Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:25](=[O:27])[CH3:26])[CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:15]1[CH:14]=[C:13]([C:25](=[O:27])[CH2:26][Br:1])[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
A solution of 2.4 mL (46 mmol) of Br2 in 45 mL of CHCl3 was added dropwise over 1 h to a chilled, stirring solution of 9.66 g (29 mmol) of 3′,5′-dibenzyloxyacetophenone (45) in 40 mL of CHCl3. The resulting solution was allowed to warm to room temperature over 1 hour with good stirring, then poured into 100 mL of cold H2O and transferred to a separatory funnel where the CHCl3 fraction was isolated, washed with brine solution, dried (Na2SO4), filtered, and concentrated to 10.8 g. This material was applied to 500 g of silica gel, eluting with CHCl3 to obtain 2.65 g (22%) of compound 46 as a white solid. 1H NMR (CDCl3) δ 4.39 (s, 2H), 5.08 (s, 4H), 6.85 (t, 1H, J=2.1 Hz), 7.20 (d, 2H, J=2.4 Hz), 7.31-7.44 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11]Cl)[C:9]=1[Cl:10])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:16][C:13](=[O:15])[CH3:14])[C:9]=1[Cl:10])=[O:4]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1scc(CCl)c1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1scc(COC(C)=O)c1Cl
Yield: 90 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-(chloromethyl)thiophene (48 g, 0.21 mol) in glacial acetic acid (500 mL) was added sodium acetate (35 g, 0.42 mol). The reaction was heated at reflux for 24 hours, then cooled and concentrated in vacuo. The residual oil was made basic by addition of saturated aqueous sodium bicarbonate, and the resulting solution extracted with ethyl acetate (4×150 mL). The combined extracts were dried over sodium sulfate and concentrated to afford 47 g (90% yield) of 2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene as a light brown oil; NMR (CDCl3) 7.6 (s, 1), 5.1 (s, 2), 3.9 (s, 3), 2.1 (s, 3) ppm.
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]=[C:33]([CH3:38])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:32][C:29]2([CH2:28][C:27]3[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:26]=3[CH3:25])[CH2:31][CH2:30]2)=[CH:11][CH:10]=1
Reactant: Cc1cc(C)c(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: Cc1cc(C)c(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 189 mg (1 mmol) 1-(2,4,6-trimethyl-benzyl)-cyclopropylamine. Yield: 26 mg (5%, trifluoroacetate); mass spectroscopy: [M+H]+=397.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[NH:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([C:14](O)=[O:15])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:14](=[O:15])[C@@H:12]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:13]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)c(F)cc1N
Reaction time: 3 h

Procedure:
To the mixture of 1,2-diamino-4,5-difluorobenzene (2.00 g, 13.9 mmol) and Boc-L-Ala-OH (2.63 g, 13.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.85 g, 30.5 mmol) in DCM (139 mL) was added triethylamine (6.00 mL, 43.0 mmol) at rt and stirred for 3 h. The mixture was then concentrated in vacuo and absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-tert-butyl 1-(2-amino-4,5-difluorophenylamino)-1-oxopropan-2-ylcarbamate as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (1H, s), 7.21 (1H, dd, J=11.9, 8.8 Hz), 7.11 (1H, d, J=6.7 Hz), 6.65 (1H, dd, J=12.9, 8.0 Hz), 5.04 (2H, br. s.), 4.04-4.14 (1H, m), 1.39 (9H, s), 1.25 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 338.0 [M+Na]+ and m/z 314.0 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[N:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CC=C(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-1,2,3,6-tetrahydro-pyridine hydrochloride in ethanol in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, brown solid; MS: [M+H]+=381.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[N:14]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1
Yield: 56.8 %

Procedure:
2-(3-Formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 3.2 mmol), methylamine (2M in methanol, 7.0 mL, 14 mmol) and sodium cyanoborohydride (250 mg, 4.0 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (100 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.36 g, 3.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-methyl-2-(3-methylaminomethyl-phenoxy)-nicotinonitrile fumarate (650 mg, 55%) as an off-white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[NH:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:12][C:13]1[S:16][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[N:11]=1
Reactant: N=C(N)c1cccc(F)c1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(-c2nsc(Cl)n2)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of 3-fluorobenzenecarboximidamide hydrochloride (1.75 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (2.00 g, 50.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.52 g (71.0%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl>CN(C=O)C.[Na+].[Cl-]>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:29][CH:28]=[CH:27][Cl:26])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccc(S(C)(=O)=O)cc2c1Br
Reactant: ClC=CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(C)(=O)=O)cc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.8 %

