Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[OH-].[Na+]>O1CCOCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (7.5 mg, 0.011 mmol) and sodium hydroxide (0.057 mL, 0.057 mmol) in dioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and the clear solution was purified by HPLC to provide the desired product as white solid (2.3 mg, 31%). LCMS: m/e 642.62 (M+H)+, 2.29 min (method 11). 1H NMR (400 MHz, Acetic) δ 8.00 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.80 (s, 1H), 4.70 (s, 1H), 3.59-3.28 (m, 6H), 3.25-3.11 (m, 1H), 3.09-2.73 (m, 6H), 2.31-1.15 (m, 22H), 1.73 (s, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42](=[O:44])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.Cl[C:46]1C=C2C(=CC=1)C1N(COCC[Si](C)(C)C)C(C3C(C#N)=CC=CC=3C#N)=NC=1C1C=CC(CC(=O)C)=CC2=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:44])([CH3:46])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C

Procedure:
This imidazole was prepared as described in Step 3, Example 135, substituting 2-(9-(cyclopropylmethoxy)-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 5 above for of 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19]O)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:9]([N:16]([CH2:17][CH2:18][CH2:19][Br:1])[CH2:21][CH3:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CCCO)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CCCBr)C(=O)OC(C)(C)C

Procedure:
11 g (0.0618 mol) of N-bromosuccinimide are added in the course of 5 minutes, with stirring, to a solution, which has been cooled to 0° C., of 10.49 g (0.0516 mol) of 3-(N-BOC-ethylamino)-1-propanol and 16.23 g (0.0619 mol) of triphenylphosphine in 160 ml of methylene chloride. The reaction mixture is stirred for a further 30 minutes at 0°-20° C. and is then concentrated by evaporation in vacuo. The dark-colored oily residue is stirred with 200 ml of hexane, whereupon a brown precipitate forms. After filtration and concentration of the filtrate by evaporation in vacuo, the title compound is obtained in the form of an oil, Rf value=0.71 (silica gel/tert-butyl methyl ether).
Reaction SMILES: CN1C(C(NC2C=CC=C(OC3C=CC4N(C=C(NC(=O)C(F)(F)F)N=4)C=3)C=2)=O)=CC(C)=N1.[CH3:34][N:35]1[N:39]=[N:38][C:37]([C:40]([OH:42])=O)=[N:36]1.C(Cl)(=O)C(Cl)=O.[NH2:49][C:50]1[CH:51]=[C:52]([CH:69]=[CH:70][CH:71]=1)[O:53][C:54]1[CH:55]=[CH:56][C:57]2[N:58]([CH:60]=[C:61]([NH:63][C:64]([CH:66]3[CH2:68][CH2:67]3)=[O:65])[N:62]=2)[CH:59]=1>CN(C)C=O.CN(C)C(=O)C.O1CCCC1>[CH:66]1([C:64]([NH:63][C:61]2[N:62]=[C:57]3[CH:56]=[CH:55][C:54]([O:53][C:52]4[CH:51]=[C:50]([NH:49][C:40]([C:37]5[N:38]=[N:39][N:35]([CH3:34])[N:36]=5)=[O:42])[CH:71]=[CH:70][CH:69]=4)=[CH:59][N:58]3[CH:60]=2)=[O:65])[CH2:67][CH2:68]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: Cn1nnc(C(=O)O)n1
Agent: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n1
Yield: 54.2 %

Procedure:
In the same manner as in Example 7-4 and using a mixture of 1-methyl-1H-tetrazole-5-carboxylic acid (1) and 2-methyl-2H-tetrazole-5-carboxylic acid (2) ((1):(2)≈1:1, 200 mg, 1.56 mmol), oxalyl chloride (141 μL, 1.72 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.227 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (51.5 mg, 54%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])N)[CH3:2].N([O-])=[O:13].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:8]=[CH:9][C:10]=1[CH3:11])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOc1cc(N)ccc1C
Agent: [Na+]
Solvent: O
Product: CCOc1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A suspension of 3-(ethyloxy)-4-methylaniline (Intermediate 89, 300 mg) in a mixture of water/concentrated sulfuric acid 98% (20 mL/7 mL) under argon was cooled at 0° C. A solution of sodium nitrite (151 mg, 2.182 mmol) in 4 mL of water was slowly added. The reaction mixture was stirred at 0° C. for 1 hour 30. The reaction mixture was then slowly added to a solution of water/concentrated sulfuric acid (18 mL/5 mL) pre-heated at 90° C. The reaction mixture was stirred at 90° C. for 1 hour 15. After cooling down, the reaction mixture was extracted with ethyl ether (4 times). The gathered organic phases were dried over sodium sulphate, filtered and concentrated under vacuum to afford tie compound (276 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:37])[CH2:35][CH3:36])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.65 g, 4.25 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, propionyl chloride (0.2 g, 2.13 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (60 ml) and washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed and the resulting solid was slurried in hot C2H5OH (10 ml) to give after filtration N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}propanamide (0.41 g, 64%) as a white solid: mp 219–221° C.; 1H NMR (DMSO-d6) δd 11.15 (s, 1H), 8.42 (t, J=5.8 Hz, 1H), 7.87–7.67 (m, 3H), 5.19–5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.98–2.84 (m, 1H), 2.65–2.48 (m, 2H), 2.26–2.17 (m, 2H), 2.09–2.04 (m, 1H), 1.05 (t, J=7.8 Hz, 3H); 13C NMR (DMSO-d6) δ d 173.52, 172.81, 169.79, 167.53, 167.01, 139.52, 134.79, 133.20, 131.55, 127.10, 121.86, 48.89, 37.69, 30.95, 28.43, 22.03, 9.90; Anal. Calcd. For C17H17N3O5+0.19 H2O: C, 58.88; H, 5.05; N, 12.12. Found: C, 58.77; H, 4.97; N, 12.12.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCCC(O)C2)cc1

