Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:47][CH2:48][O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][O:51]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)[C:22]([CH2:40][O:41][CH2:47][CH2:48][O:49][CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(COCCOC3CCCCO3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in N,N-dimethylformamide (4 ml), then thereto is added sodium hydride (28 mg) under ice-cooling, and the mixture is stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (0.15 ml) is added to the reaction solution, and the mixture is stirred at room temperature for 2 hours and 30 minutes. After addition of sodium hydride (28 mg) and 2-(2-bromoethoxy)-tetrahydropyran (0.15 ml), the mixture is stirred at 50° C. for 2 hours and 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, followed by extraction with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R*,4S*)-4-[[3,5-bis(trifluoromethyl)benzyl]-(5-{2-[(tetrahydropyran-2-yl)oxy]ethoxymethyl}pyrimidin-2-yl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (201 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.CC(C)(O)[C:14]#[N:15]>>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([OH:8])([C:14]#[N:15])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CC(C)(O)C#N
Product: CC1(C)CC(O)(C#N)CC(C)(C)N1

Procedure:
A solution of 97 g 2,2,6,6-tetramethyl-4-piperidone and 67 g of acetone cyanohydrin were stirred at room temperature for 30 hours to precipitate the desired cyanohydrin. The precipitate was collected, washed with petroleum ether and air dried to yield 70 g (61.4%); mp 129°-132° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[NH2:36][N:37]=[CH:38]S(O)(=O)=O>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([O:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:38]=[N:37][NH2:36])[CH2:2][CH2:3]2)[CH:10]=1)(=[O:18])=[O:19]
Reactant: Cc1cc(OCC2CCNCC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: NN=CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CCN(C=NN)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Yield: 36.3 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]-5-methylphenyl ester (396 mg, 1.0 mmol), as prepared in the preceding step, in DMF (10 mL), N,N-diisopropylethylamine (0.5 mL) and aminoiminomethanesulfonic acid (248 mg, 2.0 mmol) was stirred at room temperature overnight. The DMF was removed in vacuo and the residue was purified by flash column chromatography (90:10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (159 mg, 36%). 1H-NMR (300 MHz, CDCl3) δ 1.45 (m, 2H), 1.92 (m, 3H), 2.21 (s, 3H), 3.07 (t, 2H), 3.69 (d, 2H), 4.09 (d, 2H), 6.46 (d, 1H), 6.49 (s, 1H), 6.56 (s, 1H), 7.28 (s, 3H), 7.39 (t, 1H), 7.62 (m, 2H), 7.95 (dd, IH). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C20H24N3O4SCl: 438.1 (M+H), 460.1 (M+Na), Found: 438.3, 460.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[O:25]([NH2:27])[CH3:26].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:10][C:11]([NH:27][O:25][CH3:26])=[O:12])=[CH:17][CH:18]=1)#[N:23]
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Reactant: CON
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CONC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Yield: 91.8 %

Procedure:
Part A. A solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.15 gm, 0.49 mmol), methoxylamine hydrochloride (0.041 gm, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethhylcarbodiimide hydrochloride (0.14 gm, 0.73 mmol) and 4-dimethylaminopyridine (0.15 gm, 1.22 mmol) in 5 mLs DMF under a nitrogen atmosphere was stirred for 18 hrs. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic layer was washed with 1 N HCl (2×), water, brine, dried over magnesium sulfate and concentrated to give the crude product as a colorless viscous oil. The product was purified by flash chromatography on silica gel (50 mLs) eluting methylene chloride:ethyl acetate (v:v, 60:40) to give 4-(cyano)-beta-(3-cyanophenyl)-N-methoxybenzene pentanamide as a colorless vicous oil 0.15 gm (91%) 1H NMR (CDCl3): 8.03(bs, 1H), 7.56-7.42(m, 6H), 7.15(d, 2H), 3.58(s, 3H), 3.28(m, 1H), 2.8-1.85(m, 6H).
Reaction SMILES: C1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[N:10]C=C[CH:13]=2)C=CC=CC=1.C([Li])CCC.ClCCN1CC2CC3CC(CC1C3)C2.Cl>C1CCCCC1>[CH:14]12[CH2:7][CH:8]3[CH2:13][CH:16]([CH2:17][CH:18]([NH:10][CH2:9]3)[CH2:19]1)[CH2:15]2
Reactant: c1ccc(C(c2ccccc2)c2cccnc2)cc1
Agent: Cl
Agent: ClCCN1CC2CC3CC(C2)CC1C3
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: C1NC2CC3CC1CC(C3)C2