Procedure:
A stirred solution of 203 (2.29 g, 5.72 mmol) in dry DMF (20 mL) was treated portionwise at 0° C. with NaH (275 mg, 60% in oil, 6.88 mmol). The mixture was warmed to room temperature for 30 min, then cooled to 0° C. and treated with 1,3-dichloropropene (1.66 mL, 18 mmol, mixed isomers). The mixture was stirred at room temperature for a further 6 h, then diluted with 10% aqueous NaCl and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (19:1) to give crude tert-butyl 1-bromo-7-(methylsulfonyl)-2-naphthyl(3-chloro-2-propen-1-yl)carbamate (204) (2.63 g, 97%) as a foam: 1H NMR [(CD3)2SO] (mixture of rotamers and B and Z forms) δ 8.78 (s, 1H), 8.32 (dd, J=8.6, 2.2 Hz, 1H), 8.18, 8.17 (2 d, J=8.7 Hz, 1H), 8.13-8.06 (1, 1H), 7.75, 7.70 (2 d, J=8.7 Hz, 1H), 6.44-6.29 (m, 1H), 6.20-6.01 (m, 1H), 4.58-4.48, 4.43-4.22, 4.16-4.05 (3 m, 21H), 3.35 (s, 3H), 1.50, 1.27 (2 s, 9H). HRMS (FAB) calcd. for C19H2279Br35ClCNO4S (m/z 474.0141, found 474.0143.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide (example 262) (0.480 g, 0.912 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.25 g, 46%). MS (ISP) 469.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>O1CCCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[N:8][NH:9]3)=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)=[O:36]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cn1cc(-c2n[nH]c3cc(-c4ccc(CN)cc4)ccc23)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2n[nH]c3cc(-c4ccc(CNC(=O)c5cccc(F)c5)cc4)ccc23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 0° C. suspension of Example 31B (70 mg, 0.231 mmol) in tetrahydrofuran (15 ml) was treated with triethylamine (1.00 ml, 7.17 mmol) followed by 3-fluorobenzoyl chloride (0.014 ml, 0.115 mmol) added dropwise. The reaction was allowed to warm to room temperature slowly and after 2 hours was treated with an additional 14 uL acid chloride, stirred for 18 hours, then partitioned between brine and ethyl acetate. The organic extract was dried with MgSO4, concentrated and the residue was purified via by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3 H) 4.55 (d, J=5.95 Hz, 2 H) 7.35-7.81 (m, 10 H) 7.99 (s, 1 H) 8.06 (d, J=8.33 Hz, 1 H) 8.37 (s, 1 H) 9.19 (t, J=5.95 Hz, 1 H) 12.98 (s, 1 H). MS (ESI(+)) m/e 426 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3cccs3)ccc2C)cc1
Reaction time: 18 h
Yield: 106 %

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (280 mg) and thiophene-2-carbonyl chloride (161 mg) in dichloromethane (5 ml) containing triethylamine (222 mg) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (425 mg)
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].S(OC)(OC)(=O)=O.COS([O-])(=O)=O.CO[N+:25]1C(C)=CC=C[C:26]=1C.[C-]#N.[K+]>O>[CH3:7][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:8])[N:1]=1)[C:26]#[N:25]
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: CO[n+]1c(C)cccc1C
Agent: COS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc(C#N)cc(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a stirred quantity of 2,6-lutidine-1-oxide (12.3 g, 100 mmol) was slowly added dimethyl sulphate (12.6 g, 100 mmol) at such a rate that the temperature of the reaction mixture was maintained at 80° C. throughout the addition. When the addition was complete (about one hour) the solution was stirred at that temperature for an additional 2 h. The salt crystallised upon cooling and was recrystallised from anhydrous acetone giving white prisms; m.p 96-97° C. Yield 18 g (73%). To a solution of this 1-methoxy-2,6-dimethylpyridinium methyl sulphate (11.65 g, 50 mmol) dissolved in water (50 ml), under nitrogen, was added a solution of potassium cyanide (10 g, 150 mmol) dissolved in 50 ml of water. The solution was allowed to stand at room temperature for 2 days at which time the nitrile, which had separated from the solution as long white needles, was removed by filtration, yielding 2.8 g of pure product (42%) δH (CDCl3, 500 MHz) 2.44 (6 H, s, 2×CH3), 4.2 (2 H, d, J 5, NHCH2), 6.78 (2 H, s, ArH); δC (CDCl3, 500 MHz) 157.83 (2×C), 122.71 (C), 118.2 (2×CH), 24.28 (2×CH3)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:32])(=[O:31])[N:17]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:12]2[N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:14](=[O:33])[C:15]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([N:26]([CH3:1])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=2[S:18](=[O:31])(=[O:32])[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C(O)C2CCCCCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Potassium carbonate (0.067 g, 0.488 mmol) and iodomethane (0.017 mL, 0.268 mmol) were added sequentially to a solution of N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 33b, 0.128 g, 0.244 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between ethyl acetate (30 mL) and water (2×20 mL). The organic layers were washed with saturated aqueous brine solution (50 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 30-80% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (0.045 g, 0.084 mmol, 34%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.00 (d, 6H, J=7.1 Hz), 1.40-2.24 (m, 14H), 2.88 (d, 3H, J=2.1 Hz), 2.94-3.09 (m, 1H), 3.30-3.53 (m, 2H), 3.37 (d, 3H, J=3.1 Hz), 3.95-4.09 (m, 1H), 7.17-7.23 (m, 1H), 7.67-7.73 (m, 1H), 7.77-7.80 (m, 1H). LC-MS (ESI) calcd for C24H34N4O6S2 538.19, found 539.4 [M+H+].
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:35](Cl)(=[O:53])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].O>C(Cl)Cl>[NH:1]([C:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:53])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:11])[OH:12])=[O:5])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Yield: 93.7 %

