The solution is then stirred for 1.5 hours and treated with water (200 mL) and then ethyl acetate. The organic layer is washed with water, cold saturated sodium bicarbonate and water, dried over sodium sulfate and evaporated to dryness to yield 4-biphenylmethyl bromide, m.p. 79°-80° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]4[O:19][CH2:18][CH2:17][C:16]=4[CH:20]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].N#N>COCCOC.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>[O:19]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:20][C:16]=2[CH2:17][CH2:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2nnn(Cc3ccc4c(c3)CCO4)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
To a solution of 6-bromo-1-(2,3-dihydro-benzofuran-5-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (50 mg, 0.15 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.165 mmol), and sodium carbonate (48 mg, 0.45 mmol) in DME/water (4 mL/1 mL) degassed with N2 was added Pd(PPh3)2Cl2 (5 mg, 0.008 mmol). The reaction solution was degassed with N2 again and stirred for 16 hours at 80° C. The reaction mixture was filtered through celite, concentrated, and purified with a reverse-phased preparative HPLC eluting with acetonitrile-water having 0.1% acetic acid to give 1-(2,3-dihydro-benzofuran-5-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (12 mg, 24% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(N(CC)CC)C.[CH:31]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][NH:23][S:37]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:39])=[O:38])[CH:3]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CNS(=O)(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To a stirred solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (0.6 g, 1.8 mmol) and triethylamine (0.7 mL, 5 mmol) in 100 mL of DCM was added cyclohexanesulfonyl chloride (0.3 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. After majority of the solvent was removed under vacuum, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated, the crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow powder (112 mg, yield 13%). MS calcd for (C20H26BN3O6S2): 479.1. MS found (ESI negative): (M−H)−=478.0. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.03 (s, 1H), 9.17 (bs, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.33 (t, J=6.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8, 2 Hz, 1H), 6.81 (d, J=2 Hz, 1H), 6.40 (dd, J=8.8, 2.4 Hz, 1H), 4.86 (s, 2H), 4.44 (d, J=6.4 Hz, 2H), 2.93 (m, 1H), 2.02 (m, 2H), 1.80 (m, 2H), 1.64 (m, 1H), 1.33 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@@H:35]([CH2:38][CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC[C@H](N)CO
Product: CC[C@@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (S)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2[(M+H)+] 557.2352, observed 557.2356.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[N:15][CH:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.NC1C(NCC2C=C[C:41]([O:44]C)=CC=2)=NC(C2C=CC=C3C=2C=CC=N3)=CN=1>FC(F)(F)C(O)=O.ClCCl.C1(S)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[C:6]([C:11]3[N:12]=[C:13]4[NH:18][C:41](=[O:44])[NH:17][C:14]4=[N:15][CH:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N
Reactant: COc1ccc(CNc2nc(-c3cccc4ncccc34)cnc2N)cc1
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2[nH]1
Temperature: 70 °C
Yield: 57 %

Procedure:
5-(5-Quinolyl)pyrazine-2,3-diamine. (3-Amino-6-(5-quinolyl)pyrazin-2-yl)[(4-methoxy phenyl)methyl]amine (see Example 1.B) (0.210 g, 0.588 mmol) was dissolved in trifluoroacetic acid/dichloromethane (2 mL:2 mL) with PS-thiophenol as a scavenger. The solution was heated to 70° C. in a sealed tube for two hours and then concentrated under reduced pressure and diluted with methanol. The methanol/product solution was filtered through a Phenomenex Strata-X-C solid phase extraction column to remove TFA. Additional water was added to the eluted compound to induce precipitation. The precipitate was filtered and dried under vacuum to afford the title compound (0.080 g, 57% yield). MS (ESI) m/z 238.1 [M+1]+.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[C:19]1([NH:25][C:26](=[S:27])[NH:2][N:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: S=C=Nc1ccccc1
Reactant: NN1Cc2ccccc2C1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=C(Nc1ccccc1)NN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 1.7 g (0.01 mole) of N-amino dihydroisoindole hydrochloride in 10 ml of dimethyl formamide was added 1 ml of triethylamine followed by 1.35 g (0.01 mole) of phenylisothiocyanate. The reaction mixture was allowed to stir at room temperature overnight. Water (25 ml) was added, the mixture stirred for 1 hr., and filtered. After drying there was obtained 2.6 g of the desired product, mp: 192°-193° dec. The IR and NMR were consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]1CCO[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1>>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:18]([O:23][CH3:24])[CH:17]=1)=[O:11]
Reactant: NC(=O)c1ccc(F)cn1
Reactant: COc1cc(C2OCCO2)ccc1O
Product: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Yield: 16.2 %