Procedure:
Reaction of 2.5 parts of diphenyl-3-pyridylmethane in 60 parts by volume of cyclohexane with an equivalent amount of butyl lithium at 10° C under nitrogen is followed by the addition of 2.1 parts of 4-(2-chloroethyl)-4-azatricyclo[4.3.1.13,8 ]undecane [preparable by mixing the hydrochloride thereof (U.S. Pat. No. 3,845,038) with excess aqueous sodium carbonate, extracting the mixture with toluene, and consecutively washing the extract with water, drying it over anhydrous sodium sulfate, filtering out the drying agent, and removing the solvent by vacuum distillation]. Quenching of the reaction with water and isolation by extraction with ether, washing, drying and evaporation of solvent provides 4-[3,3-(diphenyl)-3-(3-pyridyl)propyl[-4-azatricyclo[4.3.1.13,8 ]undecane having the following structural formula ##STR52##
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[C:4]([C:16]([OH:18])=O)=[CH:3][CH:2]=1>C1(C)C(C)=CC=CC=1>[CH:10]1[C:9]2[C:7](=[O:8])[C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[C:16](=[O:18])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Yield: 78.7 %

Procedure:
A mixture of 2.50 g of 2-aminobenzophenone-2'-carboxylic acid in 50 ml of xylene is stirred at reflux for 23 hours. The mixture is filtered to give 1.82 g of the desired product as a solid.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[CH2:36][N:11]2[C@H:12]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]2[CH2:9]1)(=O)C.O>CO>[CH:23]([C@H:12]1[N:11]2[CH2:36][C@@H:8]([OH:7])[CH2:9][C@H:10]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)O[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Sodium methoxide in methanol (5M, 27 μl ) was added into a solution of tert-butyl (4R,7S,8aS)-7-acetoxy-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (628 mg) in methanol (10 ml) at room temperature. After being stirred for 1 hour at the same temperature, the reaction mixture was poured into water (10 ml). The whole was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (521 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.[NH2:25][CH:26]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:27]#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:26]([C:27]#[N:28])[NH:25][C:15]([C:14]2[C:13]([CH3:18])=[N:12][N:11]3[C:6]([O:5][CH2:4][C:3]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:2]=4[F:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=23)=[O:17])=[CH:34][CH:33]=1
Reactant: N#CC(N)c1ccc(Cl)cc1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NC(C#N)c3ccc(Cl)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged in a 96-well deep well multititre plate. A solution of 17 mg (0.10 mmol) of rac-amino(4-chlorophenyl)acetonitrile in 0.4 ml of DMF and a solution of 45.6 mg (0.12 mol) of HATU in 0.4 ml of DMF were added successively. After adding 20.2 mg (0.20 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. Then the mixture was filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 0.7 mg (1.5% of theory) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([CH3:28])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([CH3:28])[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12](NCC(OC)=O)=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1>>[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Reactant: NCCS(=O)(=O)O
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCS(=O)(=O)O)c2Cl)ccc1O

