Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:34][O:35][CH:36]1[CH:41]([O:42][CH3:43])[CH:40]([O:44][CH3:45])[CH:39]([CH3:46])[O:38][CH:37]1[O:47][C:48](=O)[O:49]C1C=CC([N+]([O-])=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:34][O:35][C@@H:36]1[C@H:41]([O:42][CH3:43])[C@@H:40]([O:44][CH3:45])[C@H:39]([CH3:46])[O:38][C@H:37]1[O:47][C:48](=[O:49])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: COC1C(C)OC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)C1OC
Reactant: Nc1ccc(-c2ccnc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(-c3ccnc(-c4ccc(C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture cooled in an ice bath of 126 mg (0.40 mmol) of 4-[2-(4-trifluoromethylphenyl)-pyrimidin-4-yl]-phenylamine in 1 mL of dry toluene was added dropwise via syringe 1.6 mL (0.80 mmol) of a 0.5 M solution of potassium hexamethyldisilazide in toluene over a 10-15 minute period. To this mixture was then added dropwise a solution of 148 mg (0.400 mmol) of carbonic acid 4-nitrophenyl ester 3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl ester in 2 mL of toluene. The contents were allowed to gradually warm to room temperature and stir overnight and were added to cold saturated sodium bicarbonate. The mixture was extracted two times with chloroform and the combined extracts were dried (MgSO4). Concentration gave 130 mg which was purified by chromatography on silica gel using 9:1 DCM/EtOAc to afford 64 mg (29%) of Compound 232. 1HNMR (300 MHz, CDCl3) δ 8.87 (d, J=5.2 Hz, 1H), 8.71 (d, J=8.2 Hz, 2H), 8.26 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.65 (d, J=5.2 Hz, 1H), 7.63 (d, 2H), 6.86 (br s, 1H), 6.26 (d, J=1.9 Hz, 1H), 3.74-3.70 (m, 2H), 3.61 (s, 3H), 3.60 (s, 3H), 3.57 (s, 3H), 3.53 (m, 1H), 3.24 (t, J=9.5 Hz, 1H), 1.36 (d, J=6.0 Hz, 3H); MS (API-ES+) 549 ([M+H]+, 10), 358 (100); mp 176-179° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Sn](C)(C)C)[N:10]=1.[Br:15]C1SC=C(Br)N=1.C1(S)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([Br:15])[N:10]=1
Reactant: Brc1csc(Br)n1
Reactant: C[Sn](C)(C)c1csc(-c2cccs2)n1
Agent: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1csc(-c2cccs2)n1
Temperature: 45 °C
Yield: 84 %

Procedure:
Synthesis of 2-Thiophenyl-4-(trimethylstannyl)thiazole 381 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in ethanol (0.1 M) and treated with thiophenol (3.0 equiv) and solid sodium hydroxide (3.0 equiv). The reaction mixture was heated at 45° C. for 4 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-thiophenyl-4-bromothiazole 380, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:48][S@@](C(C)(C)C)=O)([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:16][C:17]2[N:18]=[N:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)([NH2:48])[CH2:16][C:17]2[N:18]=[N:19][NH:20][N:21]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:11])[F:12])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@](Cc1nn[nH]n1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-trityl-2H-tetrazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.079 mmol) in MeOH (3 mL) was added 4 N HCl in dioxane (1 mL). The reaction mixture was stirred at room temperature for 20 min, then concentrated to yield (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine. LCMS: RT=2.66 min [M+H] 418.55 (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 4 min gradient, flow rate 4 mL/min, wavelength 220 nm). To a solution of ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2H-tetrazol-5-yl)ethanamine in THF (3 mL) and MeOH (0.5 mL) was added (diazomethyl)trimethylsilane (2.0 M in hexanes, 0.05 mL). After stirring at room temperate for 20 min, the reaction mixture was concentrated and purified by ISCO flash column chromatography (silica gel, EtOAc) to give ((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-(2-methyl-2H-tetrazol-5-yl)ethanamine (10 mg, yield: 30%). LCMS: RT=2.83 min [M+H] 432.57 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[C:27]([CH2:33][CH3:34])[NH:28][C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:25]1[N:26]=[C:27]([CH2:33][CH3:34])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a mixture of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (197 mg, 0.573 mmol), 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (100 mg, 0.573 mmol) and HATU (218 mg, 0.573 mmol) in DMF (4.0 ml) was added diisopropylethyl amine (0.200 ml, 1.146 mmol) and the mixture was stirred for 1 hr at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-ethyl-1H-imidazole-5-carboxamide (135 mg, 0.269 mmol, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (s, 2H), 7.80 (s, 1H), 7.74 (s, 1H), 7.50 (dd, 1H), 7.36 (t, 1H), 4.52 (d, 2H), 2.58 (q, 2H), 1.16 (t, 3H). LC-MS (ES+) m/z 501.10, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.I[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
