Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:4]=12)[NH2:2].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]([CH:32]=O)[CH:30]=O.C1(C)C=CC=CC=1>>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:9]1[C:5]2=[N:6][CH:7]=[CH:8][C:3]([N:1]3[CH:30]=[C:29]([C:21]4[O:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:32]=[N:2]3)=[C:4]2[CH:11]=[CH:10]1
Reactant: O=CC(C=O)c1nc2ccccc2o1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NN)ccnc21
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-n3cc(-c4nc5ccccc5o4)cn3)ccnc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To 4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 3782-117-1 and 1,3-benzoxazol-2-ylmalonaldehyde (obtained from Matrix Corp, 0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added molecular sieves. The mixture was heated in a sealed tube at 70° C. (an oil bath) with stirring for 2 h. The solvent was removed in vacuo and the crude product was purified by FCC on silica using ethyl acetate:hexanes 3:7 to give 2-[1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]-1,3-benzoxazole (0.090 gm) as an oil, LC/MS (M+H)+: 432.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[N:13]1([C:4]([C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[F:1])=[O:5])[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2,4-difluorobenzoyl chloride (1.14 g, 6.46 mmol) in CH2Cl2 was added azetidine hydrochloride (1.46 g, 15.6 mmol) and Et3N (2.70 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (100 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give an off-white solid (896 mg, 76% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52-7.59 (m, 1 H) 6.91-6.98 (m, 1 H) 6.81-6.87 (m, 1 H) 4.21 (t, J=7.71 Hz, 2 H) 4.11 (t, J=7.71 Hz, 2 H) 2.30-2.38 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]1[CH2:15][NH2:14])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCC1C=CC=CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A solution of 2-nitrobenzenesulfonylchloride (16.62 g, 0.075 mol) in dry CH2Cl2 (120 mL) was added dropwise via cannula to a stirred solution of 2-(aminomethyl)pyridine (5.41 g, 0.05 mol) and Et3N (13.9 mL, 0.10 mol) in dry CH2Cl2 (150 mL) under nitrogen. The reaction mixture was stirred for three hours at room temperature, and then quenched with water (20 mL). The aqueous layer was separated and extracted with EtOAc (5×80 mL). The combined organic extracts were dried (MgSO4) and evaporated to small volume to give a white precipitate which was collected by filtration and washed with cold CH2Cl2 to give the desired product (11.37 g, 78%) as a white solid: 1H NMR (Acetone-d6) δ4.46 (s, 2H), 7.19 (dd, 1H, J=7.4, 4.5 Hz), 7.25-7.35 (br s, 1H), 7.39 (d, 1H, J=7.7 Hz), 7.68 (ddd, 1H, J=7.7, 7.5, 1.8 Hz), 7.76-7.88 (m, 2H), 7.94 (dd, 1H, J=7.7, 1.5 Hz), 8.04 (dd, 1H, J=7.5, 1.8 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[O:14][C:13]([C:17]3[C:22]4[O:23][CH2:24][CH2:25][O:26][C:21]=4[C:20]([NH:27]C(=O)OCC4C=CC=CC=4)=[C:19]([Cl:38])[CH:18]=3)=[N:12]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br>C(O)C>[ClH:38].[NH2:27][C:20]1[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[C:17]([C:13]2[O:14][C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[N:12]=2)=[CH:18][C:19]=1[Cl:38].[ClH:38]
Reactant: CCCCN1CCC(n2nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)c4c3OCCO4)oc2=O)CC1
Agent: Br
Solvent: CCO
Product: CCCCN1CCC(n2nc(-c3cc(Cl)c(N)c4c3OCCO4)oc2=O)CC1
Product: Cl

Procedure:
The preparation is carried out as described in Example 9.2, from phenylmethyl [8-[4-(1-butylpiperidin-4-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-6-chloro-2,3-dihydro-1,4-benzodioxin-5-yl]carbamate and hydrobromic acid, and the hydrochloride is formed by treatment with hydrochloric acid in ethanol. Melting point: 280-283° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of commercially available methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), DMAP (17.2 g, 140 mmol) and then dropwise a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after a trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:20]([O-])=O)=[C:10]([NH:12][C:13](=[O:19])[N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Zn]>[NH2:20][C:9]1[CH:8]=[CH:7][C:6]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:11][C:10]=1[NH:12][C:13](=[O:19])[N:14]([CH3:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCN(C)C(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCCN(C)C(=O)Nc1cc(C2=CCCC2)ccc1N
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a stirred solution 3-(5-(cyclopent-1-en-1-yl)-2-nitrophenyl)-1-methyl-1-propylurea (0.17 g, 0.56 mmol, 1.0 equiv.) in MeOH were added Zn (0.18 g, 2.80 mmol, 5.0 equiv.) and HCOONH4 (0.28 d, 4.48 mmol, 8.0 equiv.) at room temperature. The reaction was stirred for 2 h then filtered through celite. The organic layer was concentrated and the crude residue was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford 3-(2-amino-5-(cyclopent-1-en-1-yl)phenyl)-1-methyl-1-propylurea (0.12 g, 78% yield). ESI+ MS: m/z 274 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 7.61 (s, 1H), 7.08 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.0, 1.5 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.94-8.90 (m, 1H), 4.77 (s, 2H), 3.24 (t, J=7.5 Hz, 2H), 2.92 (s, 3H), 2.58-2.52 (m, 2H), 2.46-2.40 (m, 2H), 1.95-1.86 (m, 2H), 1.52 (sext, J=7.5 Hz, 2H), 0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.CO.[NH4+].[OH-]>C(O)(=O)C>[NH2:30][CH2:29][C:25]1[N:24]=[C:23]([C:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:14]=[C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][NH2:2])[N:8]=3)[N:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2cc(-c3cccc(C#N)n3)nc(-c3cccc(C#N)n3)c2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3cccc(CN)n3)nc(-c3cccc(CN)n3)c2)cc1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
6,6"-Dicyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (1.556 g, 4.0 mmole) prepared in example 14 was dissolved in Ultrex acetic acid (130 mL, Baker) in a Parr hydrogenation bottle by warming to 50° C. for 25 minutes. The solution was sparged with argon for 5 minutes, 10% Pd/C (470 mg) was added under argon, and the reaction mixture was hydrogenated at 45 psi and 45° C. for 19 hours in a Parr hydrogenation apparatus. After venting excess hydrogen and replacing it with argon, the catalyst was removed by filtration using 5 mL of acetic acid as a wash. Most of the solvent was then evaporated under reduced pressure at 35° C. Residual acetic acid was removed by a series of consecutive additions and co-evaporations using 2×30 mL aliquots of toluene, then 2×30 mL aliquots of methylene chloride, and finally 2×30 mL aliquots of ethanol. The product was then dried under vacuum at 30° C. overnight to give 2.3 g (99.5 % recovery) of product as an off-white solid. Thin layer chromatography (silica gel; 85% methylene chloride, 5% methanol, 10% NH4OH, v/v/v) showed the desired product as a spot with an Rf of 0.3 (with some streaking) plus a trace amount of a small spot at the origin. Infrared and mass spectra were in good agreement for the desired product. 1H NMR (DMSO-D6) 3.85 (s, 3H, OCH3), 4.07 (s, 4H, CH2 --N), 7.16 (d, 2H), 7.55 (d, 2H), 7.99 (d, 2H), 8.03 (t, 2H), 8.52 (d, 2H) and 8.78 ppm (s, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCOC(=O)Cl
Agent: Cl
Product: CCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-butyl chloroformate. Yield: 34% of theory, C33H39N7O5 (613.7); EKA mass spectrum: (M+H)+=614; (M+H+Na)++=318.7; (M+Na)+=636.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.[H][H]>CC(C)=O.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 73.4 %

Procedure:
A stirred solution of (R)-5-(2benzenesulfonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (34.0 g) in acetone (200 mL) was treated with methanesulfonic acid (8. 5871 g) then 5% palladium on carbon (50% wet) (34.0 g) added and the mixture exposed to hydrogen (50 psi) at ambient temperature. When conversion was judged to be complete the mixture was filtered (washing with acetone--85 mL and mixed acetone/water--81 mL/4 mL). The combined filtrate and washings were diluted with water (800 mL) and the pH adjusted (with stirring) to about 11 by addition of 40% aqueous sodium hydroxide. After granulation of the precipitate the solids were collected by filtration to give the title compound (25.08 g) as that produced in Example 32).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)Nc1ccccc1Oc1ccccc1
Yield: 71.4 %

Procedure:
N-(2-Phenoxyphenyl)-N′-(pyridin-2-yl)urea (109 mg, 72%) was prepared from 2-phenoxyphenylisocyanate (106 mg, 0.5 mmol) and 2-aminopyridine (60 mg, 0.6 mmol) following the general procedure E.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15]>ClCCl>[N:1]1([C:14]([O:16][CH:17]([Cl:19])[CH3:18])=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
Under a nitrogen atmosphere, pyrrolidine (363.9 μL, 4.4 mmol) and triethylamine (555.2 μL, 4.00 mmol) were dissolved in dichloromethane (5.0 mL), and the mixture was cooled to 0° C. While maintaining the reaction temperature at 0° C., 1-chloroethyl chloroformate (431.6 μL, 4.00 mmol) was added, and the mixture was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The residue was then purified by silica gel column chromatography (dichloromethane, Rf=0.35) to obtain 424.2 mg (60% yield) of 1-chloro-ethyl pyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C@H:8]([CH3:12])[C:9]([NH:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4].[N:78]1([C:82]([O-:84])=[O:83])[C:79]2[C:75](=[CH:74][CH:73]=[CH:81][CH:80]=2)[CH:76]=[N:77]1
Reactant: C[C@H](C(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1)C(=O)OC(C)(C)C
Product: O=C([O-])n1ncc2ccccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (R)-2-(tert-butoxycarbonyl)propanoic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(R)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (95 mg, 69%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: COCCOCc1cccc(CN)c1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COCCOCc1cccc(CNc2ccc3nc(NCc4ccccc4OC)ccc3c2)c1

Procedure:
The title compound, MS: m/e=458.5 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 3-(2-methoxy-ethoxymethyl)-benzylamine.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:31][C@H:32]1[C@@H:39]2[N:35]([C:36](=[O:53])N(C3C4CCCCC=4C(C#N)=CC=3)[C:38]2=[O:40])[CH2:34][CH2:33]1>>[OH:31][C@H:32]1[C@@H:39]2[N:35]([C:36](=[O:53])[N:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:3]([C:1]#[N:2])=[CH:9][CH:8]=3)[C:38]2=[O:40])[CH2:34][CH2:33]1
Reactant: N#Cc1ccc(N)cc1-c1ccccc1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1-c1ccccc1

Procedure:
The title compound was prepared from compound 47A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 96% at 3.24 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 334 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl.[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>O.C(Cl)(Cl)Cl>[ClH:11].[C:6]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: NCCN
