Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([N+:19]([O-])=O)[CH3:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O.[C].[Pd]>[CH3:13][O:12][C:10](=[O:11])[C@H:9]([CH2:14][CH2:15][CH2:16][C:17]([CH3:22])([CH3:18])[NH2:19])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CCCC(C)(C)N)NC(=O)OC(C)(C)C
Yield: 77.3 %

Procedure:
Methyl (S)-2-t-butoxycarbonylamino-6-methyl-6-nitroheptanoate (500 mg, 1.57 mmol) was dissolved in methanol (8 ml) and water (0.5 ml), and 5% palladium-carbon (219 mg, 50% wet) and ferrous sulfate 7 hydrate (1.32 g, 4.75 mmol) were added. The mixture was stirred at a hydrogen pressure of 3 atm and room temperature for 3 h. Palladium-carbon was removed by filtration and methanol was evaporated by concentration under reduced pressure. Ethyl acetate (50 ml), water (50 ml) and sodium carbonate were added for pH adjustment to 10 and extraction. After layer partitioning, the aqueous layer was extracted again with toluene-isopropyl alcohol (1:1, 100 ml). The organic layers were combined and the solvent was evaporated by concentration under reduced pressure to give the objective compound (350 mg, yield 77.3%).
Reaction SMILES: [NH2:1]O.[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=O>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[C:7]#[N:1]
Reactant: NO
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O
Product: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 3.5 h

Procedure:
A solution of 1.7 g of hydroxylamine, O-sulfonic acid in 6 ml of water is added to a solution of 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 25 ml of water, subsequently stirred at 65° for 3.5 hours, cooled, the separated precipitate is filtered off under suction and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in a water-jet vacuum. The crystals obtained are recrystallized from ethyl acetate/n-hexane. There is obtained 3,4-dihydroxy-5-nitrobenzonitrile in the form of yellow crystals of m.p. 194°-195°.
Reaction SMILES: Cl.C([NH:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1)(=O)C>>[NH2:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1
Reactant: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Agent: Cl
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(=O)OC
Yield: 42.2 %

Procedure:
To 100 parts of a hydrochloric acid solution 6N were added 5.65 parts of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate and the whole was stirred and refluxed for 30 minutes. After cooling, the precipitated product was filtered off and crystallized from 80 parts of 2-propanol at 0° C. The product was filtered off and dried, yielding 1.9 parts (42.2%) of methyl 4-amino-2-ethoxy-5-nitrobenzoate; mp. 210° C.; (intermediate 33).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:49]([CH2:51][NH2:52])[OH:50]>ClCCl>[OH:50][CH2:49][CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: NCCO
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
See FIG. 20(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.0669 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (0.029 mL, 0.48 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed with water and brine solution. The DCM layer was dried over sodium sulphate, evaporated to get the crude compound which was purified by column chromatography. Yield-52.7%. ES+MS m/z: 356.4 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H) 3.39-3.65 (m, 4 H ) 3.93 (s, 3 H ) 4.84 (t, J=5.09 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.80 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:14])[C@@H:6]([OH:13])[CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:2]=[CH2:3].IC.[C:17](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5](=[O:14])[C@@H:6]([OH:13])[CH2:7][N:8]([CH3:17])[S:9]([CH3:12])(=[O:10])=[O:11])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOC(=O)[C@@H](O)CNS(C)(=O)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCOC(=O)[C@@H](O)CN(C)S(C)(=O)=O
Yield: 86.6 %

