Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[NH:8][C:7](=[O:31])[C:6]=2[CH:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[C:9](=[N:10][CH:11]=[CH:12][C:13]=4[NH:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[NH:8][C:7](=[O:31])[C:6]=3[CH:32]=2)[CH2:70][CH2:69]1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(Cl)ccc4c23)cc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
275 (44 mg, 0.10 mmol), Pd(OAc)2 (6 mg 0.02 mmol), X-Phos (19 mg, 0.04 mmol), and 1-methylpiperazine (0.02 mL, 0.20 mmol) were suspended in dioxane (3 mL), and stirred overnight at 100° C. for overnight. The crude reaction mixture purified via HP-LC to provide 276. LC-MS (M+H=505, obsd.=505).
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[CH2:17]([C:24]#[N:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C.CO.CCOC(C)=O>[C:18]1([CH:17]([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)[C:5]3=[CH:4][CH:3]=2)[C:24]#[N:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCc1ccccc1
Reactant: Fc1ccc2c(-c3ccncc3)n[nH]c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC(c1ccccc1)c1ccc2c(-c3ccncc3)n[nH]c2n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of Example 227C (0.96 g, 4.48 mmol) in DMF (20 mL) at −35° C. was added benzyl cyanide (1.55 mL, 13.4 mmol) and then NaH (0.57 g of 95% NaH, 22.4 mmol). The resulting dark red mixture was stirred 15 min while being slowly warmed to ˜−20° C. At this time most of the bubbling had stopped and the reaction mixture was then quickly warmed to room temperature and then to 100° C. overnight. The reaction mixture was cooled to room temperature and saturated aqueous NH4Cl was added. The mixture was extracted with EtOAc and the organic extracts washed twice with H2O and once with brine. Silica gel was added and the volatiles removed on a rotary evaporator. Flash chromatography (60-80-100% EtOAc-3% MeOH/EtOAc) gave 1.14 g (82%) of as an orange solid. Rf=0.40 (5% MeOH/EtOAc); MS m/z 312 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 6.17 (s, 1 H) 7.40 (m, 4 H) 7.52 (m, 2 H) 8.00 (m, 2 H) 8.70 (m, 2 H) 8.74 (d, J=8.48 Hz, 1 H) 14.36 (s, 1 H); Anal Calcd for C19H13N5: C, 73.30; H, 4.21; N, 22.49. Found: C, 73.09; H, 4.10; N, 22.58.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][N:10]([CH2:15][C:16]([OH:18])=O)[CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[CH2:19][N:20]([CH2:25][C:26]([OH:28])=O)[CH2:21][C:22]([OH:24])=[O:23]>N1C=CC=CC=1>[C:2]([O:1][C:2]1[C:3]([CH2:19][N:20]2[CH2:25][C:26](=[O:28])[O:23][C:22](=[O:24])[CH2:21]2)=[CH:4][CH:5]=[C:6]([CH2:9][N:10]2[CH2:11][C:12](=[O:14])[O:13][C:16](=[O:18])[CH2:15]2)[C:7]=1[O:8][C:7](=[O:8])[CH3:6])(=[O:1])[CH3:3]
Reactant: O=C(O)CN(CC(=O)O)Cc1ccc(CN(CC(=O)O)CC(=O)O)c(O)c1O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(CN2CC(=O)OC(=O)C2)ccc(CN2CC(=O)OC(=O)C2)c1OC(C)=O
Temperature: 70 °C
Yield: 99.9 %

