Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(Cl)CCl>[Cl:1][C:2]1[C:3]([C:4]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1ccc(NC(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloronicotinic acid (6.3 g) and 4-isopropylaniline (5.26 ml) and DIEA (10 ml) in CH2Cl2 (200 ml) was added EDC (10 g) and HOBt (5.4 g). The reaction was stirred at RT overnight and washed with 2N NaOH (100 ml), H2O (250 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and evaporated to give (2-chloro(3-pyridyl))-N-(4-isopropylphenyl) carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17]CC4C=CC=CC=4)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26]>C(O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=3[CH:10]=[C:9]2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26]
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1-c1ccc(O)c(F)c1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2c(O)cccc2n1-c1ccc(O)c(F)c1
Yield: 50.2 %

Procedure:
To a solution of 2-fluoro-4-{2-methyl-4-[(phenylmethyl)oxy]-1H-indol-1-yl}phenol (D3) (85 mg, 0.24 mmol) in ethanol (7 mL) was added a solution of tetra-n-butylammonium chloride (170 mg, 0.61 mmol) in ethyl acetate (1 mL). The solution was hydrogenated in an H-cube over a 10% Pd/C catalyst. The resulting solution was concentrated and the product purified by MDAP to yield the title compound (E3) (31 mg).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][N:6]1[C:10]([NH2:11])=[CH:9][CH:8]=[N:7]1.C(OCC)(=O)C>O.C(O)(=O)C>[CH3:5][N:6]1[C:10]([NH:11][C:2]([NH2:3])=[O:1])=[CH:9][CH:8]=[N:7]1
Reactant: Cn1nccc1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cn1nccc1NC(N)=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.2 %

Procedure:
A solution of sodium cyanate (52 g) in water (400 ml) was added dropwise to a solution of 1-methyl-5-aminopyrazole (19.4 g) in acetic acid (96 ml) and water (192 ml), and the mixture was stirred at ambient temperature for 7 hours. The reaction mixture was poured into a mixture of water (400 ml) and ethyl acetate (400 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to give 1-methyl-5-ureidopyrazole (14.6 g).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].IC>C1COCC1.C(OCC)(=O)C>[CH3:11][S:10][C:2]1[S:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2cccnc2s1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To the suspension of thiazolo[5,4-b]pyridine-2-thiol (168 mg, 1.0 mmol) in THF (3.3 ml) was added potassium carbonate (193 mg, 1.4 mmol), followed by iodomethane (68.2 μl, 1.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h. Additional iodomethane were mixed in (40 uL) and stirred at room temperature for another 3 h. LCMS showed reaction was complete. The crude reaction mixture was suspended in ethyl acetate and washed with water, then brine, dried over sodium sulfate, filtered, and concentrated to give 2-(methylthio)thiazolo[5,4-b]pyridine (182 mg, 1.0 mmol, 100% yield) as a tan solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>[Cu]I.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.C(N(CC)CC)C>[F:8][C:5]1[C:4]([C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[O:12][C:11](=[O:21])[NH:10]2)=[CH:3][C:2]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cccc(F)c2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a sealable microwave vial was added (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (105 mg, 0.296 mmol), copper(I) iodide (1.689 mg, 8.87 μmol), triphenylphosphine (23.26 mg, 0.089 mmol) and triethylamine (4 mL). The solution was stirred and ethynyltrimethylsilane (43.6 mg, 0.443 mmol) was added and the reaction mixture was degassed with nitrogen for 10 min. To this mixture was added bis(triphenylphosphine)palladium(II) chloride (4.15 mg, 5.91 μmol) in one portion and the reaction vessel was sealed and heated to 90° C. overnight. The reaction was cooled to room temperature, the solvent was evaporated in vacuo and the crude solid was added to a silica gel column and eluted with 20% EtOAc/80% Hexanes affording (4R,5R)-4-(2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (77 mg, 0.207 mmol, 69.9% yield) as an off white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.04 (dd, J=8.0, 4.0, 1H), 7.47-7.41 (m, 1H), 7.18-7.12 (m, 3H), 5.44 (brs, 1H), 5.36 (d, J=4.0, 1H) 5.00 (d, J=5.0, 1H), 0.30 (s, 9H), LC/Mass spec. (Analytical HPLC method 2): RT=2.23 min. Mass=373.19 (MH)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.69 (br s, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.46 (quintet, J=7.6 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.88 (t, J=7 Hz, 3H); Rf=0.16 (25% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].N(OCCC(C)C)=O.[I:27]CI>N1CCCCC1.CC#N>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([I:27])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: C1CCNCC1
Solvent: CC#N
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (10.9 g, 45.2 mmol), iso-amyl nitrite (36.5 ml, 271.4 mmol) and diiodomethane (23 ml, 271.4 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept at this temperature for 8 hours. The reaction mixture to room temperature and then added to a stirred solution of piperidine/CH3CN (V:V=90 ml:90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with n-hexane, followed by n-hexane/ethyl acetate (20:1), giving 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester as white yellow solid (10.5 g, 66%).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH:24]1([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:28]2[CH2:32][CH2:31][N:30]([C:33]3[S:34][C:35]([C:39]([NH2:7])=[O:40])=[C:36]([CH3:38])[N:37]=3)[C:29]2=[O:42])[CH2:26][CH2:25]1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(N)=O
Yield: 5 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 5% yield: mp 198-200° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.29 (s, 2H), 4.02-3.97 (m, 2H), 3.67-3.62 (m, 2H), 3.10 (d, J=7.1 Hz, 2H), 2.45 (s, 3H), 0.99-0.90 (m, 1H), 0.52-0.46 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.5, 157.5, 154.7, 155.7, 118.2, 47.7, 41.9, 41.8 17.0, 8.8, 3.1; MS (ES+) m/z 281.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:49]=[CH:48][CH:47]=[CH:46][C:14]=1[C:15]([NH:17][C:18]1[CH:43]=[CH:42][C:21]([C:22]([N:24]([CH3:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([NH:64][N:65]2[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]2)=[O:39])=[O:23])=[CH:20][C:19]=1[O:44][CH3:45])=[O:16])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)NN2CCN(C)CC2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 72.8 %

