Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](C)[CH2:8][CH:9]=O.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(=O)C.N1CCCCC1>[C:12](/[C:14](=[CH:9]\[CH2:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: CC(CC=O)c1cnccn1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)/C(C#N)=C/CCc1cnccn1
Yield: 35.5 %

Procedure:
A solution of 13e (0.191 g, 1.27 mmol) in 0.17 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.115 g, 1.27 mmol, 0.1 mL, 1.0 equiv), then a premixed solution of piperidine (0.0038 g, 0.04318 mmol, 4.4 mL, 3.4 mol %) and 50 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 25-65% EtOAc/hexanes) afforded 15e (0.098 g, 0.282 g theoretical, 35%). For 15e: 1H NMR (CDCl3, 400 MHz) d 8.52 (dd, 1H, J=1.6, 2.5 Hz, Pyr C5-H), 8.46 (d, 1H, J=1.6 Hz, Pyr C3-H), 8.44 (d, 1H, J=2.5 Hz, Pyr C6-H), 7.59 (dd, 1H, J=7.8, 7.8 Hz, CH=C), 3.82 (s, 3H, OCH3), 3.23 (ddq, 1H, J=6.4, 7.0, 7.2 Hz, PyrCH), 3.07 (ddd, 1H, J=7.2, 7.8, 14.9 Hz, CHH), 2.91 (ddd, 1H, J=6.4, 7.8, 14.6 Hz, CHH), 1.39 (d, 3H, J=7.0 Hz, CH3); IR (neat) nmax 2967, 2360, 2341, 1737, 1626, 1437, 1407, 1282, 1259, 1060, 1017, 850, 761, 668 cm-. See FIG. 19d.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].[CH3:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1S(C)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:21]3[N:20]([CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[N:22]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccnc21
Temperature: 150 °C
Yield: 63.4 %

Procedure:
To a solution of 4-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)phenol (100 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (88 mg) in DMF (3 mL) was added NaH (60% in oil, 17 mg) at room temperature, and the mixture was heated at 150° C. for 1.5 h under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (98 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.C(OC([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][C@@H:46]1[CH3:51])=O)(C)(C)C>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[N:6]=[CH:7][C:2]([N:48]6[CH2:49][CH2:50][NH:45][C@@H:46]([CH3:51])[CH2:47]6)=[N:3][CH:4]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCN[C@@H](C)C5)cn3)C4)n[nH]c2c1
Yield: 25.8 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (200 mg, 386 μmol) and (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 773 μmol) using the method from Example 61. After purification by HPLC Method E and deprotection using HCl/dioxan, the title compound (58 mg, 25% yield over two steps) was obtained as off-white solid (HCl-salt).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[C:37](=[O:39])[CH3:38])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: CC(=O)Cl
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
1.6 cm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 75 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding dropwise thereto 0.66 cm3 of acetyl chloride, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent:dichloromethane/methanol (98/2 by volume)]. 1.2 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)acetamide are obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ in ppm). A mixture of rotamers is observed. *2.06 and 2.14 (2s:3H in total); 2.97 (mt:2H); 3.43 (mt:2H); 4.20 and 4.25 (2s:1H in total); 4.54 and from 4.75 to 4.80 (mt:1H in total); 4.68 and 4.78 (broad 2s:2H in total); 6.70 (mt:3H); 7.24 (broad s :8H)].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:41]([CH:38]3[CH2:40][CH2:39]3)=[O:42])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)C2CC2)cc1
Yield: 51 %

Procedure:
Following the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with cyclopropanecarbonyl chloride. Flash chromatography of the crude product on silica gel (gradient elution with 0.3-1% MeOH in CH2Cl2) gave a 51% yield of the title compound as white crystals, mp 187°-189° C.; satisfactory purity by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 599 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[C:4]2[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]4)=[N:3][C:4]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(-c2cnn3ccc(Cl)nc23)c1
Reactant: NC1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CC[C@H](Nc2ccn3ncc(-c4cccc(C(F)(F)F)c4)c3n2)CC1