Procedure:
1-(4-Nitrophenyl)piperidin-3-ol was synthesized as described in General Procedure A using 1-fluoro-4-nitrobenzene (4.41 g, 31.2 mmol) and piperidin-3-ol (4.3 g, 31.2 mmol) to give an orange solid (6.8 g, 30.6 mmol, 98% yield). Anal. Calcd. for C11H14N2O3 m/z 222.2, found: 223.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.14-7.98 (m, 2H), 6.83 (d, J=9.35 Hz, 2H), 3.89 (d, J=3.85 Hz, 1H), 3.72 (dd, J=12.92, 3.57 Hz, 1H), 3.53 (ddd, J=13.06, 5.91, 3.02 Hz, 1H), 3.33-3.16 (m, 2H), 2.10-1.97 (m, 2H), 1.96-1.84 (m, 1H), 1.75-1.50 (m, 2H).
Reaction SMILES: [CH:1]([OH:3])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][N:43]2[C:51]3[C:46](=[C:47]([O:52][CH3:53])[CH:48]=[CH:49][CH:50]=3)[C:45]([NH:54][S:55]([C:58]3[S:59][C:60]([Cl:63])=[CH:61][CH:62]=3)(=[O:57])=[O:56])=[N:44]2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[Cl:63][C:60]1[S:59][C:58]([S:55]([NH:54][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][CH3:53])[N:43]([CH2:42][C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][NH:34][CH:1]=[O:3])[CH:37]=3)[N:44]=2)(=[O:56])=[O:57])=[CH:62][CH:61]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: O=CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of formic acid (5 μL, 0.13 mmol) in dry DMF (0.3 mL) was added TBTU (34.7 mg, 0.108 mmol) followed with triethylamine (50.2 μl, 0.360 mmol). This mixture was stirred at room temperature for about 10 min before adding N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (45 mg, 0.09 mmol). The resultant pale yellow mixture was stirred at room temperature overnight. LCMS showed very little reaction, so more acid (˜0.25 mL), followed with TBTU (˜30 mg) were added. This addition was repeated 3 more times over 20 h until by LCMS analysis, there was more product than SM. The reaction mixture was partitioned between ethylacetate (2 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous was extracted with ethyl acetate (×2). The combined organic solutions were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to leave a pale oil which crystalised on standing. This was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by Mass Directed AutoPrep on supelcosil ABZ+Plus column eluting with a gradient of MeCN-Water (95:5+0.05% Formic acid)−Water (+0.1% Formic acid). The solvent was evaporated in vacuo to give the title compound (15.9 mg, 36%) as a pale yellow powder: LCMS (System A) RT=1.02 min, ES+ve m/z 491/493 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C([Li])CCC.[I:15]N1C(=O)CCC1=O>C1COCC1.O.CCCCCC.C1COCC1.C(Cl)Cl>[I:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: c1ccn2ccnc2c1
Reactant: O=C1CCC(=O)N1I
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Ic1cnc2ccccn12