Procedure:
2,2′,2″,2′″-(2,3-dihydroxy-1,4-phenylene)bis(methylene)bis(azanetriyl)tetraacetic acid (5 g, 12.5 mmol) was added to acetyl anhydride (10 ml) followed by pyridine (3 ml). The reaction was heated at 70° C. for 5 h. The excess anhydride and pyridine were removed under reduced pressure and the residue was recrystallized in acetyl anhydride. 2.8 g of 3,6-bis((2,6-dioxomorpholino)methyl)-1,2-phenylene diacetate was obtained as white solid (yield: 51%). 3,6-bis((2,6-dioxomorpholino)methyl)-1,2-phenylene diacetate (2.24 g, 10 mmol) was added to the solution of ammonia in methanol (7N, 20 ml). The reaction was stirred at room temperature for 1 hour. After removing methanol, the residue was recrystallized in methanol and acetone. 3.5 g of product was obtained as white solid (yield: 88%).
Reaction SMILES: CN(C)[C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23].[OH-].[Na+].CCCC[OH:32].Cl>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]2[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[C:5]([CH2:4][C:3]([OH:24])=[O:32])[CH:10]=1)[CH3:12]
Reactant: CCCCO
Reactant: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
N,N-Dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (26 g, 0.073 mol) and 6N NaOH (150 ml) are stirred as a two phase solution with n-BuOH (150 ml) at reflux temperature for 14 hours. After cooling to room temperature, the reaction is poured over ice (500 ml). Toluene (500 ml) is added and the mixture transferred to a separatory funnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. The organic layer is separated and the aqueous phase re-extracted with toluene (250 ml). The combined organic layers are dried (MgSO4) and concentrated under high vacuum (35-50 mbar) on a rotovap taking care not to warm above 50°. Small white needles are obtained by crystallization of the residue from hexane, m.p. 164-166°. Recrystallization from cyclohexane gives 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid a white solid, m.p. 165-169°.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53]Cl)=[O:51])(=[O:44])=[O:43]>C(#N)C>[NH2:41][S:42]([C:45]1[C:46]([Cl:63])=[CH:47][C:48]([NH:56][CH2:57][C:58]2[O:59][CH:60]=[CH:61][CH:62]=2)=[C:49]([CH:55]=1)[C:50]([O:52][CH2:53][N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:51])(=[O:43])=[O:44]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (720). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>CC(C)=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
A stirred solution of methyl 3-methyl-1H-indole-6-carboxylate (0.5 g, Reference Example 30) in acetone (35 ml) was treated with 1-bromo-3-phenylpropane (0.577 g) and sodium hydroxide (0.116 g). The mixture was stirred at room temperature for 12 hours then poured into water (35 ml) and then extracted three times with ethyl acetate (50 ml). The combined extracts were washed with dilute hydrochloric acid (50 ml, 1N) then with saturated sodium bicarbonate solution (50 ml), then dried over magnesium sulphate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (50:1, v/v) to yield the title compound (0.58 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](O)=[O:11])=[C:5]([CH3:16])[N:4]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)[N:3]=1.C(=O)(O)[O-].[NH4+].[N:44]1C=CC=CC=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:44])=[O:11])=[C:5]([CH3:16])[N:4]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][C:26]([NH:28][S:29]([C:32]3[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=3)(=[O:31])=[O:30])=[O:27])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(=O)O)c4)c3C)cc2)cc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4cccc(C(N)=O)c4)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 3-[3,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-pyrazol-4-yl]benzoic acid (step 6, 270 mg, 0.52 mmol) in N,N-dimethylformamide (1 mL) was added ammonium bicarbonate (45 mg, 0.57 mmol), pyridine (0.35 mL) and a solution of di-t-butyldicarbonate (120 mg, 0.57 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 1 day. After dilution with water (10 mL), extraction with ethyl acetate (30 mL×3) was followed. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure. The crude products was purified by TLC with dichloromethane/methanol (10:1) to afford 46 mg (10%) of the title compound as white solids: MS (ESI) m/z 532 [M+H]+, 530 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14](OC)=[O:15])[C:9]2=[O:18])[CH:5]=[CH:4]1.[NH3:19]>CO>[OH:1][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:19])=[O:15])[C:9]2=[O:18])[CH:5]=[CH:4]1
Reactant: N
Reactant: COC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Solvent: CO
Product: NC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Reaction time: 13 h

