Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O[C@H]1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1N1CCC[C@H](O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (S)-3-hydroxypiperidine and triethylamine in DMF yielding (S)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:19][CH:18]([CH2:20][CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][CH2:20][CH:18]([OH:19])[CH2:17][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCC(O)CO)CC1
Yield: 30.2 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 6.28 mmol, Lancaster) and toluene-4-sulfonic acid 2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester (1.98 g, 6.6 mmol, prepared from (2,2-dimethyl-[1,3]dioxolan-4-yl)-ethanol and tosyl chloride) and potassium carbonate (1 g, Fisher) were stirred in acetonitrile (22 mL) overnight at room temperature. After aqueous workup, the residue was purified by flash column chromatography to give 4-(3,4-dihydroxy-butyl)-piperazine-1-carboxylic acid tert-butyl ester (0.52g), which was deprotected with 1 N hydrochloric acid in methanol at 50° C. to give 4-piperazin-1-yl-butane-1,2-diol hydrochloride (360 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]2CC[C:10]=12>C(Cl)Cl>[C:9]1([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc2c1CC2
Solvent: ClCCl
Product: O=C(O)/C=C\C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.80 g (28.55 mmole) of maleic anhydride was dissolved completely in about 60 ml of methylene chloride. To this solution was added the freshly prepared 4-aminobenzocyclobutene (3.35 g., 28.11 mmole). Immmediately, bright yellow precipitates formed quantitatively. The reaction was quite exothermic as evidenced by the self-refluxing of methylene chloride. Additional 30 ml of methylene chloride was added to moderate the reaction temperature. Finally, the resultant bright yellow heterogeneous mixture was stirred overnight at room temperature. The reaction mixture was filtered and the yellow solid product collected was washed with methylene chloride (3 ×25 ml) and air-dried. Yield: 5.03 g (82.4%). Anal Calc. for C12H11NO3 : C, 66.35; H, 5.10; N, 6.45. Found: C, 66.66; H, 5.27; N, 6.34.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][N:13]2[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: BrC1CCCC1
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in one portion to a room temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester in 125 mL anhydrous DMF. After 20 minutes, 3.89 mL (36.6 mmol, 1.3 equiv) cyclopentyl bromide were added dropwise, and the reaction was mixture allowed to stir overnight at room temperature. The mixture was then poured into 1 L H2O and extracted 3×450 mL ethyl acetate. The organic extracts were combined, washed 3×400 mL H2O, 1×200 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave an amber oil, which was purified on a silica gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a clear oil: 1H NMR (300 MHz, CDCl3) d 8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, J=7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); HRMS calcd for C16H20N2O2; 272.1526. Found: 272.15078.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:14][O:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([OH:12])=[N:11][C:2]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(O)nc(Cl)nc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N3CCCC3)nc2c1
Temperature: 100 °C

Procedure:
2-chloro-7-methoxyquinazolin-4-ol (165 mg, 0.783 mmol) and pyrrolidine (0.130 mL, 1.567 mmol) were dissolved in THF (2 mL) and heated to 100° C. for 2 h in a sealed tube. The reaction was cooled and the volatiles were removed under vacuum. The crude solid was collected and washed with water, filtered and dried to give 7-methoxy-2-(pyrrolidin-1-yl)quinazolin-4-ol which was carried to the next step without further purification. MS: MS m/z 246.2 (M++1).
Reaction SMILES: [Na+].[I-].C1(OC)C=CC=CC=1.C[Si](Cl)(C)C.[NH2:16][C:17]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][C:20]([CH2:21][C@H:22]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][C:18]=1[Cl:52]>C(#N)C>[NH2:16][C:17]1[C:47]([C:48]([F:50])([F:49])[F:51])=[CH:46][C:20]([CH2:21][C@H:22]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)[CH2:35][CH2:34]2)=[O:32])[CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=1[Cl:52]
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CC#N
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
5.75 g (38.4 mmol) of NaI, 3 mL of anisol and 4.92 mL (38.4 mmol) of trimethylsilylchloride were added to the solution of 7.0 g (12.8 mmol) of tert. butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo-butanoate in 375 mL acetonitrile. The reaction mixture was stirred for 90 min at 40° C., combined with another 5.75 g (38.4 mmol) of NaI and 4.92 mL (38.4 mmol) of trimethylsilylchloride and stirred for a further 2 h at 40° C. The mixture was evaporated down i. vac. and further reacted as the crude product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C=O>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCCN2CCOCC2)ncn1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 58.1 %