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethylenediamine (15 mmol, 10.1 cm3) in water (150 cm3) at 0° C. was adjusted to pH 8.5 with 3N HCl. To this, was added a solution of methacryloyl chloride (16.5 mmol, 16.1 cm3) in chloroform (100 cm3), dropwise, over 2 h. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 2 h. The organic and aqueous layers were then separated, and the aqueous layer extracted with chloroform (3×50 cm3). The aqueous layer was then collected and conc. in vacuo (freeze-dryer) to give a white solid. The residue was subjected to repeated fractional recrystallization from room temperature methanol, and the filtrate concentrated to give N-methacryloyl-ethylenediamine monohydrochloride as a clear, yellow oil (14.32 g. 58%). N-methacryloyl-ethylenediamine monohydrochloride (16 mmol, 20.0 g) was stirred in 2M NaOH (60 cm3) for 10 min. This solution was subsequently diluted to a volume of 160 cm3 with water, and stirred at 0° C. To this mixture was added a solution of acryloyl chloride (17.6 mmol, 14.3 cm3) in chloroform (300 cm3), dropwise, over 3 h. After the addition was complete, the reaction mixture was then stirred at 0° C. for a further 2 h. The organic and aqueous layers were separated, and the aqueous portion extracted with chloroform (3×100 cm3). The organic extracts were combined and concentrated to give the crude product as a white solid. Recrystallization from acetonitrile then gave N-acryloyl, N′-methacryloyl-ethylenediamine as colorless needles (10.70 g, 37%), m.p. 140-142/C. δH (400 MHz; CDCl3) 6.84 (1H, br s), NH; 6.74 (1H, br m), NH; 6.27 (1H, dd, J 16.9, 1.5 Hz), HC═CHaHb; 6.13 (1H, dd, J 17.0, 10.2), HC═CHaHb; 5.74 (1H, s), (H3C)C═CHcHd; 5.65 (1H, dd, J 10.3, 1.6 Hz), HC═CHaHb; 5.34 (1H, br m), (H3C)C═CHcHd; 3.49 (4H, m), 2×CH2; 1.95 (3H, s), CH3. δC (75.4 MHZ:CDCl3) 169.4, NHOC(H3C)C═CH2; 167.0, NHOCHC═CH2; 139.2, (H3C)C═CH2; 130.7, HC═CH2; 126.2, HC═CH2; 120.1, (H3C)C═CH2; 40.4 CH2CH2; 39.5, CH2CH2; 18.4, CH3. Found: M+. 182.1059.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4].C(N(CC)CC)C>C(O)C>[CH2:3]([N:5]1[C:9]([Cl:1])=[N:8][C:7]([OH:10])=[N:6]1)[CH3:4]
Reactant: ClCl
Reactant: CCn1cnc(O)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1nc(O)nc1Cl
Reaction time: 2 h

Procedure:
71.5 g of chlorine is passed into a solution of 75.5 g of 1-ethyl-3-hydroxy-1,2,4-triazole and 185 ml of triethylamine in 800 ml of absolute ethanol. The exothermic reaction is kept at 20° to 30°C while cooling. Triethylamine hydrochloride is precipitated. The batch is further stirred for 2 hours after the chlorine has been passed in. Triethylamine hydrochloride is filtered off and the filtrate concentrated. The residue is dissolved in 500 ml of ether and 500 ml of water. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ethereal extracts are dried over sodium sulphate. The drying agent is filtered off and the filtrate concentrated. The residue is recrystallised from a mixture of 400 ml of xylene and 250 ml of ligroin and dried in vacuo. Yield: 28.7 g (29 % of theory); m.p. 108°-110°C.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CC[C@@H](COC)n1cc(Br)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 115–117° C.; 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1 H), 6.66 (m, 1 H), 6.58 (d, J=2.2 Hz, 1 H), 5.00–4.90 (m, 1 H), 4.38 (t, J=8.1 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.2, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.92–1.70 (m, 2 H), 0.94 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Br (M+H)+: 422.1079; Found m/z 422.1096.
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:27](O)[CH3:28]>>[N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([O:19][CH2:27][CH3:28])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 30 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-oxepin-8-yl)-propionic acid in 0.5 ml of ethanol and 2 ml of ethanol saturated with hydrogen chloride gas was stirred at room temperature for 1 hour. The mixture was alkalified with saturated sodium hydrogencarbonate and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain oily substance, which was chromatographed over silica gel, eluted with chloroform/benzene(1/4-1/3), and there was obtained 30 mg of ethyl 2-(5,6-dihydro benzo[b]pyrido-[3,2-f]oxepin-8-yl)-propionate as colorless oil.