Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:28][C:29]([CH3:31])=[CH2:30]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:30][C:29]([CH3:31])=[CH2:28])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)CN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82.1 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine tert-butyl ester (3.97 g, 17.2 mmol) in DMF (70 mL) at 0° C. was added sodium hexamethyldisilazide (3.78 g, 20.6 mmol) and the resulting mixture was stirred for 25 min., then allowed to warm to room temp. The resulting solution was treated with 3-bromo-2-methylpropene (2.60 mL, 25.7 mmol), stirred at room temp. for 10 min., and diluted with EtOAc (300 mL). The EtOAc solution was sequentially washed with water (4×500 mL) and a saturated NaCl solution (4×500 mL), dried (MgSO4), and concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)-N-(2-methylprop-2-enyl)glycine tert-butyl ester (4.03 g, 82%): TLC (10% EtOAc/hex) Rf0.51.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]([O:13]CC)=[O:12])=[CH:6][N:5]=1>C(O)C>[CH3:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]([OH:13])=[O:12])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(C)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(=O)O)c(C)n1
Yield: 59.2 %

Procedure:
A solution of potassium hydroxide (67 g, 1.0 mol) in 95% ethanol (300 mL) was added to a solution of ethyl 2,4-dimethyl-5-pyrimidinecarboxate (73 g, 0.40 mol) in 95% ethanol (100 mL) and the mixture was heated under reflux for 5 hrs. Ethanol was evaporated under reduced pressure, and the residue was dissolved in water, and the aqueous solution was acidified with conc. hydrochloric acid. Precipitated solids were collected by filtration, washed with water and dried to give the title compound (36 g, yield 58%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Br:11][C:12]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][N:13]=1>>[Br:11][C:12]1[CH:17]=[C:16]([CH2:18][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])[CH:15]=[CH:14][N:13]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1NCc1ccnc(Br)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-bromo-pyridine-4-carbaldehyde (prepared as described in WO 2004/013102 A1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
To a suspension of 5-bromo-2-chloro-3-nitropyridine (75.0 g, 1 wt, 1 eq) in methanol (300 mL, 4 vols), is added a solution of sodium methoxide in methanol (25 wt %, 88.6 g, 1.3 eq) over approximately 1 hour so as to maintain the internal temperature at 20±5° C. The mixture is stirred at 20° C. for at least 0.5 hr, then monitored for completion by HPLC. Water (375 mL, 5 vols) is then added to the mixture at such a rate as to maintain the internal temperature below 30° C., then aged at this temperature for at least 0.5 hr. The batch is then concentrated to 6 vols in vacuo. The resulting slurry is allowed to cool to 20-25° C., then collected by vacuum filtration, washed with water and dried in vacuo with a nitrogen bleed at 20-25° C. to constant weight to afford 5-bromo-2-methoxy-3-nitropyridine as a white solid.
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([OH:17])=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].C(N(CC)CC)C.[CH2:25](OC(Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:3][P:2]([CH2:14][C:15]([O:17][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:1]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CP(=O)(O)CCCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a well stirred solution of [hydroxy-(4-phenylbutyl)phosphinyl]acetic acid (prepared as described in Example 23 of U.S. Pat. No. 4,602,092) (422.5 g, 1.65 mole) in tetrahydrofuran (4700 ml, alumina purified) maintained at -5° C. to -10° C. was gradually added triethylamine (290 ml, 2.08 mole). This was then followed by the dropwise addition of a solution of benzylchloroformate (275 ml, 1.93 mole) in purified tetrahydrofuran (1320 ml). After removing the cooling bath, stirring was continued for three hours. After this time, the reaction mixture was filtered. The solids were washed with ethyl acetate (2×1000 ml). The combined filtrates were concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (4000 ml) and washed with water (2×1000 ml), 2.5% hydrochloric acid (2×600 ml) and brine (2×1000 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was triturated with 1:1 ether/hexane (2×500 ml) and collected by filtration. The solid was washed on the frit with 1:1 ether/hexane then dried in vacuo at 30° C. overnight to yield 509 g of colorless crystalline product m.p. 