Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH:34]=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[BH3-]C#N.[Na+]>ClCCCl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH2:34][NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[O:13])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C(C)(C)C=O)cc1OC
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(C(C)(C)CNc2cc(OC)c(OC)cc2C(=O)c2ccc(C(C)C)cc2)cc1OC
Reaction time: 1 h

Procedure:
After one hour stirring a mixture of 143 mg (0.476 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 98 mg (0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde, 1.1 g molecular sieves 4 Å pore size, 5 ml 1,2-dichloroethane and 31 μl (0.476 mmol) acetic acid 41 mg (0.666 mmol) NaCNBH3 are added. Over the duration of 4 days three additional portions of 31 μl acetic (0.476 mmol) and 41 mg NaCNBH3 (0.666 mmol) are added. Excess hydride is destroyed by addition of 1 M hydrochloric acid and the reaction mixture is basified by means of 1 M sodium hydroxide. {2-[2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone is isolated by filtration followed by extraction with dichloromethane and reversed phase preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#N)=[N:23][CH:24]=1.CC[O:29]CC>CCCCCC>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)=[O:29])=[N:23][CH:24]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
At −78° C. under Ar a dry 250 mL 3 neck flask was charged with 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (4.5 g, 0.018 mol). Dry ether (100 mL) was added and to the stirred solution, nBuLi (9.2 mL, 0.018 mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at −78° C. for 30 min. 5-chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a thick slurry in dry ether (approx 10 mL) via wide neck funnel. The resulting solution turned dark red in color and was stirred at −78° C. for 1 hr. LCMS indicated that the reaction was complete and, at −78° C. the reaction mixture was quenched with 1.0M HCl (approx 50 mL). The cooling bath was removed and as the reaction mixture reached ambient temperature, (22° C.), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (20 mL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15 mL) and loaded directly onto a silica gel ISCO cartridge (330 g, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20 mins and (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanone (4.1 g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf 0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+1] 304.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.98 min (4 min gradient, MeOH/H2O 0.2% PPA Purity 98%; NMR: 400 MHz 1H (CDCl3) 8.69 ppm, 1H, d, J=2.64 Hz; 8.22 ppm, 1H, s; 8.13 ppm, 1H, d, J=8.36 Hz; 8.07 ppm, 1H, brd, J=8.4 Hz; 7.93 ppm, 1H, dd, J=2.2 and J=8.36 Hz; 7.57 ppm, 1H, brd, J=8.4 Hz.
Reaction SMILES: CS(Cl)(=O)=O.Cl[CH2:7][Cl:8].OC[CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]>C(N(CC)CC)C>[Cl:8][CH2:7][CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]2[O:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]1=[O:23]
Reactant: ClCCl
Reactant: Cc1cc2c(=O)n(CCCO)ccc2o1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(=O)n(CCCCl)ccc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methane sulfonyl chloride (0.24 ml) was added to a dichloromethane solution (10 ml) of 5-(3-hydroxypropyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and triethylamine (0.45 ml). The mixture was stirred at room temperature for two days. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.16 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3S[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.ClC1C=CN=C2C=C(CN3CC[O:40][CH2:39][CH2:38]3)SC=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH2:14][N:18]3[CH2:38][CH2:39][O:40][CH2:16][CH2:17]3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Reactant: Clc1ccnc2cc(CN3CCOCC3)sc12
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(CN4CCOCC4)sc23)c(F)c1

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 131, title compound 132 was obtained as a yellow solid (110 mg, 69% yield). MS (m/z) 390.1 (M+H).
Reaction SMILES: C(OC([N:8]([CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH2:9][C:10](O)=[O:11])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:43]CCl>>[ClH:43].[N+:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:16]([N:15]1[CH2:14][CH2:13][NH:8][CH2:9][C:10]1=[O:11])(=[O:18])=[O:17])([O-:27])=[O:26]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cl
Product: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine (8.06 g, 20 mmol) in dichloromethane (100 ml) was added dicyclohexyl carbodiimide (5.16 g, 25 mmol). After stirring for 2 hours at room temperature, the precipitate was removed by filtration. The filtrate was concentrated and the residue was dissolved in ethyl actate (50 mL) and cooled to 0° C. The precipitate solid was removed and to the filtrate was added 2N-HCl in ethyl acetate (100 mL). The mixture was stirred for additional 10 h at ambient temperature. The precipitate product was filtered off, washed with ethyl acetate (500 mL), and dried in vacuo to afford the title compound as a white solid 5.39 g (79%). 1H-NMR (500 MHz; DMSO-d6) δ 9.95 (br.s, 2H), 8.38 (d, 1H), 8.04˜7.95 (m, 2H), 4.09 (dd, 2H), 3.96 (s, 2H), 3.56 (dd, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][NH2:31]>C(O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:30][NH2:31])[CH:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN
Reactant: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(F)c2)cc1
Solvent: CCO
Product: NNc1cc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)cccc23)ccn1
Yield: 65 %

