Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:3]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:4]1[O:5][CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1)[CH3:2].[Li]N(C)CCN(C)C.FC(F)(F)S(O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O>[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([Si:3]([CH2:11][CH3:12])([CH2:1][CH3:2])[C:4]1[O:5][C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:7]([CH:9]=[O:10])[CH:8]=1)[CH3:14]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: O=S(=O)(Oc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]N(C)CCN(C)C
Product: CC[Si](CC)(CC)c1cc(C=O)c(-c2ccccc2)o1

Procedure:
Treatment of 2-triethylsilyl-4-furaldehyde with lithio N,N,N'-trimethylethylenediamine, followed by phenyl trifluoromethanesulfonate in the presence of anhydrous zinc chloride and tetrakis (triphenylphosphine) palladium (o) and work up gives the titled aldehyde.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:29][CH2:30]Cl)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.CC1C=CC(CN2CCN(C(C)C([O-])=O)CC2)=CC=1>>[C:13]([O:12][C:10]([NH:9][CH2:8][C@H:3]([N:2]1[CH2:30][CH2:29][N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(CN(CCCl)CCCl)cc1
Agent: Cc1ccc(CN2CCN(C(C)C(=O)[O-])CC2)cc1
Agent: Cl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(Cc2ccc(C)cc2)CC1

Procedure:
In a manner analogous to example 17.4, using 5.1 g (20 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 4.9 g (20 mmol) of bis(2-chloroethyl)(4-methylbenzyl)amine, 4.1 g (53%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-(4-methylbenzyl)piperazin-1-ylpropanoate are obtained in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1.I[CH2:32][CH3:33]>C(#N)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:32]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:33]
Reactant: CCI
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O[C@@H]3CCCNC3)ccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1CCC[C@@H](Oc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
To a solution of (R)-4-(piperidin-3-oxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (84 mg, 0.20 mmol) in acetonitrile (1.0 mL) was added iodoethane (24 uL, 0.30 mmol), and the mixture was heated at 50° C. for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow oil, which was used in the next step without any further purification (46 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33](O)=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[N:99]1([CH2:105][CH2:106][OH:107])[CH2:104][CH2:103][NH:102][CH2:101][CH2:100]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([C:33]([N:102]6[CH2:103][CH2:104][N:99]([CH2:105][CH2:106][OH:107])[CH2:100][CH2:101]6)=[O:34])[CH:36]=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(CCO)CC4)c3)cn2)cc1
Yield: 93.6 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (68.1 mg, 0.103 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and 1-piperazineethanol (26.0 μl, 0.211 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (74.4 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-125) as a yellow powder (31.7 mg, 58%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([NH:16][N:17]=[C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](OCC)=O.[Cl-].[NH4+].CC1C(C)=C(C)C(C)=C(C)C=1.FC(F)(F)C(O)=O>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.O1CCCC1.ClCCl.CCOCC>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:18]1[NH:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[C:19]=1[CH2:20]2
Reactant: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCCC
Product: COc1ccc2c(c1)CC1=C2NN(C(=O)OC(C)(C)C)C1c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of lithium diisopropylamide (11.3 ml of a 20M solution in heptane/THF/ethylbenzene) was added dropwise to a stirred solution of 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone (2.5 g) in tetrahydrofuran (100 ml) at −78° C. under nitrogen. The mixture was stirred at this temperature for 1.5 hours and then a solution of ethyl thiophene-2-carboxylate (1.69 g) in tetrahydrofuran (10 ml) was added dropwise. After the addition the mixture was stirred for 30 minutes at −78° C. and then allowed to warm to ambient temperature. After stirring for a further 20 minutes at ambient temperature, saturated ammonium chloride solution (100 ml) was added and the mixture was stirred vigorously for ten minutes. The layers were separated and the aqueous layer was extracted with ether (3×75 ml). The combined organics were washed with 1M hydrochloric acid, then brine, and then dried, filtered and evaporated to give a yellow gum which was suspended in dichloromethane (25 ml) and pentamethylbenzene (1.34 g) was added. The mixture was cooled to 0° C. and trifluoroacetic acid (0.2 ml) was added. The mixture was stirred for 64 hours and then concentrated under reduced pressure to give an oil which was dissolved in ether (200 ml), washed with saturated sodium bicarbonate solution (100 ml), then brine, then dried, filtered and evaporated to give a gum which was purified by flash column chromatography using petroleum ether, b.p. 60-80° C./ethyl acetate (4:1) as the mobile phase to give 6-methoxy-2-tert-butyloxycarbonyl-3-(2-thienyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 163-165° C.
Reaction SMILES: N[C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:23]>O1CCOCC1.O.[Cu]Br>[Br:23][C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Temperature: -5 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile (0.5136 g, 2.07 mmol) in hot 1,4dioxane (1 ml) was added 48% aqueous hydrobromic acid (7 ml) and the mixture was cooled to −5° C. before adding dropwise a solution of sodium nitrite (0.1657 g, 2.40 mmol) in water (0.5 ml) over 5 min so that the temperature did not rise above −4° C. The resulting mixture was stirred at −5 to 2° C. for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (0.4452 g, 3.10 mmol) in 48% hydrobromic acid (3 ml). The mixture was stirred for 5 min then heated to 46° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The combined organic extracts were washed with 10% aqueous ammonia (25 ml), then saturated aqueous NaCl (20 ml), dried (MgSO4), and evaporated in vacuo. Purification by chromatography (silica gel, 20% EtOAc/isohexane) gave 0.3790 g (59%) of 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as a white solid.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)SC)#[N:2].[CH2:25]([NH2:28])[C:26]#[CH:27]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=[N:28][CH2:25][C:26]#[CH:27])#[N:2]
Reactant: C#CCN
Reactant: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Solvent: CC#N
Product: C#CCN=C(NC#N)NCCSCc1cc2ccc(CN(C)C)cc2o1

