Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[C-]#N.[Na+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH2:16][CH2:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccc(Cl)c(F)c1
Reaction time: 3 h

Procedure:
Under argon atmosphere, to a solution of 4-chloro-3-fluoro-benzaldehyde (10 g) in N,N-dimethylformamide (50 ml) was added sodium cyanide (620 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. Then, to the mixture was added dropwise a solution of ethyl acrylate (5.2 ml) in N,N-dimethylformamide (25 ml), and the resulting mixture was stirred at the room temperature for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=20:1) to obtain ethyl 4-(4-chloro-3-fluorophenyl)-4-oxobutyrate (9.4 g) as pale yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=O.[C:16](#[N:18])[CH3:17]>>[CH3:17][C:16]1[N:18]=[CH:4][C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CC#N
Product: Cc1ncc2ccccc2n1

Procedure:
In this method, 2-aminobenzophenone derivative (IV) is reacted with acetonitrile to yield 2-methylquinazoline derivative (IX), which is then brominated to 2-bromomethylquinazoline derivative (II-4). The reaction of compound (IV) and acetonitrile is carried out in the same manner as method D. Bromination of compound (IX) is carried out in the same manner as the bromination of compound (VII) by method C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([CH3:26])([CH3:27])[C:28](=[O:29])[N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N2CCCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 17.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), pyrrolidine (0.0083 mL, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#N.C(O)=[O:13].O.[Al]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:13]
Reactant: O=CO
Reactant: N#Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Al]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 100 °C
Yield: 93 %

Procedure:
Add 2,4,6-trichlorobenzonitrile (206 mg, 1.0 mmol) to 96% formic acid (5 mL, 96%) and water (1 mL). Add nichol/aluminum alloy (206 mg) to the mixture. Heat at 100° C. for 4 hours. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 2,4,6-trichlorobenzaldehyde (195 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[C:16]1([CH:22]([NH2:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH:22]([NH:29][C:12](=[O:14])[C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:15])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)NC(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
N-Benzhydryl-2-(1-methyl-1H-indol-3-yl)-2-oxo-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and C,C-diphenyl-methylamine. Yield (11%). HPLC ret. time 3.79 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 9.56 (d, J=9.1 Hz, 1H), 8.65 (s, 1H), 8.24 (m, 1H), 7.61 (m, 1H), 7.43-7.26 (m, 12H), 6.32 (d, J=9.1 Hz, 1H), 3.90 (s, 3H); ESI-MS 369.1 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:27])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1cnc(NS(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 2 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]methanesulfonamide (0.097 g, 0.256 mmol) in DMF (2 mL) was added Cs2CO3 (0.083 g, 0.256 mmol) and MeI (0.04 g, 0.28 mmol, dissolved in DMF). After stirring for 2 hours, additional MeI (0.02 g, 0.14 mmol) was added. The product mixture was concentrated. The residue was partitioned between CHCl3 and pH 7 buffer. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: O1C2C=CC([C:10]3[C:19](N4CCC[C@@H]4C)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=4)[N:11]=3)=CC=2OC1.[OH-].[Na+]>CO.O>[N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:26]([OH:28])=[O:27])=[CH:14][CH:13]=2)[N:18]=[CH:19][CH:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nccnc2c1
Reaction time: 0.14 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-((S)-2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (94 mg, 0.24 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (58.9 mg, 1.47 mmol, 5.00 equiv) in water (3 mL) dropwise with stirring. The resulting solution was stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting solids were collected by filtration. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 80% in 8.5 min, hold 80% in 1 min, up to 100% in 0.1 min, hold 100% in 0.8 min); Detector, UV 220&254 nm. This resulted in 40 mg (44%) of 2-(benzo[d][1,3]dioxol-5-yl)-3-(S)-2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5]1.O.NN>CCO>[NH2:12][CH2:11][CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(CCO)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCN1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
2-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-ethyl}-isoindole-1,3-dione (370 mg, 1.2 mmol) is dissolved in EtOH (8 mL) and hydrazine hydrate (88 mL, 1.8 mmol) is added at RT. The reaction mixture is then refluxed for 3 h and allowed to cool to RT again. The precipitated product is isolated by filtration, washed subsequently with cold EtOH and dried in HV to give the title compound as a white powder. ES-MS: M+H=174.2. 1HNMR (MeOH-d4) δ 4.24 (bs, 2H), 3.41 (t, 2H), 2.62 (t, 2H), 2.54-2.50 (m, 2H), 2-39-2.201 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:19]2[CH:20]=[CH:21][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:10]=1
Reactant: CC(C)(C)c1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CC(C)(C)c1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and tert-butylbenzene.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[NH2:21].Cl>C(#N)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[CH:24]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Cl
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(OC)cc(OC)c1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A 200 mL RB flask was charged with ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (2.76 g, 11.1 mmol) in 40 mL acetonitrile. To the solution was added 3,5-dimethoxy aniline (1.784 g, 11.4 mmol), and conc. HCl solution (494 uL, 5.6 mmol), the reaction mixture was stirred at 60˜70° C. for 2 hours. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO3 solution. It was stirred for an additional 5 minutes. The separated organic layer was dried over MgSO4, and condensed under reduced pressure yielding the residue. The residue was recrystallized from acetonitrile, dried under reduced pressure providing pale yellow solids (2.92 g, 72%). MS m/z: 364.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].C(O[CH:16](OC(C)(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CN(C=O)C>[CH3:16][N:17]([CH:19]=[C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][C:2]1=[O:10])[CH3:18]
Reactant: O=C1Cc2cccnc2N1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)Nc2ncccc21