Procedure:
Using a method similar to Example 388 Part D, using 5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol) and 4-[1,3]dioxolan-2-yl-2-methoxyphenol (Example 386, Part C2) (0.560 g, 2.85 mmol) gives the title compound (0.126 g, 16%): MS ES+ 272.9 (M+H)+: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.01% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=11.1 min. 97.2% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:18]([Cl:19])=[CH:17][S:16][CH:15]=1)=S.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[Cl:19][C:18]1[C:14]([NH:13][C:11]2[NH:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[N:1]=2)=[CH:15][S:16][CH:17]=1
Reactant: Nc1cc(F)c(F)cc1NC(=S)Nc1cscc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc2nc(Nc3cscc3Cl)[nH]c2cc1F
Yield: 39.8 %

Procedure:
To 1-(2-amino-4,5-difluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (773 mg) in THF (20 ml) a solution of NaOH (240 mg) in water (9 ml) was added followed by a solution of p-toluenesulfonyl chloride (528 mg) in THF (10 ml). Following the analogous description in example 54b) the desired product (275 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]4[CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:24]N1C(=O)CCC1=O.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]4[C:23]=3[Cl:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccn2cc(CCc3ccc4nc(N)oc4c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccn2c(Cl)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 2-amino-6-[2-(7-methoxyimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.0 g) and N-chlorosuccinimide (0.43 g) in dioxane (15 ml) was stirred for 2 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 1 with 6N hydrochloric acid. The separated aqueous layer was adjusted to pH 8 with 20% potassium carbonate aqueous solution and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by silica gel column chromatography eluting with a solution of chloroform and methanol (19:1, V/V). The fractions containing object compound were concentrated to give 2-amino-6-[2-(3-chloro-7-methoxyimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.41 g).
Reaction SMILES: Br.[C:2]([O:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[C:11]([O:23][Si](C(C)(C)C)(C)C)[CH:10]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4].[F-].[K+].Cl>C(#N)C.ClCCl>[C:2]([O:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([OH:15])[CH:14]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: C=C(C)C(=O)OCc1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: Br
Agent: Cl
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: C=C(C)C(=O)OCc1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated hydrobromic acid (48%, 2.25 ml) was added dropwise to 3,5-di-tert-butyldimethylsilyloxybenzyl methacrylate (15.0 g, 34.4 mmole) and anhydrous potassium fluoride (7.5 g, 129 mmole) in acetonitrile (75 ml). After the solution was stirred overnight at room temperature, hydrochloric acid (4.5 ml conc. HCl in 30 ml of water) and 75 ml of dichloromethane were added to the pink solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water and brine. The solution was dried twice over sodium sulfate, filtered over silica and after addition of toluene concentrated in vacuo. The oily residue was dissolved in isopropyl ether (38 ml) and precipitated in hexane (500 ml). The product was filtered off and recrystallized from isopropyl ether/hexane.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14]=2)=[O:9].[OH-].[Na+].CO.Cl>O>[OH:20][C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:8]([NH:7][CH2:6][CH2:5][C:4]([CH3:29])([CH3:28])[C:3]([OH:30])=[O:2])=[O:9]
Reactant: COC(=O)C(C)(C)CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A mixture of 4-[(4-Hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-butyric acid methyl ester (25 mg, 0.064 mmol) and (1/1) 1 N NaOH aqueous solution/MeOH (2 mL) was stirred at room temperature for 2 days. It was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried in vacuo to provide the title product 6.5 mg (0.016 mmol) in 26% yield. LC-MS ESI−: 393.10 (M−1)−.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]([N:16]([CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:14][NH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>CCOCC>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]([N:13]2[CH2:14][CH:15]([N:16]([CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:24])[Cl:23])=[O:18])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)=[N:12]2)=[O:38])=[CH:34][CH:35]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCCOc1ccc(C2=NNCC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCOCC
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To an ether solution of 3-(4-propoxyphenyl)-4-(N-propyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole (Example 585e) (≤85 mmole) was added 12.7 g (68 mmole) of 4-trifluoromethylphenyl isocyanate. After stirring for 30 minutes, the mixture was concentrated in vacuo and dissolved in 200 ml of 50/50 diethyl ether/hexanes and cooled to -20° C. Crystals of the desired compound formed and were filtered yielding 23 g of the desired compound, mp 162°-163° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:14])[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:12][C:10]1[CH2:11][C:6]([CH3:14])([CH3:5])[CH2:7][C:8](=[O:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
Acetyl chloride (1.1 ml, 15.65 mmol) was added to a stirred solution of 5,5-dimethyl-cyclohexane-1,3-dione (2.1 g, 14.23 mmol) and pyridine (1.14 ml), in chloroform (50 ml). The mixture was stirred at room temperature for about 1.5 hours, then washed with water, 0.1N HCl, saturated aqueous sodium hydrogen carbonate and water. The organic phase was dried over sodium sulfate and evaporated to dryness to give 2.5 g (96%) of the title compound as a colourless oil, which was used as such without any further purification.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:19](/B(O)O)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:19](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Brc1cnc2ccc(NCc3cccnc3)nn12
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NCc3cccnc3)nn12
Yield: 50 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (75 mg, 50%) as a brown solid; 1H NMR (300 MHz, CD3OD) δ 8.60 (s, 1H), 8.42-8.40 (m, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.57 (d, J=9.7 Hz, 1H), 7.41-7.37 (m, 2H), 6.71-6.47 (m, 3H), 4.60 (s, 2H), 2.24-2.18 (m, 2H), 1.44-1.32 (m, 4H), 0.93 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 154.8, 149.5, 148.6, 137.9, 137.5, 137.4, 133.2, 129.1, 128.7, 125.9, 125.2, 116.7, 113.2, 43.9, 34.4, 32.8, 23.3, 14.4; HPLC tR=11.4 min (Luna), 96.0%; ES-MS: (M+H)=308 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2cccc(C(F)(F)F)c2)nc2cccnc21
Yield: 88.3 %

