Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=O)=[CH:17][N:16]=1.Cl.[C:26](N)(=[NH:28])[CH3:27]>CN(C=O)C.C(OC(=O)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[NH:28][C:26]([CH3:27])=[N:22][N:21]=2)=[CH:17][N:16]=1
Reactant: CC(=N)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)[nH]1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid hydrazide (300 mg, 0.6 mmol) and acetamidine hydrochloride (87 mg, 0.9 mmol) in DMF (6 mL) was heated at 120° C. for 2 h. A second portion of acetamidine hydrochloride (174 mg, 1.8 mmol) was added. After 8 h the mixture was cooled to room temperature and diluted with ethylacetate (40 mL). The mixture was filtered and the filtrates collected and washed with water (3×10 mL) and brine (10 mL) then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, 0-5% dichloromethane:methanol=100:0 to 95:5) followed by purification by HPLC (acetonitrile:water=2:8) gave the title compound (42 mg, 20%) as a white solid. MS: m/e=348.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[C:25]([O:29][C:30](=[O:37])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:37])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23]
Reactant: COC(=O)CC1Cc2ccc(O)cc2N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)NCCCCBr
Product: COC(=O)CC1Cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared using the conditions of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of [7-(3-tert-butoxycarbonylaminopropoxy)-1-benzyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].O1CCCC1.[Cl:10][C:11]1[C:12]([NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]Cl)=[CH:24][C:23]=2[CH3:31])=[N:13][CH:14]=[N:15][C:16]=1[CH3:17]>O>[Cl:10][C:11]1[C:12]([NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:4][CH2:2][CH3:3])=[CH:24][C:23]=2[CH3:31])=[N:13][CH:14]=[N:15][C:16]=1[CH3:17]
Reactant: Cc1cc(CCCl)ccc1OCCNc1ncnc(C)c1Cl
Reactant: CCS
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCSCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1

Procedure:
0.5 g of the sodium salt of ethyl mercaptan was added to 30 ml of anhydrous tetrahydrofuran. 1.7 g of 5-chloro-4-{2-[4-(2-chloroethyl)-2-methylphenoxy]ethylamino]-6-methylpyrimidine was added to the mixture, which was then heated for 3 hours whilst stirring. At the end of this time, water was added to the mixture, and the oily product which separated was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under reduced pressure. The oily product obtained was subjected to column chromatography (Wakogen C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate), to afford 1.2 g of the title compound as a pale yellow oily liquid, n20.8 =1.5478.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN1CCN(c2ncc(N)cn2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ncc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
216 mg (0.98 mmol) of 2-(4-Allylpiperazin-1-yl)pyrimidin-5-ylamine from Example 16.2 and 215 mg (0.98 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, after which 0.4 ml (3.0 mmol) of triethylamine was added dropwise and the mixture was stirred at room temperature overnight. After the solvent had been evaporated down to dryness, water was added to the resulting residue. The aqueous reaction mixture was made acid using 1N aqueous hydrochloric acid and extracted twice with diethyl ether. The aqueous phase was made alkaline to pH 9-10, using a 1N solution of sodium hydroxide and then extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate. The residue which was obtained after filtering off the drying agent and evaporating the solvent down to dryness was thoroughly stirred with a mixture composed of heptane and diethyl ether, filtered off with suction and dried, with 71 mg (18% of theory) of the title compound being obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][C:16]1[N:47]=[C:19]2[N:20]([CH:43]([CH3:46])[CH2:44][CH3:45])[C:21](=[O:42])[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]2[N:17]=1>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][C:16]1[N:47]=[C:19]2[N:20]([CH:43]([CH3:46])[CH2:44][CH3:45])[C:21](=[O:42])[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]2[N:17]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogen carbonate (0.73 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-(methoxymethyl)-4-(1-methylpropyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.072 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.084 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 49%).
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH3:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[Pd]>[ClH:1].[ClH:1].[OH:21][CH2:20][CH2:19][CH2:18][N:16]([CH3:17])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CN(CCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: CN(CCCO)C1CCNCC1
Reaction time: 2 h
Yield: 183.4 %