Procedure:
In a similar manner as described in Example 29, from N-cyclopentyl-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (45 mg, 0.12 mmol) and anhydrous hydrazine (0.5 mL) in ethanol (4 mL) at 100° C. for 13 hours was formed N-cyclopentyl-2-(4-fluorophenyl)-3-(2-hydrazino-4-pyridinyl)pyrazolo[1,5-α]pyridin-7-amine (30 mg, 65%) as a solid. 1H NMR (CDCl3): δ 8.05 (d, 1H), 7.61 (m, 2H), 7.20 (t, 1H), 7.09–6.99 (m, 4H), 6.71 (s, 1H), 6.63 (d, 1H), 6.03–5.96 (m, 3H), 4.01 (broad m, 2H), 2.14 (m, 2H), 1.84–1.68 (m, 6H); 19F NMR (CDCl3) δ −113.66; MS m/z 403 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[Cl:11])=[CH:5][CH:4]=1.[CH3:21][N:22]([CH2:24][C:25](=[S:27])[NH2:26])[CH3:23]>C(O)C>[ClH:11].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:26]=[C:25]([CH2:24][N:22]([CH3:23])[CH3:21])[S:27][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reactant: CN(C)CC(N)=S
Solvent: CCO
Product: COc1ccc(-c2nc(CN(C)C)sc2-c2ccc(OC)cc2)cc1
Product: Cl
Temperature: 25 °C
Yield: 19.2 %

Procedure:
A mixture of 1,2-bis(4-methoxyphenyl)-2-chloroethanone (11.05 g) and 2-(N,N-dimethylamino)ethanethioamide 5.39 g) in ethanol (100 ml) was refluxed for 2 hours. After allowing to cool to room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in chloroform (500 ml) and aqueous solution of sodium hydrogencarbonte (500 ml). The separated organic layer was washed with water and brine, dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo. The resulting residue was dissolved in diethyl ether, added ethanol solution of hydrogen chloride, and the resulting precipitate was collected by filtration. The resulting crude compound was recrystallized with ethanol (30 ml). And the resulting crystal was collected by filtration, washed with ethanol and diethyl ether, and dried to give 4,5-bis(4-methoxyphenyl)-2-(N,N-dimethylaminomethyl)thiazole hydrochloride (2.85 g).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].FF.[Cl:11]Cl>Cl>[Cl:11][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: ClCl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Agent: FF
Product: O=c1[nH]cc(Cl)c(=O)[nH]1

Procedure:
In a suitable reaction vessel as in the previous examples a suspension of uracil (1.00g) in an aqueous solution of 18% HCl (10 ml, representing 5 ml of concentrated HCl and 5 ml of water) was introduced. Gaseous fluorine (0.024 moles) was bubbled through the suspension when the reaction temperature of 72°-80°C was reached. The reaction continued for about 140 minutes until the presence of fluorine was detected leaving the reaction vessel. The ratio of fluorine to uracil was 2.73. During the course of the reaction the odor of chlorine gas was observed. A white solid was present throughout the reaction and a final product of 0.98g was collected by filtration. Elemental analysis of the compound detected no fluorine and indicated the compound to be 5-chlorouracil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=O)[CH2:2][CH3:3].[NH2:14][C:15]1[C:23]([C:24](=[O:26])[NH2:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].[OH-].[Na+].O>N1C=CC=CC=1.C(O)C>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:15]=1[N:14]=[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])[NH:25][C:24]2=[O:26])(=[O:18])[NH2:19]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cccc(C(N)=O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(C(N)=O)cccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
2-n-Propoxybenzoyl chloride (7.27 g, 0.366 mol) was added dropwise to a stirred suspension of 2-amino-3-carbamoylbenzamide (Preparation 17; 2.63 g, 0.0147 mol) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 3 days, then the solvent evaporated under vacuum. The residue was treated with water (100 ml) and, on chilling the solution, colorless crystals formed. The product was collected by filtration and then suspended in a stirred mixture of sodium hydroxide (1.73 g, 0.043 mol), water (90 ml) and ethanol (20 ml). The mixture was heated under reflux for 3 hours, allowed to cool and filtered. The filtrate was acidified to pH 2 with concentrated hydrochloric acid and extracted with a methanoldichloromethane mixture (2:98, 3×100 ml). The organic extracts were combined, washed sequentially with saturated aqueous sodium carbonate solution (3×100 ml) and brine (3×50 ml), dried (Na2SO4) and evaporated under vacuum. Crystallization of the residue from ethyl acetate-methanol gave the title compound as a white solid (1 g, 40%), m.p. 226°-227° C. Found: C,67.00; H,5.40; N,12.90. C18H17N3O3 requires C,66.86; H,5.30; N,13.00%.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][CH:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][CH:23]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2cnc(Cl)s2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(CCN)Cc2cnc(Cl)s2)cc1

