Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[CH3:2].S(OC)(O[CH3:18])(=O)=O>[OH-].[Na+]>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([O:11][CH3:18])[CH:7]=[C:8]([OH:10])[N:9]=1)[CH3:13]
Reactant: COS(=O)(=O)OC
Reactant: CCN(CC)c1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc(O)cc(OC)n1

Procedure:
500 cc of sodium hydroxide solution 1N are added while stirring to 91.5 g (0.5 mol) of 2-diethylamino-4,6-dihydroxy-pyrimidine. The solution is stirred at 50° for a short period and then cooled to 20°. 63 g (0.5 mol) of dimethyl sulphate are added dropwise, over the course of 1 hour, to the clear solution; by further addition of sodium hydroxide solution 1N the pH value is kept between 7.5 and 8. A total of approximately 100 cc of sodium hydroxide solution 1N is further used. The mixture is stirred for a further 5 hours at room temperature and filtered off at 5° from the precipitated crystals; then it is washed with water. The crystalline product is subsequently decomposed with 1500 cc of carbon tetrachloride by means of a vibration mixer. The undissolved parts are suction filtered and the carbon tetrachloride solution is then concentrated by evaporation, whereupon crystallization commences; 200 cc of petroleum ether are then added. The mixture is suction filtered, washed with petroleum ether and dried at 80° in a high vacuum. Optionally it may be recrystallized from benzene. M.P.: 165°-166°.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>CN1CCCN(C)C1=O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1ccccc1OCc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C(=O)OC)c1ccccc1COc1ccccc1C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion) (15.4 g) in 90 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2[1H]-pyrimidinone (DMPU), cooled in an ice-water bath, was added dropwise a solution of dimethyl malonate (44 mL) in DMPU (150 mL). The mixture was stirred 20 minutes after the addition was completed, and then 1-iodo-2 -[(2-methylphenoxy)methyl]benzene (62.5 g) and cuprous iodide (73.3 g) were added. The resulting mixture was stirred at 100° C. for 5 h, then stirred at 25° C. overnight. The mixture was diluted with 1 N. HCl (~150 mL) and extracted with diethyl ether (3×400 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to a semi-solid, which was purified by flash chromatography on silica get (5:2 hexane:ethyl acetate as eluant). The major material was collected and concentrated to a white solid, which was triturated in hexane and collected by filtration to yield 56.9 g (79% of the title compound of Step C as a white solid, mp 99-103° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][N:11]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[CH:23][C:24](S(O)(=O)=O)=[CH:25][CH:26]=1.[CH3:31][N:32]([CH:34]=[O:35])C>C1COCC1>[NH2:11][C:10]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]([O:35][C:34]2[CH:2]=[CH:3][N:4]=[C:31]([NH:19][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:32]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc2[nH]nc(OCCN3CCOCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Nc3ccc4[nH]nc(OCCN5CCOCC5)c4c3)n2)c2ccccc12
Temperature: 90 °C