4-Chloroaniline (15.5 g, 122 mmol), ethyl iodoacetate (14.4 mL, 122 mmol) and sodium acetate (20.0 g, 244 mmol) were stirred in water (24 mL) at 90° C. for 3 hours. After cooling to room temperature the precipitate was collected by filtration, washing with water (40 mL), to yield the title compound (25.6 g, 98%) as brown prisms. 1H NMR (400 MHz, CDCl3) δ 1.29 (3H, t), 3.86 (2H, s), 4.22 (2H, q), 6.53 (2H, d), 7.14 (2H, d).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@H:8]([C:10](=[O:39])[NH:11][C@H:12]([C:16]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C@H:19]1[CH2:27][NH:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[CH3:6][NH:7][C@@H:8]([CH3:9])[C:10]([NH:11][C@H:12]([C:16]([N:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH2:20][C@H:19]1[CH2:27][NH:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:39]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccc2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1CNc1ccc2ccccc2c1)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl-((S)-1-{(S)-2-methyl-1-[(S)-2-(naphthalen-2-ylaminomethyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-propylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester (27 mg, 0.05 mmol) in 1,4-dioxane (0.5 mL) was added 4 M HCl in dioxane (0.5 mL) dropwise at 0° C. The reaction mixture was stirred at rt for 3 h and then the solvent was removed in vacuo to give (S)-2-methylamino-N—{(S)-2-methyl-1-[(S)-2-(naphthalen-2-ylaminomethyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-propyl}-propionamide hydrochloride (23 mg), m/z=460 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.O>O1CCCC1.CN(C)C=O>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([O:3][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COCCOCCl
Reactant: COc1cc(O)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
1.8 g (41.2 mmol) of 60% sodium hydride is added in portions to a solution at 0° C. of 5.7 g (37.5 mmol) of 4-hydroxy-2-methoxy-benzaldehyde diluted in 30 ml of tetrahydrofuran and 30 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 30 minutes and then 4.7 ml (41.2 mmol) of 2-methoxyethoxymethyl chloride is added dropwise. The reaction mixture is stirred at room temperature for 45 minutes and then the reaction mixture is treated by adding water and extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The raw product is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 70/30 to give 8.6 g (95%) of 2-methoxy-4-(2-methoxy-ethoxymethoxy)-benzaldehyde in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:54][C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 0.9 mL DMF was stirred at room temperature for 3 hours, then meta-toluidine (0.016 mL, 0.15 mmol) added and the reaction continued for 23 hours at room temperature. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as a light tan solid (22 mg, 62%). 1H NMR (DMSO-d6) δ: 10.07 (s, 1H), 8.13 (s, 1H), 7.54-7.62 (m, 2H), 7.50 (s, 1H), 7.31-7.41 (m, 2H), 7.19-7.26 (m, 2H), 6.92 (d, J=7.6 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.31 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]=[C:21]([NH2:24])[NH:22][CH3:23])=[O:19])=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]=[C:21]([NH2:24])[NH:22][CH3:23])=[O:19])=[CH:12]2
Reactant: CNC(N)=NC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2cc(O)ccc2[nH]1
Temperature: 25 °C

Procedure:
