Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)=[CH:6][C:5]=1[O:23][CH:24]([CH3:26])[CH3:25])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)Oc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 95.8 %

Procedure:
A solution of 2.76 g of 2-methylpropan-2-yl 4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate in 60 ml of methanol is hydrogenated on 300 mg of palladium-on-carbon (10%) at a pressure of 10 bar and at ambient temperature for 3 h. The catalyst is removed by filtration on Celite and the filtrate is evaporated to dryness so as to obtain 2.44 g of 2-methylpropan-2-yl 4-[4-amino-3-(propan-2-yloxy)phenyl]piperidine-1-carboxylate in the form of a pink powder.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1.O>CS(C)=O>[CH:9]([C:10]1[N:14]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1)=[O:8]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(Cn2cncc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (13.8 ml/99.6 mmol) and then SO3-pyridine complex (9.89 g/62.25 mmol) are added in succession to a solution of 4.6 g (24.9 mmol) of the compound obtained in Step A in 120 ml of DMSO, and the reaction mixture is stirred at room temperature for 30 minutes. The whole is then brought to 0° C., hydrolysed with H2O, and then extracted several times with AcOEt. The organic phases are combined, washed with a saturated NaCl solution, dried over MgSO4, and evaporated to dryness to yield the title product.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][C:8]2=[O:17])[C@H:4]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH2:3]1.[H-].[Na+].[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[S:43](Cl)(=[O:45])=[O:44].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C)C=O>[CH3:33][O:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:36]=1[S:43]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([N:5]2[CH2:6][C@H:2]([F:1])[CH2:3][C@H:4]2[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[C:8]1=[O:17])(=[O:44])=[O:45]
Reactant: COc1ccccc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(C)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(C)ccc32)c(OC)c1
Reaction time: 0.5 h

Procedure:
620 mg of the compound obtained in step 15-1 (diastereoisomer mixture) was added under ice cooling and a nitrogen atmosphere to a 10 mL N,N-dimethylformamide solution of 67 mg of sodium hydride, and the reaction mixture was stirred for 40 minutes. After this, a 2 mL N,N-dimethylformamide solution of 400 mg of 2,4-dimethoxybenzenesulfonyl chloride was added dropwise. The reaction mixture was stirred for 30 minutes at the same temperature, after which 5 mL of ethyl acetate and 10 mL of a 5% potassium carbonate aqueous solution were added, and the reaction mixture was stirred at room temperature overnight. The precipitated solids were filtered off and separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone=99/1; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 184 mg (isomer A: colorless, amorphous) and 256 mg (isomer B: colorless, amorphous).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[N+:22]([C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33](Cl)=O)[CH:28]=[CH:29][CH:30]=1)([O-])=O>>[NH2:22][C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]2[NH:1][C:2]3=[CH:3][C:4]4[C:5]([CH3:21])([CH3:20])[C:6](=[O:19])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]=4[CH:9]=[C:10]3[N:11]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: O=C(Cl)/C=C/c1cccc([N+](=O)[O-])c1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(/C=C/c4cccc(N)c4)nc3cc21
Yield: 52.9 %