Procedure:
A mixture of N-[3-[[3-(trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester (22.0 g, 0.06 mole) and ethylene glycol (100 ml) was heated at reflux for 40 minutes. The reaction mixture was poured into water (300 ml) and cooled. The solid was collected by filtration, washed with water (200 ml), and dried. The solid was recrystallized from isopropyl ether/tetrahydrofuran to give in 2 crops 18.4 g (0.053 mole) of crude 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. This solid together with potassium hydroxide pellets (4.7 g, 0.084 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted wth methylene chloride (2×30 ml). The aqueous portion was acidified with glacial acetic acid and filtered after precipitation was complete. The filter cake was suspended in water (200 ml) and filtered. Recrystallization from tetrahydrofuran-isopropyl ether gave 15.3 g (91%). A 1.6-g sample was recrystallized from tetrahydrofuran-isopropyl ether to give 1.0 g of an off-white solid, mp 240°-241.5° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([O:59][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:67])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tertbutyldimethylsiloxy)-12-[2'-(4"-azido-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (38 mg) in acetonitrile (1 ml) was added a solution of 2% HF in aqueous acetonitrile (150 μl), and the mixture stirred at room temperature. After 4.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (22.5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[O-2].[Mg+2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Cc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a mixture of 4-nitro-fluorobenzene (250 mg, 1.77 mmol) and 4-amino-toluene (195 mL, 1.77 mmol) in 4 mL of water in a sealed tube was added magnesium oxide (86 mg, 2.126mmol). The suspension was stirred at 200° C. for 2 days. The reaction was cooled to ambient temperature and the suspension was diluted with water and filtered to remove insoluble material. The aqueous layer was extracted 3 times with ethyl acetate (50 mL) and the combined organic layers were washed with boronic acid (5%, 50 mL) and water, dried over magnesium sulfate and concentrated in vacuo to provide (4-nitro-phenyl)-p-tolyl-amine (190 mg, 47% yield). ). API MS: 229.20 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[NH:7][C:6]1=[O:16].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[N:7]([CH3:22])[C:6]1=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1Nc1cccc(Cl)c1Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c(C(F)(F)F)cc(=O)n(Nc2cccc(Cl)c2Cl)c1=O
Temperature: 25 °C

Procedure:
52.5 g (0.154 mol) of 3-(2,3-dichloroanilino)-6-trifluoromethyluracil and 42.67 g (0.309 mol) of potassium carbonate are introduced into 700 ml of acetone. 27.74 g (0.22 mol) of dimethyl sulfate are added, with stirring, at room temperature. The mixture is subsequently refluxed for one hour. After cooling, the solids are filtered off with suction, and the filtrate is concentrated in vacuo. The pale brown crystalline residue is stirred with 500 ml of diisopropyl ether and filtered off with suction. This gives 49.5 g (91% of theory) of 3-(2,3-dichloroanilino)-1-methyl-6-trifluoromethyluracil with a melting point of 179° C. and a retention value of 0.49 (silica gel, hexane/ethyl acetate 1:1).