Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1>[Cu]I.CS(C)=O>[F:40][C:39]([F:42])([F:41])[C:36]1[CH:37]=[CH:38][C:33]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[CH:34][CH:35]=1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Nc1ncccc1-c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-4-(trifluoromethyl)benzene (725 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (690.4 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CN1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(CNC(=O)c2cc(F)cc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure as above, the acid 3 (60 mg, 0.21 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (54 mg, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-((1-methylpiperidin-4-yl)methyl)benzamide 10. LC/MS (ESI+): m/z 395 (M+H). 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=8.8 Hz, 1H), 8.48 (d, J=10.6 Hz, 1H), 8.46-8.38 (m, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.33 (d, J=8.5 Hz, 1H), 2.90 (d, J=7.8 Hz, 2H), 2.84-2.63 (m, 4H), 2.19 (s, 1H), 2.03 (s, 3H), 1.82 (s, 2H), 1.66 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[N:4][C:5](Cl)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[CH3:32][O-:33].[Na+]>CO>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[N:4][C:5]([O:33][CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: C[O-]
Reactant: O=C(c1nc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(Cl)cc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for the preparation of example 8, [3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 21) was reacted with sodium methoxide in methanol at 50° C. to give the title compound as light yellow oil. MS: 468.3 (MH+, 1Cl).
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1cccc(CN)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cccc(C)c2C)c(=O)c1=O

Procedure:
Tetrahydrofuran (15 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol), 2,3-dimethylbenzylamine hydrochloride (0.858 g, 5 mmol, prepared according to the procedure of R. Fuller et al., J. Med. Chem., 16 (2), 101 (1973)) and triethylamine (0.506 g, 5 mmol) were refluxed 22.5 hours and then processed in a manner similar to that of Example 4, Step 3, to provide 1.337 g of crude product. Recrystallization (twice) of this material from methanol afforded 0.777 g of the title compound as a white solid: mp 196°-198° C. MS (m/z) 300 (M+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:13]=[N:14][O:15][CH2:16][CH2:17][OH:18])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:13]=[N:14][O:15][CH2:16][CH2:17][O:18][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)[CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1cncc(-c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cncc(-c4ccccc4)c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 354 mg of 2-(3-phenyl-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 11), 510 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 383 mg of triphenylphosphine and 255 mg of diethyl azodicarboxylate, 550 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[C:10]([C:22](=[O:24])[CH3:23])[C:11]([O:18][CH2:19][O:20][CH3:21])=[CH:12][C:13]=2[O:14][CH2:15][O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1c(C(C)=O)c(OCOC)cc(OCOC)c1-c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
1-[3-(3-hydroxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (25 mg, 0.064 mmol) obtained in Example 134 was dissolved in N,N-dimethylformamide (1.0 mL), and potassium carbonate (35 mg, 0.25 mmol) and benzyl bromide (0.02 mL, 0.17 mmol) were added thereto and stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted twice with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/2) to obtain 1-[3-(3-benzyloxyphenyl)-2-(2-methoxyethyl)-4,6-bis(methoxymethoxy)phenyl]ethanone (30 mg, 97%).