Procedure:
2-[(E)-2-(3-Amino-phenyl)-vinyl]-7,7-dimethyl-5-pentyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (177 mg) is prepared from A8 (251 mg) and (E)-3-(3-nitro-phenyl)-acryloyl chloride (200 mg; 1.01 mmol) as described in Example 28a and b.
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH:19]=[CH:18][O:20][CH2:21][CH3:22])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Brc1nc2cncnc2n1Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC=Cc1nc2cncnc2n1Cc1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 9-benzyl-8-bromopurine 13 (1.0 g, 3.4 mmol) bis(triphenylphosphine)-palladium(II)chloride (0.242 g, 0.30 mmol) and ethoxyvinyl(tributyl)tin (1.49 g, 4.14 mmol) in dry DMF (50 mL) was heated under N2 at 65° C. for 48 h. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The EtOAc was distilled off and the residue obtained was purified by flash chromatography. Yield 0.579 g, (59.7%). 1H NMR (CDCl3): δ 1.33 (t, 3H, CH3, J=7.5 Hz), 3.99 (q, 2H, CH2, J=13.7 Hz), 4.66 (d, 1H, CH, J=3 Hz), 5.34 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 7.30-7.38 (m, 5H, Ar—H), 9.09 (s, 1H, purine C8—H), 9.2 (s, 1H, purine C2—H). 13C NMR (CDCl3): δ 14.2, 47.3, 64.2, 91.8, 126.8, 126.8, 127.7, 128.6, 128.6, 133.1, 136.4, 148.2, 151.2, 151.9, 152.8, 153.0.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:9]([O:21][CH3:22])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].Cl>C1COCC1.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[NH2:1][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[C:9]([O:21][CH3:22])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C)CC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C#N)c(N)cc1OCC1CCN(C)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
2-nitro-4-(1-methylpiperidin-4-ylmethoxy)-5-methoxybenzonitrile (1.1 g, 3.6 mmol) in THF (20 ml) in presence of benzyltrimethylammonium chloride (334 mg, 1.8 mmol) was treated by a slow addition of Na2S2O4 (3.1 g, 18 mmol) in water (20 ml). After 0.5 h, HCl (6N, 20 ml) was added to the mixture, which was stirred at 60° C. for 5 h. The mixture was cooled to room temperature, extracted with ethylacetate. The aqueous phase was made basic with Na2 CO3 (solid), and extracted with ethylacetate. The organic phase was dried over MgSO4, concentrated, to give a yellow solid (748 mg, 75%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([N+:15]([O-])=O)=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([OH:31])=[O:30])=[CH:24][CH:23]=[CH:22]2.[OH-].[Na+]>CO.[Pd]>[NH2:15][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[O:18][C:19]1[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([OH:31])=[O:30])=[CH:24][CH:23]=[CH:22]3)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncc(N)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Pd on carbon (5 wt %, 0.015 g) was added to a solution of 6-(6,7-dimethoxy-3-nitroquinolin-4-yloxy)-1-naphthoic acid (0.149 g, 0.354 mmol) in MeOH (30 mL). The system was purged with H2 (g) and stirred under a H2 atmosphere at RT for 21 h to afford a thick suspension. The pH of the reaction was adjusted to 6-7 with 2N NaOH (aq), and Pd on carbon (5 wt %, 0.025 g) was added to the resulting solution. The mixture was purged with H2 then stirred under a H2 atmosphere at RT for 3 days (additional Pd on carbon (5 wt %, 0.025 g) was added after the first and second days). The mixture was filtered through a pad of Celite and the filtrate was concentrated to afford 6-(3-amino-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as a brown solid. MS (ESI, pos. ion) m/z: 391.1 (M+H). Mass Calc'd for C22H18N2O5: 390.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([Zn]CC)[CH3:26]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([CH2:25][CH3:26])=[CH:3][C:4]=1[C:15]([F:18])([F:17])[F:16])[CH3:10]
Reactant: CCN(CC)C(=O)c1ccc(Cl)cc1C(F)(F)F
Reactant: CC[Zn]CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1ccc(C(=O)N(CC)CC)c(C(F)(F)F)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
To a solution of 4-chloro-N,N-diethyl-2-(trifluoromethyl)benzamide (5.04 g, 18 mmol) in 100 mL of N,N-dimethylformamide was added potassium carbonate (6.2 g, 45 mmol) and diethylzinc (29.5 mL of a 1.1 M solution in toluene, 32.4 mmol). The mixture was degassed and then there was added POPd (Combiphos) (0.27 g, 0.54 mmol). The resulting solution was heated at 120° C. in a sealed tube for 18 h. The mixture was allowed to cool and was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concnentrated in vacuo. The residue was purified (ISCO, elution with 0-25% EtOAc/hexane) to afford 3.7 g (75%) of the title compound as an oil. LRMS (ESI): 274.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2nc3ccsc3c(=O)n2c1
Reaction time: 2 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (2.5 g, 0.01 mol) and 1,1'-carbonyldiimidazole (1.7 g, 0.01 mol) in dimethylformamide (25 ml) is heated at 90°-95° C. for one hour under nitrogen. The solution is cooled in an ice bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off. The precipitate is washed with tetrahydrofuran and recrystallized from dimethylformamide to give the product (1.2 g.), mp 319°-320° C.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([C:20]3[CH:25]=[N:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Reactant: Fc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)nc2)oc2cc(N)c(Br)cc12
Temperature: 50 °C
Reaction time: 10 h
Yield: 51.2 %

