Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH2:2][C:3]1([CH3:16])[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:18]=[N-:19]
Reactant: CC1(CCl)CN(c2ccc(Cl)cn2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN=[N+]=[N-])CN(c2ccc(Cl)cn2)C(=O)O1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 5-(chloromethyl)-3-(5-chloropyridin-2-yl)-5-methyl-1,3-oxazolidin-2-one (1.01 g, INTERMEDIATE 17) and sodium azide (503 mg) was heated to 140° C. in 40 ml of dimethylformamide for 40 h. The mixture was then cooled to room temperature, and diluted with 150 ml of water and extracted with 150 ml of ethyl acetate (3×). The combined organic layers were washed with water (100 ml) and brine (100 ml). Then they were dried over sodium sulfate and concentrated in vacuo (overnight to remove dimethylformamide) to provide 570 mg (55%) of the title compound. Mass spectrum (ESI) 268.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[S:36][C:37]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:38]=2[N:39]=1>>[F:44][C:42]1[CH:41]=[CH:40][C:38]2[N:39]=[C:35]([NH:34][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[S:36][C:37]=2[CH:43]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: O=C(O)c1cccnc1Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(F)cc2s1)c1cccnc1Nc1ccc(Cl)cc1
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and, 4-chloro aniline (17, 128 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain ethyl 2-(4-chloro anilino) nicotinate (24) as pure product. Ethyl 2-(4-chloro anilino) nicotinate (24, 276 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(4-chlorophenylamino)nicotinic acid (31). To a stirred solution of 2-(4-chlorophenylamino) nicotinic acid (31, 249 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 118 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (9) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])=[CH:18][C:17]=1[F:23]
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].C(=O)(O)[O-].[Na+].[I-].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:31])([F:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCOCC(F)(F)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCC(F)(F)c1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 140 °C

Procedure:
To a solution of (8-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one (V) (4.80 g, 9.83 mmol) and 6-(2,2-Difluoro-2-phenylethoxy)hexyl]amine (IV) (3.04 g, 11.8 mmol) in dimethylsulfoxide (13.5 mL) was added sodium bicarbonate (2.49 g, 29.4 mmol) and sodium iodide (2.22 g, 14.8 mmol). The mixture was heated at 140° C. for 2 hours. After cooling, the reaction was diluted with water (40 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water (2×10 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.40 g, 98%) as oil.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39][C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][C@@H:40]1[CH2:44][CH2:43][N:42]([C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:22][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[NH:15][C:11]=3[CH:10]=2)[CH2:41]1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: F[C@@H]1CCNC1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CC[C@@H](F)C2)cc1