Procedure:
This compound was made in a manner analogous to that set forth in Step C of Example 1, using 0.3 gram (0.0007 mole) of (tert-butoxy)-N-(2-{[(2-chloro(1,3-thiazol-5-yl))methyl][(4-methoxyphenyl)methyl]amino}ethyl)carboxamide and 3 mL (excess) of trifluoroacetic acid in 20 mL of methylene chloride. The yield of subject compound was 0.20 gram. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:21][C:22](=O)[CH2:23][C:24](=[O:26])[CH3:25]>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:21][C:22]1[N:1]=[C:2]2[S:3][C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][C:6]2=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:23]=1[C:24](=[O:26])[CH3:25]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc(-c3ccccc3)cc2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a stirred solution of 55 mg (0.197 mmol) (2-amino-5-phenyl-thiophen-3-yl)-phenyl-methanone-in-5 ml-acetic acid was added 0.016 ml (0.239 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 19 mg (28%) 1-(6-methyl-2,4-diphenyl-thieno[2,3-b]pyridin-5-yl)-ethanone as a light grey solid. ES-MS m/e (%): 344 (M+H+, 100).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[N:13][CH:14]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cncc(N)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of methyl 5-tert-butoxycarbonylamino-3-pyridinecarboxylate (5.7 g) and conc. hydrochloric acid (11.4 ml) in methanol (57 ml) was stirred for 1 hour at 40° C. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml) under stirring, and adjusted to pH 9.0 with 10% potassium carbonate aqueous solution. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether-methanol to afford methyl 5-amino-3-pyridinecarboxylate (2.03 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]1[CH3:15].C(N1CC[O:22][CH2:21][CH2:20]1)=O.C(O)[CH2:26][OH:27]>>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([C:21](=[O:22])[CH3:20])=[C:9]([CH:26]=[O:27])[CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]1[CH3:15]
Reactant: OCCO
Reactant: CC1CC(C)(C)c2ccc(Br)cc2C1(C)C
Reactant: O=CN1CCOCC1
Product: CC(=O)c1cc2c(cc1C=O)C(C)(C)C(C)CC2(C)C

Procedure:
This compound was prepared according to Example 1 by acetylation of 1,1,2,4,4-Pentamethyl-7-bromo-1,2,3,4-tetrahydonaphtalene, ketalisation with ethyleneglycol, and Grignard-reaction with N-formylmorpholine.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23](Cl)=[O:24])[CH2:18][C:17]2=[O:26]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:24])[CH2:18][C:17]2=[O:26]
Reactant: C1CCN(CC2CSCCN2)C1
Reactant: O=C1CC(C(=O)Cl)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCSCC2CN2CCCC2)c2ccc(Cl)cc21
Yield: 67.7 %

Procedure:
The procedure described in Example 24 was repeated, but using 3.7 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 3.42 ml of triethylamine and 4.56 g of 5-chloro-3-oxoindan-1-carbonyl chloride, to afford 2.8 g of the title compound, melting at 200°-205° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]4([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37]4)=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OCC)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 42 %

Procedure:
A solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.4 g), ethyl 1-bromocyclobutanecarboxylate (1.5 mL) and cesium carbonate (3 g) in dimethylacetamide (14 mL) was stirred at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.76 g, 42%) as a pale-yellow liquid.
Reaction SMILES: C(OC([NH:8][C:9]([NH:27]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[ClH:35].[CH3:26][O:25][C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:27])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: COC(=O)c1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxycarbonylpyridin-2-yl)phenyl)guanidine (203 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methoxycarbonylpyridin-2-yl)phenyl-guanidine dihydrochloride (142 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](Br)[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH4+].[OH-].[CH3:20][N:21](C)C=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:20]#[N:21])[C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C#N)c(OC)ccc12
Temperature: 180 °C

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.139 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ 3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3)δ 3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR DMSO-d6) δ 4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.CC(O)=O>CC(N(C)C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Cl)c3n2)nc1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Cl)cccc23)n[nH]1
Temperature: 100 °C
Yield: 16.4 %

Procedure:
To 4,8-dichloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (263 mg, 0.77 mmol) in DMA (2.0 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (300 mg, 1.53 mmol) and HOAc (0.102 mL), and the mixture was heated at 100° C. for 5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC (diphenyl column eluting over 40 mins with a gradient of 25 to 80% acetonitrile (containing 0.05% HOAc) and water (containing 0.05% HOAc) to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (51 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.87 (br s, 1H), 8.65-8.67 (m, 2H), 8.01-8.08 (m, 3H), 7.61 (dd, J=9, 6 Hz, 1H), 5.94 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 405 (M+H)+.