Procedure:
L-Ala-D-Glu(OH)OBzl (1) (942 mg) was suspended in methylene chloride (40 ml), and bis(trimethylsilyl)acetamide (1.20 g) was added to the suspension under stirring. The resulting solution was treated with stearoyl chloride (900 mg) at ambient temperature and left for an hour. Evaporation of the solvent gave an oily residue which was treated with water to give white solides. The solides were collected by filtration, washed with water and dried over magnesium sulfate to give stearoyl-L-Ala-D-Glu(OH)OBzl (2) (1.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CS(=O)(=O)CC1=Cc1ccc(Cl)cc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccc(Cl)cc3)CS(=O)(=O)CC2C1c1ccc(Cl)cc1
Yield: 43 %

Procedure:
A mixture of 5.1g of tetrahydro-3,5-bis[(4-chlorophenyl)methylene]-4H-thiopyran-4-one-1,1-dioxide and 0.96g of n-propyl hydrazine in 250ml of methanol is heated at reflux temperature for 45 minutes. The solids which precipitate out are collected by filtration. The crude product is recrystallized twice from acetone/hexane to give 2.5g of the title compound, melting point 208°-210°C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[C:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52](Cl)=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])([CH3:29])([CH3:28])[CH3:27].S(=O)(=O)(O)O>C(OCC)C>[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52]([O:15][CH2:14][CH2:13][CH2:12][C:7]2[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[OH:16])=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:35]=1[OH:36])([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1cc(CCCO)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(CCC(=O)OCCCSCCC(=O)Cl)cc(C(C)(C)C)c1O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1cc(CCCOC(=O)CCSCCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c(C(C)(C)C)c1
Yield: 66.7 %

Procedure:
Into a 50 ml reactor were charged 3.40 g (15.29 mmol) of 3-(3-tert-butyl-2-hydroxy-5-methylphenyl)-1-propanol, 20 ml of diethyl ether and 1.94 g (16.00 mmol) of N,N-dimethylaniline. The atmosphere in the reactor was replaced with dry nitrogen. To the reactants was added dropwise 7.09 g (16.00 mmol) of 3-[3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy]propylthio]propionyl chloride. The reactants were heated and refluxed for 6 hours in the nitrogen stream. After the completion of the reaction, diethyl ether was added and the reaction product was neutralized with 10% sulfuric acid. After liquid separation, washing with saturated aqueous solution of sodium chloride and dehydration with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure. After separation by silica gel chromatography (solvent: chloroform), 6.42 g (10.20 mmol) of the desired product was obtained. The yield was 67%. The physical properties of the product are shown below.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:40][C:41]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]1>C1COCC1>[N:3]1[CH:4]=[C:5]([C:7]([NH:40][C:41]2([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]2)=[O:9])[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1cncnc1
Reactant: CCOC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Reaction time: 8 h

Procedure:
A solution of 6.80 g (54.8 mmol) of pyrimidine-5-carboxylic acid, 18.82 mL (135 mmol) of triethylamine and 19.27 g (60 mmol) of TBTU in 200 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (55 mmol) of ethyl 1-amino-cyclopropanecarboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down, the residue was stirred with 200 mL water and the crude product was extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).