Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=C[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].ClC1C(Cl)=CC=CC=1[NH2:23].ClC1C(F)=C(C=CC=1)N>>[NH2:1][C:2]1[C:7]([C:8]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:12]=2[F:11])=[O:10])=[N:23][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Nc1cccc(F)c1F
Reactant: Nc1ncccc1C(=O)O
Agent: Nc1cccc(Cl)c1F
Product: Nc1nccnc1C(=O)Nc1cccc(F)c1F

Procedure:
To a solution of 3-aminopyrazine-2-carboxylic acid (2.0 g, 14.38 mmol) in anhydrous DMF (20 mL) was added 2,3-difluoroaniline (2.2 g, 17.04 mmol) and DIEA (7.6 mL, 43.63 mmol). The mixture was stirred at room temperature while PyBOP (7.5 g, 14.41 mmol) was added. The stirring was continued for another 14 hours until HPLC detected no starting material. The reaction solution was then poured into saturated sodium bicarbonate solution. The crude product was collected by vacuum filtration and washed with water. After drying on vacuum pump for 24 hours, the off-white product (2.9 g, 80%) was used directly in the next reaction without further purification. LC-MS m/e=250.8 (M+H); 1H-NMR (500 MHZ, DMSO-d6): 10.42 (s, 1H), 8.33 (d, 1H), 7.94 (d, 1H), 7.72 (m, 1H), 7.60 (br, 2H), 7.25 (m, 2H). Using the same procedure, 3-amino-N-(2,3-dichlorophenyl)pyrazine-2-carboxamide and 3-amino-N-(3-chloro-2-fluorophenyl)pyrazine-2-carboxamide can be produced by reacting 3-aminopyrazine-2-carboxylic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively. Analogously, this procedure can be used to produce 2-amino-N-(2,3-difluorophenyl)pyridine-3-carboxamide, 2-amino-N-(2,3-dichlorophenyl)pyridine-3-carboxamide, and 2-amino-N-(3-chloro-2-fluorophenyl)pyridiine-3-carboxamide by reacting 2-amino-pyridine-3-carboxylic acid with 2,3-difluoroaniline, 2,3-dichloroaniline, and 3-chloro-2-fluoroaniline, respectively.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:17]O>>[ClH:1].[CH3:17][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1
Reactant: CO
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Product: CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 18 h

Procedure:
Dry methanol (200 ml) was saturated with HCl(g) in a two-necked round bottom flask cooled to -10° C. p-Nitrophenylalanine (10.0 g, 47.6 mmol) was added in one portion and left to stir for about 18 hours, the solution was evaporated to near dryness on a rotary evaporator and the precipitated product collected in a Buchner funnel. After drying under vacuum at about 50° C., the yield was 10.97 grams (88.3%). A TLC (thin layer chromatography) of the free amino ester run in CHCl3 :MeOH (4:1) revealed an Rf =0.85-0.88. 1H NMR (220 MHz, D2O, pH 1.5) 8.20 (d,2 J=10.0), 7.53 (d,2,J=10.0), 4.55 (t,l,J=5.00), 3.84 (s,3), 3.43 (m,2); CI-MS 225 ((M+1)/z). Anal. Calcd. for C10H13N2O4Cl: C, 46.07; H, 5.03; N, 10.74; Cl, 13.60. Found: C, 45.87; H, 5.08; N, 10.48; Cl, 13.58.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:15])[CH:10]=3)[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: BrCC1CO1
Reactant: Fc1ccc2c(c1)[nH]c1ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1ccc(F)cc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a stirred solution of 2,6-difluoro-9H-carbazole (0.460 g, 2.3 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.179 g, 2.7 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.375 mL, 4.5 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.55 g, 94%). 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=8.7, 5.7 Hz), 7.68 (dd, 1H, J=8.7, 2.7 Hz), 7.38 (dd, 1H, J=8.7, 4.2 Hz), 7.20 (td, 1H, J=9.0, 2.7 Hz), 7.13 (dd, 1H, J=9.9, 2.1 Hz), 6.98 (ddd, 1H, J=9.6, 9.0, 2.4 Hz), 4.64 (dd, 1H, J=15.9, 2.7 Hz), 4.29 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.56 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:2]1[CH:3]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[O:8])[NH:5][CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Br)c[nH]2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c[nH]2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of tert-butyl 4-(4-bromo-1H-pyrrole-2-carbonyl)piperazine-1-carboxylate (350 mg, 0.98 mmol), (2,4-dichlorophenyl) boronic acid (280 mg, 1.47 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 (312 mg, 2.94 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (273 mg, 59% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[C:9](O)=[N:8][C:7]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=2)[CH:6]=[C:7]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:8]=1
Reactant: COCCOc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Temperature: 160 °C
Yield: 62.7 %

