Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([CH:17]=[CH:18]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O.C(OC(=O)C)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:31])=[C:13]([CH:17]=[CH:18][S:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)[CH2:14][S:15](=[O:16])[C@H:10]12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3S(=O)C2)cc1
Reactant: Sc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS(=O)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzhydryl 7-tert-butoxycarbonylamino-3-(2-tosyloxyvinyl)-3-cephem-4-carboxylate-1-oxide (trans isomer) (7 g) and 3-mercaptopyridine (1.33 g) in dimethylformamide (50 ml) containing diisopropylethylamine (4.5 g) was stirred at ambient temperature for 2 hours. The resulting solution was poured into a mixture of ice-cooled water (200 ml) and ethylacetate (200 ml). The separated organic layer was washed in turn with water, 10% aqueous hydrochloric acid and a saturated aqueous solution of sodium bicarbonate and brine. The solvent was evaporated in vacuo to give benzhydryl 7-tert-butoxycarbonylamino-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate-1-oxide. (trans isomer) (5.2 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH2:11][OH:12].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1.[H-].[Na+]>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:12][CH2:11][C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OC[C@H]1COC2(CCCCC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(CSc2nc(Cl)cc(OC[C@H]3COC4(CCCCC4)O3)n2)c1F

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using (2S)-1,4-dioxaspiro[4.5]decane-2-methanol (0.46 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (ii) (0.75 g) in THF (8 mL) and 60% sodium hydride (39 mg) to give the subtitle compound as a pale yellow solid. Yield: 0.70 g.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=[S:9].C([O-])(=O)C.[Zn+2:15].C([O-])(=O)C.[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[NH:23][CH2:22]1.[Zn]>O>[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[N:23]([C:8]([S-:10])=[S:9])[CH2:22]1.[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[N:23]([C:8]([S-:10])=[S:9])[CH2:22]1.[Zn+2:15]
Reactant: S=C=S
Reactant: CC1CNC(C(Cl)(Cl)Cl)O1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CN(C(=S)[S-])C(C(Cl)(Cl)Cl)O1
Reaction time: 8 h

Procedure:
A mixture of 412.0 g. (4.0 moles) triethylamine, 60.8 g. (0.8 mole) carbon disulfide, 73.2 g. (0.4 mole) anhydrous zinc acetate and 163.6 g. (0.8 mole) 5-methyl-2-trichloromethyloxazolidine was stirred at 40° C. for 1 hour. After standing overnight at room temperature, the reaction mixture was diluted with water and filtered to give 417.8 g. of the desired crude product sintering at 89° C. and melting with decomposition at 128°-150° C. Extraction with chloroform and repeated crystallization from benzene gave an analytical sample melting at 170°-176° C. with decomposition. It had the following analysis: Found: N, 4.30; Zn, 10.16. Calc. for C12H14Cl6N2O2S4Zn: N, 4.48; Zn, 10.47.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:27]=[C:26]4[O:28][CH2:29][C:23]5[C:24]6[C:25]4=[C:16]([CH2:17][O:18][C:19]=6[CH:20]=[C:21]([C:30]4[NH:34][C:33]([C@@H:35]6[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]6[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]6[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=6)=[N:32][CH:31]=4)[CH:22]=5)[CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:55][O:56][C@H:57]([CH3:67])[C@H:58]([NH:62][C:63]([O:65][CH3:66])=[O:64])[C:59](O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:66][O:65][C:63]([NH:62][C@@H:58]([C@H:57]([O:56][CH3:55])[CH3:67])[C:59]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:27]=[C:26]3[O:28][CH2:29][C:23]4[C:24]5[C:25]3=[C:16]([CH2:17][O:18][C:19]=5[CH:20]=[C:21]([C:30]3[NH:34][C:33]([C@@H:35]5[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]5[C:41](=[O:54])[C@H:42]([NH:49][C:50](=[O:53])[O:51][CH3:52])[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[N:32][CH:31]=3)[CH:22]=4)[CH:15]=2)=[CH:12][N:13]=1)=[O:60])=[O:64]
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reaction time: 1 h

Procedure:
A mixture of methyl (R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (90 mg, >0.123 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (26 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1 hour. An additional 0.135 mmol of (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid and HATU were added and stirring continued for 3 hours. The crude product was purified by reverse phase HPLC to product (22 mg) as a trifluoroacetate salt.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: Cc1ccccc1Cc1cn(Cc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1Cc1c[nH]cn1

Procedure:
12.3 g of N-benzyl-4-(2'-methylbenzyl)imidazole are dissolved in 100 ml of ethanol. 0.3 g of 10% palladium-on-carbon is added and the reaction mixture is stirred vigorously at 70° C. in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is cooled and filtered. Subsequent treatment as described in Example 54 above affords the desired product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.[BH4-].[Na+]>CO>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CNC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium borohydride (525 mg) in small portions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2×20 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give 4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crude product was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[I-].[K+]>CC(N(C)C)=O>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Temperature: 140 °C
Yield: 50.4 %