Procedure:
To a solution of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (500 mg, 1.61 mmol) in dioxane/H2O (5 mL/0.5 mL) was added 5-bromo-2-fluoropyridine (420 mg, 2.42 mmol), Pd(dppf)Cl2(10 mg) and K3PO4.3H2O (855 mg, 3.21 mmol). The mixture was stirred at 50° C. for 10 h. The mixture was evaporated and washed with MeOH to obtain the yellow solid as the product of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3-carboxamide (300 mg, yield: 51%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.76 (s, 1H), 8.44˜8.51 (m, 2H), 7.75 (s, 1H), 7.39˜7.42 (m, 1H), 7.09 (s, 1H), 5.71 (s, 2H), 2.88 (d, J=8.4 Hz, 3H). (M+H)+: 364/366.
Reaction SMILES: [CH3:1][C:2]1([C:8]#[N:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH2:8][NH2:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC1(C#N)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CN)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methyltetrahydro-2H-pyran-4-carbonitrile (1.8 g, 14.38 mmol) in THF (30 mL) was added carefully 1M LAH/THF (21.57 mL, 21.57 mmol) at 0° C. The reaction mixture was stirred for 15 min at 0° C., allowed to warm to ambient temperature and stirred for ˜3 hours at ambient temperature. To the reaction mixture was carefully added water (0.9 mL), 1N aqueous NaOH (2.7 mL) and water (0.9 mL) [Caution: gas development!]. The mixture was vigorously stirred for 30 min. The precipitate was filtered off and rinsed with THF. The solution was concentrated in vacuo providing crude (4-methyltetrahydro-2H-pyran-4-yl)methanamine as a yellowish solid, which was directly used in the next step without further purification. Yield: 1.54 g. LCMS (m/z): 130.1 [M+H]+; Retention time=0.21 min.
Reaction SMILES: [CH2:1]([CH:6](O)[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C(=O)CC([OH:23])C=1)CCCC>O>[CH2:1]([CH:6]1[CH:7]([OH:11])[CH:8]=[CH:9][C:10]1=[O:23])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CC(O)CC1=O
Reactant: CCCCCC(O)c1ccco1
Solvent: O
Product: CCCCCC1C(=O)C=CC1O
Temperature: 100 °C

Procedure:
In the same flask as used in Example 1, there were charged α-n-pentylfurfuryl alcohol (I-3) (33.6 g) and water (1680 g), and the mixture was stirred at 100° C. while adjusting to a pH of 4.6-5.0. The reaction mixture was treated in the same manner as in Example 1 to give a mixture (29.2 g) of 2-n-pentyl-3-hydroxy-4-cyclopentenone (II-3) and 2-n-pentyl-4-hydroxy-2-cyclopentenone (III-3). Yield, 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][CH:37]([CH:42](C(O)=O)[C:43]([OH:45])=[O:44])[C:38]([F:41])([F:40])[F:39])=[CH:32][C:31]=3[F:49])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][C:26]=3[O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][CH:37]([C:38]([F:40])([F:39])[F:41])[CH2:42][C:43]([OH:45])=[O:44])=[CH:32][C:31]=3[F:49])[CH:21]=2)=[N:18][CH:19]=1)[CH2:9][CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(C(C(=O)O)C(=O)O)C(F)(F)F)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(CC(=O)O)C(F)(F)F)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.9 %