Procedure:
A mixture of 6-Methoxy-7-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol (1.0 g, 1.45 mmol) in POCl3 (20 ml) was sealed in 2 microwave process vial (20 ml). The mixture was heated at 160° C. for 30 minutes under microwave irradiation. After removal of excess solvent, the residue was poured into ice-water, neutralized by 2M NaOH, extracted by EtOAc. The organic layer was concentrated and the residue was purified by flash column chromatography to give product as solid (0.33 g, 62.7%). LC-MS: m/e 363 (MH+).
Reaction SMILES: [CH:1]([C:9]1=[CH:10][C:11]([O:13][C:14]1=[O:15])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=[O:19].[Li+]>CO>[CH:1](/[C:9](/[C:14]([OH:13])=[O:15])=[CH:10]/[C:11]([OH:19])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CO
Product: O=C(O)/C=C(/C=Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 30 h

Procedure:
0.5 g of the styrene-maleic anhydride polymer (molecular weight: 1600) was mixed with 1.5 g of polyethyleneoxyglycol (molecular weight: 600) and 0.5 g of lithium trifluoromethane sulfonate salt. The mixture was dropped on an ion-conducting glass electrode and heated in an oven at 100° C. under nitrogen stream. After 30 hours, the mixture was cooled to room temperature and immersed in methanol and dried. A thin membrane of styrene-maleic acid polyethyleneoxy ester copolymer of an excellent adhesive strength and mechanical strength was prepared. The ion conductivity of the polymer thin membrane prepared as above was 7×10-7S/cm at room temperature.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N+:23]([O-])=O)[CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(O)C.CCCCCC>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH2:23])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[O:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2N)CC1
Product: Nc1cc(Cl)ccc1OC1CCC(O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %
Yield: 16 %

Procedure:
Stannous chloride (3.2 g, 16.98 mmol) was added to a solution of tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane (1.28 g, 3.32 mmol) in a mixture of ethanol and ethyl acetate (1/1, 40 mL) and the resulting mixture was stirred at room temperature for 24 hours. Ice and an aqueous solution of sodium bicarbonate (5%, 150 mL) were added and the solid formed was filtered, washed with ethyl acetate and discarded. The layers of the filtrate were separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered through a CELITE™ pad and evaporated under reduced pressure. The yellow oily residue was purified by flash chromatography (EtOAc/hexane, from 5/95 to 80/20) to give 0.5 g (42% yield) of 2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenylamine as a yellow oil and 803 mg (16% yield) of 4-(2-amino-4-chloro-phenoxy)-cyclohexanol.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.N1CCOCC1.P(Cl)(Cl)Cl>>[CH2:7]([C:8]([P:1]([OH:4])([OH:3])=[O:2])([P:1]([OH:4])([OH:3])=[O:2])[OH:10])[CH2:6][NH2:5]
Reactant: NCCC(=O)O
Reactant: OP(O)O
Solvent: C1COCCN1
Solvent: ClP(Cl)Cl
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The mixture of 5 eq. phosphorous acid and β-alanine is heated to form a melt. Morpholine (1 eq.) is slowly added. The reaction is cooled to about 70° C. and 2 eq. of PCl3 are added. The mixture is heated for about 3.5 hours. Then the reaction is hydrolyzed in aqueous acid at about 75° C. for about 0.5 hours. Crystallization from aqueous acid/IPA, affords pamidronate.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:12]=3[OH:26])[CH2:5]2)[O:3]C1.C(O)(=O)C(O)=O.CO.O>CCOCC>[CH3:25][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH2:5][C:4](=[O:3])[CH2:9][CH2:8][C:7]=2[CH3:10])=[C:12]([OH:26])[CH:13]=1)([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC(C)(C)c1ccc(C2=C(C)CCC3(C2)OCCO3)c(O)c1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCCCCCC(C)(C)c1ccc(C2=C(C)CCC(=O)C2)c(O)c1

Procedure:
A mixture of 4.08 g. (0.1 mol.) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-methyl-cyclohex-3-enone ethylene ketal, 50 ml. of 2 N oxalic acid and 50 ml. of methanol was stirred at 25° C. for 6 hours. The reaction mixture was added to 500 ml. of water-250 ml. of ether. The ether extract was washed once with 250 ml. of saturated sodium bicarbonate, once with 250 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified via column chromatography on 400 g. of silica gel eluted with 50% ether-pentane to yield the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:28][O:27][C:25]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[NH:14][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2])(=[O:13])=[O:12])=[O:26]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2c1CCCC2
Temperature: 60 °C