68°-70° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]#[C:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)=O>C(Cl)(Cl)Cl.O>[CH:1]1([NH:4][CH2:23][C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]#[C:34][C:35]3[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#C/C=C/c2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Cyclopropylamine (99 μL), acetic acid (27 μL) and sodium triacetoxyborohydride (0.10 g) were added to a chloroform (4.0 mL) suspension of 1-formyl-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (0.20 g) as obtained in Example 23-(3), and the mixture was stirred for 1 hour and 10 minutes at room temperature. Sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1 hour and 15 minutes at room temperature. Further, sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1 hour and 15 minutes at room temperature. Water and chloroform were added to isolate the organic layer, and the extract was washed with water and brine sequentially. The washed extract was dried over anhydrous sodium sulfate, and the desiccant was filtered out. Then, the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=50/1→10/1) to obtain 1-[(cyclopropylamino)methyl]-4-[(1E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-1-en-3-yn-1-yl]benzene (orange oil) (0.18 g, 83%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:25]1([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Br[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[O:46][CH2:45][CH2:44][C:43]=2[CH:47]=1>O1CCCC1.O>[O:46]1[C:42]2[CH:41]=[CH:40][C:39]([CH2:38][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:47][C:43]=2[CH2:44][CH2:45]1
Reactant: BrCc1ccc2c(c1)CCO2
Reactant: CCOC(=O)Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1ccc2c(c1)CCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium hexamethyldisilazide solution, prepared from 1,1,1,3,3,3-hexamethyldisilazane (37.4 g, 0.232 mol), n-butyllithium (127 mL, 1.6 M hexane solution) and tetrahydrofuran (150 mL), was added a solution of ethyl phenylacetate (33.3 g, 0.203 mol) in tetrahydrofuran (20 mL) at -78° C. The mixture was stirred for 15 minutes and then a solution of 5-bromomethyl-2,3-dihydrobenzofuran (41.0 g, 0.193 mol) in tetrahydrofuran (50 mL) was added. The mixture was stirred for further 20 minutes, diluted with water and warmed up to room temperature. The product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as an oily product (yield 54.5 g, 95%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1>>[C:39]([NH:38][C:34]1[CH:33]=[C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][NH:22][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:27][CH2:28]2)[CH:37]=[CH:36][CH:35]=1)(=[O:43])[CH:40]([CH3:42])[CH3:41]
Reactant: CCCCCC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCCCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 11 was prepared from 2,2-diphenylheptanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.40 (m, 1H), 7.37–7.19 (m, 11H), 6.88 (d, 1H, J=7.3 Hz), 6.34 (t, 1H, J=4.5 Hz), 3.34–3.27 (m, 3H), 2.94–2.87 (m, 2H), 2.52 (septet, 1H, J=6.9 Hz), 2.46–2.34 (m, 4H), 2.27 (t, 2H, J=6.9 Hz), 2.00–1.91 (m, 2H), 1.77–1.69 (m, 2H), 1.69–1.52, (m, 5H), 1.30–1.20 (m, 12H); ESMS m/e: 568.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH:6]1[CH2:16][CH2:15][CH:9]([C:10]([O:12]CC)=[O:11])[CH2:8][CH2:7]1>>[CH:1]1([CH2:4][N:6]2[CH2:7][CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:15][CH2:16]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CC1CC1
Product: O=C(O)C1CCN(CC2CC2)CC1

Procedure:
The title compound was prepared from cyclopropanecarboxaldehyde and ethyl isonipecotate using similar procedures to those described for Example E15.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Product: ClCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-3-chloropropane: 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.19 (tt, 1H, J=1.4, 7.3 Hz), 3.67 (t, 2H, J=6.6 Hz), 3.08 (t, 2H, J=6.6 Hz), 2.06 (qt, 2H, J=6.6 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:17]1([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15][B:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[O:18]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OB(C2=CCNCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Letters, 2000, 44, pp 3705-3708, 500 mg, 1.617 mmol) was added 2 mL DCM and 2 mL TFA. The mixture was stirred at room temperature for 3 hours. The solvents were evaporated in vacuo to afford the title compound (323 mg, 96% yield). The product was not further purified for next step. MS (ES+): m/z 210.19 (100) [MH+]; HPLC: tR=0.55 min (UPLC, Analytical).