Procedure:
In 1 ml of methanol was dissolved 75 mg of methyl 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. At room temperature, 25% aqueous solution of ammonia was added and stirred for 13 hours, and then the solvent was removed under reduced pressure. Isopropanol was added to the residue, and the solid product was collected by filtration to obtain 20 mg of 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a white-colored solid product.
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[C:21]([CH2:31][CH2:32][CH2:33][CH3:34])([CH3:30])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[CH2:31]([C:21]1([CH3:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]([OH:29])=[C:19]([C:14]2[NH:13][C:12]3[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:18])(=[O:17])[N:15]=2)[C:20]1=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.6 %

Procedure:
A solution of Example 27G (1.00 g, 1.94 mmol) in tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (0.100 g, 10% weight) and stirred at 25° C. under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (0.824 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.54 (m, 1 H) 0.69 (m, 3 H) 0.86 (m, 1 H) 1.10 (m, 2 H) 1.56 (m, 3 H) 2.14 (m, 2 H) 7.18 (m, 2 H) 7.56 (m, 2 H) 7.76 (m, 2 H) 8.16 (m, 1 H) 10.40 (m, 1 H) 13.68 (m, 1 H). MS (ESI−) m/z 425 (M−H)−.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].N>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccccc1Cl
Agent: N
Product: Clc1ccccc1-c1cc(-c2cccnc2)no1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-2-ethynylbenzene (Apollo, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43-7.56 (m, 3H), 7.56-7.70 (m, 2H), 7.98 (dd, J=5.9, 3.6 Hz, 1H), 8.39 (dt, J=7.9, 2.0 Hz, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 9.12 (d, J=2.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C1(B(O)O)C=CC=CC=1.[CH3:22][C:23]([CH3:27])=[CH:24][CH:25]=O.C1(O)C=CC=CC=1>C(O)(=O)C.C1(C)C=CC=C(C)C=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[O:11][C:23]([CH3:27])([CH3:22])[CH:24]=[CH:25]2
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(C)=CC=O
Agent: OB(O)c1ccccc1
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Solvent: Cc1cccc(C)c1
Product: COC(=O)Cc1ccc2c(c1)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
175.6 g methyl-4-hydroxyphenylacetate and 128.9 g phenylboronic acid were added to 3.5 l m-xylene. 88.9 g 3-methylbut-2-enal, and 130 ml of glacial acetic acid were added to this mixture. The mixture was heated to 140° C. in a Dean-Stark apparatus under a nitrogen atmosphere until approximately 70% of the phenol had reacted (approximately 48-72 hours). Then the reaction mixture was allowed to cool to room temperature, the mixture was filtered, and the solvent was evaporated at reduced pressure. The remaining residue was dissolved in a 1:1 mixture of tetrahydrofuran (THF) and a 25%-strength aqueous ammonia solution (v/v) and stirred for 2 hours. The THF was largely evaporated off at reduced pressure and ethyl acetate was added. The organic phase was separated, washed in succession with an aqueous 1 N NaOH and a saturated aqueous common salt solution and finally dried over sodium sulfate. The solvent was largely evaporated at reduced pressure, and the remaining residue was chromatographed on silica gel (mobile phase: n-hexane/EA 15:1 to 10:1 v/v). Drying of the product fractions in an oil pump vacuum yielded 106 g methyl-(2,2-dimethyl-2H-chromen-6-yl)acetate as pale yellow oil, which was used without further characterization for the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][C:4]=2[F:16])=[CH:9][CH:10]=1)#[N:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)cc1F
Reaction time: 16 h
Yield: 68.2 %