Procedure:
To a solution of N-(2-hydroxyethyl)morpholine (1.09 g, 8.27 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (364 mg, 9.10 mmol, 60% dispersion in oil) in portions. The mixture was stirred at room temperature for 1 h and at 45° C. for 1.5 h. The greenish solution was added dropwise over 5 min to a solution of 4,6-dichloropyrimidine (3.0 g, 20.1 mmol) in N,N-dimethylformamide (5 mL). The solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified on a silica gel column using ethyl acetate as the eluent affording 1.17 g (58% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 6.80 (s, 1 H), 4.53 (t, J=6 Hz, 2 H), 3.72 (t, J=5 Hz, 4 H), 2.77 (t, J=6 Hz, 2 H), 2.55 (t, J=4 Hz, 4 H); 13C NMR (CDCl3, 100 MHz) δ 170.0, 160.7, 158.1, 108.0, 66.9, 64.6, 57.1, 53.9; MS (ESP) m/z 244 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:22]([O:21][C:19]([N:8]([CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:37])[CH2:26][C:27]([OH:29])=[O:28])=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C(=O)OC(C)(C)C

Procedure:
A suspension of 250 mg (0.48 mmol) of 3-[(benzyloxy)carbonyl]-N-[(tert-butoxy)carbonyl]-N-[-(1-tert-butoxyformamido)ethyl]-L-alanine tert-butyl ester and 50 mg of palladium/carbon (5%) in 10 ml of ethanol is hydrogenated at room temperature under normal pressure. Thereafter, the catalyst is filtered off and the solution is evaporated under reduced pressure. 1-tert-Butyl 4-hydrogen N-(tert-butoxycarbonyl)-N-[2-(1-tert-butoxyformamido)ethyl]-L-aspartate is obtained as a colourless foam: MS: 433 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH3:15])=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(OCC3C=CC=CC=3)=O)=[CH:19][CH:18]=2)[N:6]=1>CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:7]2[N:6]=[C:5]([NH:4][CH2:3][CH2:2][OH:1])[N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[CH2:14][CH3:15])=[CH:18][CH:19]=1
Reactant: CCn1cnc2c(Nc3ccc(NC(=O)OCc4ccccc4)cc3)nc(NCCO)nc21
Agent: [Pd]
Solvent: CO
Product: CCn1cnc2c(Nc3ccc(N)cc3)nc(NCCO)nc21

Procedure:
0.45 g (1 mmol) of 2-(2-hydroxy-ethyl-amino)-6-(4-benzyloxycarbonylamino-phenyl-amino)-9-ethyl-9H-purine (prepared according to Example 107) are hydrogenated with 0.1 g of 10% Pd/C in 8 ml of methanol at RT for 5 h. The catalyst is filtered off, the residue on the filter is rinsed with dioxane/water (95:5) and the solvent is removed in vacuo. The desired compound, 6-(4-amino-phenyl-amino)-9-ethyl-2-(2-hydroxy-ethyl-amino)-9H-purine, can be isolated in crystalline form by this procedure; m.p. 210° C.; FAB-MS: (M+H)+=314; Rf=0.15 (methylene chloride:methanol=9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>ClCCl.O>[CH:21]([NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)N=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of tert-butyl (2-amino-4-(thiophen-2-yl)phenyl)carbamate (0.20 g, 0.70 mmol, 1.0 equiv.) in dichloromethane (4 mL) was added isopropyl isocyanate (0.07 mL, 0.83 mmol, 1.2 equiv.) and TEA (0.19 mL, 1.37 mmol) at 0° C. The reaction was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20% EtOAc/hexanes) to give tert-butyl (2-(3-isopropylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.18 g, 70% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[S:16]([CH2:22][C:23]#[N:24])([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>C(O)C.N1CCCCC1>[C:20]([CH2:19][S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])#[N:21]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)C)c1O

Procedure:
A mixture of 500 mg of 3,5-diisopropyl-4-hydroxybenzaldehyde and 700 mg of sulfonyl diacetonitrile in 6 ml of ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide 50 mg of M27 along with 30 mg of M29.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:30][CH2:31]1
Reactant: Cc1ccc(CC2(N)CC2)c(C)c1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c(C)c1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(2,4-dimethyl-benzyl)-cyclopropylamine. Yield: 176 mg (36%, trifluoroacetate); mass spectroscopy: [M+H]=383.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>CO.C(Cl)Cl>[OH:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: OCC1CCCN1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCCC3CO)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.169 mmol) with 2-hydroxymethylpyrrolidine (46 mg, 0.45 mmol) as described in General Procedure X to afford Iw (42.0 mg, 65.6%) as a tan solid, tlc Rf=0.15 (10% MeOH/CH2Cl2-0.25% Et3N), m/z obs=382 (M+1).
Reaction SMILES: [C:1]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24]>C1COCC1>[C:1]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:20][CH:21]=1)[C:23]([F:25])([F:24])[F:22])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@](=O)C(C)(C)C)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a 50-mL oven-dried round-bottom flask charged with tert-butyl 4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate (0.16 g, 0.5 mmol), tetra-n-butylammoniumdifluoro-triphenylsilicate (0.30 g, 0.55 mmol), THF (8 mL) was slowly added (trifluoromethyl)trimethylsilane (0.94 mL, 0.60 mmol) in THF (2 mL) slowly at −45° C. The mixture was stirred at this temperature for 2 h, then warmed to −30° C. and stirred for 1 h. The reaction was quenched with addition of sat. NH4Cl (5 mL) and EtOAc (10 mL) at −30° C. After warming to rt, the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried (MgSO4), and concentrated. Purification via flash chromatography (10% EtOAc-hexanes to 20% EtOAc-hexanes) afforded tert-butyl 4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate (0.136 g, 72%) as a white solid. 1H NMR (Methanol-d4, 300 MHz) δ 7.98 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 5.15 (d, J=7.9 Hz, 1H), 1.59 (s, 9H), 1.23 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[C:2]([CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ccccc1[N+](=O)[O-]
Yield: 101 %