Procedure:
42.8 g of 1-benzyl-4-[(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are dissolved in 450 ml of methaol, combined with 5 g of 5% palladium/charcoal and hydrogenated at about 50° C. with hydrogen at a pressure of 4-5 bar. The catalyst is filtered off, the methanol is distilled off and the residue is stirred into acetone. Ether is added, the mixture is left to stand for about two hours and then the crystals are suction filtered. 28.7 g of 4-[(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are obtained as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>COCCOC.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Sc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of 2,5-dibromopyridine (12.0 g) and thiophenol (5.46 mL) in DME (50 mL) was added sodium tert-butoxide (5.35 g) at room temperature and the mixture was stirred at 100° C. for 15 h. The reaction mixture was poured into brine, extracted with EtOAc, washed with brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 30:1) to give 5-bromo-2-(phenylsulfanyl)pyridine (13.69 g) as an oil.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[CH:32][C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=4[F:47])[C:38]([CH3:48])=[C:37]([OH:49])[C:36]3=[O:50])=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:28]1[C:29]2[CH:34]=[C:33]([N:35]3[CH:39]([C:40]4[CH:45]=[C:44]([Br:46])[CH:43]=[CH:42][C:41]=4[F:47])[C:38]([CH3:48])=[C:37]([O:49][CH3:3])[C:36]3=[O:50])[CH:32]=[CH:31][C:30]=2[N:26]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(Br)ccc1F
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: OCCO
Solvent: CO
Product: COC1=C(C)C(c2cc(Br)ccc2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 g, 267.8 mmol in water), diazald (20 g, 93.37 mmol, 5 eq), ethylene glycol/Et2O (2/1 v/v, 140 mL) 1-(1H-benzo[d]imidazol-5-yl)-5-(5-bromo-2-fluorophenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (2 g, 5.57 mmol, 1 eq) and MeOH (50 mL); yield: 1.3 g (57.2%); MS m/z: 416.3 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.76 (s, 3H), 3.95 (s, 3H), 6.00 (s, 1H), 7.13 (m, 1.3H), 7.25-7.27 (m, 1.6 H), 7.47-7.49 (m, 1.6H), 7.47-7.52 (m, 1.5 H), 7.65 (m, 1.5H), 8.15 (s, 1H); HPLC (METHOD [A]): rt 12.55 min (98.5%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[S:27]([CH3:26])(=[O:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CCCCC(Nc1ccc(F)cc1)c1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCC(c1cccnc1)N(c1ccc(F)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 5.5 g. portion of 3-[1-(4-fluorophenylamino)pentyl]pyridine was dissolved in 40 ml. of dichloromethane, and to it were added 3.4 g. of potassium carbonate and 1.9 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and then an additional 1.9 ml. of methanesulfonyl chloride was added and the mixture was stirred for 3 days with gentle heating. It was then cooled and extracted with aqueous sodium bicarbonate solution, and then with water, and it was then dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in chloroform and was purified over silica gel, eluting with chloroform, to obtain 0.7 g. of the desired product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[OH:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:10][C:11]1[CH:12]=[C:13](/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:25]=2)=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1O
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3cccnc3)c2)cc1O
Temperature: 40 °C
Reaction time: 5 h
Yield: 11.1 %

Procedure:
3-Chloromethyl-pyridine hydrochloride (0.59 g 3.6 mmol) was added to a mixture of (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-(3-hydroxy-phenyl)-acrylamide (0.39 g, 1.2 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in dry DMF (5 mL) at RT. After stirring at 40° C. for 5 hrs, the resulting mixture was poured into ice, and the resulting precipitate was filtered, washed with water and dried. The resulting raw material was taken up, without further purification, with a 3N methanolic solution of hydrochloric acid (5 mL-15 mmols) and stirred at RT for 2.5 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a residue that, after neutralization, was purified by silica gel column chromatography (eluant DCM/MeOH 98/2) to obtain 50 mg of the title (E)-3-(3-hydroxy-4-methoxy-phenyl)-N-[3-(pyridin-3-ylmethoxy)-phenyl]-acrylamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1)=[O:12].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:15]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)CCCCCNc3ccc(F)c(F)c3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCCCNc1ccc(F)c(F)c1)Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Into a solution of tert-butyl 4-(3-{[6-(3,4-difluoroanilino)hexanoyl]amino}phenyl)-1-piperidine carboxylate (11.2 mg, 0.0224 mmol) in dichloromethane (0.500 mL) at 0° C. was slowly added trifluoroacetic acid (25.5 mg, 2.24 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in i-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (8.98 mg, 99%): 1H NMR (400. MHz, CDCl3) δ 7.39-7.08 (m, 5H), 7.06-6.94 (m, 2H), 6.91-6.81 (m, 1H), 6.77-6.67 (m, 1H), 3.54-3.42 (m, 2H), 3.25-3.04 (m, 3H), 2.91-2.80 (m, 1H), 2.45-2.32 (m, 2H), 2.11-1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.62 (m, 4H), 1.55-1.40 (m, 2H), 1.34-1.23 (m, 1H); ESMS m/e: 402.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C:2]([F:1])([F:25])[CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1(F)F
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4,4-difluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate and triethylamine in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4,4-difluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 329.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.O.O.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)cc2Cl)cc1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in MeOH (20 mL), and treated with SnCl2.2H2O (50 mmol), according to General Procedure I. The reaction mixture was heated under reflux until completion, as indicated by TLC or HPLC. The solvent was removed in vacuuo and the residue was treated with 4.0 N aqueous NaOH to pH ˜8. The residue was extracted with EtOAc (2×50 mL), washed with 1.0 N aqueous NaOH (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6](N)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[FH:21].N1C=CC=CC=1>>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([F:21])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Nc1nccc2c(Br)csc12
Reactant: F
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1nccc2c(Br)csc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of 3-bromothieno[2,3-c]pyridin-7-amine (51 mg, 0.22 mmol) in pyridine hydrofluoride (1.2 mL) was added sodium nitrite (23.1 mg, 0.334 mmol). The reaction stirred at room temperature for 18 h. The reaction was then neutralized by addition of saturated aqueous sodium bicarbonate (40 mL). The mixture was extracted with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated to afford 33 mg (59%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.20 (dd, J=5.6, 1.3 Hz, 1 H), 7.76 (s, 1 H), 7.62 (dd, J=5.6, 2.8 Hz, 1 H); MS (ESI): 232.04, 234.04 [M+H]+; HPLC tR=3.49 min (ZQ3, polar—4 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:13][OH:14])[CH2:10][C@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:15](OC=C)(=[O:17])[CH3:16].CC(CC(O)=O)=O>CCOC(C)=O.CCCCCCC>[C:15]([O:12][CH2:11][C@@H:9]1[CH2:10][C@:8]1([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:13][OH:14])(=[O:17])[CH3:16]
Reactant: C=COC(C)=O
Reactant: OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Agent: CC(=O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Temperature: 22.5 °C
Yield: 100.6 %