Procedure:
A solution of Example 379A (3.04 g, 7.54 mmol) in methanol (70 mL) and distilled water (7.8 mL) was treated with lithium hydroxide monohydrate (1.58 g, 37.7 mmol), heated to 60° C. overnight, cooled to room temperature, treated with 1N HCl, and concentrated. The aqueous layer was washed with dichloromethane two times and the combined organic phases were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 388 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 14.00 (br s, 1H), 8.85 (br s, 1H), 7.83 (d, 1H), 7.73 (m, 2H), 7.64 (m, 1H), 7.13 (s, 2H), 3.63 (s, 3H), 2.67 (br s, 2H), 2.51 (br s, 2H), 1.65 (br m, 4H).
Reaction SMILES: [CH2:1]([CH:8]([C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[S:25]([C:28]1[CH:29]=[N:30][C:31]([NH:34][NH2:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH3:23].C([O-])(=O)C>>[CH2:1]([C:8]1[C:9](=[O:11])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([S:25](=[O:27])(=[O:26])[N:24]([CH2:22][CH3:23])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:29][N:30]=2)[NH:35][C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Reactant: CCOC(=O)CC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: CC(=O)[O-]
Product: CCOC(=O)Cc1[nH]n(-c2ccc(S(=O)(=O)N(CC)c3ccccc3)cn2)c(=O)c1Cc1ccccc1

Procedure:
According to the process described in Example 1.3, starting with 5 g (17.1 mmol) of diethyl 2-benzyl-3-oxopentanedioate and 5 g (17.1 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 3 g of ethyl 4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)acetate are obtained in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])[CH:5]=[CH:6][CH:7]=1.CN(C)/[CH:28]=[N:29]/[N:30]=[CH:31]/N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[CH:31]=[N:30][N:29]=[CH:28]5)[CH:3]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: CN(C)/C=N/N=C/N(C)C
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(-n2cnnc2)c1
Yield: 38 %

