Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>CN(C=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][C:11](=[N:17][OH:18])[CH2:10]1
Reactant: NO
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ON=C1CCCC(c2ccc(O)cc2O)C1
Reaction time: 3 h
Yield: 86 %

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclohexanone (13 mg), hydroxylamine hydrochloride (0.0065 g), and triethylamine (16 μl) were heated at 80° C. in DMF (3 ml). After 3 hr, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 3:2 v/v) to furnish the title compound as a white solid (12 mg, 86%). δH(CD3OD) 1.4-2.0 (6H, overlapping m), 2.10 (0.5H, m), 2.20 (0.5H, m), 2.35 (0.5H, m), 2.46 (0.5H, m), 2.94 (1H, m), 6.22-6.26 (2H, overlapping m), 6.92-6.95 (1H, overlapping m); m/z (ES+) 222 (M+H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[OH-].[NH4+:11]>COCCOC.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(N)cc(Cl)n1
Temperature: 23 °C
Reaction time: 336 h
Yield: 60 %

Procedure:
A stirred suspension of 4,6-dichloro-2-methylpyrimidine (39.5 g, 244 mmol) in 1,2-dimethoxyethane (50 mL) in a sealable pressure reaction vessel was treated with concentrated aqueous ammonium hydroxide (40 mL). The mixture was vigorously stirred at 23° C. for 14 days in the sealed vessel. The mixture was then diluted with water and filtered. The isolated white solids were rinsed with water and dried in vacuo to afford 6-chloro-2-methyl-4-aminopyrimidine (20.94 g, 146 mmol, 60% yield): mp 191°-192° C.; Rf 0.49 (EtOAc); 1H NMR (DMSO-D6, 200 MHz)δ7.09 (br s, 2H, NH), 6.24 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].[Br:9][C:10]1[N:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][CH:11]=1>>[Br:9][C:10]1[N:15]=[C:14]([CH2:16][N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]([OH:8])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=C(O)C1CCCN1
Product: O=C(O)C1CCCN1Cc1cccc(Br)n1

Procedure:
15] 2-Pyrrolidine carboxylic acid (0.68 g, 5.92 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (1.0 g, 5.38 mmol) to give 1-(6-bromopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid as a white solid. MS m/z: 285.1 (M+H). Calc'd for C11H13BrN2O2—285.14.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 43.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.56 g, 7.5 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.26 g, 7.5 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.7 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.OS(O)(=O)=O.[NH4+].[OH-].[CH3:19]O>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:19])=[O:10])[CH2:7][CH2:8]1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)C1CCC(CO)CC1
Reaction time: 2 h
Yield: 83 %

Procedure:
To 4-hydroxymethylcyclohexanecarboxylic acid (TCI-JP, 0.50 g, 3.2 mmol) in 10 mL CH3OH was added 0.50 mL concentrated H2SO4. This mixture was warmed to reflux and allowed to stir for 2 h. The reaction mixture was then cooled and NH4OH was added until the solution tested basic using pH paper. The mixture was then extracted with 3×5 mL ethyl acetate. The combined organic extracts were washed with saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 0.45 g of the title compound (0.26 mmol, 83% yield). MS (DCI/NH3) m/z 190 (M+NH4)+.
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17].[CH:19](=O)[CH2:20][CH3:21].[BH4-].[Na+].C(O)(=O)C>CO>[NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:19][CH2:20][CH3:21])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CCC=O
Reactant: CC(C)OCN1C(=O)C2=C(CN)C=NC2=NC1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNCC1=C2C(=O)N(COC(C)C)C(N)N=C2N=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
In 5.0 ml of dry methanol were dissolved 251 mg of 2-amino-5-aminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one and 64 mg of propionaldehyde and the solution was allowed to stand under stirring at room temperature for 30 min. Then, 20 mg of sodium borohydride was added and the mixture was reacted at room temperature for an hour. The excess reagent was decomposed with a small amount of acetic acid, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 76 mg of 2-amino-5-propylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of this product was dissolved in 30 ml of 2 N--HCl and, after nitrogen purging, hydrolyzed under heating at 70° C. for 6.5 hours. The solvent was then evaporated off under reduced pressure to give 73 mg of the desired compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[CH3:28][N:29]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30]1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Product: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN(C(=O)C(F)(F)F)[C@H]2C3)cn1
Yield: 32 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and 1-methyl-pyrazol-4-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 32% of theory; LC (method 1): tR=3.88 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N[C:14](N)=[O:15]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[NH:11][C:14](=[O:15])[NH:12][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: NC(N)=O
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2[nH]1

