Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:51]=[CH:50][NH:49][N:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)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>[NH:48]1[CH:47]=[CH:51][C:50]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:3]=2)=[N:49]1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 130 °C
Yield: 51.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.32 mmol), sodium carbonate (43 mg, 0.41 mmols) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.02 mmol) in 1.5 mL dimethylformamide under argon conditions. The mixture was heated at 130° C. overnight. The mixture was poured into water and was extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 39 mg (66% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-(1-tert-butoxycarbonylpiperidin-4-yl)benzoic acid and l-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-fluorophenol (10 g, 89 mmol) and 4-fluorobenzaldehyde (11.07 g, 89 mmol) in DMF (200 mL) was added K2CO3 (13.33 g, 96 mmol). The mixture was heated at 140° C. for 4 h. After cooling to room temperature, the mixture was poured into of ice water (300 mL), and left stand overnight. The solid was collected by filtration, washed with water, re-dissolved in EA (200 mL) and washed with brine (100 mL). The organic phase was dried with sodium sulfate, filtered and concentrated to afford the title compound (17 g, 75 mmol, 84% yield) as yellow solid. LCMS: rt=1.52 min, [M+H+]=217
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].C1COCC1.Cl[C:46]([O:48][C:49]1[CH:58]=[CH:57][C:52]([C:53]([O:55]C)=[O:54])=[CH:51][CH:50]=1)=[O:47]>O>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:46]([O:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=2)=[O:47])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a mixture of 192 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 157 mg of sodium hydrogen carbonate were added 3 mL of THF and 1.5 mL of water, followed by addition of 133 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). It was stirred at room temperature for 1 hour, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to 327 mg of the obtained residue were added 4 mL of THF, 2 mL of methanol, and 2.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. The reaction mixture was neutralized by addition of 2.6 mL of 1 M hydrochloric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 228 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([CH2:20][NH2:21])[OH:19]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH2:20][CH2:18][OH:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCO
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCO

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.7 g) (British Specification No. 1397436) and ethanolamine (1.34 g) in ethanol (50 ml) was heated under reflux for 19 hours. Concentration followed by chromatographic purification on a column of silica gel with chloroform-methanol (10:1) as eluant and final recrystallisation from isopropyl alcohol--acetonitrile gave the title compound, m.p. 146°-7°. (Found: C, 46.8; H, 6.5; N, 29.6; S, 11.2%. C11H18N6OS requires: C, 46.8; H, 6.4; N, 29.8; S, 11.4%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)C.CN(C)C(=O)C>[CH3:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]3[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:10][C:11]=2[N:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cc2ccccc2cc1N
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1nc2cc3ccccc3cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 4.74 g of 2,3-diaminonaphthalene in 150 ml of ethanol and 30 ml of N,N-dimethylacetamide was added 4.86 g of triethyl orthoacetate, and the mixture heated at 60° C. for 2 hours. An additional 5.5 ml of triethyl orthoacetate was added and stirring continued at 60° C. overnight. The solvent was removed and the residue treated with chloroform. The solids were filtered and the filtrate concentrated to a small volume, treated with ether and filtered. The solids were combined to give 4.07 g of the product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].Br[CH2:15][CH2:16][Si:17]([CH2:20][CH2:21]Br)([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:18][Si:17]1([CH3:19])[CH2:20][CH2:21][N:1]([CH2:2][CH2:3][NH:4][C:5](=[O:13])[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:15][CH2:16]1
Reactant: C[Si](C)(CCBr)CCBr
Reactant: NCCNC(=O)CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si]1(C)CCN(CCNC(=O)CN2CCCC2=O)CC1
Yield: 15 %