Reaction SMILES: [OH:1][C:2]1([CH2:14][S:15][CH3:16])[CH2:6][S:5][C:4](=[S:7])[N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[BH4-].[K+]>CO.O.C1CCCCC1.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:3][C:4](=[S:7])[S:5][CH2:6][CH:2]([OH:1])[CH2:14][S:15][CH3:16]
Reactant: CSCC1(O)CSC(=S)N1c1ccccn1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CSCC(O)CSC(=S)Nc1ccccn1
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 4-hydroxy-4-methylthiomethyl-3-(pyrid-2-yl)-thiazolidine-2-thione (13.6 g) in methanol (160 cc) and a solution of potassium borohydride (2.7 g) in distilled water (40 cc) are used as the starting materials at a maximum of 30° C. The reaction is allowed to proceed for 150 minutes at between 20° and 30° C. The crude product (13.5 g) is dissolved in a mixture of cyclohexane (80 cc) and ethyl acetate (20 cc). The solution is chromatographed on silica (0.2-0.5 mm, 300 g) contained in a column of diameter 4 cm. Elution is carried out first with a mixture of cyclohexane (800 cc) and ethyl acetate (200 cc), this eluate being discarded, and then with a mixture of cyclohexane (1,600 cc) and ethyl acetate (450 cc), this eluate being collected and evaporated under reduced pressure (20 mm Hg) at 45° C. and then dried under reduced pressure (0.2 mm Hg) at 50° C. 2-Hydroxy-3 -methylthiopropyl pyrid-2-yldithiocarbamate (12.3 g) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N-]=C=O.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12
Reactant: NC1=c2ccoc2=NCN1c1cccc(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [N-]=C=O
Product: NC1=c2ccoc2=NCN1c1cccc(NC(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The compound was prepared following the procedure described Example 232(b), using 4-chlorophenyl isocyanate as the isocyanate of choice and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine of choice. MS(ES) m/e 380 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
16.1 g (0.138 mol) of chlorosulfonic acid are slowly added dropwise to a solution of 13.05 g of 4-fluorophenoxybenzene (0.069 mol) cooled to 0° C. After the addition is complete, the mixture is stirred at room temperature for a further 4 hours. For work up, 50 ml of dichloromethane are added, and the mixture is washed once with H2O. The aqueous phase is separated off and extracted twice more with 50 ml of dichloromethane each time. The combined organic phases are dried with MgSO4 and concentrated, resulting in the title compound as a colorless solid. Yield: 11.03 g; 60%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O>CC(O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]2[N:1]=[C:2]3[N:6]([CH:13]=2)[C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[S:3]3)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Temperature: 0 °C
Yield: 65 %

Procedure:
This product was prepared according to J. Med. Chem. 2009, 52, 7808-7816 with some modifications. A mixture of 2-amino-1,3-benzothiazol-6-ol (2.0 g, 12.18 mmol) and 2-bromo-4′-nitroacetophenone (2.97 g, 12.18 mmol) in IPA (40 ml) was heated to reflux for 24 h. The reaction mixture was then cooled to 0° C. and the resulting precipitate was filtrated and washed with IPA to afford 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol (65% c.y.). To a DMF (52 ml) solution of 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol was added potassium carbonate (2.94 g) and 4-(2-chloroethyl)morpholine hydrochloride (1.97 g). The reaction mixture was heated to 85° C. and stirred at the same temperature for 48 h. Then it was poured into water (100 ml), filtered and washed with water and ethyl ether to give 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole (86% c.y.). A mixture of 7-(2-morpholin-4-yl-ethoxy)-2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole and ammonium chloride (0.77 g) in ethanol (50 ml) was heated to reflux, and then iron powder (3.0 g) was added. The mixture was refluxed for 5 h and then immediately filtered though Celite and washed with hot ethanol. The filtrate was concentrated, neutralized with saturated NaHCO3 solution and extracted with DCM. The organic solution was dried with Na2CO3 and the solvent was removed under reduced pressure to afford the desired product [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline (32% c.y.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31][CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B using 1-(4-tert-butylphenyl)-4-chloro-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH2:13](Cl)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].[OH-].[Na+]>CO>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][S:10][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[nH]c(SC/C=C(\C)CCC=C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the 5-methoxy-2-mercaptobenzimidazole (2.5 g, 0.014M) in methanol (100 mL) was added geranyl chloride (2.4 g, 0.014M). The solution was taken to pH 11 (2N NaOH), stirred overnight at ambient temperature, evaporated, dissolved in CH2Cl2, washed with saturated NaHCO3 +brine, and dried over Na2SO4. The solvent was evaporated to oil which was flash chromatographed (Rf=0.76) (5% MeOH (CH2Cl2)) to give 2-[(3,7-dimethyl-2,6-(E)-octadienyl)thio]-5-methoxy-1H-1,3-benzimidazole (free base) which was converted to its oxalate salt (0.74 g). m.p. 113°-116° C. NMR (DMSO-d6)δ7.8(m,3H), 5.2 (m, 2H), 3.9(d, J=7 Hz, 2H), 3.8(s, 3H), 2.02(m, 4H),1.7(s,3H), 1.6(s, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][C:16]=1[O:17][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:10]=[O:9]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1cccnc1