Procedure:
A mixture of 14 g (0.074 mol) of 4-chloro-5-nitro-1,2-benzenediamine and of 13.44 g (0.226 mol) of urea is heated at 180° C. for 4 hours. The reaction mixture is cooled and evaporated to dryness. The residue is taken up in methanol and evaporated again. The residue is triturated in ether and a solid is obtained which is filtered. The product is used as is in the subsequent stages.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]12)=O.[C:22]([NH2:25])(=[O:24])[CH3:23]>>[CH3:23][C:22]1[O:24][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]=2[CH2:7][CH2:8][N:9]2[C:19](=[O:20])[CH2:18][NH:17][C:16](=[O:21])[CH:15]=[C:10]23)[N:25]=1
Reactant: O=C1C=C2c3cccc(C(=O)CBr)c3CCN2C(=O)CN1
Reactant: CC(N)=O
Product: Cc1nc(-c2cccc3c2CCN2C(=O)CNC(=O)C=C32)co1
Temperature: 130 °C
Yield: 53.9 %

Procedure:
111-3. A flask was charged with 9-(2-bromoacetyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (230 mg, 0.66 mmol) and acetamide (233 mg, 3.95 mmol) and the solid mixture was heated to 130° C. for 15 min. The resulting brown liquid mass was partitioned in AcOEt and H2O. The org. phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH (100:0 to 90:10) gave the title compound (110 mg) as a beige powder. UPLC-MS: MS 310.2 (M+H+); UPLC rt 0.67 min.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:39])[CH3:38]>>[Cl:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:38])[CH3:39])=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: NC(=O)c1c(OCc2c(F)cc(Cl)cc2F)nsc1NC(=O)Oc1ccccc1
Reactant: CC(C)NCCC(O)CCN
Product: CC(C)NCCC(O)CCNC(=O)Nc1snc(OCc2c(F)cc(Cl)cc2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-chloro-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H), 3.34 (t, 2H, J=6.4 Hz), 2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:27]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (0.97 g, 3 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.21 g, 3.15 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.9 g, 2.7 mmoles).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@H:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]([OH:37])=[O:36])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), D-phenylalanine (296 mg, 1.8 mmol) and NaOMe (73 mg, 1.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-60% EtOAc/hexanes+2% AcOH) to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 1 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as an off-white solid. MS: (+) m/z 469.02 (M+1).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[CH2:15][C:14]3=[C:16]([C:34]#[N:35])[C:17]([Cl:33])=[CH:18][C:19]([CH:20]([N:22]4[C:26]5=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]5[C:24]([CH3:32])=[N:23]4)[CH3:21])=[C:13]3[O:12][CH:11]([CH3:36])[CH2:10]2)[CH2:6]1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C=O>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:20]([C:19]3[C:13]4[O:12][CH:11]([CH3:36])[CH2:10][N:9]([CH:7]5[CH2:6][CH:5]([NH:4][C:44](=[O:46])[CH3:45])[CH2:8]5)[CH2:15][C:14]=4[C:16]([C:34]#[N:35])=[C:17]([Cl:33])[CH:18]=3)[CH3:21])[N:23]=[C:24]([CH3:32])[C:25]=12
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(N)C2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CC(N2Cc3c(C#N)c(Cl)cc(C(C)n4nc(C)c5c(N)ncnc54)c3OC(C)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 4-(3-aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (10 μL, 0.1 mmol). To this mixture was added acetic anhydride (7.7 mg, 0.075 mmol). The reaction was stirred for 1 h at room temperature, and the reaction was purified without workup by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers: Peak #1 (Example 67): LCMS calculated for C25H30ClN8O2 (M+H)+: m/z=509.2; found: 509.2; Peak #2 (Example 68): LCMS calculated for C25H30ClN8O2 (M+H)+: m/z=509.2; found: 509.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[O:15][CH2:14][CH2:13][N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[Cu](C#N)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[O:15][CH2:14][CH2:13][N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1)#[N:34]
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CSc2ccccc2Br)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CSc2ccccc2C#N)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution (7.8 mL) of tert-butyl (6R,7R)-6-{[(2-bromophenyl)sulfanyl]methyl}-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (424 mg) in DMF was added copper cyanide (139 mg), and the mixture was stirred under an argon atmosphere at 150° C. overnight. The reaction mixture was filtered through celite, distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (146 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][N:11]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CN2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCC2CN2)cc1
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 2-[(benzyloxy)methyl]-1-tritylaziridine (1.28 g, 3.16 mmol) in dichloromethane (13 mL), trifluoroacetic acid (1 mL) and triethylsilane (2.0 mL) was added and stirred at the temperature for 1 h. The resultant mixture was concentrated under vacuum, and the residue was partitioned between ether and brine. The organic extract was dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 50-100% THF in hexane. Collection and concentration of appropriate fractions provided 2-[(benzyloxy)methyl]aziridine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:9]O)[CH:5]=[N:6][C:7]=1[CH3:8].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]([CH2:9][Cl:15])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(CO)cnc(C)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1c(CCl)cnc(C)c1Cl
Reaction time: 3 h