Procedure:
3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 13/200 mg, 0.43 mmol), pyrrolidine (178 μL, 2.14 mmol) and potassium iodide (0.43 mmol) were mixed in DMA (2 ml). The mixture was heated at 140° C. for 3 minutes in a microwave reactor. The crude mixture was then filtered and purified by preparative HPLC (column beta-basic, Hypercil 51 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient). After evaporation of the solvents, the remaining solid was triturated in ether, filtered and dried to give the title compound (101 mg, 51%); NMR Spectrum: 1.66 (br s, 4H), 2.54 (br s, 4H), 2.88 (t, 2H), 4.42 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.55-7.58 (m, 2H), 7.86-7.90 (m, 2H), 8.29 (s, 1H), 8.60 (br s, 2H); Mass Spectrum: 466 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]([CH3:15])=[N:6]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]([CH3:15])=[N:6]1
Reactant: CCOC(=O)c1cc(C)nn1CCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCn1nc(C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To a suspension of sodium hydride (310 mg, 7.8 mmol) in N,N-dimethylformamide (10 mL) was slowly added a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) in N,N-dimethylformamide (5 mL) under ice-cooling, and the mixture was stirred at 0° C. for 10 min, then at room temperature for 20 min. To the reaction mixture was added a solution of 1-bromo-2-methoxyethane (1090 mg, 7.8 mmol) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 7 hr. The solvent was evaporated under reduced pressure, and ethyl acetate/tetrahydrofuran and water were added to the residue. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→70/30) to give ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) as a colorless liquid. To a solution of the obtained ethyl 1-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxylate (430 mg, 2.0 mmol) in tetrahydrofuran (6 mL) was added 8N aqueous sodium hydroxide solution (1.3 mL), and the mixture was stirred at room temperature for 3 hr. 1N Hydrochloric acid (13 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (310 mg, 83%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:5]([O:6][C:7]2[C:8]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=2)=[C:4]([N+:36]([O-])=O)[CH:3]=1.C(O)C>[Pt]=O.C(OCC)(=O)C>[NH2:36][C:4]1[CH:3]=[C:2]([F:1])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:5]=1[O:6][C:7]1[C:8]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, platinum oxide, ethanol and ethyl acetate is stirred for 1.5 hours at room temperature under hydrogen atmosphere. The reaction system is purged with nitrogen, then, the reaction solution is filtrated through Celite, and the filtrate is concentrated to obtain 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine.
Reaction SMILES: C(O[CH2:9][CH2:10][C:11]1([CH2:16][CH:17]2[CH:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:25]3[C:20](=[C:21]([F:38])[CH:22]=[CH:23][C:24]=3[F:37])[O:19][CH2:18]2)[O:15][CH2:14][CH2:13][O:12]1)C1C=CC=CC=1.[H][H].CS(Cl)(=O)=O.CCN(CC)CC>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].C(Cl)Cl.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([C@@:26]23[CH2:9][CH2:10][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:16][C@H:17]2[CH2:18][O:19][C:20]2[C:21]([F:38])=[CH:22][CH:23]=[C:24]([F:37])[C:25]3=2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CC1(CCOCc2ccccc2)OCCO1
Agent: [Pd+2]
Agent: CS(=O)(=O)Cl
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)[C@@]12CCC3(C[C@H]1COc1c(F)ccc(F)c12)OCCO3
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-[2-(2-Benzyloxy-ethyl)-[1,3]dioxolan-2-ylmethyl]-4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman (6.3 g, 11.2 mmole) was dissolved in 200 ml EtOAc and Pd(OH)2 (0.5 g) was added. Hydrogen was introduced via a balloon. The reaction was stirred at room temperature for 45 minutes. The catalyst was filtered and the filtrate was concentrated. The residue was dissolved in 200 ml DCM and MsCl (1.4 g, 12 mmole) and NEt3 (1.7 g, 17 mmole) were added. The mixture was stirred at room temperature for ten minutes. 200 ml water and 100 ml DCM were added. The organic layer was washed with 1N HCl (100 ml), water (100 ml), brine (100 ml), dried over Na2SO4 and concentrated. The residue was dissolved in 200 ml THF and KOt-Bu (1M in THF, 14 ml) was added. The mixture was stirred at room temperature for twenty minutes. 200 ml water and 200 ml EtOAc were added. The organic layer washed with brine (200 ml), dried over Na2SO4 and concentrated. The product was purified by column (EtOAc/hexane from 0/100 to 25/75 in 45 minutes). Yield: 3.1 g, 61%. 1H NMR (CDCl3 400 MHz δ 7.61 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.07 (m, 1H), 6.42 (m, 1H), 5.23 (dd, J=11.7 and 2.9 Hz, 1H), 4.12 (d, J=11.0 Hz, 1H), 3.88-4.01 (m, 4H), 2.97 (dt, J=13.2 and 2.9 Hz, 1H), 2.53 (dt, J=13.1 and 2.9 Hz, 1H), 2.33 (ft, J=13.2 and 2.9 Hz, 1H), 1.62-1.81 (m, 3H), 1.23-1.35 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:17]3[N:13]([N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[CH:12]=[CH:11]2)=[CH:5][C:3]=1[NH2:4].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:4][C:3]1[CH:5]=[C:6]([N:10]2[C:17]3[N:13]([N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[CH:12]=[CH:11]2)[C:7]([CH3:9])=[CH:8][C:2]=1[F:1])=[O:30])#[N:25]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1cc(F)c(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1cc(F)c(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
55 mg (0.18 mmol) of the compound of Example 12A and 58 mg (85% pure, 0.18 mmol) of the compound of Example 23A were reacted and worked up analogously to the procedure of Example 38. This gave 43 mg (42% of theory) of the title compound.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[CH:41]=3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].CC1N(C(N(C)C)=O)C1.ICCC>C1COCC1.CCCCCC.C1COCC1.CCCCCC.O>[CH2:21]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]3[CH:41]=[C:42]([F:47])[C:43]([CH2:7][CH2:5][CH3:6])=[C:44]([F:46])[CH:45]=3)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1ccc(-c2ccc(CCc3cc(F)cc(F)c3)cc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: CC1CN1C(=O)N(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CCCCCc1ccc(-c2ccc(CCc3cc(F)c(CCC)c(F)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of lithium diisopropylamide (0.02 mol) in THF/hexane, prepared from 0.02 mol of diisopropylamine in 25 ml of THF and 12.5 ml of a 1.6-molar solution of n-butyllithium in hexane, is added dropwise at 25° C. to a mixture of 0.02 mol of 1-(4'-pentylbiphenyl-4-yl)-2-(3,5-difluorophenyl)ethane, 0.02 mol of N,N-dimethylpropyleneurea, 0.02 mol of 1-iodopropane and 25 ml of THF. After stirring at room temperature for 1.5 hours, the reaction mixture is poured into water, the phases are separated, and the aqueous phase is extracted with 2×50 ml of methylene chloride. Drying over magnesium sulfate, evaporation of the solvent and chromatography give the pure product.
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.Cl>O>[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: Cl
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
5.0 g of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 75 ml water and 2.55 g of 3-aminophenyl acetylene was charged at 25-30° C. Further 1.0 ml 50% hydrochloric acid was added. The reaction mass was stirred at 25-30° C. for 2 hours. The solid obtained was filtered and washed with water. The product was dried at 40-45° C. to obtain 6.1 g of erlotinib hydrochloride.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)=[CH:5][CH:4]=1.Br.[CH3:19]I>C(O)(=O)C>[OH:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cc1
Reactant: CI
Agent: Br
Solvent: CC(=O)O
Product: CSc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1
Temperature: 35 °C