Procedure:
A mixture of 1.90 g (10.3 mmol) of N-(2-aminoethyl)-2-oxo-1-pyrrolidineacetamide, 2.76 g (10.1 mmol) of bis(2-bromoethyl)dimethylsilane, 5.20 g of Huenig base, and 20 ml of chloroform was stirred and then the solvent was removed in vacuo. The resulting mixture was heated at 100°-105° C. for 8 hours. Aqueous NaHCO3 was added to the cooled reaction mixture, and the aqueous solution was extracted with chloroform. The dried chloroform solution was concentrated in vacuo and chromatographed on silica gel column to afford 450 mg (Yield: 15.0%) of the desired compound.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)[CH2:3][CH2:4][CH:5]=[CH2:6].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH:2]([F:1])[CH2:3][CH2:4][CH:5]=[CH2:6])[CH:8]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1ccc(OC(F)F)cc1
Reactant: C=CCCC(F)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: C=CCCC(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 65 °C
Yield: 54 %

Procedure:
To a solution of 1-(1-Fluoro-pent-4-enyl)-3-iodo-benzene (0.4 g, 1.38 mmol) in DMF (6 ml) were added TEA (0.96 ml, 6.9 mmol) and 1-Difluoromethoxy-4-ethynyl-benzene (0.233 g, 1.378 mmol). The reaction was degassed by bubbling argon through it for 5 minute and then dichlorbis(triphenylphospine)palladium (0.048 g, 0.069 mmol), and copper iodide (0.013 g, 0.693 mmol) were added simultaneously. The reaction mixture was heated at 65° C. for 15 min. cooled and quenched with 0.1 N HCl (15 ml). The aqueous was extracted with Et2O (3×15 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4), and concentrated. The crude material was purified by chromatography (2.5%-5% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.246 g, 54%) as a slight orange oil, identified by NMR and mass spectral analyses; MS (EI+): 330 (M+)
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][S:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, off-white solid (95 mg, 75%), MS (ISP) m/z=509.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-methanesulfonyl-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)O)C1=O

Procedure:
0.14 g of t-butyl α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetate [prepared as described in Example 7(j) above (the first fraction)] was subjected to de-t-butylation with trifluoracetic acid in the manner described in Example 3, giving the title compound as an amorphous solid in a yield of 0.09 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2C(F)(F)F)CCCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.9 %

Procedure:
A solution of 1-bromo-2-(trifluoromethyl)benzene (0.5 g, 2.222 mmol) in anhydrous THF (10 mL) was cooled to −78° C. (dry ice IPA bath) under argon atmosphere. BuLi (2.5 M in hexanes, 1.068 mL, 2.67 mmol) was added in drops with efficient stirring. The reaction mixture was stirred at −78° C. for 40 min. A solution of cyclopentanone (0.243 g, 2.89 mmol) in anhydrous THF (1.5 mL) was added slowly (in drops) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, gradually brought to room temperature, and stirred for 1 h. The reaction mixture was cooled by an ice bath, quenched with water, and acidified to pH 4-5 by addition of concentrated HCl. The solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water (2 times), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as an oil (250 mg). LCMS m/z=213.1 [M−H2O+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Yield: 55 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 5-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 197 mg of 2-[2-(5-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(O)ccn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(benzyloxy)pyridin-2-ylcarbamate (5.89 g, 19.6 mmol) in methanol was added palladium on carbon (1.04 g, 0.981 mmol). After stirring under a hydrogen balloon at room temperature for 70 minutes, the solids were removed by filtration. The filtrate was concentrated under reduced pressure and solidified under high vacuum to provide the product (4.12 g, 99%) as white solid.
Reaction SMILES: [CH2:1]([O:9][CH:10]([CH3:14])[C:11](O)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:17])=O>>[CH2:1]([O:9][CH:10]([CH3:14])[C:11]([Cl:17])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(C)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOC(C)C(=O)Cl