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[CH3:9][NH:10][NH2:11]>C(O)C>[IH:1].[CH3:9][NH:10][NH:11][C:4]1[NH:5][CH2:6][CH2:7][N:8]=1
Reactant: CSC1=NCCN1
Reactant: CNN
Agent: I
Solvent: CCO
Product: CNNC1=NCCN1

Procedure:
A 12.2 g portion of 2-methylthioimidazoline, hydroiodide was dissolved in 30 ml of ethanol. A 5.32 ml portion of methyl hydrazine was added dropwise over 1/2 hour. This mixture was refluxed overnight, then chilled in an ice bath. The solvent was evaporated and the residue triturated with ether and refrigerated overnight. The mxture was evaporated to an oil which was dissolved in methanol and added to 400 ml of ether. The resulting solid was collected, dissolved in hot methanol and poured into 100 ml of ether. The resulting solid was collected, giving 4,5-dihydro-2-(2-methylhydrazino)-1H-imidazole, hydroiodide.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[NH2:23])([O-:10])=[O:9].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>CN(C=O)C>[CH3:24][N:25]([CH3:29])[C:26]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[C:12]([NH2:23])[CH:13]=2)[CH2:22][CH2:21]1)=[O:27]
Reactant: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (0.546 g, 5.4 mmol) was added to 2-nitro-5-piperazin-1-yl-phenylamine (1.0 g, 4.5 mmol) in dry DMF (8 mL) and the mixture was cooled in an ice water bath. Dimethylcarbamyl chloride (0.581 g, 5.4 mmol) was added slowly to this reaction mixture via syringe and the mixture was brought up to room temperature and stirred overnight. After overnight stirring, the reaction mixture was slowly poured into cold water (100 mL) and stirred for 1 hour resulting in the solidification of the product. This was filtered, dried give the product, 4-(3-Amino-4-nitro-phenyl) -piperazine-1-carboxylic acid dimethylamide, as a yellow solid, 1.2 g (92.4% yield), which was used without any further purification.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15](=[CH2:26])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:27].[Na+].OO>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]([CH2:26][OH:27])[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [OH-]
Reactant: C=C(CCNC(=O)OC(C)(C)C)c1cccc(OCC2CCCCC2)c1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(CO)c1cccc(OCC2CCCCC2)c1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)but-3-enylcarbamate (90) (0.32 g, 0.89 mmol) in THF (10 ml) was added BH3 (1 M in THF, 2.4 ml, 2.4 mmol) at room temperature. After stirring for 4 hr, aqueous NaOH (1 M, 6.0 ml, 6.0 mmol) was added and the mixture was stirred at 60° C. for 2.5 hrs and room temperature for 18 hr. The mixture was added H2O2 (6 ml, 30%) and stirred at 50° C. for 2 hr. The reaction mixture was extracted with ethyle acetate (2×50 ml). Ethyle acetate part was washed with brine (50 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (30 to 75% EtOAc-hexanes gradient) gave tert-butyl 3-(3-(cyclohexylmethoxy)phenyl)-4-hydroxybutylcarbamate (92) as a colorless oil. Yield (0.2 g, 60%): 1H NMR (400 MHz, MeOD) δ 7.17 (t, J=8.0 Hz, 1H), 6.73-6.78 (m, 3H), 3.74 (d, J=6.4 Hz, 2H), 3.58-3.68 (m, 2H), 2.91 (t, J=7.8 Hz, 2H), 2.66-2.76 (m, 1H), 1.85-2.00 (m, 3H), 1.67-1.78 (m, 5H), 1.39 (s, 9H), 1.20-1.35 (m, 3H), 1.01-1.14 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH3:24][OH:25]>>[CH3:24][O:25][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:5])(=[O:6])[N:3]([CH3:23])[CH3:2])[CH:8]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were heated for 2 hours under reflux in 1 l of methanol. Subsequently the methanol was distilled off and the residue was dissolved in 0.3 l of water. A small amount of undissolved amorphous material was removed by filtration and the pH value of the filtrate was adjusted to 8 by means of concentrated aqueous ammonia, whereupon the final product precipitated immediately in a crystalline state. After it had been washed with water, it was dried on the steam bath.