Yield: 45.8 %

Procedure:
3-Bromomethylpyridine (0.30 mg, 1.2 mmol) was added to a suspension of vanillin (0.12 g, 0.79 mmol), potassium carbonate (0.33 g, 2.4 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (88 mg, 46%) was obtained as a brown oil. Piperidine (36 μL, 0.36 mmol) was added to a suspension of 3-methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (0.88 mg, 0.36 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (73 mg, 0.33 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (58 mg, 44%) was obtained as a pure brown crystalline solid; mp 245-251° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.18 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40-7.45 (m, 2H, H2′, Ar—H), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.87 (d, J=8.0 Hz, 1H, Ar—H), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.55-8.67 (m, 3H, H6, Ar—H), 11.32 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.7, 67.6, 110.8, 113.4, 116.7, 120.2, 120.3, 122.4, 122.7, 123.6, 127.9, 131.1, 132.4, 133.9, 135.9, 141.0, 141.5, 149.1, 149.2, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C23H20N2O5 [M+H]+ 404.1445 found 404.1445; vmax 758, 1257, 1509, 1586, 1671, 2931 cm−1.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.Cl>C1COCC1>[CH:3]1([C:9](=[O:11])[CH2:10][C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)C1CCCCC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCCC1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
0.88 g 60% sodiumhydrid was added 1-cyclohexyl-ethanone in 60 mL THF and stirred for 30 min. Then, 3.25 g 4-fluoro-benzoic acid methyl ester and 200 mg 18-Krone-6 was added to the reaction. The reaction was refluxed 2 h and stirred over night at RT. The reaction was added to 100 mL 1N HCl and extracted with diethylether. The organic layer was concentrated and the residue was purified by chromatography on silica gel and 3 g of the desired compound was obtained.
Reaction SMILES: Br[C:2]1[N:21]=[C:20]([N:22]2[CH2:26][C@@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[CH2:23]2)[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:19]2[C:20]([N:22]3[CH2:26][C@@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[CH2:23]3)=[N:21][CH:2]=[C:3]([C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:18]=2)[CH:34]=[N:35][CH:36]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@@H](CO)[C@H](O)C2)nc1Br
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using bromo-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 92.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.93 min, m/z=493.2 [M+H], m/z=491.4 [M−H]+, m/z=537.4 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.18 (m, 1H) 2.83-2.96 (m, 1H) 3.07-3.18 (m, 1H) 3.18-3.32 (m, 2H) 3.41-3.50 (m, 2H) 3.93-4.03 (m, 1H) 4.62-4.71 (m, 1H) 4.99 (d, J=4.27 Hz, 1H) 7.36 (d, J=9.03 Hz, 2H) 7.82-7.93 (m, 3H) 8.08 (d, J=2.38 Hz, 1H) 8.52 (d, J=1.63 Hz, 1H) 8.61 (d, J=2.63 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [C:1]1([P:7](C2C=CC=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20]P(Cl)C1C=CC=CC=1>>[Cl:20][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClP(Cl)c1ccccc1
Product: ClP(c1ccccc1)c1ccccc1

Procedure:
At virtually the same temperature, triphenylphosphine also reacts with dichloro(phenyl)phosphine to give chloro(diphenyl)phosphine (German Pat. No. A-3,215,379):
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O)=[O:13])([CH3:10])([CH3:9])[CH3:8].O1CCOCC1.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](Br)[CH:34]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[C:7]([O:11][C:12]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:33]1[CH:32]=[N:31][CH:30]=[C:29]([Br:28])[CH:34]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1cncc(Br)c1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
Cesium carbonate (165 mg), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (136 mg) and Pd(PPh3)4 (24 mg) were added to a 1,4-dioxane (4 ml) solution containing 3,5-dibromopyridine (100 mg), followed by reflux for 4 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=4:1), and a white solid of tert-butyl2-(5-bromopyridin-3-yl)-1H-pyrrol-1-carboxylate (73 mg) was thus obtained.
Reaction SMILES: C[Al](C)C.[CH:5]1([NH2:8])[CH2:7][CH2:6]1.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[CH:5]1([NH:8][C:11](=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[C:21]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[N:22][O:23][C:24]=3[CH3:25])=[N:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Reactant: NC1CC1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 410 μL, 0.8 mmol) was added dropwise (exothermic) to a solution of cyclopropylamine (47 mg, 58 μL, 0.8 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) in dioxane (2.5 mL) was added. The resulting mixture was then heated at 85-95° C. for 5 h and then cooled to room temperature and then poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (45 mg, 60%) which was obtained as an off white foam. MS: m/e=367.0 [M+H]+.