Procedure:
This compound was prepared in situ (during library synthesis) from 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and dimethylformamide di-t-butylacetal in DMF.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C([O:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30]Br)=[CH:26][C:25]=1[F:34])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:15][CH:14]=3)[CH2:13][CH2:12]2)=[CH:26][C:25]=1[F:34]
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: Fc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc(F)cc3)CC2)cc1F

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine hydrochloride (344 mg, 1.50 mmol), 2-(4-benzoxy-3-fluorophenoxy)ethyl bromide (487 mg, 1.50 mmol), potassium carbonate (518 mg, 3.75 mmol) in two steps as white-off solid (277 mg), mp 184-186° C. 1H NMR (CD3OD) 1.40 (m, 2 H), 1.709 (m, 3 H), 2.424 (d, J=4.8 Hz, 2 H), 2.850 (m, 2 H), 3.319 (m, 2 H), 3.443 (d, J=12.0 Hz, 2 H), 4.087 (s, 2 H), 6.50 (m, 1 H), 6.642 (m, 2 H), 6.833 (m, 2 H), 7.021 (m, 2 H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=1.ClC1C=CC(Cl)=CC=1CCl.OCC1C=CC(O)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:31][CH:32]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1ccc(OCc2cc(Cl)ccc2Cl)cc1
Agent: ClCc1cc(Cl)ccc1Cl
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Agent: OCc1ccc(O)cc1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)ccc3Cl)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 1,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1,4-dichloro-2-chloromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 265 (M−237).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[O:40]1[CH2:41][CH2:42][N:37]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:2]3[CH:11]=[C:10]([C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)=[O:13])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:35][CH:34]=2)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCN1CCCC1)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2ccccc12
Temperature: 130 °C
Yield: 74.2 %