Procedure:
Following General Procedure A, the title compound (548 mg, 95%) was prepared from 2-amino-4-chlorobenzenethiol (441 mg, 2.76 mmol), 1-(bromomethyl)-2-nitrobenzene (398 mg, 1.84 mmol) and K2CO3 (1.27 g, 9.21 mmol) in DMF (20 ml).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](N(CC)CC)[CH3:23].C(Cl)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]2[N:14]=[C:22]([CH3:23])[O:16][N:15]=2)=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzamidine (reference example 3-1) (35 g), triethylamine (31 mL) and tetrahydrofuran (31 mL) was added acetyl chloride (8.2 mL) under ice-bath cooling. The mixture was stirred at the same temperature for 1 hour. Insoluble materials were removed by filtration. To the filtrate was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 89 mL). After stirring at the same temperature for 2 hours, water and ethylacetate were added to the mixture. The separated organic layer was washed with 1 mol/L hydrochloric acid, a 1 mol/L aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (31.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]2[CH3:55])=[CH:14][N:13]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=3)=[CH:16][C:15]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:52])=[O:53])[CH2:47][C@@H:46]3[CH3:55])=[CH:14][N:13]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)cnc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Product: COc1cc(Nc2ncc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc(N)n2)cnc1Cl

Procedure:
The title compound was prepared from 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 534 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.99-12.52 (m, 1H) 8.76-9.96 (m, 1H) 8.15-8.63 (m, 3H) 6.57-8.07 (m, 2H) 4.09-5.06 (m, 2H) 3.94 (s, 3H) 3.59-3.86 (m, 2H) 2.86-3.35 (m, 7H) 2.46 (s, 3H) 0.96-1.58 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10](C)[C:11](=O)OC(C)(C)C)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH3:11])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Br)cn(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1cc(Br)cn(C)c1=O
Temperature: 30 °C
Yield: 66.6 %

Procedure:
To a solution of tert-butyl N-(5-bromo-1-methyl-2-oxopyridin-3-yl)-N-methylcarbamate (94.8 mg, crude) in DCM (10 mL) was added HCl/dioxane (1 mL, 4 M) dropwise with stirring at 30° C. The reaction mixture was stirred at 30° C. for 30 min. The mixture was filtered and the filter cake collected. The filtrate was adjusted to pH=9 with saturated aqueous NaHCO3, extracted with ethyl acetate (20 mL), dried over Na2SO4, filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg). 1H NMR (CDCl3 400 MHz): δ 6.74 (d, J=2.4 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 5.15 (s, 1H), 3.53 (s, 3H), 2.83 (s, 3H). LCMS (M+H)+ 217
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCCCCCCCCCBr
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCCCCCCCCCBr
Reaction time: 18 h
Yield: 85 %

Procedure:
2,2-dimethyl-propionic acid 10-bromodecyl ester was prepared in 85% yield by treatment of 10-bromodecane-1-ol with trimethylacetyl chloride in the presence of pyridine and 4-dimethylaminopyridine at room temperature in dithlcromethane. After 18 hrs, the reaction was quenched by the addition of dilute hydrochloric acid worked up and filtered through silica to provide 2,2-dimethyl-propionic acid 10-bromodecyl ester.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>CN(C)C=O>[C:1]([O:9][CH2:12][CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CCOC(CCCl)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CCOC(=O)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a stirred solution of 5.0 grams (0.034 mole) of sodium benzoate in 100 ml of dimethylformamide was added 5.2 grams (0.031 mole) of 3-chloro-1,1-diethoxypropane. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for four hours. After this time the reaction mixture was cooled to ambient temperature and was filtered to remove a solid. The filtrate was diluted with water, and the mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The nmr spectrum indicated the presence of solvents. The oil was redissolved in diethyl ether and washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was evacuated under high vacuum yielding 6.3 grams of 3-ethoxy-4-oxahexyl benzoate. The nmr spectrum was consistent with the proposed structure.