Procedure:
A solutiion of N-cyano-N'-[2-(6-dimethylaminomethyl)-2-benzofuranylmethylthio)ethyl]-S-methylisothiourea (Example 1, Step F) (6.55 g., 0.018 mole) and propargylamine (4.0 g., 0.073 mole) in acetonitrile (100 ml.) is heated in a sealed pressure vessel at 110°-120° C. for 36 hours. The reaction solution is then evaporated at reduced pressure. N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-(2-propynyl)guanidine is obtained when the residual oil is chromatographed on silica gel with elution by an 8% solution of methanol in chloroform.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([Cl:38])[CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])[CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][NH:19][C@H:20]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[C:33]([Cl:38])[CH:34]=5)[CH:29]=4)(=[O:26])=[O:27])[CH2:21]3)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Product: CC(C)(C)OC(=O)N1CCc2sc(CN[C@H]3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)C3)cc2C1

Procedure:
In the same manner as in Referential Example 321, a reaction was effected using 5-tert-butoxycarbonyl-2-formyl -4,5,6,7-tetrahydrothieno[3,2-c]pyridine (WO94/21599) and (3S)-3-amino-1-[(6-chloronaphthalen-2-yl)sulfonyl]pyrrolidine as starting materials, whereby the title compound was obtained.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]([F:42])([F:41])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][C:30]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[N:29]2)=[CH:24][CH:23]=1.[Cl-].[NH4+]>C1COCC1>[C:15]([O:14][C:12](=[O:13])/[CH:11]=[CH:37]/[C:36]1[CH:39]=[CH:40][C:33]([C:30]2[N:31]=[CH:32][N:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][C:20]([F:41])([F:19])[F:42])=[CH:23][CH:24]=3)[N:29]=2)=[CH:34][CH:35]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (NaH, 60% suspension in mineral oil; 440 milligrams (mg), 11.0 millimoles (mmol)) was suspended in THF (20 milliliters (mL)), and the mixture was cooled to 0° C. t-Butyl diethylphosphonoacetate (2.57 mL; 11.0 mmol) was added over 2 minutes (min). The mixture was stirred at 0° C. for another 15 min, during which time the grey slurry turned clear within 5 min. 4-[1-(4-Trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (3.04 grams (g); 9.13 mmol) was suspended in THF (20 mL) and then added dropwise via cannula to the solution above. The mixture was then warmed to 25° C., poured into saturated (satd) aqueous (aq) ammonium chloride (NH4Cl; 200 mL), and extracted with 50% ethyl acetate (EtOAc)/hexanes (3×100 mL). The combined organic extracts were then dried over sodium sulfate (Na2SO4) and concentrated in vacuo. The yellow solid residue was dissolved in dichloromethane (CH2Cl2; 10 mL) and rapidly stirred as hexanes (100 mL) was added dropwise over 30 min. The light yellow crystals were collected on a Büchner funnel and dried in vacuo to afford the title compound ((2.93 g, 74%). The filtrate was concentrated in vacuo and purified by chromatography on silica gel (gradient elution with 15% to 40% to 80% EtOAc in hexanes) to afford additional product (0.215 g, 5%): mp 167-169° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.20 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.9 Hz, 2H), 7.63 (d, J=15.8 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.44 (d, J=16.0 Hz, 1H), 1.54 (s, 9H); HRMS-ESI (m/z) [M]+ calcd for C22H20F3N3O3, 431.146; found, 431.1457.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([C:63](O)=O)[CH2:62][CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH:59]5[CH2:60][CH2:61][CH2:62]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)C1CCC1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C2CCC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclobutanecarboxylic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (22.72 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(F)c1

