Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH:40]4[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CI)C1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (152 mg, 286 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (85.1 mg, 286 μmol) and cesium carbonate (280 mg, 859 μmol) in dimethylformamide (3 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water, washed with water, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate that was used directly without purification. MS (M+H)+=702.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of i-Pr2NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0° C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture was cooled to −78° C. 4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorous stirring for 10 minutes, a mixture of the 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after 30 minutes, and the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was treated with a 10% aqueous HCl solution (15 mL), extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride gave 0.21 g (77%) desired product. MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [OH-:1].[Na+:2].C([OH:5])C.[CH:6]1[N:10]=[CH:9][N:8]([CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH:7]=1>O>[CH:6]1[N:10]=[CH:9][N:8]([CH2:11][C:12]([P:14]([O-:17])([OH:16])=[O:15])([P:18]([O-:20])([OH:21])=[O:19])[OH:13])[CH:7]=1.[OH2:5].[OH2:1].[OH2:5].[OH2:5].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (5% v/v)/Ethanol (95% v/v, 10 volumes per grams of ZLD-Ac form I) (8 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (5% v/v)/Ethanol (95% v/v, 10 volumes per grams of ZLD-Ac) (45 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 19.5 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Ethanol (1×10 ml) and dried in a vacuum oven at 50° C. for 20 hours to give 4.9 g (84%) of Zoledronate disodium crystal form XIII (LOD by TGA=3.4%). Purity by HPLC 99.9%.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:25])[N:15]([CH3:24])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C(=O)NC2CCCCC2)c(O)c2ccccc21
Yield: 69.5 %

Procedure:
Cyclohexylamine (2.0 mL, 18.20 mmol) was added to a solution of Compound 1 (2.25 g, 9.1 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered to yield 1.9 g (70%) of white solids. M.P. 145° C. 1H NMR (DMSO-d6): δ 1.26 (m, 1H), 1.38 (m, 4H), 1.54 (m, 1H), 1.68 (m, 2H), 1.86 (m, 2H), 3.62 (s, 3H), 3.87 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 10.46 (s, 1H), 17.46 (s, 1H). EIMS m/z 301 (M+1), 323 (M+23). Anal. (C17H20N2O3) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:61](O)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([C:61](=[O:68])[C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCN(C(=O)c2ccccc2)CC1
Yield: 14.2 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol), HATU (73 mg, 0.19 mmol), and benzoic acid (24 mg, 0.19 mmol) in DMF (5 mL) was stirred for 12 hours at room temperature The reaction mixture concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (17 mg, 14%). MS: 629.5 (MH+); HPLC Rf: 2.5 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:27])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:28][CH3:29])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2OC)nc1Cl
Yield: 87 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (102e) (90 mg, 0.21 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (3 mL), to obtain 74 mg of the title compound as a light pink solid (85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[I:32].[C:33](OCC)(=O)C>CN(C=O)C>[I-:32].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N+:22]2([CH3:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)c3cccc(OCc4ccccc4)c3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 3-benzyloxy -4′-(piperidinomethyl)benzanilide (560 mg) dissolved in DMF (3 ml) was added methyl iodide (261 μl), and the resulting mixture was stirred at room temperature for 14 hours. Ethyl acetate (100 ml) was added to this reaction mixture, and the resulting precipitate was collected by filtration to obtain 1-[4-(3-benzyloxybenzoylamino)benzyl]-1-methylpiperidinium iodide (compound 87) (724 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1.[CH3:18][N:19]=[C:20]=[S:21]>C(O)C>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:20]([NH:19][CH3:18])=[S:21])[CH2:11]2)[N:9]=1
Reactant: CN=C=S
Reactant: CN=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: CCO
Product: CN=C(N)Nc1nc(C2CCCC(NC(=S)NC)C2)cs1
Yield: 90.5 %