Procedure:
By use of 2-aminoethylsulfonic acid in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH:36]([F:38])[F:37].C([O-])(=O)C.[K+].[B:44]1(B2OC(C)(C)C(C)(C)O2)[O:48]C(C)(C)C(C)(C)[O:45]1>O1CCOCC1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([B:44]([OH:48])[OH:45])=[C:3]([CH:36]([F:37])[F:38])[CH:4]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27](=[O:28])[NH:29][CH3:30])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(B(O)O)c(C(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 6-(N-(4-bromo-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.20 g, 0.33 mmol), potassium acetate (0.13 g, 1.32 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.027 g, 0.033 mmol), and bis(pinacolato)diboron (0.25 g, 0.99 mmol) in 1,4-dioxane (4.12 ml) was degassed, purged with nitrogen and heated at 80° C. for 3 h 45 mins. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in 10 mL THF, and 5 mL 1M HCl. NaIO4 (0.56 g, 2.63 mmol) was added and the suspension was stirred for 1 h and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4), filtered, evaporated and purified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid)) to afford the title compound (0.085 g, 45%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.90-7.97 (m, 2H), 7.87 (s, 1H), 7.43-7.61 (m, 3H), 7.30 (s, 1H), 7.21-7.29 (m, 2H), 6.65-7.01 (m, 1H), 3.33 (s, 3H), 2.94 (s, 3H), 2.08-2.21 (m, 1H), 0.35-1.10 (m, 4H). LCMS (m/z, ES+)=573.3 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][C:19]2[C:27]3[O:26][C:25]([C:28]([O:30]CC)=[O:29])=[N:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[C:27]3[O:26][C:25]([C:28]([OH:30])=[O:29])=[N:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
0.66 g of ethyl 7-(4-(quinoline-2-ylmethyloxy)phenoxymethyl)benzoxazole-2-carboxylate and 0.7 g sodium bicarbonate are combined in 50 ml of ethanol and 5 ml of water. After refluxing for 1.5 hours the mixture is concentrated and the residue diluted with ether. The resulting solid is collected, suspended in water and the pH adjusted to 6 with 1 molar hydrochloric acid. The resulting solid is crystallized from aqueous acetic acid, then tetrahydrofuran/hexane to give 7-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)benzoxazole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.C(N(CC)CC)C.[OH-].[Na+].Cl>O1CCCC1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=4[CH:10]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (300 mg, 0.681 mmol) produced in Example A3(iv) in tetrahydrofuran (8.0 mL) were added a solution of 2-chloro-2-oxoethyl acetate (77 μL, 0.715 mmol) in tetrahydrofuran (2.0 mL) and triethylamine (141 μL, 1.02 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture were added 2-chloro-2-oxoethyl acetate (154 μL, 1.43 mmol) and triethylamine (290 μL, 2.10 mmol), and the mixture was further stirred at room temperature for 1.5 hr. To the reaction mixture was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at room temperature for 30 min and neutralized with 1N hydrochloric acid. The obtained mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (220 mg, 65%) as a colorless solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29]N1C(=O)CCC1=O>C(#N)C>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[C:18]([Cl:29])[N:17]=[CH:16]2)=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH4Cl solution, H2O and Et2O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:13][CH2:12][CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(SCCO)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A homogeneous mixture of 2-[(5-nitro-2-pyridinyl)thio]ethanol (7) (45 mg, 0.22 mmol), 4-chlorobenzoyl chloride (33 μL, 0.26 mmol) and pyridine (45 μL, 0.56 mmol) in anhydrous dichloromethane (1.5 mL) was stirred at room temperature for 48 h. The reaction mixture was quenched with 1N HCl and the organic phase was washed with saturated aqueous solution of NaHCO3, brine and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethyl 4-chlorobenzoate (8). LCMS: purity: 90%; MS (m/e): 340 (M+)
Reaction SMILES: C(ON=O)CC(C)C.N[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31].CO.C(Cl)(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:26]=3[C:27]([F:30])([F:29])[F:28])[C:17]2=[O:20])=[CH:12][C:11]=1[F:31]
Reactant: Nc1cc2c(cc1F)CCN(c1cnccc1C(F)(F)F)C2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)CCON=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(Cl)c(F)cc2CCN1c1cnccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Isoamylnitrite (107.7 mg, 0.91 mmol) was added to the stirred solution of 7-amino-6-fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-79b: 100 mg, 0.306 mmol) in CCl4 (10 mL). The resulting mixture was stirred for 1 hour at 70° C. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 10 mg of the product (10% yield).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:14])[CH:6]=1>[Fe].C(Cl)(Cl)Cl>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[CH:6][C:7]([CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Bromine (3.87 mL, 0.076 mol) was added dropwise at 5° C. to a mixture of 4-methoxy-2-methylbenzoic acid (10 g, 0.060 mol), Fe (0.20 g, 3.61 mmol) and chloroform (10 mL). After the reaction mixture was warmed to room temperature, it was stirred overnight. After chloroform (600 mL) was added, this suspension was washed with 10% sodium hydrogensulfate (200 mL×2) and brine, and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the pale yellow powder obtained by evaporating the solvent under reduced pressure was recrystallized from methanol twice to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (4.96 g, 34%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]#[C:23][NH2:24].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=S)CCCCC1>C(#N)C.C(N(CC)CC)C>[C:23]([NH:24][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:22]
Reactant: S=C(NCCCCOc1ccccc1)Nc1cccnc1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: S=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1cccnc1)NCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Phenoxybutyl)-N'-3-pyridylthiourea (1.41 g) was dissolved in acetonitrile (10 ml), and cyanamide (400 mg), N,N'dicyclohexylcarbodiimide (1.95 g) and triethylamine (0.08 ml) were added. The mixture was stirred for 3 days at room temperature, when it was filtered, washed with acetonitrile, and ether to yield a solid mixture of the crude product and N,N'-dicyclohexylthiourea. The pure compound was obtained by extracting the mixture with 0.5N hydrochloric acid (16 ml), filtering and re-precipitation by addition of 9N sodium hydroxide to the filtrate.