Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([N-:17][CH2:18][CH3:19])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[N+](C1C=CC([O:32][C:33](=O)[C@H:34]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:39]([O:38][C:36]([NH:35][C@H:34]([C:33]([NH:2][C@H:3]([C:11]([N:13]1[CH2:22][CH2:21][CH2:20][C@H:14]1[C:15]([N-:17][CH2:18][CH3:19])=[O:16])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:9])[NH2:10])=[O:32])[CH2:46][CH:47]([CH3:48])[CH3:49])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N
Agent: Cl
Solvent: CN(C)C=O
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A solution of 18.6 g. of L-arginyl-L-prolyl-N-ethylamide hydrochloride and 7.2 g. of Nα -benzyloxycarbonyl-L-leucine p-nitrophenylester in 30 ml. of dimethylformamide is allowed to stand for four days, warmed to 50° C. for a half hour and evaporated at reduced pressure and 40° C. to yield an oil. A solid product is obtained by chromatography over silica gel, eluting with chloroform with increasing percent of methanol. Fraction selection is made on the basis of analytical thin layer chromatography and the product, Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-N-ethylamide hydrochloride, obtained solid by precipitating from methanol with ethyl acetate and then by dropping a methanol solution into ethyl ether. The solid is dried at 40° C. and reduced pressure; [α]D25 -68.4° (c 1, methanol).
Reaction SMILES: [CH:1]1([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:3][CH2:2]1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[Li+].CC([N-]C(C)C)C.[NH4+].[Cl-]>C1COCC1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][C:1]1([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Reaction time: 5 h
Yield: 36.6 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of tert-butyl cyclopropanecarboxylate (80.05 g, 0.507 mol) and 1,4-dibromobutane (219.3 g, 1.01 mol) in dry THF (800 mL) was added drop wise to a solution of LDA (2 M in THF/heptane/ethylbenzene, 380 mL, 0.76 mol) in 1.5 h. Stirring was continued for 5 h, during which the reaction mixture was allowed to slowly reach rt. After that, the reaction mixture was poured into saturated aqueous NH4Cl (1 L). The organic layer was separated and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×200 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2×400 mL) and brine (400 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation under reduced pressure to give tert-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (51.4 g, 94% pure by GC, 34%) as a slightly yellow oil. bp: T=93-96° C. (p=0.075-0.087 Torr), 1H NMR (CDCl3): δ=3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1 Hz, 2H), 1.65-1.46 (m, 4H), 1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H), 0.60 (q, J=3.5 Hz, 2H). 13C NMR (CDCl3): δ=174.0, 79.8, 33.6, 33.2, 32.8, 27.9 (3×), 26.3, 23.9, 15.1 (2×). HRMS calcd for C12H21BrO2 (MH+): 277.0803. found: 277.0807.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br.C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-diisopropylaniline (2.0 mL, 11 mmol) in methanol (80 mL) was treated dropwise with bromine (543 μL, 10.6 mmol). The solution was stirred at room temperature for 15 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to an orange liquid. Kugelrohr distillation (110° C. @ 0.06 Torr) afforded a colorless liquid (2.22 g 79%): 1H NMR (400 MHz) δ1.25 (d, J=6.4 Hz, 12H), 2.88 (m, 2H), 3.70 (brs, 2H), 7.11 (s, 2H); 13C NMR δ22.1, 27.9, 111.0, 125.6, 134.5, 139.3; Anal calcd for C12H19BrN: C, 56.26; H, 7.08; Br, 31.19; Found, C, 56.24; H, 7.07; Br, 30.98.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:22][CH2:23][C:24]1[CH:45]=[CH:44][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:29])=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([CH2:18][NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:29])=[CH:44][CH:45]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(C=O)cnc2n1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CNCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 3.0 g (10.9 mmol) of 2-pivaloylamino-4-hydroxy-6-formylpyrido[2,3-d]pyrimidine, 4.47 g of diethyl N-(p-aminomethylbenzoyl)-L-glutamate hydrochloride (12.25 mmol), and 1.0 g (12.25 mmol) of sodium