Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][CH2:34][CH3:35].FC1C=CC=C(F)C=1C(NC1C=CN(CC2C=C(O)C=CC=2C)N=1)=O>CN(C)C=O>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: Cc1ccc(O)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(89 mg, 0.40 mmol), potassium carbonate (83 mg, 0.60 mmol) and 1-(bromomethyl)-2-(butyloxy)benzene (for a preparation see Intermediate 2)(114 mg, 0.47 mmol) were weighed into a vial with a stirrer. N,N-dimethylformamide (1 ml) was added, the vial was capped and the mixture was stirred at room temperature for 28 h. The reaction mixture was filtered (hydrophobic frit), washing with MeOH to give a total volume of 2 ml. This solution was purified by MDAP (Sunfire column, formic acid buffer) (Method B). The solvent was removed to give the title compound as a colourless solid (9.4 mg); LCMS: (System 4) MH+=386, tRET=3.17 min.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[C@H:11]([CH2:12][CH2:13][CH3:14])[N:10]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:9]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(=O)(=O)(O)[O-:26].[Na+]>O1CCOCC1.CCOCC>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][NH:10][C@@H:11]([CH2:12][CH2:13][CH3:14])[C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([OH:22])=[O:26]
Reactant: O=S(=O)([O-])O
Reactant: CCC[C@H]1[C@@H](CC2CCCCC2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC[C@H](NOC1CCCCO1)[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
(3R,4S)-3-Cyclohexylmethyl-4-propyl-1-(2-tetrahydropyranyloxy)azetidin-2-one (2.25 g, 7.27 mmol) is dissolved in 10 mL of 1,4-dioxane. 2.5 N Aqueous sodium hydroxide solution (8.73 mL, 21.8 mmol) is added and the reaction stirred for 18 h at 25° C. The solution is diluted with 50 mL of ether and shaken. The organic phase is discarded and the aqueous layer is acidified with solid sodium bisulfate and then extracted with two 25-mL portions of ether. The combined organic phases are dried over sodium sulfate and concentrated in vacuo giving (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid as an oil (2.02 g, 85% yield).
Reaction SMILES: [ClH:1].Cl.N[C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cl
Reactant: CN1CCc2c(N)ccc(Sc3ccccc3)c2CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(Cl)ccc(Sc3ccccc3)c2CC1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 17.9 g. (0.05 mole) of 9-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine dihydrochloride in 50 ml. of water and 50 ml. of concentrated hydrochloric acid at 0°-5° C. is added dropwise a solution of 4.2 g. (0.06 mole) of sodium nitrite in 25 ml. of water. After being stirred at 0°-5° C. for 30 minutes, the resulting diazonium solution is added to a solution of 6.0 g. (0.06 mole) of cuprous chloride in 25 ml. of concentrated hydrochloric acid. The mixture is stirred for 16 hours at 25° C., then it is warmed to 60°-80° C. for 1 hour. After being cooled to 15°-20° C., the mixture is made alkaline and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to leave 9-chloro-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine which is purified by chromatography or by recrystallization of appropriate acid addition salts; hydrochloride salt m.p. 231°-232° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].[BH4-].[Na+]>CO.CCOC(C)=O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([NH2:4])=[C:6]([N+:13]([O-:15])=[O:14])[CH:7]=1)[CH3:3]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CNC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of dimethylamine (4.0 mL, 2 M, 8.0 mmol) in MeOH (4 mL) was added Ti(OiPr)4 (1.15 g, 4 mmol) and the solution was stirred at room temperature for 15 minutes Then 4-amino-3-nitro-benzaldehyde (160 g, 1.0 mmol) in MeOH (2 mL) was added and the solution was stirred at room temperature overnight. Then NaBH4 (78 g, 2 mmol) was added and the solution was stirred at room temperature for 1 hour. LCMS showed major product peak. The solution was diluted with EtOAc (60 mL) and washed with water (2×100 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solution was evaporated to dryness and 130 mg of crude product was collected, which was used for the next step without further purification, 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.35 (br s, 2H), 7.31 (dd, 1H), 6.97 (d, 1H), 3.26 (s, 2H), 2.12 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:34]([C:36]1[CH:37]=[CH:38][C:39]([N:42]2CCNCC2)=[N:40][CH:41]=1)#[N:35]>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:9]([N:11]2[CH2:12][CH2:13][N:42]([C:39]3[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][N:40]=3)[CH2:15][CH2:14]2)=[O:10])[C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: N#Cc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc(C#N)cn3)CC2)cc1
Yield: 75.8 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and N-(5-cyano-2-pyridyl)piperazine (166 mg). This was purified by silica gel column chromatography to give the title compound (284 mg) as a white powder.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[N:13][C:12]=1[CH2:23][CH3:24])=[O:10].[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=1>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:13][C:12]=2[CH2:23][CH3:24])=[O:10])=[CH:34][CH:35]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCc1nc(-c2ccccc2Cl)oc1C(=O)ON1C(=O)CCC1=O
Product: CCc1nc(-c2ccccc2Cl)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H23ClN4O3 (m/e) 414, obsd 415 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(O)c1ccncc1F
Product: Cc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 4-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.13 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.25 (d, 2H, J=7.9 Hz), 7.15 (d, 2H, J=7.8 Hz), 4.50 (s, 2H), 2.28 (s, 3H). [M+H] calc'd for C14H14N2O2, 243. Found 243.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:18]1([CH2:24][CH:25]=[CH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:4]([C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:25]([CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)C=CCc1ccccc1
Reactant: C=CCN[C@@H](C)c1ccccc1
Agent: [Li]CCCC
Product: C=CCN([C@H](CC(=O)OC(C)(C)C)Cc1ccccc1)[C@@H](C)c1ccccc1
Yield: 82.3 %