In 50 ml of methanol was dissolved 0.83 g (2.58 mmol) of 5-benzyloxy-1-methyl-2-indoloylguanidine obtained in Example 32. While stirring at room temperature, 0.30 g of 10% palladium/carbon was added to the solution in a nitrogen flow and catalytic hydrogenation was then conducted at ambient temperature under normal pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-hydroxy-1-methyl-2-indoloylguanidine. The 5-hydroxy-1-methyl-2-indoloylguanidine was further treated with hydrogen chloride/methanol to give 0.37 g (68.6%) of 5-hydroxy-1-methyl-2-indoloylguanidine hydrochloride.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].Br[CH:5]([C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:6](=O)[CH3:7].C(=O)(O)[O-].[Na+]>ClCCl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]2[O:2][CH:1]=[N:3][C:6]=2[CH3:7])=[CH:10][CH:11]=1)#[N:14]
Reactant: NC=O
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C#N)cc1
Yield: 63.9 %

Procedure:
A stirred, two-phase mixture of formamide (0.6 ml, 15 mmol) and 4-(1-bromo-2-oxopropyl)benzonitrile (0.8 g, 3.4 mmol) was heated to 120° for 2 hours. After cooling, dichloromethane (15 ml) and saturated aqueous sodium bicarbonate (10 ml) were added, the organic phase was separated, dried (magnesium sulphate) and the solvent removed under reduced pressure to yield 0.4 g of an amorphous yellow solid. The product was purified by silica gel chromatography, eluting with dichloromethane to yield the title compound (0.29 g, 47%) as a pale yellow solid, m.p. 120°-121° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([Cl:19])[CH:10]=1)(=O)=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl:19][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][O:17][CH3:18]
Reactant: COCOc1ccc(CCCOS(C)(=O)=O)cc1Cl
Reactant: c1c[nH]cn1
Product: COCOc1ccc(CCCn2ccnc2)cc1Cl
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(3-chloro-4-methoxymethoxyphenyl)propyl methanesulfonate was reacted with imidazole to obtain 1-[3-(3-chloro-4-methoxymethoxyphenyl)propyl]imidazole as an oil. The yield was 65%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH2:15])=[C:10]([CH3:16])[CH:9]=1.O>C(#N)C>[CH2:5]([O:4][C:2](=[O:3])[NH:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[CH3:16])[CH3:6]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 97 %

Procedure:
Ethyl chloroformate (0.55 g, 0.48 mL, 5 mmol) was added to a solution of 4-bromo-2,6-dimethyl-phenylamine (1.0 g, 5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.32 g, 97% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:28])([F:27])[CH2:15][CH:16]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17].[I:29]I>O1CCCC1>[F:28][C:14]([F:13])([F:27])[CH2:15][C:16]([I:29])([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: CC(CC(F)(F)F)S(=O)(=O)c1ccccc1
Reactant: II
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(I)(CC(F)(F)F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of 28.5 mmol diisopropylamine in 18 ml tetrahydrofuran at −78° C. was added dropwise 28.5 mmol n-butyllithium solution (1.6 M in hexane) and the mixture was then warmed to room temperature. The resulting solution was then added dropwise over 50 min to a solution of 19.0 mmol rac-(4,4,4-trifluoro-butane-2-sulfonyl)-benzene in 30 ml tetrahydrofuran at −78° C. and stirring continued for a further 15 min at −78° C. Finally, a solution of 20.9 mol iodine in 15 ml tetrahydrofuran was added dropwise over 15 min and stirring continued for a further 15 min at −78° C. and then the reaction mixture was allowed to warm to −20° C. The reaction mixture was quenched by addition of 1 M hydrochloric acid and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed sequentially with aqueous sodium thiosulfite solution and with brine and then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a yellow oil (yield 87%). EI-MS (m/e): 377.9 (M+, 4%), 237.0 ([M−PhSO2]+, 40%), 142.0 (PhSO2H+, 100%), 125.1 (PhSO+, 93%), 78.2 (PhH+, 40%), 77.2 (Ph+, 31%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])=[O:11])=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:21])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S, 4R)-2-[(t-butoxycarbonylamino)methylcarbonyl]aminomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.30 g) in a mixture of anisole (1 ml) and trifluoroacetic acid (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated under reduced pressure to give (2S, 4R)-2-(aminomethylcarbonyl)aminomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. To a solution of the compound obtained above in a mixture of water (25 ml) and tetrahydrofuran (25 ml) was added a solution of potassium cyanate (4.75 g) in water (15 ml) at 40°~50° C., keeping the pH between 4-5 with concentrated hydrochloric acid. Tetrahydrofuran was removed by evaporation to give an aqueous solution. The aqueous solution was adjusted to pH 6.0 with 1N hydrochloric acid, subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (50 ml), washed with water, and eluted with a mixture of methanol and water (50:50 v/v). The fractions containing the desired compound were collected, concentrated under reduced pressure, and recrystallized from a mixture of methanol and diisopropyl ether to give (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[(ureidomethylcarbonyl)aminomethyl]pyrrolidine (3.93 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].S(O)(O)(=O)=O.ON.[OH-].[Na+].ONS(O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc(C=CC(=O)O)ccc1[N+](=O)[O-]
Agent: NO
Agent: O=S(=O)(O)NO
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(CCC(=O)O)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
3-methoxy-4-nitrocinnamic acid (6.2 g) and 12.3 g of hydroxyamine sulfate were dissolved in 250 ml of water. To the solution was added 7.1 g of sodium hydroxide, and further alternately added a solution of 18 g of sodium hydroxide in water (27 ml) and 19.2 g of hydroxyamine-o-sulfonic acid little by little, maintaining the pH at 9. The mixture was stirred at 5° C. for 6 hours and then insoluble substances were removed by filtration. The resultant filtrate was cooled on ice and was added with 6 N sulfuric acid to adjust the pH to 2. Crystals formed were collected by filtration, washed with water and dried; 1.27 g of crystalline 3-(3-methoxy-4-nitrophenyl)propionic acid was thus obtained.
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH3:7])[C:4]([NH2:6])=[O:5].C([O-])(=O)C.[Na+].[Cl:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[C:15]=1[CH:16]=O.[B-]C#N.[Na+].Cl>CO>[Cl:13][C:14]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[C:15]=1[CH2:16][NH:2][C@@H:3]([CH3:7])[C:4]([NH2:6])=[O:5]
Reactant: C[C@H](N)C(N)=O
Reactant: O=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Br
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: C[C@H](NCc1c(Cl)ccc([N+](=O)[O-])c1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a homogeneous solution of 8.42 parts of (S)-2-aminopropanamide monohydrobromide, 12.26 parts of sodium acetate and 79 parts of methanol there were added 10.96 parts of 2,6-dichloro-3-nitrobenzaldehyde and, after 1/2 hour, a mixture of 3.77 parts of sodium cyanotrihydroborate and 7.9 parts of methanol. The whole was stirred for 45 min at room temperature. After acidifying to pH 1 with HCl (3N), stirring was continued overnight. The reaction mixture was evaporated and the residue was basified with NaHCO3 (sat.). The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was recrystallized from 2-propanol, yielding 10.29 parts (70.7%) of (S)-2-[[(2,6-dichloro-3-nitrophenyl)methyl]amino]propanamide (interm. 69).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16]([NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17].[NH2:36][C:37]1[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=1.CN(C)C=O>C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16](/[N:18]=[C:19](\[NH:36][C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1)/[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17]
Reactant: O=C(NC(=S)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Reactant: Nc1cncc(O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(/N=C(\Nc1cncc(O)c1)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (43 mg, 0.278 mmol), 3,4-difluoro-N-((3-(trifluoromethyl)phenyl)carbamothioyl)benzamide (100 mg, 0.278 mmol) and 5-aminopyridin-3-ol (31 mg, 0.278 mmol) and were combined in a glass vial and dry dimethylformamide (1.5 mL) was added. The vial was capped and the mixture was heated at 65° C. for 2 h. After cooling the mixture to room temperature, the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was evaporated onto silica gel and the product was purified by chromatography eluting with 50-100% ethyl acetate in hexanes to give (Z)-3,4-difluoro-N-(((5-hydroxypyridin-3-yl)amino)((3 (trifluoromethyl)phenyl)amino)methylene)benzamide as a colorless oil.