Procedure:
A mixture of 7-(3-aminophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (0.100 g, 0.285 mmol), N,N-dimethylformamide azine (Bartlett, R. K.; Humphrey, I. R. J. Chemn. Soc. C 1967, 1664) (41.3 mg, 0.290 mmol), and p-toluenesulfonic acid (10 mg, 0.053 mmol) in toluene (4 ml) was heated at reflux under nitrogen for 7 days, adding more p-toluenesulfonic acid (10 mg, 0.053 mmol) and some DMSO after 1 day. The solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-15% MeOH/CH2Cl2), then trituration in hot MeOH-CH2Cl2, to leave 0.0436 g (38%) of the title compound as a yellow solid; mp >350° C.; 1H NMR (360 MHz, DMSO-d6) δ2.29 (3H, s), 7.41 (2H, d, J 9.1 Hz), 7.59 (1H, d, J 7.7 Hz), 7.70 (1H, t, J 7.7 Hz), 7.79 (1H, dd), 7.87 (1H, fine t), 8.11 (2H, d, J 8.9 Hz), 8.62 (1H, s), 9.18 (2H, s), 12.52 (1H, br s); MS (ES+) m/z 403/405 1MH]+. Anal. found: C, 61.14; H, 3.79; N, 20.29. C21H15ClN6O.0.5H2O requires: C, 61.24; H, 3.92; N, 20.41%.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CCN(CC)CC.Br.[NH2:22][C:23]1[S:24][C:25]([Br:28])=[CH:26][N:27]=1>CN(C=O)C.C1COCC1>[Br:28][C:25]1[S:24][C:23]([NH:22][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=2)=[N:27][CH:26]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ncc(Br)s2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol), Et3N (1.5 ml, 10.78 mmol), DMF (5 ml) and THF (5 ml) isobutyl choroformate (0.70 ml, 5.36 mmol) was added dropwise at −10° C. After stirring for 1 h, a solution of 2-amino-5-bromothiazole hydrobromide (1,55 g, 5.96=mol) and Et3N (0.83 ml, 5.96 mmol) in DMF (6 ml) and THF (4 ml) was added dropwise to the mixture at the same temperature.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.[C:21]([O:25][C:26](=[O:51])[NH:27][C:28]1[C:29]([NH:40][C:41](=[O:50])[C:42]2[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=2)=[N:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:32][CH:33]=1)([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:14](=[O:15])[NH:49][CH2:48][C:45]1[CH:44]=[CH:43][C:42]([C:41]([NH:40][C:29]2[C:28]([NH:27][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:51])=[CH:33][CH:32]=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:30]=2)=[O:50])=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine-2-methanol (0.0345 ml, 0.358 mmol) was added to a 0° C. cooled mixture of CDI (58.0 mg, 0.358 mmol) in THF (5 mL) and the reaction was stirred at room temperature for 1 h. Tert-butyl(2-{[4-(aminomethyl)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate (150 mg, 0.358 mmol) was added to the reaction with TEA (0.050 ml, 0.358 mmol) and DBU (0.054 ml, 0.358 mmol) and the reaction stirred for 2 hours. LC/MS indicated the presence of the addition of the free amine to the CDI and thus another equivalent of pyridine-2-methanol (0.345 ml, 0.358 mmol) was added and the reaction stirred overnight. LC/MS indicated the formation of the desired product. Following evaporation of THF, water was added and the organic product was extracted (3×) with EtOAc, washed with brine and dried over sodium sulfate. The residue was purified by column chromatography on silica gel Biotage 25S, eluting with EtOAc/hexanes (0%-100%). MS: cal'd 554 (MH+), exp 554 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH:18][C:19](=[O:36])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[CH:22][CH:21]=1)[CH3:17].C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH2:16]([NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([CH3:35])=[C:22]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:11]4[CH2:15][CH2:14][O:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:21]=1)[CH3:17]
Reactant: Brc1ccc2c(C3CCOC3)n[nH]c2c1
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCOC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
A mixture of 6-bromo-3-(tetrahydro-3-furanyl)-1H-indazole (Intermediate 9, 84 mg) N-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate, 10, 91 mg) aqueous sodium hydrogen carbonate (1M, 630 μL) and tetrakis(triphenylphosphine)palladium(0) (7 mg) in isopropanol (4 ml) in a sealed vial was stirred at 150° C. for 15 min in a microwave oven. The solvent was removed under vacuum and the residue was purified by chromatography on a silica column, eluting with a cyclohexane:ethyl acetate gradient, to give the title compound as a white solid (36 mg).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:3])[NH2:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:17][CH2:16][CH2:15][NH2:18])(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccccc1OCC1CO1
Reactant: NCCN
Product: NCCNCC(O)COc1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
1-(o-Carbamoylphenoxy)-2,3-epoxypropane (20 g.) is added to ethylenediamine (125 ml.) and the mixture is stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. The residue is stirred with water (150 ml.), the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from acetonitrile and there is thus obtained a residue 1-(o-carbamoylphenoxy)-3-(β-aminoethyl)aminopropan-2-ol, m.p. 91°-93° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[N+:15]([O-:17])[CH:16]=1.[OH-].[Na+]>>[Br:10][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][C:14]([CH3:18])=[N+:15]([O-:17])[CH:16]=1
Reactant: Cc1ccc(Br)c[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
6.0 mL nitric acid were added dropwise to 6.0 mL conc. sulphuric acid while cooling with ice and stirring. Then 3.6 g (21 mmol) 5-bromo-2-methylpyridine-1-oxide were added batchwise and the reaction mixture was stirred for 18 h at 60° C. After cooling to RT the reaction mixture was added to ice water and neutralised with 4N aqueous sodium hydroxide solution. The precipitated solid was suction filtered and dried at 50° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([CH2:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Cc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CCC(Cc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 26.6 %

Procedure:
The mixture of (R)-4-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (18.6 mg, 0.0000490 mol) and lithium hydroxide (12.9 mg, 0.000539 mol) in ethanol (1 mL, 0.02 mol) and water (0.50 mL, 0.028 mol) was heated to reflux overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography with MeOH/CH2Cl2 (10:90 to 80:20) to give (R)-2-amino-2-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)propan-1-ol as a white solid (4.6 mg, 26%). LCMS: Rf=1.76 min 337.36 [M−NH2]+. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.56 (s, 1H), 7.52 (dd, J=1.8, 8.7 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 3.82-3.75 (m, 1H), 3.72-3.67 (m, 1H), 2.80 (d, J=8.0 Hz, 2H), 2.69 (br. s., 1H), 2.08 (br. s., 1H), 1.64 (d, J=12.9 Hz, 2H), 1.56 (br. s., 5H), 1.46 (tt, J=4.0, 13.0 Hz, 2H), 1.38-1.24 (m, 2H), 1.03 (tt, J=3.1, 11.9 Hz, 1H), 0.91 (s, 9H).