Procedure:
To a solution of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(5-carboxypent-1-yl)oxy-4-methylphenyl]benzamide (250 mg) and N-methylmorpholine (37 mg) in dichloromethane (5 ml) was added pivaloyl chloride (45 mg) at -15° C. After being stirred at the same temperature for 5 minutes, to the mixture was added 1-amino-4-methylpiperazine (47 mg) and the mixture was stirred at -15° C. for 1 hour and then stirred at ambient temperature for additional 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogen carbonate solution (20 ml) and the solution was extracted with chloroform (15 ml×3). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified on silica gel column chromatography (SiO3 30 g, 1-15% methanol in chloroform) to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-[5-(4-methylpiperazine-1-yl)aminocarbonylpent-1-yl]oxy-4-methylphenyl]benzamide (208 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].O.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:13](=[O:14])[NH:11][C:4]=2[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Chloroanthranilic acid (10.0 g, 56.5 mmol) was dissolved at room temperature with stirring in 190 mL of distilled water containing 8.98 g (84.7 mmol) Na2CO3. When the 4-chloroanthranilic acid was completely dissolved, a 20% w/v solution of phosgene in toluene (84 mL) was added dropwise via a dropping funnel over 45 minutes. The resulting suspension was stirred at room temperature overnight under nitrogen. The product was collected by filtration and washed well with water. The resulting gray-white solid was dried in a vacuum oven at 60° C. overnight to provide 7-chloro-1,4-dihydro-2H-3,1-benzoxazine-2,4-dione (10.3 g, 52.3 mmol, 93%): 1H NMR (DMSO-d6): δ 11.93 (br s, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.28 (dd, J=1.6 and 8.2 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].N1C=CC=CC=1.C(Cl)Cl.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>CCOC(C)=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cccc(OC(F)(F)F)c1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Add 3-(trifluoromethoxy)aniline (1.0 g, 5.65 mmol), pyridine (0.89 g, 11.3 mmol) to DCM (20 mL) and cool to 0° C. Add dropwise phenyl chloroformate (1.15 g, 7.34 mmol). After addition, stir for 1 hr. TLC (PE:EtOAc=3:1) shows the reaction is complete. Add water to the mixture, extract with DCM (10 mL×3), combine the organic layer, wash with 1N HCl solution, brine sequentially, and dry over anhydrous Na2SO4. Concentrate under reduced pressure to get the product (1.50 g, 89%).
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[Na+].Cl.[NH2:7]O.[C:9]([C:11]1[C:12](=[O:39])[N:13]([CH:17]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[O:22][CH2:21][CH2:20][N:19]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18]2)[CH:14]=[CH:15][CH:16]=1)#[N:10].O>CS(C)=O>[Cl:31][C:26]1[CH:25]=[C:24]([CH:23]2[O:22][CH2:21][CH2:20][N:19]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:18][CH:17]2[N:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:9]3[NH:7][C:1](=[O:4])[O:2][N:10]=3)[C:12]2=[O:39])[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(n2cccc(C#N)c2=O)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(n2cccc(-c3noc(=O)[nH]3)c2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Sodium hydrogen carbonate (145 mg) and hydroxylamine monohydrochloride (120 mg) were added to a solution of tert-butyl (6RS,7SR)-6-(3-cyano-2-oxopyridin-1(2H)-yl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMSO (4 mL), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (10 mL), diazabicycloundecene (0.032 mL) and CDI (52 mg) were added, and the mixture was heated under reflux for 1 hr. To the reaction mixture was added 1 N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56 mg).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:9]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1cc(-c2ccccc2Cl)nn1
Product: Clc1ccccc1-c1cn(CCC#Cc2ccccn2)nn1
Yield: 34.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole (200 mg, 0.86 mmol, Example 259(B)) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 93.4 mg (0.30 mmol, 35%) of 2-(4-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17]>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.[Cu]I>[NH2:5][C:4]1[CH:3]=[C:2]([CH2:17][C:16]#[C:15][N:14]([CH3:18])[CH3:13])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: C#CCN(C)C
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)C#CCc1cc(N)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES−): 241 (M−H)−. Calc'd C12H13F3N2—242.24.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.CC(C)(C)C([O:14][C:15]1[C:20](=[O:21])[N:19]([CH3:22])[CH:18]=[N:17][C:16]=1[C:23](OC)=[O:24])=O.O.C(#N)C>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([C:16]2[N:17]=[CH:18][N:19]([CH3:22])[C:20](=[O:21])[C:15]=2[OH:14])=[O:24])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ncn(C)c(=O)c1OC(=O)C(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1cnc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C