acetate in 70 mL of glacial acetic was stirred at 25° C. for 18 hours. To this solution was added 0.42 g (0.54 mL, 3.65 mmol) of borane-triethylamine complex. This mixture was stirred at 25° C. for 2 hours and the solvent then removed under reduced pressure. The residue was taken up in methylene chloride (200 mL), extracted once with water, and then twice with a saturated aqueous solution of sodium bicarbonate. The aqueous layers were combined and back extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give 3.4 g (52% yield) of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-4-aminomethylbenzoyl]-glutamate; mp 149°-151° C.; 1H NMR (Me2Sod6) delta 1.10-1.17 (m, 6H), 1.22 (s, 9H), 1.9-2.15 (m, 2H), 2.40 (t, 2H, J=7.4 Hz), 3.75 (s, 2H), 3.77 (s, 2H), 3.97-4.10 (m, 4H), 4.36-4.44 (m, 1H), 7.41-7.44 (m, 2H, AA'BB'), 7.80-7.83 (m, 2H, AA'BB'), 8.345 (d, 1H, J=2.09 Hz), 8.65 (d, 1H, J=7.38 Hz), 8.76 (d, 1H, J=2.09 Hz). Anal. Calcd for C30H38N6O7 : C, 60.59; H, 6.44; N, 14.13. Found: C, 60.75; H, 6.68; N, 14.33.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C(OOC(C)(C)C)(C)(C)C>O.C(O)(=O)C>[C:10]([C:5]1[N:4]=[CH:3][C:2]([C:7]([OH:9])=[O:8])=[N:1][CH:6]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cnccn1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc(C(=O)c2ccccc2)cn1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a stirred, cooled (0° C.) solution of 2-pyrazine carboxylic acid (3.0 g, 24.2 mmol) and benzaldehyde (7.4 mL; 73 mmol) in a 50% aqueous solution of sulfuric acid (40 mL) and 25 mL of acetic acid was added FeSO4 7 H2O (20.3 g, 73 mmol dissolved in 50 mL of water) and t-butyl peroxide (9.2 mL; 73 mmol) simultaneously. After stirring for 1 hour, the reaction was treated with 200 mL of water. A precipitate formed which was filtered and washed with methylene chloride (3×100 mL) to yield a tan solid (36% yield).
Reaction SMILES: [C:1]([C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:2][CH2:1][C:3]12[CH2:10][CH2:9][N:6]([CH2:7][CH2:8]1)[CH2:5][CH2:4]2
Reactant: N#CC12CCN(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC12CCN(CC1)CC2
Yield: 91 %

Procedure:
To a solution of 4-cyanoquinuclidine (500 mg, 3.64 mmol, prepared by the method described in EP-269,991-A) in dry THF (5 mL) was added a 1M solution of lithium aluminum hydride (8 mL, 8.0 mmol). The reaction was heated under reflux for 2.5 hours, then subjected to a Fieser workup to yield 4-aminomethylquinuclidine (460 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:23](=[O:25])[CH3:24])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
3.36 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.87 g of acetyl chloride is added dropwise thereto under ice-cooling. The mixture is stirred at room temperature for one hour. Then, the mixture is diluted by addition of chloroform. The diluted mixture is washed with 10% hydrochloric acid and water, and then evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby 3.37 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as needles.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[S:18]1(=[O:30])(=[O:29])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=[C:2]([N:21]2[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:18](=[O:30])(=[O:29])[CH2:19][CH2:20]2)[CH:11]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: O=S1(=O)CCNCc2ccccc21
Solvent: CCCCO
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A mixture of 2,4-dichloro-6-(trifluoromethoxy)quinoline (250 mg, 0.89 mmol), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (210 mg, 1.06 mmol) and n-butanol (2 mL) was heated with stirring in a 5 mL of microwave process vial for 3 hours at 150° C. under microwave irradiation. The mixture was filtered. The formed solid was collected by filtration and washed with 10 mL of mixture solution of petroleum ether and ethyl acetate (V/V=10/1) to afford 0.3 g of the product (yield was 77%).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:13][C@H:12]1[CH3:28])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:28][C@@H:12]1[CH2:13][N:14]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15](=[O:18])[CH2:16][CH2:17][NH:11]1
Reactant: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(CCCN2CCCCC2)C(=O)CCN1