Procedure:
A solution of Intermediate E2 (223 mg, 0.738 mmol), 3-(2-morpholinoethoxy)-1H-indazol-5-amine (215 mg, 0.738 mmol) and p-TSA (140 mg, 0.738 mmol) in a mixture of DMF and THF (1:1 v/v, 20 mL) was heated to 90° C. for 6 h and then cooled to RT and maintained at that temperature for a further 64 hr. The reaction mixture was partitioned between saturated aq. NaHCO3 (50 mL) and EtOAc (50 mL). The aq layer was separated and extracted with EtOAc (50 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-10% [0.1% NH3 in MeOH] in DCM, gradient elution) to afford the title compound, Intermediate B17, as a black solid (201 mg, 49%); Rt 1.32 min (Method 2, acidic); m/z 498 (M+H)+ (ES+).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Li]CCCC.[Li]>C(OCC)(=O)C.C1COCC1>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:10])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)CCCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 6-oxo-heptanoic acid 7-1(100 g, 694 mmol), NEt3 (111.3 ml, 763.4 mmol) and THF (2000 mL) at -78° C. was added pivaloyl chloride (98.7 ml, 763.4 mmol). The mixture was warmed to 0° C. for 1.0 h and then recooled to -78° C. To a stirred solution of (S)-(-)-4-benzyl-2-oxazolidinone (136 g, 763.4 mmol) and THF (2000 ml) at -78° C. was added nBuLi (306 ml, 765 mmol, 2.5M in hexanes) dropwise over 30 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 20 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was azeotroped with xylenes to give 7-2 as a colorless foam.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cn1
Yield: 41.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 31 and using (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (2 g) described in Preparation Example 23 and (R)-4-methyloxazolidin-2-one (288 mg) described in Preparation Example 25, the title compound (510 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: Nc1ccc(I)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (5.0 g, 21 mmol) in pyridine (30 mL) at 0° C. was added methanesulfonyl chloride (2.5 mL, 32 mmol) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated. Purification by chromatography (SiO2, 33% EtOAc/Hexanes) afforded the title compound (5.0 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.71 (dd, J=9.9, 1.9 Hz, 1H), 7.56 (ddd, J=8.4, 1.9, 1.0 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 3.03 (s, 3H); MS (ESI; M−H) m/z 314.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15](OC)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[NH2:19]CC1C=NC=CC=1.[CH2:27]([OH:29])C>O>[CH3:27][O:29][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH2:19])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: CCO
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Solvent: O
Product: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (0.10 g, 0.38 mmol) and 3-(aminomethyl)pyridine (1.0 mL, 9.5 mmol) in ethanol (4 mL) was heated at 100° C. for 9 minutes in a microwave reactor. The mixture was diluted with water, then cooled to r.t. and the formed precipitate was collected by filtration and dried. The crude product was purified by prep. HPLC to give the title compound (71 mg) as a solid. 1H NMR (CHLOROFORM-d) δ 8.75 (d, 1 H) 8.66 (d, 1 H) 8.56 (dd, 1 H) 8.11 (dd, 1 H) 7.89 (d, 1H) 7.66-7.76 (m, 1 H) 7.34 (d, 1 H) 7.26-7.31 (m, 2 H) 7.07 (dd, 1 H) 6.50 (d, 1 H) 5.18 (t, 1 H) 4.67 (d, 2 H) 3.90 (s, 3 H); MS m/z (M+H) 348.9.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[S-:13][C:14]#[N:15].[K+].O>C(O)(=O)C>[CH3:2][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:15][C:14]1=[S:13]
Reactant: CNCC(=O)c1ccccc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2ccccc2)[nH]c1=S
Temperature: 140 °C
Yield: 47.3 %

Procedure:
An adaptation of the method reported by Kjellin and Sandström, Acta Chem. Scand. 1969, 23, 2879-2887 was used. A mixture of 2-methylamino-1-phenyl-ethanone hydrochloride (0.754 g, 4.06 mmol) (see e.g. Hyde et al. J. Am. Chem. Soc. 1928, 50, 2287-2292; Shang et al. Chem. Eur. J. 2007, 13, 7780-7784) and potassium thiocyanate (0.434 g, 4.46 mmol) in acetic acid (12 mL) was heated at 140° C. for 10 minutes using a microwave synthesizer. Dilution with water (50 mL) and cooling in an ice bath caused the product to precipitate. It was collected by filtration, washed with water, and vacuum dried to yield the title compound (0.365 g, 47%) pure as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ12.66 (br s, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.60 (s, 1H), 7.39 (t, J=7.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[I:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(N(CC)CC)C>C1COCC1>[I:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][C:6](=[O:7])[NH:20][N:19]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc(I)c2)o1
Temperature: 25 °C