Procedure:
4-Fluorobenzylamine (3 eq.) was added to a solution of the crude product of Step 4 in DMF and the reaction mixture was heated to 90° C. for one hour. The title compound was obtained by RP-HPLC (C18, eluting with water and acetonitrile containing 0.1% TFA).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=O.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>>[OH:15][C:14]1[N:1]=[C:2]2[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]2=[CH:9][C:13]=1[C:11]#[N:12]
Reactant: Cc1nn(C)c(N)c1C=O
Reactant: CCOC(=O)CC#N
Product: Cc1nn(C)c2nc(O)c(C#N)cc12
Temperature: 25 °C

Procedure:
A solution of 5-amino-1,3-dimethylpyrazole-4-carbaldehyde (6.15 g) in ethyl cyanoacetate (10 mL) was stirred at 185° C. for 3 hrs. The reaction mixture was allowed to cool to room temperature. The precipitated solid was filtered, washed with ethyl acetate, and dried under high vacuum to give 6-hydroxy-1,3-dimethylpyrazolo-[5,4-b]pyridin-5-carbonitrile as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C:7](=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[C:6]2=[O:25].[H][H]>[Pd].C(OCC)(=O)C.O1CCCC1>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][CH:7]1[C:6](=[O:25])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][C:8]1([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)(C)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)C(C)(C)O2
Yield: 99 %

Procedure:
A mixture of 7.3 g (0.0125) of the product of Example 110 and 700 mg 5% palladium on carbon in 200 mL ethyl acetate and 50 mL tetrahydrofuran was shaken in a Parr hydrogenator under 30 psi hydrogen for 3 hours. The mixture was filtered through Celite and concentrated to give an oil. Flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes yielded 6.8 g (99%) of the title product as an oil. NMR (CDCl3): δ1.38 (s, 3H); 1.47 (s, 3H); 2.20 (dd, 1H); 2.90 (m, 1H); 3.00 (dd, 1H); 3.60 (s, br, 2H); 3.78 (s, 3H). MS (Cl, NH3) m/e: 329 (M+ +18), 312 (M+ +1,2 100).
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C=O>[ClH:24].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:13]2[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)cc2)c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution (7 mL) of tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg) in N,N-dimethylformamide was added sodium hydride (60% in oil, 13 mg) and the mixture was stirred for 30 min. 4-Chlorobenzenesulfonyl chloride (62 mg) was added at room temperature and the mixture was stirred for 1 hr. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→4:1), and dissolved in methanol (10 mL). 4 mol/L Hydrogen chloride-ethyl acetate solution (1.5 mL) was added and the mixture was stirred at 65° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and crystallized from ethyl acetate to give the title compound as pale-red crystals (yield 39 mg, 40%).
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].[P:7]([OH:10])([OH:9])[OH:8].Cl>>[NH2:6][C:1]([P:7]([OH:10])(=[O:8])[OH:9])([P:7]([OH:10])(=[O:9])[OH:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(N)=O
Reactant: OP(O)O
Agent: Cl
Product: CC(C)C(N)(P(=O)(O)O)P(=O)(O)O

Procedure:
Into a mixture of 87 gm of isobutyric acid amide and 82 gm of phosphorous acid, hydrogen chloride gas was introduced for 8 hours. During this time the mixture was stirred and the temperature was held at 155° -160° C. By further processing of the reaction mixture analogously to Example 1, the 1-amino-2-methylpropane-1,1 -diphosphonic acid was isolated and purified. The yield was 8 gm.