Procedure:
The above (5-chloro-4-methoxy-6-methylpyridin-3-yl)methanol (520 mg) was dissolved in 20 ml of chloroform, and thionyl chloride (0.38 ml) was then added to the solution under cooling on ice. The resulting mixture was stirred at the same temperature as above for 3 hours. Thereafter, the reaction solution was concentrated, and ethyl acetate was then added to the concentrate. The resulting mixture was washed with saturated sodium bicarbonate solution, water, and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The residue was purified by silica gel chromatography (ethyl acetate-hexane), so as to obtain the title compound (550 mg) as an oily substance.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:44][C:45](=[O:50])[C:46](Br)([CH3:48])[CH3:47])([CH3:43])([CH3:42])[CH3:41]>CS(C)=O>[C:40]([O:44][C:45]([C:46]([O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:48])[CH3:47])=[O:50])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
To ethyl (Z)-2-(hydroxyimino)-2-[2-(triphenylmethyl)aminothiazol-4-yl]acetate (46 g) were added potassium carbonate (27.6 g), tert-butyl-2-bromo-2-methylpropionate(24.1 g) and dimethylsulfoxide (300 ml), and then the solution was stirred for 6 hours at room temperature. Afterwards distilled water (100 ml) was added therein, the solution was stirred again for an hour. The precipitates were filtered, washed with distilled water(500 ml), and dried under reduced pressure to give the above-indicated compound(45.1 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[CH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(Cl)c(Cl)c1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(C=Cc2ccc(Cl)c(Cl)c2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture comprising 7.0 g of 1-{2-(3,4-dichlorophenyl)vinyl}-2-nitroiminoimidazolidine, 7.5 g of 2-chloro-5-chloromethylpyridine, 6.4 g of potassium carbonate and 50 ml of dimethylsulfoxide was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgS04) and concentrated o give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 5.7 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(3,4-dichlorphenylvinyl) -imidazolidine.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].O.[OH-].[Li+]>CS(C)=O>[CH2:11]([O:10][C:8]([C:3]1[N:4]=[C:5]([CH3:7])[S:6][C:2]=1[NH:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])=[O:9])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1nc(C)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1nc(C)sc1Nc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g; 645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) in dimethylsulphoxide (1 L) to a 2 L 3-necked RB flask equipped with reflux condenser, thermometer, mechanical stirrer. Add lithium hydroxide monohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3 hours under nitrogen. Cool the purple solution and pour onto ice/water, allow to stir for one hour, filter and wash with water, dry at 50° C. under reduced pressure to give 190 g (96%) as an orange solid: mass spectrum (m/e): 308 (M+1); 1HNMR(300 MHz, DMSO, ppm): 1.25 (tr, 3H), 2.56 (s, 3H), 4.25 (q, 2H), 7.20 (m, 1H), 7.78 (m, 2H), 8.20 (d, 1H), 11.42 (s, 1H, NH). 13CNMR(75 MHz, DMSO, ppm): 24.4, 29.2, 71.2, 127.8, 132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula: C13H13N3O4S.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([Si:4]([CH3:25])([CH3:24])[O:5][CH2:6][CH:7]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:8][O:9][Si:10]([CH3:16])([CH3:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:3].[CH2:27](O)[CH:28]([CH3:30])[CH3:29].[I-].[K+]>O.ClCCl>[CH2:27]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH:7]([CH2:8][O:9][Si:10]([CH3:15])([CH3:16])[C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:6][O:5][Si:4]([CH3:24])([CH3:25])[C:2]([CH3:26])([CH3:1])[CH3:3])=[CH:18][CH:19]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CO
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1ccc(C(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)aniline (193.1 mg, 0.488 mmol), isobutanol (0.090 mL, 0.976 mmol), potassium iodide (162 mg, 0.976 mmol), [Cp*IrCl2]2 (3.89 mg, 4.88 μmol) and water (3 mL) was prepared in a microwave vial. The reaction vessel was sealed and heated by microwaves to 150° C. for 1.5 hours. After cooling, the solution was diluted with water and dichloromethane (20 mL), then the organic phase separated (hydrophobic frit) and concentrated in vacuo. The crude was purified by flash silica (Si) chromatography (using a 0-100% dichloromethane-cyclohexane gradient) to give the desired product, 155.9 mg. LCMS (M+1) 452, RT 1.96 mins.