Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10](=[O:17])[NH:11]3)=[CH:6][C:5]=2[O:4]1.I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10]([O:17][CH:25]([CH3:27])[CH3:26])=[N:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC(C)I
Reactant: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(-c2ccccc2)c2cc3c(cc2n1)OCCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion, 44 mg, 1.07 mmol) in 1 mL of DMF was added a suspension of 6,7-ethylenedioxy-4-phenylquinazolin-2(1H)-one (100 mg, 0.36 mmol) in 4 mL of DMF and stirred at rt for 15 min. 2-Iodopropane (150 μL, 1.45 mmol) was then added and the mixture was heated to ˜60-70° C. for 1.5 h. Excess sodium hydride was quenched with water and the solution extracted with 25 mL of 9:1 EtOAc:hexane. The extract was washed with 2×25 mL water and brine, then dried with MgSO4 and concentrated in vacuo. The crude solid was subjected to flash column chromatography eluting with acetone:hexane to give the title compound 6,7-ethylenedioxy-2-isopropoxy-4-phenylquinazoline (95 mg, 83%). 1H NMR (CDCl3): 7.75 (d, 2H), 7.52 (m, 3H), 7.44 (s, 1H), 7.29 (s, 1H), 5.49 (m, 1H), 4.43-4.30 (m, 4H), 1.46 (d, 6H), followed by the title compound 6,7-ethylenedioxy-1-isopropyl-4-phenylquinazolin-2(1H)-one (9 mg, 8%). 1H NMR (CDCl3): 7.70 (d, 2H), 7.50 (m, 3H), 7.30 (s, 1H), 7.05 (s, 1H), 5.15 (m, 1H), 4.41-4.26 (m, 4H), 1.68 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O.[C:29](Cl)(Cl)=[S:30].[OH-].[Na+]>O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]=[C:29]=[S:30])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N=C=S
Yield: 31.7 %

Procedure:
To a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.100 g, 0.4 mmol) in 1 ml H2O and TFA (0.040 g, 0.4 mmol) was added thiophosgene (0.040 g, 0.4 mmol). After 1 h the mixture was neutralized with 2 M NaOH and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(2-isopropyl-5-isothiocyanato-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.042 g, 36%) as brown foam [MH]+=334.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:31]([C:33]1[C:38]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][C:40]2=[O:45])=[CH:37][CH:36]=[CH:35][C:34]=1[S:46](Cl)(=[O:48])=[O:47])[CH3:32]>C(Cl)Cl>[CH2:31]([C:33]1[C:38]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][C:40]2=[O:45])=[CH:37][CH:36]=[CH:35][C:34]=1[S:46]([NH:1][C@H:2]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]1[CH3:21])=[O:14])[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6])(=[O:47])=[O:48])[CH3:32]
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)Cl
Reactant: C[C@H]1COCCN1C(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)N1CCOC[C@@H]1C
Reaction time: 1.25 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid [(S)-2-amino-3-((S)-3-methyl-morpholin-4-yl)-3-oxo-propyl]-amide, Intermediate 3 (95 mg, 0.287 mmol) was dissolved in 2 ml DCM and DIPEA (151 μl, 0.861 mmol). 2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonyl chloride, Intermediate 7 (91 mg, 0.3 mmol) in 2 ml DCM was slowly added and the reaction was stirred for 75 min. After that the solution was evaporated to dryness and purified by prep. HPLC. After lyophilization the title compound was obtained as colorless, amorphous solid. Yield: 108 mg, 63%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(Cl)c(Cl)c3)CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 3(3,4-dichlorophenyl)propanoic acid (35 mg, 0.16 mmol) in N,N-dimethylfonnarnide (4 ml) was added 1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol) and 1-(3dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl)methanesulfonamide (Peparation 53, 52 mg, 0.17 mmol) and triethylarnine (33 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 amnionia (300:8:1) to afford the title compound as a white foam (38 mg, 51%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[F:13][C:14]([F:22])([F:21])[CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([C:14]([F:22])([F:21])[F:13])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(F)ncn1
Reactant: FC(F)(F)C1CCCNC1
Solvent: Cc1ccccc1