Procedure:
(S)-2-Hydroxy-3-((methylsulphonyl)amino)propanoic acid 2-propenyl ester (0.9 g, 4.04 mmol), iodomethane (9 ml) and potassium carbonate (0.64 g) in acetone (50 ml) were heated at reflux for 20 h. The solvent was evaporated and the residue dissolved in water/ethyl acetate. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.83 g).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[N+:40]([C:43]1[CH:44]=[C:45]([C:52]([F:55])([F:54])[F:53])[CH:46]=[C:47]([CH:51]=1)[C:48](O)=[O:49])([O-:42])=[O:41]>>[N+:40]([C:43]1[CH:51]=[C:47]([CH:46]=[C:45]([C:52]([F:53])([F:54])[F:55])[CH:44]=1)[C:48]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:49])([O-:42])=[O:41]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-nitro-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=O.FC(F)(F)C([O-])=O.[NH4+:33]>O>[C:20]1([C:2]2[N:33]=[C:5]([CH:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: c1ccc(CN2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A mixture of N-(2-oxo-2-phenylethyl)-4-(phenylmethyl)-2-morpholinecarboxamide (850 mg, 2.51 mmol) and ammonium trifluoroacetate (1317 mg, 10.05 mmol) was heated at 150° C. under microwave condition with stirring for 1 hour. Water (150 mL) was added to the residue, and extracted with EtOAc (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford the crude title compound (1.3 g) as a brown oil. This material was combined with another batch of crude title compound (250 mg) and purified by silica gel chromatography using as eluent EtOAc (1600 mL) in hexanes (400 mL) to afford the title compound (900 mg, 2.82 mmol) as a brown solid. LC-MS (ES) m/z=320 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[O:21]=[C:16]1[NH:17][C:18](=[O:20])[C:19](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])[S:15]1
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Yield: 85.7 %

Procedure:
A mixture of methyl 5-formyl-2-methoxybenzoate (490 mg), thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid (0.8 ml) and benzene (10 ml) was submitted to Dean-Stalk dewatering apparatus to reflux for 4 hours under heat. After cooling, the crystals deposited were collected by filtration, washed with benzene and with 20% aqueous solution of acetone, and then dried to obtain 634 mg (86%) of aimed compound as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:18])[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([CH3:17])[C:12]([N:14]([CH3:15])[CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)N(C)C)N(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.78 g of the compound obtained in Step 79-1 in DMF (30 ml) was added 0.66 g of NaH under ice cooling. The solution was stirred at room temperature for one hour, then, 3.58 g of [(2-bromoethoxy)methyl]benzene was added. The solution was stirred at room temperature for two hours, then, water was added, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: n-hexane/EtOAc=2/3; v/v) to obtain 3.22 g of the title compound (pale yellow oil).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[N:8][N:7]=[C:6]2Cl)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[C:6]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([Cl:15])[CH:17]=2)=[N:7][N:8]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: N#Cc1ccc2c(Cl)nnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl

Procedure:
6-Cyano-1,4-dichlorophthalazine (66.2 g) prepared in Preparative Example 3 and 3-chloro-4-methoxybenzylamine (92 g) were suspended in 1200 ml of tetrahydrofuran, followed by the addition of 250 ml of triethylamine. The obtained mixture was heated under reflux for 6 hours.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CS(C)=O>[F:1][C:2]1[C:21]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Temperature: 20 °C
Yield: 46.9 %