Procedure:
The procedure of Example 1 was repeated using (S)-N-allyl-α-methylbenzylamine (2) (0.750 g, 4.7 mmol), 1.6M butyllithium (2.52 ml, 4.0 mmol) and t-butyl 4-phenyl-2-butenoate (17) (0.678 g, 3.1 mmol) as the Michael acceptor. Flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] afforded the title compound (Rf 0.20) as a colourless oil (0.968 g, 82%). δH (300 MHz; CDCl3) 7.40-7.15 (5H, m, Ph), 5.96-5.82 (1H, m, NCH2CH=CH2), 5.19 (1H, dd, J=17.3 and 1.3, trans CH=CH2), 5.09 (1H, dd, J=10.1 and 1.3, cis CH=CH2), 3.95 (1H, q, J=6.7, PhCHCH3), 3.67-3.56 (1H, m, PhCH2CH), 3.38-3.13 (2H, m, NCH2), 2.77 (1H, dd, J=14.7 and 7.1, CH2CO2), 2.55 (1H, dd, J=14.7 and 6.0, CH2CO2), 2.08 (2H, d, J=7.1, PhCH2), 1.42 (9H, s, (CH3)3C), 1.20 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][NH2:19])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][N:19]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(C)C(CN)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C(CN=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 58.1 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 19.7 g (0.1 mol) of 2-(4-chlorophenyl)-3-methylbutylamine are stirred in 100 ml glacial acetic acid at 120° C. for 4 hours. The mixture is cooled to 20° C. and 10 ml of water are added. A colorless precipitate separates out, and is filtered off with suction and dried. 21.2 g of dichloromaleic acid N-[2-(4-chlorophenyl)-3-methylbutyl]imide of melting point 91°-92° C. are obtained. A further 10.4 g of imide can also be isolated by stirring the mother liquor with water. The total yield is: 91.3% of theory.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3OC)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:40]=[C:39](OC)[CH:38]=1>>[CH2:19]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:42]=2)=[CH:9][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cc(CCl)cc(OC)c1
Product: COCCCOc1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3)cc2)c1

Procedure:
Analogously to Method D, 0238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.122 g of 1-chloromethyl-3-methoxy-5-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=6.19.
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:28]=[C:27]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[NH:36])[NH2:35])[O:26][N:25]=1.C[O-].[Na+]>C(O)CCC>[CH2:2]([C:1]1[N:35]=[C:34]([N:30]2[CH2:31][CH2:32][CH2:33][CH:29]2[C:27]2[O:26][N:25]=[C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:28]=2)[N:36]=[C:6]([OH:7])[CH:5]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N=C(N)N1CCCC1c1cc(-c2ccccn2)no1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 44.5 %

Procedure:
A mixture of ethyl propionylacetate (350 mg, 2.4 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine-1-carboximidamide trifluoroacetate salt (Method 38) (901 mg, 2.43 mmol), sodium methoxide (144 mg, 7.7 mmol), in butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool and poured directly on to an isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with 7M methanolic ammonia to elute the product. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with DCM/methanol (98:2 increasing in polarity to 95:5) to give the title compound (360 mg, 46%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](C2C=CC([N+]([O-])=O)=C(Cl)C=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[ClH:25]>[Fe].C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[Cl:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)cc1
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Cl)cc1