Procedure:
The entitled compound was obtained as a yellow oily substance in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and (R)-3-fluoropyrrolidine.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:23]([Li])[CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C:6]1([C:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=2)[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH:24]=[CH2:23]
Reactant: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine (10 g, 34.6 mmol) in 200 mL of dry THF, and cooled to -78° C. under a nitrogen atmosphere. Added n-butyl lithium (15.2 mL of 2.5M in hexane, 38.0 mmol) dropwise via syringe. Warmed to 0° C., and stirred for 60 mins. Recooled to -78° C., and added allyl bromide (4.6 g, 3.3 mL, 38.0 mmol) dropwise via syringe. Warmed to room temperature slowly, and stirred for 5 hours. Added saturated NH4Cl, and extracted with ether. Dried the combined organic extracts with MgSO4, filtered, and evaporated. Purified the crude product by flash chromatography on silica gel eluting with 5:95:0.1 MeOH:EtOAc:NH4OH. Combined appropriate fractions, and evaporated to give 8.0 g (70% yield) of 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine as an oil. Dissolved free base in ether, and added 19 weight % HCl-EtOH until acidic. Added additional ether, and let stand to precipitate hydrochloride salt. Recrystallized salt from acetonitrile-ether.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:18]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])[C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:18]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]#[N:40])[C:19]3[C:28](=[O:29])[N:27]([CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][N:25]=4)[C:20]=3[N:31]=2)[CH2:12]1
Reactant: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2C#N)c2cccnc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)c2c(nc(C3CCCC(N)C3)n2Cc2ccccc2C#N)c2cccnc21
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
A solution of {3-[3-(2-cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-2-yl]-cyclohexyl}-carbamic acid benzyl ester (55 mg, 0.10 mmol) in 1:1 EtOH THF (8 mL) was hydrogenated at 1 atm over 10% Pd/C (54 mg, 0.05 mmol) at room temperature. After 90 min, the reaction vessel was purged with nitrogen, and the catalyst was removed by filtration, rinsing with MeOH to provide 2-[2-(3-amino-cyclohexyl)-5-methyl-4-oxo-4,5-dihydro-1,3,5,6-tetraaza-cyclopenta[a]naphthalen-3-ylmethyl]-benzonitrile (30 mg, 72% yield). The crude amine was taken up in 2 mL of EtOAc and a minimum amount of EtOH, and was treated with 0.2 mL of 1N HCl in diethyl ether. The solvent was removed to give the corresponding HCl salt as a white solid. 1H-NMR (DMSO): δ 8.65 (m, 1H), 8.53 (dd, 1H, J=7.6, 1.6 Hz), 8.11 (m, 2H), 7.95 (m, 1H), 7.59 (t, 1H, J=7.6 Hz), 7.49 (m, 1H), 7.42 (m, 1H), 6.68 (d, 1H, J=7.6 Hz), 6.04 (m, 2H), 4.61 (m, 1H), 3.70 (s, 3H), 3.17 (m, 1H), 2.18 (m, 1H), 1.97 (m, 2H), 1.82 (m, 1H), 1.71 (m, 2H), 1.51 (m, 1H), 1.41 (m, 1H). MS: calculated for C24H24N6O+H 413.2; found: 413.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1C1[C:5]2=[CH:6][CH:7]=[CH:8]C=1.CCO[CH2:27][CH3:28].CCCCCC.C([Li])CCC.Cl.[B:41](OC(C)C)([O:46]C(C)C)[O:42]C(C)C>>[CH:21]1[C:20]2[C:2]3[C:3]([C:4]4[C:13]([C:12]=2[CH:11]=[CH:23][CH:22]=1)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:28][C:27]([B:41]([OH:46])[OH:42])=[C:14]1[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOCC
Reactant: Brc1cc2c3ccccc3c3ccccc3c2c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OB(O)c1cc2c3ccccc3c3ccccc3c2c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under an argon atmosphere, 5.87 g of 10-bromobenzo[g]chrysene which had been prepared in Synthesis Example 2 was placed in a flask and 100 mL of dehydrated ether was added to this flask. The reaction solution was cooled to −40° C. and 11 ml of 1.6M n-butyllithium hexane solution was added. After heating to 0° C., the resultant was stirred for 1 hour. The reaction solution was cooled to −60° C. and 10 mL of dehydrated ether solution in which 7.72 g of triisopropyl borate was dissolved was added. The reaction solution was stirred for 5 hours with heating to room temperature. 50 mL of 10% aqueous solution of hydrochloric acid was added and stirring was conducted for 1 hour. An aqueous phase was removed and an organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting solids were washed with hexane, whereby 3.18 g (yield: 60%) of benzo[g]chrysene-10-boronic acid was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:13]([C:20]([OH:22])=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH3:3].C1C=CC2N(O)N=NC=2C=1.[N:34]12[CH2:41][CH2:40][CH:37]([CH2:38][CH2:39]1)[C@@H:36](O)[CH2:35]2.CCN(C(C)C)C(C)C>C1COCC1>[CH2:2]([O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH:13]([C:20]([O:22][C@@H:36]2[CH:37]3[CH2:40][CH2:41][N:34]([CH2:39][CH2:38]3)[CH2:35]2)=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=1)[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
3-[(Carboxy-phenyl-methyl)-amino]-benzoic acid ethyl ester hydrochloride (I66) (161 mg, 0.48 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (218 mg, 0.57 mmol), and HOBT (88 mg, 0.57 mmol) are dissolved in dry THF (10 mL). (R)-Quinuclidin-3-ol (61.0 mg, 0.48 mmol) and DIPEA (0.17 mL, 0.96 mmol) are added and the mixture is stirred under inert atmosphere overnight. THF is evaporated and the crude residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The recovered organic layer is dried (Na2SO4), filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to afford the title compound as a yellow oil (154 mg, 79% yield, mixture of diastereoisomers).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[C:24](=O)([O-:26])[O-:25].[K+].[K+].Br[CH2:31][CH2:32][OH:33]>CC#N>[CH:24]([O-:26])=[O:25].[OH:33][CH2:32][CH2:31][N@H+:21]1[CH2:20][CH2:19][C@@H:18]([C:16]2[S:15][CH:14]=[C:13]([C:11]([N:1]3[CH:10]4[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:4][CH2:3][CH2:2]3)=[O:12])[CH:17]=2)[CH2:23][CH2:22]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: O=C([O-])[O-]
Reactant: OCCBr
Agent: [K+]
Solvent: CC#N
Product: O=C(c1csc(C2CC[NH+](CCO)CC2)c1)N1CCCC2CCCCC21
Product: O=C[O-]
Temperature: 60 °C
Reaction time: 5 h