Procedure:
A suspension of 0.93 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine- 3-carboxylic acid in 0.6 g of 1-methylpiperazine and 20 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 5 minutes. After cooling to about 20° C., the reaction mixture is poured into 30 cm3 of water, 1.5 cm3 of 2N methanesulphonic acid are added and the product is drained and washed with 3 times 5 cm3 of water. After recrystallizing from 30 cm3 of dimethylformamide containing 30% of ethanol, 0.55 g of 7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a brown solid melting at 270° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN(C)CCCN
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCN(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1), N(1)-dimethyl-propane-1,3-diamine in an analogous manner to Example 1396. Product isolated as a yellow foam (27 mg, 45%). LCMS (m/e) 552 (M+H): 1H-NMR (CDCl3, 400 MHz) δ 11.62 (s, 1H), 8.91 (s, 1H), 8.72 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.47 (d, 1H, J=7.9 Hz), 7.46-7.40 (m, 1H), 7.36 (s, 1H), 7.30-7.23 (m, 1H), 7.10-7.00 (m, 2H), 6.96 (s, 1H), 3.64-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.70 (m, 6H), 2.55 (t, 2H, J=5.4 Hz), 2.33 (s, 6H), 1.84-1.75 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:26][CH:27]1[C:47](=[O:48])[N:29]2[C:30]([C:44]([OH:46])=[O:45])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH2:41][CH:42]=[CH2:43])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([NH:26][CH:27]2[C:47](=[O:48])[N:29]3[C:30]([C:44]([OH:46])=[O:45])=[C:31]([CH2:34][S:35][C:36]4[N:40]([CH2:41][CH:42]=[CH2:43])[N:39]=[N:38][N:37]=4)[CH2:32][S:33][C@H:28]23)=[O:12])[N:8]=1)=[O:2]
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)O)c1csc(NC=O)n1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Yield: 33.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid (syn isomer, 1.86 g.) and 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.77 g.) were treated in similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:26][CH2:27][O:28][CH3:29])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO.[Pd].[C]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([N:21]([CH2:26][CH2:27][O:28][CH3:29])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: COCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
6 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-(2-methoxyethyl)methanesulfonamide were dissolved in 100 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. The crude product was crystallized using diisopropyl ether, 4.6 g, m.p. 115-117° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>CO>[CH3:27][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[CH2:8][CH2:9]1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CN([C@H]1CC[C@H](C#CCCCI)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCCNC
Solvent: CO
Product: CCCN(C)CCCC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
320 mg (corresponds to 0.59 mmol) of crude trans-N-[4-(5-Iodo-pent-1-ynyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml MeOH was treated with 0.6 ml (5.93 mmol) of N-methylpropylamine. The reaction was stirred overnight at 65° C. and partitioned between aqueous 1N NaOH/Et2O (3×), the organic phases were dried over Na2SO4 and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2, then CH2Cl2/MeOH 95:5 to 9:1) gave 128 mg (47% over two steps) of trans-N-Methyl-N-{4-[5-(methyl-propyl-amino)-pent-1-ynyl]-cyclohexyl}-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+). The following compounds can be obtained in analogy:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (536 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28]Cl>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: COc1ccc(CCl)cc1F
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5ccc(OC)c(F)c5)o4)cc23)cc1
Yield: 86 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluoro-4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 86%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([NH:29][C:30]([C:32]2[CH:36]=[CH:35][S:34][CH:33]=2)=[O:31])[CH:23]=[CH:22]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([NH:29][C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[O:31])[CH:23]=[CH:22]4)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cc(-c3cccc4[nH]ncc34)ccc2c1)c1ccsc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
4-bromo-1H-indazole (37.9 mg, 0.192 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (145.7 mg, 0.384 mmol), Fibercat palladium catalyst (Johnson-Matthey, 64.7 mg), and K2CO3 (2 M in water, 0.75 ml, 1.5 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (2.3 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (3×10 ml). The organic extracts were combined, washed with water (3×5 ml), dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->75% EtOAc/hexanes). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (7.4 mg, 10%). MS (ESI pos. ion) m/z: 370 (M+H). Calc'd Exact Mass for C22H15N3OS: 369.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:20]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(C(O)CNCc2cccc(C)c2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3cc(C)ccc32)cc1OC
Yield: 51.4 %

Procedure:
1.8 g of α-[[(3-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 13.5 ml of trifluoroacetic acid, and after adding thereto 0.41 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 40 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with chloroform 2 times, and after adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform-methanol-28% aqueous ammonia (15:1:0.1); a material of Rf being 0.46 (Kiesel gel 60F254 plate, chloroform-methanol-28% aqueous ammonia (15:1:0.1)] was collected, recrystallized from chloroform-n-hexane, and recrystallized from the same solvent system several times, giving 870 mg of 4-(3,4-dimethoxyphenyl)-7-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 129°-131° C.
Reaction SMILES: Cl[CH:2]([CH2:15]Cl)[CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Na]>C1(C)C=CC=CC=1>[CH2:4]([Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[CH2:3][CH:2]=[CH2:15]
Reactant: CCO[Si](CCC(Cl)CCl)(OCC)OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: C=CCC[Si](OCC)(OCC)OCC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A mixture of 578.6 g 3,4-dichlorobutyl triethoxysilane (2.0 moles) and 750 ml toluene is combined at reflux temperature within 2 hours with 92.0 g molten sodium in a heatable (approximately 130° C.) dropping funnel. In order to complete the reaction, the mixture is subsequently agitated for 30 minutes more at 120° C. After the workup already described in b), 417.3 g crude product=95.4% of theory are obtained which yield 366.0 g 3-butenyl triethoxysilane as a main fraction in the subsequent vacuum fractionation, corresponding to 83.7% of theory.