Product: CC#CCOc1cc(N2CCCC(C(F)(F)F)C2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.2 g of 4-(2-butynyloxy)-6-fluoropyrimidine and 0.15 g of 3-trifluoromethylpiperidine are added to 1 ml of toluene, then the mixture is stirred at room temperature for 30 minutes. Then the reaction mixture is subjected to silica gel column chromatography to obtain 4-(2-butynyloxy)-6-(3-trifluoromethylpyperidino)pyrimidine (referred as the present compound (10) hereinafter).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(N(CC)CC)C.ClC1([C:17]([OH:33])([CH2:26][N:27]2[C:31]([SH:32])=[N:30][CH:29]=[N:28]2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])CC1>ClCCl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:17]([OH:33])[CH2:26][N:27]1[C:31]([S:32][C:2]([O:4][CH3:5])=[O:3])=[N:30][CH:29]=[N:28]1
Reactant: COC(=O)Cl
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Sc1ncnn1CC(O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At temperatures between 0 and 5° C., first a solution of 1.28 ml (6 mmol) of methyl chloroformate in 10 ml of absolute dichloromethane and then 0.84 ml (6 mmol) of triethylamine are added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol and 10 ml of absolute dichloromethane. After the addition, the reaction mixture is stirred at room temperature for a further 2 hours and then diluted with dichloromethane and washed with ice-cold aqueous sodium carbonate solution. The organic phase is dried over sodium sulphate and subsequently concentrated under reduced pressure. The 1.7 g of crude product that remain are chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate=1:1. Concentration of the eluate gives 0.7 g (35% of theory) of 2-(]-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-methoxycarbonylthio-1,2,4-triazol-1-yl)-propan-2-ol in the form of an oil.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:35][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([CH3:25])[N:27]=3)[CH2:32]2)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2c(n1)CCC(N)C2
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2nn(C)cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine hydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a faint yellow solid compound.
Reaction SMILES: C[OH:2].S(=O)(=O)(O)O.[F:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](C(C)=C)=[CH:14][CH:13]=1.OO>O>[F:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:2])=[CH:14][CH:13]=1
Reactant: C=C(C)c1ccc(OCCF)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: Oc1ccc(OCCF)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Then, a mixture of 30 ml of methanol and 2 ml of concentrated sulfuric acid was warmed to 40° C., and 9.0 g of the resulting crude 4-(2-fluoroethoxy)-isopropenylbenzene prepared as above and a 30% aqueous solution of hydrogen peroxide were separately added dropwise to the warmed mixture over the course of 20 minutes. The reaction was continued for 1 hour. The reaction mixture was cooled, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 7.3 g of crude 4-(2-fluoroethoxy)phenol. The resulting crude phenol was recrystallized to give 6.8 g of pure 4-(2-fluoroethoxy)phenol as crystals.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:16]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28](O)=[O:29])([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:28](=[O:29])[C@H:27]3[CH2:31][CH2:32][CH2:33][N:26]3[S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)n2cc(-c3ccccc3)c3ccccc32)cc1

Procedure:
condensing a 3-phenyl indole with an N-tosyl-D-proline to form a 3-phenyl-1-(N-tosyl-D-prolyl) indole,
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[ClH:21].C(=O)([O-])O.[Na+]>C(O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][Cl:21])[OH:16])[CH3:8]
Reactant: Cl
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC1C(O)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of fumagillol (200 mg) in ethanol (2 ml) was added 0.5N hydrochloric acid (1 ml), and the mixture was stirred at room temperatures for one hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent:hexane-ethylacetate=3:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(chloromethyl)-1,4-cyclohexanediol (200 mg: yield 90%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[Cl:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC(C#N)n1cc(Cl)cn1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)n1cc(Cl)cn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution of sodium ethoxide, prepared by adding solid sodium (420 mg, 18.2 mmol) into ethanol (20 mL), was added to a solution of 2-(4-chloro-1H-pyrazol-1-yl)propanenitrile (2530 mg, 13.0 mmol) in ethanol (4 mL). The reaction mixture was stirred at 70° C. for 3 h. 1H NMR analysis of the reaction mixture showed desired product. The mixture was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.30 (t, 3H), 1.75 (m, 3H), 4.19 (m, 2H), 4.86 (m, 1H), 7.47 (s, 1H), 7.52 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]3([CH3:26])[NH:23]C(=O)N[C:20]3=[O:25])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC[OH:29].[OH-].[Na+].Cl>O>[NH2:23][C:19]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:18]=2)([CH3:26])[C:20]([OH:25])=[O:29]