Procedure:
5-(4-Methoxybenzyl)-2-thiouracil (105 g) was refluxed in glacial acetic acid (800 ml) and 48% aqueous hydrobromic acid (400 ml) for 3 hrs. The solution was cooled to ca. 35° C., methyl iodide (53 ml) was added and the solution was refluxed for a further 2 hours. The mixture was evaporated to dryness in vacuo and water (500 ml) added to the residue. Sodium hydroxide was added to raise the pH to ca. 5. The solid which formed was filtered off and recrystallised from ethanol giving 4-hydroxybenzyl-2-methylthio-4-pyrimidone (43.1 g) m.p. 243°-4° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH:24]([C:5]1[S:1][C:2]([C:6]#[C:7][C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:3][CH:4]=1)=[O:25]
Reactant: CN(C)C=O
Reactant: C(#Cc1cc2ccccc2s1)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2cc3ccccc3s2)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.6 %

Procedure:
A stirred solution of 10 grams (0.042 mole) of 2-(thien-2-ylethynyl)benzothiophene (prepared as in Example 2, Steps A and B) in 100 ml of tetrahydrofuran was cooled to -70° C., and 20 ml (0.050 mole) of n-butyl lithium (2.5 molar in hexane) was added portionwise, keeping the reaction mixture below -60°C. Upon completion of addition, the reaction mixture was stirred for 45 minutes as the reaction mixture temperature returned to -70°C. After this time 3.8 grams (0.052 moles) of dimethylformamide as added. Upon completion of addition, the reaction mixture was stirred at -70°C. for 5 minutes and then was allowed to warm to ambient temperature. The reaction mixture was then quenched with an aqueous solution saturated with ammonium chloride, and washed in sequence with water and then with an aqueous solution saturated with sodium chloride. The organic layer was absorbed into 15 grams of silica gel which was in turn placed on a 2.5 cm long silica gel column. Elution was accomplished with a 1:1 hexane and ethyl acetate mixture. The eluate was concentrated under reduced pressure to a brown solid residue. The dried solid residue was suspended in hexane, and the hexane was decanted from the solid. The solid was dried, yielding 2.1 grams of 2-(5-formylthien-2-ylethynyl)benzothiophene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Cl:10])[N:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[Cl:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(CCl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
2,6-Bis(chloromethyl)pyridine (352 mg) was suspended in 4 mL of ethanol, and 372 mg of N-(t-butoxycarbonyl)piperazine was added into the suspension at ice temperature, and then the suspension was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was added to water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-ethanol=30:1) to give 250 mg of t-butyl 4-(6-chloromethylpyridin-2-ylmethyl)piperazine-1-carboxylate as a colorless oil.