Procedure:
Iron powder (2.5 g) was added to a stirred mixture of 4-(4-acetamidophenyl-sulphonyl)-2-chloro-nitrobenzene (Method 13) (0.67 g), water (2 ml), concentrated hydrochloric acid (0.5 ml) and ethanol (10 ml). The mixture was heated under reflux for 1 hour then evaporated to near dryness and partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×15 ml). The organic extracts were combined and dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-2% methanol/DCM to give the title compound (0.18 g) as a solid. NMR: 2.05 (s, 3H), 6.4 (s, 2H), 6.8 (d, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.8 (q, 4H), 10.3 (brs, 1H); MS (ESP−): 323.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[CH3:39][C:40]1([CH3:49])[CH2:45][CH:44]([NH2:46])[CH2:43][C:42]([CH3:48])([CH3:47])[NH:41]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH:44]3[CH2:45][C:40]([CH3:49])([CH3:39])[NH:41][C:42]([CH3:48])([CH3:47])[CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NC2CC(C)(C)NC(C)(C)C2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 2,2,6,6-tetramethyl-4-piperidinamine: LC-MS m/z 629 (M+H)+, 2.0 min (ret time).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[OH-].[NH4+:19]>C(O)C>[NH2:19][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:3][C:1]#[N:2]
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(NC(N)=NC#N)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the compound produced in Step A (1.0 g) and ammonium hydroxide (2 ml) in ethanol (20 ml) was heated at 70° C. in a sealed tube for 3.5 hours. The reaction mixture was cooled to room temperature and reduced to half its volume. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the above compound (389 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16](OC)=[S:17])=[CH:5][CH:4]=1.[H-].[Na+].[C:22]([OH:25])(=[O:24])[CH3:23]>O1CCCC1.CN(C)C=O>[C:22]([O:25][C:10]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:16]=2[S:17][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: COC(=S)c1ccncc1Cc1ccc(OC)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cnccc3c2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 0.200 g (0.69 mmol) of methyl 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylate in 2 mL of dry tetrahydrofuran was added to a suspension of 83 mg (2.1 mmol) of 60% dispersion of sodium hydride in 2 mL of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 3 hours, then poured onto ice water and acidified with glacial acetic acid. The solid material (product) was collected by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate extract was dried, concentrated and combined with the solid precipitate that had been collected. This material was heated at reflux with 100 mg sodium acetate in 2 mL of acetic anhydride for 2 hours, then was partitioned between ethyl acetate and water. The aqueous layer was washed with two portions of ethyl acetate and the combined extracts were dried and concentrated. The residue was crystallized from methanol to afford 100 mg (48%) of white crystalline material, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.CC(C[AlH]CC(C)C)C.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCCCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1CN1CCCCC1
Reaction time: 1.5 h

Procedure:
(2-Methoxy-4-nitro-phenyl)-piperidin-1-yl-methanone (Stage 87.3; 200 mg, 0.76 mmol) is dissolved in THF (8 ml) at −20° C. DIBAH (1 M in THF: 2.3 ml) then is added. After 90 min at −20° C., another portion of DIBAH (0.8 ml) is added and stirring continued for 2 h. Then the reaction mixture is hydrolysed by water (30 ml) and a saturated solution of sodium potassium tartrate (25 ml) and extracted 3 times with AcOEt. The organic phases are washed with brine, dried (Na2SO4) and concentrated. The crude product is dissolved in AcOEt, SiO2 is then added and the solvent evaporate off in vacuo. The resulting powder is put on top of a chromatography column (SiO2; AcOEt) and the title compound eluated with AcOEt: 1H-NMR (DMSO-d6): 7.83 (dd, 1H), 7.73 (d, 1H), 7.60 (d, 1H), 3.91 (s, H3CO), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m, 4H), 1.39 (m, 2H).
Reaction SMILES: CCCCCCCC(OOC(C)(C)C)=[O:9].C(OCCCC)(=O)[C:17]1[C:18](=[CH:26]C=CC=1)[C:19]([O:21][CH2:22][CH2:23]CC)=[O:20]>>[C:19]([O:21][CH2:22][CH2:23][OH:9])(=[O:20])[C:18]([CH3:17])=[CH2:26]
Reactant: CCCCCCCC(=O)OOC(C)(C)C
Reactant: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Product: C=C(C)C(=O)OCCO
Reaction time: 8 h

Procedure:
2 h after the end of the addition, 1 g of tert-butyl peroctoate is fed in. The total polymerization time is 8 h. After the end of polymerization, the mixture is diluted with 590.0 g of dibutyl phthalate. An almost clear, viscous solution is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-n2ccnn2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-n2ccnn2)c1
Yield: 101.6 %

Procedure:
1-(3-Nitro-phenyl)-1H-[1,2,3]triazole (9.66 g, 51 mmol) were dissolved in 300 ml methanol and 70 ml THF. Palladium on charcoal (10%, 500 mg) were added and the reaction mixture was stirred with a hydrogen balloon for 36 h. Palladium on charcoal was filtered off and washed with methanol. The solvent was evaporated off to yield the title compound (8.3 g, 100%) as an off-white solid, mp 71-73° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C[O-].[Na+]>CCOCC.CO>[F:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[C:2](=[O:3])[CH2:1][C:14]([C:13]([F:20])([F:19])[F:12])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1cc(F)ccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
28.5 g of 2,5-difluoroacetophenone and 26 g of ethyl trifluoroacetate were stirred in 400 ml of anhydrous ether and cooled in an ice bath. 42 ml of 25 wt % sodium methoxide in methanol was then added over 5 minutes. After stirring 1 hour at room temperature, the reaction mixture was extracted with water, the water acidified and extracted with methylene chloride to give 42 g of 1-(2,5-difluorophenyl)-3-(trifluoromethyl)propane-1,3-dione.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[CH3:12][O-:13].[Na+]>C1(C)C(C)=CC=CC=1.CO>[CH3:12][O:13][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.3 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute methanol. Then 5.4 gram for sodium methoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 4.8 gram (98% yield). Mp: 133.8-134.9° C.; MS: 166.2.0 (M+H)