Yield: 78.9 %

Procedure:
A solution of (R)-2-methyl-5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid benzyl ester 1.0 g (3 mmol) in MeOH (20 ml) was stirred with 10% palladium on charcoal under an atmosphere of hydrogen for 1 h. Filtration and concentrated afforded the title compound 0.6 g (83%) as a colorless oil. MS: 254.2 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:36]=[C:35]([F:37])[C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[C:23]([O:33][CH3:34])=[CH:22][N:21]=3)=[N:12]2)=[C:8]([F:38])[CH:7]=1)=[CH2:5])C.O.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.O>[F:37][C:35]1[CH:36]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[C:8]([F:38])[C:9]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:23]([O:33][CH3:34])=[CH:22][N:21]=2)=[N:12]1
Reactant: C=C(OCC)c1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1cnc(-c2nn(Cc3c(F)cc(C(C)=O)cc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
119 mg of 2-{1-[4-(1-ethoxyethenyl)-2,6-difluorobenzyl]-1H-indazol-3-yl}-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (0.231 mmol, 1 eq.) and 66 mg of 4-methylbenzenesulfonic acid hydrate (1:1) (0.347 mmol, 1.5 eq.) were dissolved in 2.4 ml of ethanol and 0.6 ml of water. The mixture was stirred for one hour at 80° C. bath temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC purification to yield 26 mg (0.05 mmol, 22.7%) of the analytically pure target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1>O.CN(C)C=O.C(#N)C>[F:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccc2ccc(-c3cccc(F)c3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(-c3cccc(F)c3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 54.3 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.8 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(3-fluorophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (3.5 g; m.p. approximately 195° C.) is dissolved in a boiling mixture of dimethylformamide (20 cc) and acetonitrile (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Fluorophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (2.3 g), m.p. 208° C., is obtained.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([OH:72])=O)[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44].[NH2:73][C:74]1[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=1>C1COCC1>[CH2:43]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][N:55]([C:57]([N:59]3[CH2:60][CH2:61][O:62][CH2:63][CH2:64]3)=[O:58])[CH2:54][CH:53]([C:65]3[S:66][CH:67]=[C:68]([C:70]([NH:73][C:74]4[CH:79]=[CH:78][N:77]=[CH:76][CH:75]=4)=[O:72])[N:69]=3)[CH2:52]2)=[CH:47][CH:46]=1)[CH3:44]
Reactant: CCc1ccc(C2CC(c3nc(C(=O)O)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: Nc1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C2CC(c3nc(C(=O)Nc4ccncc4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.9 %

Procedure:
145 mg (0.279 mmol) of PYBOP and 169 mg (1.304 mmol) of N,N-diisopropylethylamine were added to a mixture of 80 mg (0.186 mmol) of the compound from Example 143A in 0.5 ml of THF. The reaction mixture was stirred at room temperature for 40 minutes. 21 mg (0.223 mmol) of 4-aminopyridine were then added, and stirring of the mixture at RT was continued overnight. For work-up, the solvent was evaporated and the residue was taken up in ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Diastereomer separation of the cis/trans isomer mixture according to Method 12C gave 14 mg of the title compound (cis isomer) and 23 mg of the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O.[I-].[K+]>[F:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:10][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]=1[NH2:9]