Procedure:
In a 1 L three-necked flask, imidazo[1,2-a]pyridine (4.1 g, 34.7 mmol), in THF was treated with butyllithium (14.6 ml, 36.4 mmol) at −50° C. N-iodosuccinimide (8.59 g, 38.2 mmol) in 50 ml THF and added slowly and temp allowed to rise to 0° C. This was diluted with water and hexane. The organic layer was washed with 10% brine/water (2×), dried (MgSO4) and evaporated to give a solid. The solid was dissolved in THF/DCM and purified by flash chromatography (80-100% ethyl acetate/hexane) to give the desired isomer 3-iodoimidazo[1,2-a]pyridine. 1H NMR (300 MHz, DMSO-d6) δ: 8.32 (m, 1H) 7.72 (s, 1H) 7.62 (m, 1H) 7.34 (m, 1H) 7.06 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1.[CH3:31][S-:32].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][S:32][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(Br)cc12
Reactant: C[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CSc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)C1)CN2C(=O)OCC[Si](C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (300 mg, 0.603 mmol) was dissolved in xylene (10 mL). Thereafter, sodium thiomethoxide (85 mg, 1.21 mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg, 0.11 mmol), and xantphos (87.0 mg, 0.15 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at 150° C. for 1 hour. Thereafter, the reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(methylthio)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (192 mg, 69%) in the form of a white amorphous product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]([CH2:21][CH2:22]Cl)[CH2:18][CH2:19]Cl)[CH3:13]>ClC1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:25])[C@@H:16]([CH3:24])[N:17]1[CH2:18][CH2:19][N:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH2:22][CH2:21]1)[CH3:13]
Reactant: CCOC(=O)[C@@H](C)N(CCCl)CCCl
Reactant: Nc1cccc2c1OCCO2
Solvent: Clc1ccccc1
Product: CCOC(=O)[C@@H](C)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 130 °C

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-5-amine (0.327 g; 2.16 mmol) in chlorobenzene (2 mL) is added to a solution of N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester (trifluoromethanesulfonic acid salt; 0.850 g; 2.16 mmol) in the same solvent (2 mL). The stirred reaction mixture is heated at 130° C. for 15 hours, the volatiles are removed on a rotavap, and the semi-solid residue is partitioned between 10% sodium bicarbonate (15 mL) and ether. Organic extracts are washed with brine, dried over magnesium sulfate, and filtered. TLC (chloroform) shows formation of a new product with RF 0.15, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester. Upon addition of 1N ethereal HCl, (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acid ethyl ester is converted into its hydrochloride salt that is collected by filtration; 0.615 g (80%), mp 168–171° C. The salt can be recrystallized from ethanol-ether, or acetone-ether. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7.1 Hz, 3H), 1.58 (d, J=7.2 Hz, 3H), 3.16 (m, 2H), 3.36 (m, 2H), 4.23 (m, 4H), 4.26–4.38 (m, 3H), 4.48 (b, 4H), 6.52 (d, J=7.9 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 6.76 (t, J=8 Hz, 1H), 11.3 (b, <1H).
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C(O)(=O)C.[Pd]>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 97.6 %

Procedure:
III (7.8 g, 0.0123 mole) was taken in acetic acid (80 ml) and hydrogenated in the presence of 10% Pd-C (1 g) at 40 psi. After filtering the catalyst with the aid of celite, the solvent was removed under reduced pressure, triturated with ether, filtered, washed with ether then pet. ether and dried to obtain 6.5 g of the product (yield: 97.3%), m.p. shrinks at 127° C. and decomp. at 3 145° C. Rf3, 0.24; Rf4, 0.11. Anal. Calcd. for C25H43N5O10 1/2H2O: C 54.52, H 8.05, N 12.7%. Found: C 54.32, H 8.02, N 12.59%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[Cl:44]>>[Cl:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccc(Cl)c(Cl)c3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3,4-dichlorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:37])=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.Cl.[CH3:39][NH:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:37])=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:40]([CH3:41])[CH3:39]
Reactant: CNC
Reactant: Cc1c(F)c(NCCCOS(C)(=O)=O)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)c(NCCCN(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
1.02 g (1.89 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-7-methyl-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide, 1.54 g (18.9 mmol) of dimethylamine hydrochloride and 2.60 g (18.9 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 24 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:=100:1-9:1) to give 660 mg of 6,8-difluoro-5-(3-dimethylaminopropylamino)-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one (yield: 71%).
Reaction SMILES: N1C=CN=C1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:44]=[CH:45]/[C:46]([NH:48][NH:49][C:50](=[O:62])[CH2:51][CH2:52][CH2:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=O)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:44]=[CH:45]/[C:46]2[O:62][C:50]([CH2:51][CH:52]=[CH:53][C:54]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:61])=[N:49][N:48]=2)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)CCCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(/C=C/c2nnc(CC=CC(=O)c3ccccc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
IPEA (2.5 mL) was added to a suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide (500 mg) in methylene chloride (12 mL) at room temperature, and the reaction solution was stirred at room temperature for 10 minutes. 4-benzoylbutyric acid (334 mg) and BOPCl (442 mg) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for four hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (692 mg). Imidazole (494 mg), carbon tetrabromide (2.36 g) and triphenylphosphine (559 mg) were added to a suspension of 5-oxo-5-phenylpentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (634 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 515 mg of the title compound. The property value of the compound is as follows.