Procedure:
((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol (5, 7.89 g, 0.040 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (23.68 mL), under nitrogen. Lipase acrylic resin (Candida Antarctica Lipase B, Sigma-Aldrich, Saint Louis, Mo.) (417.5 mg, 5.0 wt %) was added. Vinyl acetate (5.56 mL, 0.060 mol, 1.5 equiv.) was added, and the reaction mixture was stirred at 20-25° C. while monitoring the ratio of mono-acetate and diacetate (8-9 h) by HPLC and TLC (EtOAc/Heptane=1/1). Upon reaction completion, the lipase was removed by filtration and rinsed with 2-methyl-THF (71.04 mL). The filtrate and the rinse were combined and washed with 15% NaCl aq. solution (27.63 mL) followed by sat. aqueous NaCl solution (23.68 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl acetate, 6 (9.59 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[Cl:19])(=O)=O.B([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(O)O>>[Cl:19][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: COc1ccc2c(Cl)c(-c3ccc(C(=O)O)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Followed the coupling procedure described for Example 3, starting from 1-chloro-6-methoxynaphthalen-2-yl trifluoromethanesulfonate (Intermediate 4, 1 equiv) and 4-boronobenzoic acid (1.2 equiv), where the mixture was stirred at 80° C. for 2 hours. The crude product was obtained after workup and was taken on without purification.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37](=[N:39]O)[NH2:38]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[N:39]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:38]=1
Reactant: NC(=NO)c1c(F)cccc1F
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3c(F)cccc3F)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 42 mg (39% of theory)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:19]1[C:27]2[C:22](=[C:23]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1
Yield: 100 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (200 mg), 4-indole-boronic acid (125 mg), sodium hydrogen carbonate (178 mg) and PdCl2(PPh3)2 (4 mg) in toluene (1.5 ml), ethanol (0.75 ml) and water (0.4 ml) were heated in a microwave at 120° C. for 45 min. Chloroform/water extraction and purification on silica gave 2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (257 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:16]([OH:17])=[O:15])=[CH:19][CH:20]=1)[CH:11]=[CH:10]2
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1

Procedure:
Followed Scheme 2, A conditions: Starting materials: 2-chloro-6-methoxyquinoline (Intermediate 1) (100 mg, 0.52 mmol) and (4-(methoxycarbonyl)phenyl) boronic acid. 1H NMR (DMSO-d6, 400 MHz): δ 13.06-12.90 (bs, 1H), 10.14 (s, 1H), 8.36-8.33 (d, 2H), 8.30-8.27 (d, 1H), 8.11-8.06 (m, 3H), 7.97-7.94 (d, 1H), 7.38-7.34 (dd, 1H), 7.20 (s, 1H). MS (ESI): m/z 266.08 [M+H]+.