Reactant: CCCCCCCOc1ccc2cc(C3(C)NC(=O)NC3=O)cnc2c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(C)(N)C(=O)O)cnc2c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(7-(heptyloxy)quinolin-3-yl)-5-methylimidazolidine-2,4-dione (1 g, 2.8 mmol), EtOH (2 mL), H2O (4 mL), and NaOH (2.24 g, 56 mmol, 20 eq.) was stirred for 4 day at 110° C. Then, to the reaction mixture was added HCl (40%) to adjust to pH=5 and then the desired compound was generated as yellow solid (740 mg, yield 80%), without further purification for next step. ESI-MS: 331 (M+H)+. 1H NMR (300 MHz, CD3OD) δ: 0.81-0.83 (t, 3H), 1.06-1.09 (t, 3H), 1.18-1.33 (m, 8H), 1.41-1.45 (m, 2H), 1.75-1.78 (m, 2H), 1.96 (s, 3H), 3.48-3.53 (m, 2H), 4.04 (m, 2H), 7.18-7.24 (m, 2H), 7.79-7.81 (d, 1H), 8.39 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH:14](OC)(OC)OC>>[CH3:13][N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:14]1
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: COC(OC)OC
Product: COC(=O)c1ccc2c(c1)ncn2C

Procedure:
A solution of methyl 3-amino-4-methylaminobenzoate (prepared as in DE 1990390463 A1) (2.57 g, 14 mmol) in trimethyl orthoformate (50 mL) was refluxed for 16 hours. The solvent was then removed under reduced pressure to afford 2.31 g of product.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:39])=[CH:11][C:12]([F:38])=[C:13]([CH:37]=1)[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>[Pd].CN(C=O)C.CO>[F:38][C:12]1[CH:11]=[C:10]([CH3:39])[C:9]([OH:8])=[CH:37][C:13]=1[O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(Oc3cc(OCc4ccccc4)c(C)cc3F)ccnc2cc1OCCCN1CCOCC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2c(Oc3cc(O)c(C)cc3F)ccnc2cc1OCCCN1CCOCC1
Reaction time: 3 h
Yield: 60.6 %

Procedure:
A mixture of 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(3-morpholinopropoxy)quinoline (274 mg, 0.5 mmol) and 10% palladium-on-charcoal catalyst (274 mg) in DMF (10 ml) and methanol (10 ml) was stirred under hydrogen at 5 atmospheres pressure for 3 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The resulting solid was suspended in ether, collected by filtration and washed with methylene chloride and isopropanol to give 4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(3-morpholinopropoxy)quinoline (134 mg, 25 60%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1([S:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28][CH2:29][C:30]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)CSc1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)CSc3ccccc3)CC1)O2

Procedure:
Compound 48 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (phenylthio)acetyl chloride and conditions outlined in procedure N. M.p.=155-157° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.89 (m, 2H), 7.76 (t, 1H), 7.60 (t, 1H), 7.39 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 4.11 (dd, 2H), 4.05 (s, 2H), 3.42 (t, 2H), 3.11 (s, 2H), 2.05 (m, 2H), 1.80 (m, 2H); LCMS: 452 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:25])[CH2:21][NH:22][CH2:23][CH3:24])=[C:4]([F:26])[CH:3]=1.[CH3:27][OH:28].C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]2[C:20](=[O:25])[CH2:21][N:22]([CH2:23][CH3:24])[C:27]2=[O:28])=[C:4]([F:26])[CH:3]=1
Reactant: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Reactant: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN1CC(=O)N(c2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)C1=O

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide (0.82 g) and 1,11 -carbonyldiimidazole (0.43 g) in toluene (20 ml) was heated at reflux for 2 hours, cooled and processed. Column chromatography on silica gel eluting with 2.5% methanol-methylene chloride gave a buff colored solid (0.8 g), mp 162-3° C. 1H NMR (CDCl3, TMS): 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m).