Reactant: BrC1CCCC1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (1.02 g, 6.28 mmol), potassium carbonate (1.72 g, 12.4 mmol), potassium iodide (4.0 mg, 0.024 mmol) and N,N-dimethylformamide (5 ml) as a solvent were placed in a two-necked round bottom flask (25 cc) and stirred at 80° C. for one hour. Then, cyclopentyl bromide (1.00 g, 6.71 mmol) was added thereto, followed by stirring at 80° C. for further 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (20 ml) was added thereto, and the mixuture was extracted with toluene (20 ml×3 portions). The organic layers were combined, washed with water (10 ml) and a saturated aqueous sodium chloride solution (10 ml) and dried over magnesium sulfate. After removing the drying agent, the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.43 g, 6.23 mmol, 99.0% yield). Boiling point: 143°-145° C./1.5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:15][O:14][N:13]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH:29](N(CC)C(C)C)(C)C.FC(F)(F)S(OC)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[N:15][O:14][N:13]=2)[S:11][CH3:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)[Si](OCc1nonc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CSC(=Nc1ccc(F)c(Cl)c1)c1nonc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carbothioamide (3.3 g, 7.4 mmol) in anhydrous DCM (148 mL) under N2 was added N,N-diisopropylethylamine (DIPEA) (1.4 mL). Methyl trifluoromethanesulfonate (900 μL, 8.2 mmol) was then added dropwise and stirred for 2 hrs. The reaction was stripped to dryness and purified on a 330 g silica ISCO cartridge, eluting with 25% EtOAc/hexane to yield the desired product as a yellow oil that solidified upon standing. (2.97 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ: 11.32 (s, 1H), 8.01 (dd, J=7.1, 2.7 Hz, 1H), 7.45 (dd, J=9.5, 9.5 Hz, 1H), 7.67 (m, 1H), 4.4 (s=3H), 5.13 (s, 2H), 1.1 (m, 3H); 0.99 (m, 18H); MF═C20H29ClFN3O2SSi; LCMS calculated for C20H30ClFN3O2SSi(M+H)+: m/z=458.150.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1oc2ccccc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1oc2ccccc2c1CBr
Temperature: 25 °C
Yield: 108.7 %

Procedure:
A solution of methyl 3-methylbenzofuran-2-carboxylate (1.0 g, 5.3 mmol), N-bromosuccinimide (0.95 g, 5.3 mmol) and 2,2′-azobisisobutyronitrile (87 mg, 0.53 mmol) was heated to reflux in CCl4 (40 ml) for 3 h, then cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried over magnesium sulfate and concentrated to provide crude methyl 3-bromomethylbenzofuran-2-carboxylate (1.55 g) as a yellowish solid, which was used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Sn](CCCC)(CCCC)CCCC.[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22].O>C1(C)C(C)=CC=CC=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>[CH2:20]([O:24][C:25]([N:27]([C:44]1[C:49]([O:50][CH3:51])=[N:48][C:47]([CH3:52])=[CH:46][N:45]=1)[S:28]([C:31]1[C:32]([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:39][CH:38]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(-c2ccccn2)cc1
Temperature: 125 °C
Yield: 31.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (45 mg) was added to a deoxygenated solution of (2-pyridyl)tributylstannane (294 mg) and N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-iodophenyl)pyridine-3-sulphonamide(465 mg) in xylene (15 ml). The mixture was stirred and heated under argon at 125° C. for 17 hours and then allowed to cool to ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-65% ethyl acetate/hexane to give N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-(2-pyridyl)phenyl)pyridine-3-sulphonamide (135 mg) as a foam; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.5 (dd, 2H), 7.6-7.8 (m, 4H), 7.9 (s, 1H), 8.1 (dd, 2H), 8.7 (dd, 1H), 8.9 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve ESP): 534 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16](OCC)=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])[C:8](=[O:15])[C:9]2([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)c(Cl)c2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)c(Cl)c2C(C)(C)C1=O
Yield: 97.9 %

Procedure:
A solution of ethyl 7,8-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.200 g, 0.456 mmol), glycine tert-butyl ester hydrochloride (0.0993 g, 0.592 mmol), and DIPEA (0.159 mL, 0.911 mmol) in 1,4-dioxane (5 mL) was heated to 120° C. in a 15 mL sealed vessel for 3 hours. The reaction was then diluted with deionized water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were washed with deionized water (50 mL) and then with brine (50 mL). The organic layer was then dried over MgSO4, concentrated, and dried in vacuo to give 0.338 g of the crude product. The crude product was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give the title compound (0.185 g). MS m/e 412 (M−H)−.