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (0.029 g, 0.087 mmol) was dissolved MeCN (1 mL) and potassium carbonate (36 mmol) was added followed by 2-bromoethanol (22 mg). The reaction was heated to 60° C. and stirred for 5 hours. The product was purified by flash chromatography on a SCX-2 cartridge, eluting with acetonitrile and then 2 M ammonia in methanol. The residue was further purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.046 g). LCMS m/z 377.17 min [M+H]+ RT=6.45 min (Analytical Method 2).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C(C(C(O)=O)O)O>C(O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
15.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 450 ml ethanol and 13.8 g of 3-aminophenyl acetylene was added at 25-30° C. Further 3.0 g tartaric acid was added. The reaction mass was stirred at 25-30° C. for 6 hours. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated by filtration, washed with ethanol and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0-2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40-45° C. to obtain 18.3 g of erlotinib hydrochloride.
Reaction SMILES: N[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C([N:11]([CH2:14][CH3:15])CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>CO.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:11][CH2:14][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[CH:19][CH:18]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCCC(N)C(=O)O
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CCCCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 6.0 g. (21 mMol) of the aminopentanoic acid from c) and 5.3 g. (52.5 mMol) triethylamine in 100 ml. methylene chloride are added portionwise at 0° C. 4.4 g. (21 mMol) 4-chlorobenzenesulphonic acid chloride, followed by stirring for 1 hour at 0° C. and for 1 hour at ambient temperature. The reaction mixture is shaken out with 2N hydrochloric acid and the organic phase is dried over anhydrous sodium sulphate and evaporated. There are obtained 9.8 g. of the ester in the form of a pale yellow oil which is converted into the free acid by heating with 30 ml. 2N aqueous sodium hydroxide solution in 30 ml. methanol to 50° C. and subsequent acidification with concentrated hydrochloric acid. The yield is 7.4 g. (85% of theory) of colourless crystals; m.p. 118°-120° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1.[H][H]>C(O)(C)C.[Pd]>[CH2:15]([C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCc1cccc(O)c1

Procedure:
Cardanol (500 g, 1.64 mol) was dissolved in isopropanol (2 L) and was hydrogenated in presence of 5% Pd/C (1.5 g) catalyst at 70° C. in a Parr autoclave under 600 psi hydrogen pressure. When no more hydrogen absorption was noticed, the hydrogenation was stopped. The reaction mixture was filtered to remove Pd/C. The solvent was evaporated to obtain crude product. Pure 3-pentadecylphenol was obtained after recrystallization from hexane. Yield 480 g, (95%), MP: 50-51° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13]([C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].C[N:29](C)C=O>[Cu]>[F:8][C:6]1[CH:7]=[C:2]([C:18]2[CH:20]=[CH:21][C:15]([S:13]([CH3:12])=[O:14])=[CH:16][CH:17]=2)[C:3]([N+:9]([O-:11])=[O:10])([NH2:29])[CH2:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1I
Reactant: CS(=O)c1ccc(N)cc1
Reactant: CN(C)C=O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)c1ccc(C2=CC(F)=CCC2(N)[N+](=O)[O-])cc1

Procedure:
2-Iodo-4-fluoronitrobenzene (0.2 mole) and 4-methylsulfinylaniline (0.2 mole) are refluxed in dry dimethylformamide (300 ml.) containing copper powder (5 g) and some powdered potassium carbonate (20 g) under nitrogen for 18 hours. The suspension is filtered, and the organics are washed with water (6 times 100 ml.) in benzene (600 ml.). The benzene layer is extracted with 2.5 N HCl (7×200 ml.), and the acid layer is poured onto powdered sodium bicarbonate. The basic solution is extracted with benzene (6 times 200 ml.), the benzene layer is washed with water (3 times 100 ml.), is separated, dried (MgSO4) and filtered. Evaporation of the solvent followed by chromatography on a 2 in.×24 in. column of silica-gel (Baker), eluted with various proportions of benzene-hexane mixtures, gives pure 5-fluoro-4'-methylsulfinyl-2-nitrobiphenylamine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:32]([O:34][C:35]([C:37]1[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:38]=1[C:44]([OH:46])=O)=[O:36])[CH3:33].[C:47]1([C:53]2[N:54]=[C:55]3[N:60]=[C:59]([NH2:61])[CH:58]=[CH:57][N:56]3[CH:62]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.O>[CH2:32]([O:34][C:35]([C:37]1[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:38]=1[C:44](=[O:46])[NH:61][C:59]1[CH:58]=[CH:57][N:56]2[CH:62]=[C:53]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[N:54]=[C:55]2[N:60]=1)=[O:36])[CH3:33]
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1cnn(CC)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
TBTU (1.1 g) and diisopropylethylamine (1.1 g) were added to a solution of 2-ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (610 mg) in DMF (7 ml), and the mixture was stirred for 30 min at RT. 2-Phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 725 mg) was added to the light yellow solution, and the mixture was stirred over the weekend at RT. Water (15 ml) was added, and the mixture was stirred for an additional 15 min. For purification, the precipitate was suspended in DMF (5 ml) and water (10 ml), and filtered; this process was repeated 4 times. The thus obtained title compound (150 mg, 13%) was dried under vacuum.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.C1C=CC=CC=1.P(Br)(Br)[Br:26].O>C1(C)C=CC=CC=1>[Br:26][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1
Reactant: O=C1Cc2ccccc2Sc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Cc2ccccc2Sc2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 4.43 g. of the alcohol of Step 1 in 100 cc. of benzene and add 1 cc. (10.5 mmole) of phosphorous tribromide. Stir at room temperature for 1 hour, add water and then dilute with toluene. Wash three times with water, dry and strip to a solid residue.