Procedure:
In a sealed 5 ml microwave tubed, a suspension of 2-chloro-N-(2-pyrrolidin-1-ylethyl)quinoline-4-carboxamide (preparation 11) (200 mg, 0.66 mmol), 4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (preparation 2) (399 mg, 1.31 mmol), potassium phosphate (419 mg, 1.97 mmol) and tetrakis(triphenylphosphine)palladium (0) (22 mg, 0.02 mmol) in DMF/Water 3/1 (4 ml) was heated at 130° C. under microwave irradiation for 30 minutes. The reaction was filtered through Celite™ and solvents were removed under reduced pressure. The resulting residue was taken up in DCM (50 ml) and washed with NaHCO3 saturated aqueous solution (25 ml). The organic layer was separated and dried over MgSO4 before concentration to dryness. The reaction crude was purified by preparative HPLC. The fractions containing product were pooled together and freeze dried to obtain the desired compound as a white solid (220 mg, 0.49 mmol, Yield 57%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:3][CH2:2]1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][CH2:35][CH2:36][NH2:37].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[C:11]([NH:37][CH2:36][CH2:35][NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]#[N:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.4 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-5-(trifluoroacetamido) quinoline-3-carbonitrile (500 mg, 1.29 mmol), N-2-pyridyl-1,2-ethanediamine (354 mg, 2.58 mmol) and triethylamine (0.36 mL, 2.58 mmol) in anhydrous DMSO (8 mL) was stirred at 60° C. for 16 h. After cooling, the reaction mixture was poured into ice-water (50 mL). The resulting precipitate was collected by filtration, washed with water and then dried. The crude product was purified by column chromatography (Hexane:EtOAc 1:1→2:3→EtOAc→CH2Cl2: MeOH 8:1) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]-5-(trifluoroacetamido)quinoline-3-carbonitrile (276 mg, 42%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:6][CH:5]=1.[CH2:20]=[C:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C.C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[CH2:20][C:21]12[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: COC(=O)c1ccc(/N=C/c2cccc(Br)c2)cc1
Reactant: C=C1CCCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(Br)c1)N2
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a stirred solution 4-{[1-(3-bromo-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (3.2 g, 10.0 mmol) in acetonitrile (16.0 mL) were added methylene-cyclopentane (4.0 mL, 40.0 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (980.0 mg, 2.0 mmol). The resulting mixture solution was stirred at 80° C. for 16 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2′-(3-bromo-phenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (1.6 g, 40%) as a light yellow solid: MS (ESI) M+1=400.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[CH2:7][CH:8]1[CH2:10][CH2:9]1)[CH3:2].[F:13][C:14]([F:32])([F:31])/[C:15](/O)=[CH:16]/[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:15]([C:14]([F:13])([F:32])[F:31])=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)=[N:11][C:6]=1[CH2:7][CH:8]1[CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C(N)CC1CC1
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Yield: 40 %

Procedure:
231 mg (1.4 mmol) 3-Amino-4-cyclopropyl-but-2-enoic acid ethyl ester were added to a solution of 819 mg (2.7 mmol) (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one in 2.7 ml acetonitrile. The mixture was heated under reflux conditions for 12 h, the solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 242 mg (0.56 mmol, 41%) of the title compound as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH:16]([CH3:32])[CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)=[O:21])[CH:16]([CH3:32])[CH2:15]2)=[O:11])[O:4][N:3]=1
Reactant: O=C(O)CCc1cc(O)no1
Reactant: CC1CC(CN)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CC(CNC(=O)CCc2cc(O)no2)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising of 3-(3-hydroxyisoxazol-5-yl)propanoic acid (40.2 mg, 0.256 mmol), 3,5-dichlorobenzyl 4-(aminomethyl)-2-methylpiperidine-1-carboxylate (step 4) (84.7 mg, 0.128 mmol), Huenig's base (89 μl, 0.511 mmol) and T3P® (50% solution in DMF)(149 μl, 0.256 mmol) in DMF (426 μl) was left stirring at room temperature 18 hours. The resulting mixture was concentrated under pressure and diluted with water. The aqueous solution was extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:11][CH:12]([OH:24])[CH2:13][N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH:16]([OH:19])[CH2:17]Cl>C1(C)C(C)=CC=CC=1>[OH:24][CH:12]([CH2:13][N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH:16]([OH:19])[CH2:17][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCCCN(CC(O)CCl)CC(O)CCl
Solvent: Cc1ccccc1C
Product: CCCCCCCCNCC(O)CN(CCCC)CC(O)CNCCCCCCCC
Temperature: 70 °C
Yield: 83.3 %

Procedure:
A reactor was charged with 371 g (2.87 moles) of octylamine, and the contents were heated to 70° C. To the contents, a solution with 70 g (0.27 mole) of N,N-bis(3-chloro-2-hydroxypropyl)butylamine dissolved in 50 g of xylene was then added dropwise over 40 minutes. The resultant mixture was aged further for 4 hours. Thereafter, xylene was distilled off under reduced pressure, and unreacted octylamine was then distilled off at 70° C. and 0.5 mmHg. A mixture of 400 ml of xylene and 400 ml of 5% aqueous sodium hydroxide was added to the residue to subject it to extraction and washing. Thereafter, a xylene layer was taken out and concentrated, thereby obtaining 99.8 g (yield: 82%) of 11,15-dihydroxy-13-butyl-9,13,17-triazapentacosane represented by the following formula. ##STR11##