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]([C@H:14]1[C:44](=[O:45])[N:43]2[CH2:46][C@@H:40]([CH2:41][C@H:42]2[C:47]([NH:49][C@:50]2([C:55](=[O:64])[NH:56][S:57]([C:60]3([CH3:63])[CH2:62][CH2:61]3)(=[O:59])=[O:58])[CH2:52][C@H:51]2[CH:53]=[CH2:54])=[O:48])[O:39][C:26]2=[N:27][C:28]3[CH:29]=[C:30]([CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=3[C:34]([OH:35])=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:65][C@H:18]2[O:17][C:16](=[O:66])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C@H:14]1[C:44](=[O:45])[N:43]2[CH2:46][C@@H:40]([CH2:41][C@H:42]2[C:47]([NH:49][C@:50]2([C:55](=[O:64])[NH:56][S:57]([C:60]3([CH3:63])[CH2:62][CH2:61]3)(=[O:59])=[O:58])[CH2:52][C@H:51]2[CH:53]=[CH2:54])=[O:48])[O:39][C:26]2=[N:27][C:28]3[CH:29]=[C:30]([CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][C:33]=3[C:34]([O:35][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:65][C@H:18]2[O:17][C:16](=[O:66])[NH:15]1)([CH3:12])([CH3:13])[CH3:11]
Reactant: BrCCN1CCOCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3cc(C(C)C)ccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3cc(C(C)C)ccc3c1OCCN1CCOCC1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 42, using the 4-(2-bromoethyl)morpholine and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-14-(propan-2-yl)-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (synthesized in the same way as Example 120 but using intermediates A2, B10 and C9). LRMS (ES+) m/z 921.55 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][Cl:21])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].Cl>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:14]([CH3:16])=[O:15])[C:12]([O:18][CH2:19][CH2:20][Cl:21])=[O:17])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCCl
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCl
Reaction time: 48 h

Procedure:
10 Grams of 3-nitrobenzaldehyde and 11 g of 2-chloroethyl acetoacetate were dissolved in 100 ml of toluene, then under an ice-cooled condition, hydrogen chloride gas was introduced into the solution for 2 hours. The reaction mixture was allowed to stand at room temperature for 2 days, and was concentrated. The residue obtained was extracted with chloroform, then the chloroform layer was washed with a saturated sodium chloride aqueous solution and with a saturated sodium hydrogen carbonate aqueous solution and dried with anhydrous magnesium sulfate. Chloroform was removed by distillation and the residue was recrystallized from isopropanol to yield 10 g of 2-chloroethyl 2-(3-nitrobenzyliden)acetoacetate in the form of colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([N:51](C(OC(C)(C)C)=O)[CH2:52][CH2:53][CH2:54][OH:55])(=[O:50])=[O:49])=[CH:44][CH:43]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])(=[O:50])=[O:49])=[CH:44][CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N(CCCO)S(=O)(=O)c1ccc(Br)cc1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(S(=O)(=O)NCCCO)cc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (120 mg) and 4-bromo-N-Boc-N-(3-hydroxy-propyl)-benzenesulfonamide (105 mg) obtained in the same manner as Example 1-D-80 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(3-hydroxy-propyl)-benzenesulfonamide was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-98) as a yellow powder (19 mg, 17%).
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[CH2:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1.C(O)(=O)C>[CH2:1]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18]1
Reactant: CCOCC
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a mixture of diethyl ether (25 mL) and 30% aqueous potassium hydroxide solution (5 mL) was added 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 2.17 g), and the mixture was stirred at room temperature for 10 min. To a solution (25 mL) of tert-butyl 4-methylidenepiperidine-1-carboxylate (1.00 g, 5.07 mmol) in tetrahydrofuran was added dropwise the above-mentioned ether layer, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added a ether layer prepared from diethyl ether (25 mL), 30% aqueous potassium hydroxide solution (5 mL), and 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 3.77 g), and the mixture was further stirred for 16 hr. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give the title compound (261 mg, 24%) as a white powder.