Procedure:
A mixture of 5-chloro-3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.336 mmol), 4-aminocyclohexanol (58.0 mg, 0.504 mmol), and DIEA (0.117 ml, 0.672 mmol) in 2-propanol (3 ml) was irradiated to 135° C. for 14 h in a Biotage microwave. After cooling, the mixture was diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. After absorbing on celite, the compound was purified by Isco (12 g silica, 1/5/4 MeOH/EtOAc/hex) to give trans-4-((3-(3-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexanol (101 mg, 80% yield) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([N+]([O-])=O)=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].C(N(CC)CC)C>CO>[C:1]1([C:7]2[C:11]([S:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])=[N:10][O:9][N+:8]=2[O-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CS
Reactant: O=[N+]([O-])c1no[n+]([O-])c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CSc1no[n+]([O-])c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4.6 g of 3-phenyl-4-nitrofuroxan, 2.4 g of methyl thioglycolate and 2.2 g of triethylamine in 50 ml of methanol is stirred under a nitrogen atmosphere. In the course of this, the mixture warms to about 40° C. After 1 hour, it is poured into ice-water, whereupon a solid separates after stirring briefly, which is filtered off with suction and recrystallised from isopropanol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].C(N(CC)CC)C.[N+](C1C=CC([O:39][C:40]([N:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][CH2:43]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44][CH2:43]1)=[O:39])(=[O:12])=[O:11]
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a solution of N-(6-Aminohexyl)-2-trifluoromethylbenzene sulfonamide Hydrochloride (0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3, 4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=O.[C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])#[N:18]>>[C:17](/[C:19](=[C:7]1/[C:8](=[O:13])[NH:9][C:10]2[C:6]/1=[CH:5][C:4]([O:3][C:2]([F:16])([F:15])[F:1])=[CH:12][CH:11]=2)/[C:20]([O:22][CH3:23])=[O:21])#[N:18]
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: COC(=O)CC#N
Product: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC(F)(F)F)cc21
Yield: 77 %

Procedure:
Following the general method as outlined for Intermediate 1, starting from 5-(trifluoromethoxy)-isatin and methyl cyanoacetate, the title compound was isolated, after evaporation, as a dark purple solid in 77% yield. This was a 7.5:1 mixture of geometric isomers.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH2:23]([NH3+:26])[CH2:24][CH3:25]>>[CH2:23]([NH:26]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH2:24][CH3:25]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CCC[NH3+]
Agent: CC(=O)[O-]
Product: CCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 68 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and n-propylammonium acetate with a yield of 68% of theory; m.p. 124°-125° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:22]([O:12][C:11](=[O:13])[C:10](=[O:14])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:16])[CH3:15])[CH3:23]
Reactant: CCO
Reactant: CC(C)(CC(=O)C(=O)O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1