Procedure:
10 ml of thionyl chloride was added to 2.0 g of α-octyloxypropionic acid, and the mixture was refluxed under heat for 2 hours. Then, excess of thionyl chloride was distilled off to obtain α-octyloxypropionic acid chloride. 20 ml of dry pyridine was added thereto, and a solution of 5.0 g of p-hydroxybenzoic acid dissolved in 40 ml of dry pyridine was further added. After the addition, the mixture was refluxed for 2 hours, charged into ice water, and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 4-α-octyloxypropanoyloxybenzoic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH3:42])(=[O:41])=[O:40])[C:23]=1[CH3:43].Cl.O1CCOCC1>CN1C(=O)CCC1>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:43])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39]([CH3:42])(=[O:40])=[O:41])=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (76 mg, 0.28 mmol) (described herein), 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (97 mg, 0.28 mmol) (described herein), 4.0 M hydrochloric acid in 1,4-dioxane (0.07 mL, 0.28 mmol), and NMP (0.476 mL). After purification 1-(7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] was obtained as an orange solid. Compound is rotameric. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16-8.30 (1H, m), 7.90 and 8.00 (1H, m), 7.75-7.85 (1H, m), 7.63-7.75 (2H, m), 7.42-7.53 (1H, m), 7.28-7.39 (1H, m), 7.06-7.18 (1H, m), 6.25-6.40 (1H, m), 5.65 and 5.81 (1H, m), 4.21 (1H, m), 3.85-4.09 (3H, m), 3.69-3.83 (5H, m), 3.63 (1H, m), 3.46-3.59 (1H, m), 3.16 (1H, s), 2.91-3.13 (6H, m), 2.09-2.24 (2H, m), 1.95 (2H, m), 1.89 (1H, m), 1.66-1.79 (1H, m). Mass Spectrum (ESI) m/e=588 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH2:9][O:8][C:7](=[O:10])[CH:6]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([Cl:21])[CH:20]=1.CO>O1CCCC1>[Cl:21][C:19]1[CH:20]=[C:15]([CH2:14][N:4]([CH2:3][CH2:2][F:1])[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH:16]=[N:17][C:18]=1[Cl:22]
Reactant: Clc1cc(CBr)cnc1Cl
Reactant: O=C1C=C(NCCF)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(CCF)Cc2cnc(Cl)c(Cl)c2)CO1
Temperature: 25 °C

Procedure:
217 mg (1.49 mmol) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one (VI-1) and 90 mg (2.24 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 2 hours. After cooling to room temperature, 360 mg (1.49 mmol) of 3-(bromomethyl)-5,6-dichloropyridine are added, and the mixture is heated under reflux for a further 3 hours. After cooling to room temperature and addition of methanol, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. After concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (5:1), 260 mg (56% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](2-fluoroethyl)amino]furan-2(5H)-one are obtained.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]([NH2:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH2:8][CH2:7]1)(OCC)=[O:2].[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[O:29]1[CH:30]=[CH:31][CH:28]=[C:27]1[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:21]=[C:20]([NH2:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[CH:18]=3)[N:13]=2)[CH2:10][CH2:11]1)=[O:2]
Reactant: CCOC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reactant: CCOCC
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To the above mixture is added slowly at -20° C., 32.9 g. (0.10 mole) of 2-(4-carbethoxypiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline dissolved in 300 ml. of ethyl ether. The reaction mixture is stirred at -20° C. for 2 hours, then allowed to warm to room temperature. The resulting mixture is hydrolyzed by addition of 100 ml. of water, and the ether layer separated. The aqueous layer is extracted with 300 ml. of ether and the combined extracts are dried over anhydrous magnesium sulfate. Evaporation of solvent affords 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline which can be further pruified if desired by silica gel column chromatography.
Reaction SMILES: [Cl:1](O)(=O)=O.[C:5]([C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1N)([CH3:8])([CH3:7])[CH3:6].N([O-])=O.[Na+]>[Cu](Cl)Cl.O>[C:5]([C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[Cl:1])([CH3:8])([CH3:7])[CH3:6]
Reactant: [O-][Cl+2]([O-])O
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a conc. chloric acid (10 ml) suspension of 2-tert-butyl-5-nitroaniline (WO 02055501) (1.94 g, 10.0 mmol) was added the H2O (5 ml) solution of sodium nitrite (690 mg, 10.0 mmol) at 0° C. The mixture was stirred at 0° C. for 20 min and to the mixture was then added the conc. chloric acid (10 ml) solution of copper chloride (900 mg, 10.0 mmol) at 70° C. The reaction mixture was stirred at 70° C. for 20 min and the resulting precipitate was collected by filtration, washed with H2O and dried under reduced pressure to furnish furnish 1.76 g (78% yield) of the title compound as a white solid.