Procedure:
To a solution of 2-(2-methylguanidino)-4-(3-aminocyclohexyl)thiazole (0.3 g.) in ethanol (50 ml.) was added methylisothiocyanate (0.1 g.) and the solution heated under reflux for 2 hours. Evaporation of the reaction mixture and crystallisation of the residue from methanol/ethyl acetate gave 2-(2-methylguanidino)-4-[3-(3-methylthioureido)cyclohexyl]thiazole (0.35 g.), m.p. 214°-215° (decomp.).
Reaction SMILES: Cl.[C:2]1([O:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][O:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NOc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-phenylhydroxylamine hydrochloride (6.9 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (6.2 mmol, 1.29 g), diisopropylethylamine (13.1 mmol, 2.28 mL) and andhydrous THF (15 mL) were combined under nitrogen. After stirring for 2 hours at room temperature, a few crystals of 4-dimethylaminopyridine were added and the flask was re-sealed. After another 2 hours, 4 mL of N,N-dimethylformamide was injected and the reaction stirred for an additional 15 hours. The resulting red solution was concentrated to an oil and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum. The resulting dark brown residue was purified by silica gel chromatography (3:1 hexanes/ethyl acetate) providing 360 mg (21%) of a redish solid. H1-NMR (CDCl3): δ7.89 (2H,d), 7.30-7.20 (3H,m), 7.11 (2H,d), 7.02 (1H,s), 7.00 (2H,d), 3.88 (3H,s).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C=O)C.C(#N)C>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[NH2:2])=[CH:14][CH:13]=1
Reactant: Nc1cccc(S)c1
Reactant: COc1ccc(CCl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CSc2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium ydride (99%, 8.22 g) was added in portions of a stirred solution of 3-aminothiophenol (44.23 g) in dry DMF (132 ml) at 0° . After 30 minutes a solution of 4-methoxybenzyl chloride (53.61 g) in acetonitrile (132 ml) was added dropwise and the mixture was stirred 30 minutes at 0° and 1 hour more at ambient temperature. The mixture was poured into ice-water (200 ml) and the resulting solid was collected by filtration and dried in air to provide the title compound, m.p. 85°-86°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.56 g, 1.2 mmol), 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (0.27 g, 1.12 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.912 g, 2.4 mmol) and iPr2NEt (1.5 mL, 8.4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (25-80 g Analgix column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (222 mg, 28%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3S+H [(M+H)+]: 660.2315. found: 660.2312.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>O1CCCC1.O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCC(O)CO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCC(O)CO
Reaction time: 40 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-1,3-dinitrobenzene (4.05 g, 20.0 mmol) and triethylamine (3.35 mL, 24.0 mmol) in tetrahydrofuran (70 mL) was added a solution of 3-amino-1,2-propandiol (3.64 g, 40.0 mmol) in tetrahydrofuran (10 mL) at room temperature. After 40 hr, the reaction mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound (5.02 g, 19.6 mmol, 98%) as a yellow solid.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[CH2:22]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CO>ClCCl>[CH2:22]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:35]([OH:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC[C@H](O)c2ccccc21
Reaction time: 0.25 h
Yield: 393.6 %

Procedure:
To a mixture of 0.5 mL of (R)-2-methyl-CBS-oxazaborolidine solution and 3 mL of dichloromethane was added dropwise 0.07 mL of 1.0M borane-dimethylsulfide complex at 25° C., and the mixture was stirred at the same temperature for 15 minutes. To the solution was added dropwise a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane over about 10 minutes. Furthermore, to the reaction solution were added 0.07 mL of 1.0M borane-dimethylsulfide complex and a solution of 141 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline in 2.5 mL of dichloromethane alternately with total 4 times. To the reaction solution was added dropwise 1 mL of methanol, and the reaction solution was concentrated. To the resulting residue were added 10 mL of dichloromethane and 10 mL of phthalate buffer (pH4.0), and the aqueous layer was removed, and then water was added. The organic layer was separated, dried over magnesium sulfate, and then filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (solvent; n-hexan/ethyl acetate=4/1) to give 559 mg of (4S)-1-benzyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroquinoline (yield: 99%, optical purity: 96% ee).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[N:7])[CH3:2].[NH2:10][OH:11]>CCO>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6](=[N:10][OH:11])[NH2:7])[CH3:2]
Reactant: CCN(CC)CCC#N
Reactant: NO
Solvent: CCO
Product: CCN(CC)CCC(N)=NO
Yield: 92.6 %

Procedure:
A solution of 3-(diethylamino)propanenitrile (1 g, 8 mmol) and NH2OH (50% in water, 0.73 cm3, 11.9 mmol) in EtOH (10·cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line until it slowly solidified to give give 3-(diethylamino)-N′-hydroxypropanimidamide (1.18 g, 92.6%) as a white solid, mp 52-54° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:9]=2)[N:5]=[C:4]([C:21]#[N:22])[N:3]=1.Cl.[NH2:24][OH:25].CCN(C(C)C)C(C)C>CCO>[OH:25][NH:24][C:21]([C:4]1[N:3]=[C:2]([CH3:1])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:9]=2)[N:5]=1)=[NH:22]
Reactant: NO
Reactant: Cc1nc(C#N)nn1Cc1cccc(N2CCN(C)CC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(C(=N)NO)nn1Cc1cccc(N2CCN(C)CC2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-1,2,4-triazole-3-carbonitrile (120 mg, 0.40 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (31 mg, 0.44 mmol) and DIPEA (141 μL, 0.81 mmol). The reaction was stirred at 80° C. for 2 h before the solvent was removed under reduced pressure. The crude product was used without further purification. MS (ES+) C16H23N7O requires: 329 found: 330 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8](=[O:14])[CH2:9][C:10]([O:12]C)=[O:11].[Li+].[OH-].O.Cl>C(Cl)Cl.C1COCC1.O>[O:14]=[C:8]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1nccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of 2-aminothiazole (2.0 g, 19.97 mmol) in dry DCM (30 ml) at 0° C. was added TEA (4.03 g, 2 eq, 39.94 mmol) and methyl 3-chloro-3-oxopropanoate (3.0 g, 1.1 eq, 21.97 mmol). The reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated to dryness, dissolved in EtOAc and washed well with water. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated. The resultant solid was triturated with Et2O and used directly in the next step with no additional purification (1.1 g, 30% yield). To a solution of the ester 128 (500 mg, 2.49 mmol) in THF/water (1:1, 20 ml) was added LiOH×H2O (209 mg, 2 eq, 4.98 mmol) and the mixture stirred for 2 hrs at room temperature. The mixture was neutralized with 1 M HCl solution and adsorbed onto silica gel. Purification by column chromatography (60% EtOAc in hexanes) afforded the acid 129 as a white solid (320 mg, 69% yield). MS (m/z): 187.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.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:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]([C:8]3[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:22]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1OCc1ccccc1
Reactant: CCOC(=O)c1ccccc1-c1ccccc1Br
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: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccccc1-c1ccccc1-c1ccc(Cl)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 47 %

Procedure:
A mixture of ethyl 2′-bromo-2-biphenylcarboxylate (153 mg, 0.5 mmol), {4-chloro-2-[(phenylmethyl)oxy]phenyl}boronic acid (144 mg, 0.55 mmol), potassium carbonate (552 mg, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was stirred and heated at 90° C. under nitrogen for 18 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:19) to give 104 mg of colourless gum.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.Cl.[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:2][C:3]2[NH:4][C:5](=[O:8])[NH:6][N:7]=2)[CH2:19][CH2:20]1
Reactant: O=c1[nH]nc(CCl)[nH]1
Reactant: Fc1ccccc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(CN2CCC(COc3ccccc3F)CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
After adding 150 mg of 5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one, 331 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture and the insoluble portion was filtered out to obtain the title compound (70 mg, 21% yield).