Reaction SMILES: [CH2:1]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[C:10]([Cl:11])=[C:9]([CH3:12])[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=1[C:29]([N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1)=[O:30]>>[Cl:11][C:10]1[C:6]([N:5]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][N:8]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][C:19]=2[C:29]([N:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:9]=1[CH3:12]
Reactant: CCCCN(CCCC)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Product: CCCCN(CCCC)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 26.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, N,N-dibutyl-4-chloro-5-methyl-1H-pyrazol-3-amine (160 mg, 0.66 mmol) and ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 1D, 258 mg, 0.79 mmol) were converted to the title compound (98 mg, 27%). 1H NMR (CDCl3, 2:1 mixture of amide rotamers) δ 8.19 (d, J=8.1 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 7.40 (d, J=8.33 Hz, 1H), 7.08-7.30 (m, 3.5H), 6.92 (d, J=7.5 Hz, 0.5H), 4.95 (d, J=17.1 Hz., 0.5H), 4.68 (d, J=17.10 Hz, 0.5H), 4.31-4.53 (m, 2.5H), 4.12 (d, J=4.1 Hz, 0.5H), 3.51-3.76 (m, 1.5H), 3.03-3.36 (m, 4.5H), 2.75-3.03 (m, 2H), 2.58 (s, 2H), 2.47 (s, 1H), 1.33-1.51 (m, 7H), 1.13-1.30 (m, 4H), 0.77-0.96 (m, 6H); MS(ESI+) m/z 551.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])[C:19]([Cl:31])=[CH:18][N:17]=1.Cl.[Na]>O.CC(O)C>[Cl:31][C:19]1[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC4CCCCNC4=O)n3)cc2CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (75 mg 0.20 mmol), 3-(2,5-Dichloro-pyrimidin-4-ylamino)-azepan-2-one (57 mg, 0.30 mmol) and 81 μl of 4N HCl in dioxanes were combined into 1 ml IPA in a microwave tube. The reaction was heated to 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-20% methanol in methylene chloride as the eluent to yield 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-azepan-2-one (22.33 mg, 19%). MP: 232-234° C.; 1H-NMR (CDCl3) δ 7.99 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.16 (s, 1H), 7.08 (d, J=8 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J=6 Hz, 1H), 6.30 (br s, 1H), 4.69 (q, J=9.9, 5.56 Hz, 1H), 3.32 (m, 2H), 2.92 (m, 4H), 2.72-2.52 (m, 6H), 2.25 (d, J=3.9 Hz, 1H), 2.05 (d, J=4.2 Hz, 1H), 1.95-1.65 (m, 2H), 1.60-1.40 (m, 2H), 1.08 (t, J=7 Hz, 3H); LC/MS (ESI+): 429 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17]CC1.CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]1
Reactant: Clc1cnccn1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 20 g (0.1746 mol) of chloropyrazine, 36 g (0.260 mol) of K2CO3, 76 g (0.5308 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 80 ml of dimethylformamide is stirred at 100° C. for 3 days. The reaction mixture is cooled, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 400 ml of 10% sulfuric acid solution and 100 ml of tetrahydrofuran are stirred at ambient temperature for 4 days, diluted with water, basified (NaOH) and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 8.4 g of title compound: IR (KBr) 1720 and 1580 cm-1 ; NMR (CDCl3) δ 8.24-7.88 (m, 3H), 3.98 (t, 4H), and 2.56 (t, 4H).