Procedure:
5.6 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid and 0.197 ml of sulfuric acid in 150 ml of ethanol are refluxed for 3 hours. The solvent is distilled off. The residue is taken up in ethyl acetate, washed with saturated sodium bicarbonate solution, dried (Na2SO4) and concentrated by evaporation. After bulb tube distillation, 5.6 g of 4-(3-fluorophenyl)-4-methyl-2-oxovaleric acid-ethyl ester with a boiling point of 130° C./0.04 hPA is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[Cl:15][C:7]([C:6]([CH3:11])([CH3:10])[CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acetoxy-2,2-dimethyl-propionic acid (example 40, step 1) (2.2 g, 13.75 mmol) in CH2Cl2 (25 ml), were added oxalyl chloride (2.62 ml, 27.50 mmol) and 2-4 drops of DMF and stirred at 25° C. for 3 hours. The solvent was evaporated and the resulting acetic acid 2-chlorocarbonyl-2-methyl-propyl ester (2.4 g) was used directly in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[CH:21][N:20]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:25]([C:24]3[C:19]([CH3:18])=[N:20][CH:21]=[N:22][CH:23]=3)=[O:26])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncncc1C(=O)O
Solvent: O=CO
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cncnc1C
Yield: 80 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-methoxy-9H-beta-carbolin-8-ylamine and 4-methyl-5-pyrimidine carboxylic acid in 80% yield. 1H-NMR (300 MHz, DMSO-d6): δ 2.75 (s, 3H), 3.92 (s, 3H), 8.19 (d, 1H), 8.41 (d, 1H), 8.50 (s, 1H), 8.96 (s, 1H), 9.20 (s, 1H), 9.25 (s, 1H), 10.63 (s, 1H), 11.67 (s,1H). Retention Time (LC, method: formic acid standard): 0.95 min. MS (M+H+): 368.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1>>[F:17][C:14]([F:15])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1CNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CC(O)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 12 h
Yield: 12 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and azetidin-3-ol according to the procedure of example 25, except that the reaction time was of 12 h. Yield: 12%; MS: m/z=405 (M+H).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>O>[CH:1]1([O:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:19][CH:21]3[O:23][CH2:22]3)=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(CCOC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(OCC2CO2)ccc1CCOC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
13.3 g (0.06 mol) of 4-(2-cyclohexyloxyethyl)-phenol, 3.04 (0.076 mol) of sodium hydroxide pellets and 50 cc of water are introduced into a round-bottomed flask. The mixture is stirred at ambient temperature and, when the solution has become homogeneous, 18.6 g (16 cc, 0.2 mol) of epichlorohydrin are introduced. The stirring is continued at ambient temperature for 16 hours. Extraction is carried out with diethyl ether and the organic phase is washed with water. It is dried over magnesium sulphate and the ether is driven off. This gives an oil, which is used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[N:22]=[C:21]([C:28](O)=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[N:22]=[C:21]([C:28]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:29])[CH:20]=[CH:19][C:18]=3[NH:17]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)NS(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (0.66 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A81. A solution of 6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (233.8 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B81. Solution B81 was added to Solution A81 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-(3-chloro-4-fluoro-phenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-methanesulfonamide (115.1 mg, 40%) as a white solid: MS (ESI) M+1=412.1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N:13]=O.[CH3:15][CH:16]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:17].O>C1(C)C=CC=CC=1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[N:13]=[C:23]1[C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:16]([CH3:17])[CH3:15])=[CH:20][CH:21]=1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CNc1ccc2ccccc2c1N=O
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc3c4ccccc4ccc3n2C)cc1
Reaction time: 1 h

Procedure:
A solution of 11.16 g (0.06 mole) of 2-methylamino-1-nitrosonaphthalene in 800 cc of toluene is hydrogenated at room temperature and at the atmospheric pressure in the presence of 3 g of Palladium-on-carbon. After one hour, when the theoretical amount of hydrogen has been consumed, 0.06 mole of 4-(1-methylethoxy)-benzaldehyde are added and the obtained reaction mixture is heated to the reflux temperature under an inert atmosphere for about 3 hours. The water which forms during the reaction distillates as binary azeotrope with toluene and is separated through a Dean-Stark apparatus. Then further 1.5 g of 5% Palladium-on-carbon are added and reflux is prolonged for two additional hours. Filtration of the hot solution followed by concentration of the filtrate to dryness under vacuum affords a residue which has been purified by cristallization from ethyl ether. M.p. 144°-5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([C@@H:12]([CH3:15])[O:13][CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[C@@H:12]([CH3:15])[O:13][CH3:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CO[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CO[C@H](C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of N,N,O-trimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-threoninamide (670 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1140 mg) in 2-propanol (10 mL) was added piperidinium acetate (488 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (890 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]2[S:17][CH2:13][CH2:14][CH2:15][S:16]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: SCCCS
Reactant: COc1ccc(C=O)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2SCCCS2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, treated with 50 ml of 1,3-propanedithiol and cooled at 0° C with stirring. 20 ml of boron trifluoride etherate are added and the mixture is left to stand in a refrigerator for 18 hours. The mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. The organic extracts are combined, dried over magnesium sulphate and evaporated. The residue is recrystallized twice from ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane of melting point 99° - 101° C.