Procedure:
5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.20 g, 0.93 mmol) was dissolved in pyridine (2.0 mL). Methanesulfonyl chloride (0.07 mL, 0.9 mmol) was added and the mixture was stirred for 16 hours, followed by the addition of water. The mixture was diluted with ethyl acetate and then was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.18 g of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorophenyl]methanesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH2:14]([N:16]([CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH3:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:23][CH3:24])[CH2:14][CH3:15]
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Reactant: CCN(CC)CCCCCN
Solvent: C1CCOC1
Product: CCN(CC)CCCCCNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinoyl chloride in about 170 mL of THF are treated by dropwise addition with 0.026 moles of 5-diethylaminopentylamine in 25 mL of THF, stirred for several hours at ambient temperature, filtered, concentrated by rotary evaporation and vacuum distilled to yield about 90% pure P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(5-diethylamino-1-pentyl)-phosphinic amide.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([F:13])[C:7]=1[F:12]
Reactant: [N-]=[N+]=NCc1ccc(Br)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Br)c(F)c1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (164 mg, 0.60 mmol) in THF (3 mL) were added polymer-supported Ph3P (2.0 eq.) and water (1 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.42 min; [M+CH3CN+H]+=263.15.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[NH2:5])[CH3:2].C([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=O)(=O)C.O=P(Cl)(Cl)Cl>>[CH2:1]([C:3]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[NH:5][C:17]1[NH:18][CH2:19][CH2:20][N:16]=1)[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1ccc(C)c(CC)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccc(C)c(CC)c1NC1=NCCN1

Procedure:
2,6-Diethyl-3-methyl aniline is reacted with N-acetyl-2-imidazolidinone in the presence of POCl3 to produce the imidazoline. This intermediate is treated with sodium hydroxide and water to remove the acetyl group and yield the name compound (VI).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3ccc(OC)cc3c2)c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (2.20 g, 7.18 mmol) with 3-methoxyphenylboronic acid (1.20 g, 7.90 (mmol) according to method A above to yield a white solid: mp 58-59° C.;1H NMR (CDCl3): δ 3.89 (3H, s), 3.93 (3H, s), 6.91-6.94 (1H, m), 7.15 (1H, dd, J=2.42 Hz, J=8.83 Hz), 7.19H, d, J=2.27 Hz), 7.23-7.25 (1H, m), 7.28-7.31 (1H, m), 7.37-7.42 (1H, m), 7.59 (1H, dd, J=1.56 Hz, J=8.46 Hz), 7.75 (1H, d, J=8.84 Hz), 7.83 (1H, d, J=8.45 Hz), 7.94 (s1H, s); MS (ESI) m/z265 (M+H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14]>CN(C=O)C.[Cu]I>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c2ccccc12
Temperature: 120 °C

Procedure:
To a stirred solution of 1-amino-4-bromonaphthalene (5 g, 22.5 mmol) in DMF (30 mL) was added CuCN (10.1 g, 112.5 mmol), CuI (8.7 g, 45 mmol) and the mixture was heated to 120° C. in a sealed tube for 24 h. After completion of the reaction (TLC), the mixture was filtered and the filtrate was evaporated to give the crude product which was purified by column chromatography over silica gel (EtOAc in Hexanes, 5%) to furnish the desired compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:44]1[C:48]2[CH:49]=[CH:50][C:51](B(O)O)=[CH:52][C:47]=2[CH2:46][CH2:45]1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>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.C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:51]4[CH:50]=[CH:49][C:48]5[O:44][CH2:45][CH2:46][C:47]=5[CH:52]=4)[CH:18]=[C:13]3[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(-c3ccc4c(c3)CCO4)cnc21
Yield: 88.7 %

Procedure:
A mixture of 47 (200 mg, 0.308 mmol), EtOH (1.5 mL), toluene (1.5 mL), 2,3-dihydrobenzofuran-5-boronic acid (50 mg, 0.308 mmol), 1M aq. Na2CO3 (0.48 mL, 0.48 mmol), LiCl (25 mg, 0.619 mmol) and PdCl2(PPh3)2 (15 mg, 0.021 mmol) was refluxed for 1 h 40 min. The reaction mixture was concentrated to afford a pale yellow solid, which was purified by silicagel chromatography using 30% ethyl acetate in hexane as eluent (gradient elution) to give the product 48 (187 mg, 86%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 3.27 (t, J=17.2, 8.6 Hz, 2H), 4.61 (t, J=17.4, 8.7 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 7.19-7.23 (m, 7H), 7.33-7.36 (m, 10H), 7.45 (t, J=15.3, 7.26 Hz, 2H), 7.54-7.58 (m, 1H), 7.65 (s, 1H), 7.74 (s, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.97 (s, 1H), 8.19-8.21 (m, 2H), 8.60 (d, J=2.1 Hz, 1H).