Procedure:
20.9 g (0.1 mol) of 3-fluoro-4-methylbenzenesulphonyl chloride are taken up in 200 ml of carbon tetrachloride and, after addition of 19.6 g (0.11 mol) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide, the mixture is heated under reflux for 5 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography with petroleum ether/toluene (4:1), 50 μm particle size, gives 12.4 g (44% of theory) of the title compound. Rf : 0.42 (petroleum ether/toluene 3:1).
Reaction SMILES: [CH2:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]([CH2:22][C:23]([O:25]C)=[O:24])[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:22][C:23]([OH:25])=[O:24])[C:10](=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH3:20])=[CH:16][CH:17]=2)=[CH:27][CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CC(=O)N(CC(=O)OC)Cc2ccc(CCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1ccc(CC(=O)N(CC(=O)O)Cc2ccc(CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
Methyl 2-(N-(4-propylbenzyl)-2-(4-propylphenyl)acetamido)-acetate (30.0 mg, 0.0786 mmol) was dissolved in 0.5 mL of methanol, and then 100 μL of 20% aqueous sodium hydroxide solution was added, and the reaction mixture was stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 2 mL of ethyl acetate and neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 26.4 mg (0.0718 mmol, 91%) of the desired compound.
Reaction SMILES: N#N.[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4].I[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>CCN(CC)CC.C1COCC1.[Cu]I>[C:3]([NH:7][C:8]1[N:13]=[C:12]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccnc(NC(C)(C)C)n1
Agent: [Cu]I
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1nccc(C#Cc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.4 %

Procedure:
To a mixture of Pd(PPh3)Cl2 (0.4 g) in Et3N (150 mL) and THF (150 mL) under a stream of N2, was added tert-butylamino-4-ethynylpyrimidine (18.6 g, 0.11 mol). After bubbling N2 into the solution for 15 min, 4-iodo-fluorobenzene (23.6 g, 0.11 mol) and CuI (0.22 g) were added sequentially. The mixture was stirred at rt for 2.5 h. The precipitate was filtered and washed with EtOAc. The filtrate was concentrated and the residue was diluted with EtOAc and loaded directly onto a short pad of silica gel. The product was eluted with 10% EtOAc in hexanes to afford the crude product, which was recrystallized from EtOAc/hexanes to give the title compound as a light yellow solid (25 g, 84%). TLC: Rf=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). 1H NMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65 (d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). 13C NMR: 164.19, (162.19, 162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94, 115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C16H16FN3: C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21][CH2:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:18]2[CH2:22][CH2:21][CH2:20][CH:19]=2)[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 2a using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (ESI) 302.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9]3[CH2:17][CH:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[CH:15]4[CH:11]([C:12](=[O:26])[NH:13][C:14]4=[O:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([O:27][CH3:28])[CH:3]=1>O=[Mn]=O>[Br:1][C:2]1[C:7]2[O:8][C:9]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:15]4[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=4[C:10]=3[C:6]=2[CH:5]=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: COc1cc(Br)c2oc3c(c2c1)C1C(=O)NC(=O)C1C(c1ccccc1Cl)C3
Agent: O=[Mn]=O
Product: COc1cc(Br)c2oc3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Yield: 67 %

Procedure:
Aromatisation of (860) prepared as described in example442 with MnO2 using the procedure described in example 79 gave the dibenzofuran (861) as a yellow solid (67%). 1H NMR δ [(CD3)2SO] 8.22 (d, J=2.6 Hz, 1H), 8.14 (s, 1H), 7.62 (m, 2H), 7.48 (m, 3H), 3.98 (s, 3H). MH−:458,457,456,454.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[C:30](=[O:31])[CH2:29][N:28]([S:32]([CH:35]=[CH:36][C:37]2[S:38][C:39]([Cl:42])=[CH:40][CH:41]=2)(=[O:34])=[O:33])C[CH:26]1CO)=O)(C)(C)C>C(Cl)Cl>[Cl:42][C:39]1[S:38][C:37]([CH:36]=[CH:35][S:32]([N:28]2[CH:2]([CH2:3][OH:5])[CH2:26][N:25]([CH2:24][C:16]3[NH:15][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH:17]=3)[C:30](=[O:31])[CH2:29]2)(=[O:34])=[O:33])=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2C(=O)CN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2CO)cc2cnccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)C(CO)CN1Cc1cc2cnccc2[nH]1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1.8 mL) is added to a solution of 2-{4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-2-(±)-hydroxymethyl-6-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.04 g) in CH2Cl2 (4.2 mL) at RT. The reaction mixture is stirred for 4 h then concentrated in vacuo. The title compound is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN and lyophilizing the appropriate product fractions. 1H NMR (DMSO-d6, 300 MHz) δ9.10 (s, 1H), 8.46 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H) 7.43 (d, 1H), 7.14 (d, 1H), 7.01 (d, 1H), 6.94 (s, 1H), 5.12 (bs, 1H), 4.80 (AB, 2H), 3.98 (d, 2H0, 3.90 (m, 1H), 3.40-3.50 (m, 4H). APCI MS, [M+H]+=467, 469.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].IC>C1COCC1>[CH3:1][C:16]1[C:15]([F:21])=[C:14]([Br:13])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)NC(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of THF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of THF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.