Procedure:
A solution of 17 (1.21 g, mixture of 17 and 18) in toluene (50 mL) was heated to reflux for 1 h then cooled to RT. The reaction mixture was then concentrated, re-dissolved in MeOH, and concentrated again. The residue was triturated with a mixture of AcOEt/hexanes. The resulting suspension (gel) was collected by filtration, rinsed with hexanes, air-dried and dried under high vacuum to afford the title compound 18 (1.157 g, 1.74 mmol, quant, yield) as an off-white solid. MS (m/z): 665.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.C(Cl)(Cl)Cl.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH:13][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCCCCCC(=O)Cl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a mixture of 2.85 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of chloroform and 2 parts by volume of triethylamine, a solution of 1.6 parts of enanthylchloride in 20 parts by volume of diethyl ether is gradually added with ice-cooling. The mixture is stirred for a while to complete the reaction. After evaporation of the solvent under reduced pressure, the residue is treated with methanol to yield 7-chloro-2-(2-enanthylhydrazino)-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of dimethylformamide and water yields colorless needles melting at 205° C to 206° C (effervescence).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:22]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=[O:26])[CH3:23].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:14][C:2]=1[NH:1][CH:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH2:28][CH2:29]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: CCOC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-ethoxycarbonylpiperidone (1.06 g, 0.932 mL, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of NaHCO3 was then added, the mixture was concentrated under reduced pressure and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. After purification by chromatography over silica gel (DCM/EtOH 93:7) 2.187 g of title compound were obtained as a white solid (95% yield).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8]([F:12])[CH:9]=[C:10]([F:11])[C:4]=2[O:3]1.[Li]C(CC)C.[I:19]I.[NH4+].[Cl-]>O1CCCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([F:12])[C:9]([I:19])=[C:10]([F:11])[C:4]=2[O:3]1
Reactant: II
Reactant: Fc1cc(F)c2c(c1)OC(F)(F)O2
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cc2c(c(F)c1I)OC(F)(F)O2
Temperature: -70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2,2,4,6-Tetrafluorobenzo[d][1,3]dioxole (500 mg, 2.6 mmol) was dissolved in dry tetrahydrofuran (7 mL), cooled to −70° C., treated dropwise with sec-BuLi (1.3 M; 2.1 mL, 2.7 mmol) and stirred for 1 h at −70° C. This mixture was treated dropwise with a solution of iodine (1.1 g, 4.4 mmol) in tetrahydrofuran (5 mL) over 10 min. After 2 h at −70° C., the mixture was treated with saturated NH4Cl, extracted with ethyl ether, dried (Na2SO4) and evaporated. The material was purified by reverse phase HPLC with 85% acetonitrile-water to give the title compound (250 mg; 30%): 1H NMR (400 MHz, CDCl3) δ 6.80-6.77 (d, J=8.7 Hz, 1H), 6.77-6.75 (d, J=8.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −48.72, −99.73, −132.62; EIMS m/z 320.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.O[CH2:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][CH2:39][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]2([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[CH2:12][CH2:13]2)=[O:15])=[CH:18][C:19]=1[F:37])[CH3:44]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Reactant: CCN(CC)CCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCCOc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydroxypropyldiethylamine (0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10 mL) was added DIAD (0.17 mL, 0.86 mmol). The resulting mixture was stirred at room temperature for 12 hours, after which time, the solvent was removed under reduced pressure. The residue was extracted with EtOAc and 1N HCl (6×) and brine (1×) followed by drying with Na2SO4. Concentration of the organic fraction in vacuo afforded ′N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide as a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Further purification by preparatory HPLC using ammonium acetate afforded the product in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)+. 1H NMR (DMSO-d6) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([Br:7])[N:6]=1.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:16]=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([C:2]2[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([Br:7])[N:6]=2)[CH:20]=[CH:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: CCOC(=O)c1sc(Br)nc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Yield: 53 %

Procedure:
A mixture of ethyl 2,4-dibromothiazole-5-carboxylate (0.500 g, 1.59 mmol), N-(4-(trimethylstannyl)pyridin-2-yl)acetamide (0.569 g, 1.90 mmol), tetrakis(triphenylphosphine)palladium(0) (91.7 mg, 0.0794 mmol), copper(I) iodide (90.7 mg, 0.476 mmol), and lithium chloride (202 mg, 4.76 mmol) in dioxane (29.1 mL) was degassed with nitrogen and heated at reflux for 1 hr. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→50/50) to give 312 mg of the title compound. (44% yield). LC/MS (FA) ES+ 370, 372. 1H NMR (400 MHz, CDCl3) δ: 8.71 (s, 1H), 8.39 (d, 1H, J=5.2 Hz), 8.25 (bs, 1H), 7.68 (dd, 1H, J=5.2, 1.6 Hz), 4.41 (q, 2H, J=7.2 Hz), 2.26 (s, 3H), 1.41 (t, 3H, J=7.2 Hz).