Procedure:
A solution of N,N-carbonyldiimidazole (800 mg, 5.0 mmol) in 5 mL of dry THF was added dropwise to an ice-cold solution of the product from Step A (1.048 g, 4.0 mmol) and triethylamine (0.60 mL, 4.0 mmol) in 12 mL of dry THF. The resultant mixture was allowed to warm to room temperature overnight, and was then concentrated under reduced pressure. The residue was partitioned between diethyl ether and water, and the ether layer was washed sequentially with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure to afford a white powder. Recrystallization from ethyl acetate-hexanes afforded the title compound as a fluffy white solid. LC/MS 289.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial was charged with tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.454 g, 0.791 mmol), 2-fluoropyridin-3-ylboronic acid (0.167 g, 1.186 mmol), potassium carbonate (0.546 g, 3.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.091 g, 0.079 mmol). The vial was flushed with Ar (g), then Dioxane (5.27 mL) and water (2.64 mL) were added in sequence. The vial was sealed and heated at 80° C. for one hour. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-50% EtOAc:Hex) to afford tert-butyl 3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a light yellow solid. MS m/z=545.1. Calc'd for C24H20BrFN4O3S: 543.41
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]1C[O:39][CH2:38][CH2:37]1>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:38](=[O:39])[CH:37]=[CH2:36])=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 23 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was prepared from (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine instead of N,N-diethylethanamine, THF instead of methylpyrrolidin-2-one and dichloromethane using Method G (23% yield). HPLC: 93%, RT=4.014 min. MS: m/z=423 [M+H]+, RT=3.16 min. 1H-NMR (DMSO-d6) δ 8.99 (s, 1H), 8.36 (d, 1H), 8.18 (s, 1H), 8.08 (d, 2H), 7.89-7.83 (m, 4H), 7.65-7.48 (m, 7H), 7.25 (d, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.05 (d, 1H), 4.98 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[H-].[Na+].[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[C:10]([CH2:36][CH2:35][C:34]([O:38][CH2:39][CH3:40])=[O:37])([C:26]([O:27][CH2:28][CH3:29])=[O:30])[N:9]=1
Reactant: C=CC(=O)OCC
Reactant: CCc1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCC1(C(=O)OCC)N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (10.0 g) and 60% sodium hydride (2.0 g) were added to diethyl carbonate (150 ml), and the mixture was refluxed under heating under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to 50° C. Ethyl acrylate (5.37 ml) was added and the mixture was further stirred for 3 hours. The reaction mixture was added to water. 1M Hydrochloric acid was added with vigorous stirring to adjust the aqueous solution to pH 4. The solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate. The residue was purified by silica gel column chromatography (developing solvent:ethyl acetate-hexane) to give 3.2 g of ethyl 4-(2-chlorophenyl)-6-(2-ethoxycarbonylethyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine-6-carboxylate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH:20]([O:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26])([CH2:22][CH3:23])[CH3:21]>ClCCl>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH:27][C:25]([O:24][CH:20]([CH2:22][CH3:23])[CH3:21])=[O:26])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCC(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCC(C)OC(=O)C=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 4(p-trifluoromethylphenoxy)benzaldehyde (30 g) and sec butyloxycarbonyl methylene triphenylphosphorane (50 g) dissolved in dichloromethane was allowed to stand for 1 hour at room temperature. After evaporation of the solvent the white solid was tritiated with petroleum ether to give a solution which on evaporation yielded sec butyl 4-(p-trifluoromethylphenoxy)cinnamate (40 g) b.p. 150°/0.007 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]2[C:20]3[CH:28]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:65]([NH2:69])([CH3:68])([CH3:67])[CH3:66]>CN(C=O)C>[C:65]([NH:69][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:20]4[CH:28]=[C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:17][C:2]=2[CH3:1])[CH:6]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)O)c1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)NC(C)(C)C)c1
Yield: 35.2 %

Procedure:
A solution of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid (72 mg, 0.16 mmol), HATU (93 mg, 0.24 mmol), NEt3 (50 mg, 0.48 mmol), and tert-butyl amine (24 mg, 0.33 mmol) in DMF (1.5 mL) was shaken at 60° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give a yellow solid (28 mg, 35%). LRMS: 497.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.65 (s, 1H), δ 8.81 (s, 1H), δ 8.36 (s, 1H), δ 7.77-7.81 (m, 3H), δ 7.54 (d, J=7.78, 1H), δ 7.42 (t, J=7.78, 1H), δ 7.34-7.35 (m, 1H), δ 7.14 (s, 1H), δ 7.00-7.069 (m, 2H), δ 3.50-3.54 (m, 4H), δ 2.21 (s, 3H), δ 2.00-2.09 (m, 4H), δ 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH2:26]2)[CH2:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3([O:29][CH2:30][CH2:31][O:32]3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1
Reactant: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1

Procedure:
The compound (4) was dissolved in a mixed solvent of toluene (150 ml) and isopropyl alcohol (100 ml), and palladium on carbon catalyst (NX type of 5% Pd/C; 50% wet; made by N. E. Chemcat; hereinafter referred to as Pd/C) (3.06 g) and potassium carbonate (0.52 g) were added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 26.35 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohexyl}-1,4-dioxa-spiro[4,5]decane (5). The yield based on the compound (4) was 44.6%.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 4-(3-hydroxypropyl)benzonitrile (13 g, 0.081 mol; see step (iii) above) and triphenylphosphine (42.3 g, 0.16 mol) in DCM (150 mL) was added, dropwise at 0-5° C., a solution of CBr4 (53.5 g, 0.16 mol) in DCM (100 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the product was purified by column chromatography over silica gel, using petroleum ether in ethyl acetate as eluent, to yield 12.5 g (69%) of the sub-title compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:26]1([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and 1-naphthyl isocyanate (94 mg) in dry dioxane (3 ml) was stirred at room temperature for 3 hours. The precipitates were collected and washed with isopropyl ether to give 4-[3-[3-(1-naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine